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Ivosidenib - Servier

Drug Profile

Ivosidenib - Servier

Alternative Names: Tuoshuvo; AG-120; CS 3010; ivonib tablet; S-95031; TIBSOVO; Tosuvo; Tuoshuwo

Latest Information Update: 23 Feb 2024

At a glance

  • Originator Agios Pharmaceuticals
  • Developer Agios Pharmaceuticals; Bristol-Myers Squibb; CStone Pharmaceuticals; HOVON Foundation; Servier; University of Pittsburgh Medical Center
  • Class Antineoplastics; Cyclobutanes; Nitriles; Pyridines; Pyrrolidines; Small molecules
  • Mechanism of Action Isocitrate dehydrogenase 1 inhibitors
  • Orphan Drug Status

    Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

    Yes - Cholangiocarcinoma; Glioma; Acute myeloid leukaemia
  • New Molecular Entity Yes

Highest Development Phases

  • Marketed Acute myeloid leukaemia; Cholangiocarcinoma; Myelodysplastic syndromes
  • Phase II Glioma; Solid tumours

Most Recent Events

  • 04 Jan 2024 Institut de Recherches Internationales Servier completes a phase I trial in Solid tumours (Late-stage disease, Second-line therapy or greater) in the US and France (NCT02073994)
  • 21 Dec 2023 Servier acquires Ivosidenib from CStone Pharmaceuticals in China, Hong Kong, Macau, Taiwan and Singapore
  • 21 Dec 2023 Ivosidenib is no longer licensed to CStone Pharmaceuticals in China, Hong Kong, Macau, Taiwan and Singapore

Development Overview

Introduction

Ivosidenib is an orally available small molecule inhibitor of mutated cytosolic isocitrate dehydrogenase 1 (IDH1m inhibitor), being developed by Servier for the treatment of multiple cancers with isocitrate dehydrogenase-1 (IDH1) mutations. The candidate was originally developed by Agios Pharmaceuticals. Ivosidenib specifically inhibits a mutated form of IDH1 in the cytoplasm, subsequently inhibiting the formation of the oncometabolite, 2-hydroxyglutarate (2HG). This induces cellular differentiation and inhibits cellular proliferation in IDH1-expressing tumour cells. IDH1 is an enzyme in the citric acid cycle, is mutated in a variety of cancers and initiates and drives cancer growth by both blocking cell differentiation and catalysing the formation of 2HG. The product is launched for the treatment of relapsed or refractory acute myeloid leukaemia (AML) in the US and China and as a first-line therapy for newly diagnosed AML ineligible for standard therapy in the US. The product is available in the US and approved in Australia for the treatment of cholangiocarcinoma. The drug is approved in the EU for the treatment of previously untreated IDH1-mutated AML as a first line treatment, in combination with azacitidine, and for the treatment of previously treated, locally advanced or metastatic IDH1-mutated cholangiocarcinoma. The drug is approved for relapsed/refractory and recurrent myelodysplastic syndrome with IDH1 mutation in the US. The product is also under regulatory review in Taiwan for the treatment of AML with an IDH1 mutation. Clinical development for acute myeloid leukaemia, cholangiocarcinoma, myelodysplastic syndromes, glioma and solid tumours is ongoing worldwide.

A marketing authorisation application was submitted in the EU, for the treatment of adult patients with relapsed or refractory acute myeloid leukaemia with IDH1 mutation. However, it was withdrawn by the company, later. As at July 2020, no recent reports of development had been identified for phase I development in acute myeloid leukaemia, cholangiocarcinoma, myelodysplastic syndromes, glioma and solid tumours conducted in the US and France.

In April 2021, Servier aquired oncology portfolio from Agios Pharmaceuticals [1] .

Ivosidenib had emerged from a research programme of small molecule therapeutics targeting cancer metabolism, initiated by Agios and Celgene [see Adis Insight drug profile 800031414].

Agios Pharmaceuticals and Abbott are collaboratively developing ivosidenib companion diagnostic to help in the identification of AML patients with IDH mutations, who will be benefited with the ivosidenib treatment [see AdisInsight drug profile 800048251].

Company Agreements

In April 2021, Servier, successfully completed its acquisition of Agios Pharmaceutical's commercial, clinical, and research-stage oncology portfolio for up to $US2 billion plus royalties including ivosidenib [see Adis Insight Drug profile 800040155], vorasidenib [see Adis Insight Drug profile 800042899], AG 270 [see Adis Insight Drug profile 800051488], enasidenib [see Adis Insight Drug profile 800038591]. Under the terms of agreement, Agios received an upfront payment of $US1.8 billion from Servier and is eligible to receive an additional $US200 a potential future milestone payment for vorasidenib, as well as 5% royalties on U.S. on net sales of ivosidenib tablets from sales after the closing through loss of exclusivity and 15% royalties on U.S. net sales of vorasidenib from the first commercial sale through loss of exclusivity. The transaction has been approved by both companies' respective boards of directors and Agios' shareholders. All regulatory clearances have been received from government authorities outlined in the agreement. Under the transaction, US based Agios employees who primarily support the oncology business will join Servier Pharmaceuticals LLC, an US subsidiary of Servier. [2] [3] [1]

In June 2018, Agios Pharmaceuticals and CStone Pharmaceuticals entered into an exclusive collaboration and license agreement for the development and commercialisation of ivosidenib (TIBSOVO®) in Mainland China, Hong Kong, Macau and Taiwan (“Territory”), either as a monotherapy or in combination with other therapies. CStone Pharmaceuticals will be responsible for conducting the development and commercialisation activities for ivosidenib in hematologic and solid tumor indications in the territory, with an initial focus in acute myeloid leukemia (AML) and cholangiocarcinoma and will be responsible for all costs associated with development and commercialisation activities for ivosidenib conducted in the territory as per the agreement. Agios will retain all rights to ivosidenib in the rest of the world. Under the terms of the agreement, Agios will receive an upfront payment of $US12 million and will be eligible to receive up to $US412 million in milestone payments, of which $US147 million are related to development and regulatory events and $US265 million to the achievement of certain sales levels. Approximately half of the milestone payments are related to the development and commercialisation of ivosidenib in AML, cholangiocarcinoma and other potential indications. The other half are payable only if development and commercialization of ivosidenib in brain cancer indications, including glioma, are pursued as part of the collaboration at a later date. In addition, CStone Pharmaceuticals will pay Agios tiered royalties ranging from the mid to high-teens as a percentage of annual net sales of ivosidenib in the territory. [4]

In December 2023, Servier acquired all the exclusive rights to develop and commercialize ivosidenib (TIBSOVO®) in Greater China and Singapore from CStone Pharmaceuticals. Under the terms of the agreement, CStone will transfer the ivosidenib business, in the territories, to Servier for $US44 million, followed by a payment of up to $US6 million upon completion of the transition. As a result, the licensing agreement with Servier will be terminated and CStone will be released from payment obligations of any remaining development and commercialization milestones. In 2021, Servier acquired the oncology business of Agios Pharmaceuticals that had, since 2018, an exclusive collaboration and license agreement with CStone to develop and commercialize ivosidenib in Greater China and Singapore [5] .

In May 2016, Agios Pharmaceuticals gained the option to conduct the development and commercialisation of ivosidenib worldwide, including the US. Previously, Agios held US rights for ivosidenib from Celgene [6] . In June 2014, Agios Pharmaceuticals and Celgene entered into an agreement, wherein the latter exclusively exercised the option of licensing ivosidenib outside the US. In February 2014, Agios exercised its option for US development and commercialisation rights for the IDH1 programme, including ivosidenib, under the terms of the collaboration with Celgene. Celgene was eligible to receive royalties on the US sales of the product, whereas Agios was to receive up to $US120 million in milestone payments as well as royalties on sales outside the US. Agios and Celgene agreed to extend this programme by one year, in October 2011, for which Agios received $US20 million from Celgene. The agreement was extended for another year, under similar terms, in December 2013. Celgene retains the ability to extend this exclusive collaboration further for additional payments [7] [8] [9] [10] [11] [12] . In April 2010, Agios Pharmaceuticals and Celgene Corporation had entered into a three year global collaboration to develop therapeutics targeting cancer metabolism. Under terms of the agreement, Agios was to receive an upfront payment of $US130 million, including an equity investment and will be entitled to milestone payments and royalties. Agios will lead discovery and early development in the cancer metabolism research programme. Celgene had an exclusive option to license any resulting clinical candidates at the end of phase I, and lead and fund global development and commercialisation of licensed programmes [13] .

Key Development Milestones

Acute myeloid leukaemia

In May 2022, the US FDA approved TIBSOVO® (ivosidenib tablets) in combination with azacitidine, for the treatment of newly diagnosed IDH1-mutated acute myeloid leukaemia (AML) in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. The US FDA had accepted the Servier's supplemental New Drug Application (sNDA), in March 2022. The sNDA was granted priority review and is supported by the results from the phase III AGILE trial [14] [15] .

In July 2018, ivosidenib 250mg tablet (TIBSOVO®) was approved by the US FDA and subsequently launched for the treatment of adult patients with relapsed or refractory acute myeloid leukaemia (R/R AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA approved test [16] [17] . Agios Pharmaceuticals, in February 2018, announced the acceptance of a New Drug Application (NDA) for ivosidenib. The NDA was granted Priority Review and was given a Prescription Drug User Fee Act (PDUFA) action date of August 21, 2018. In December 2017, Agios Pharmaceuticals submitted the NDA to the FDA, which was supported by data from the ongoing phase I dose-escalation and expansion trial [see NCT02074839] [18] [19] .

In May 2019, the US FDA approved ivosidenib (TIBSOVO®), for the treatment of patients with newly diagnosed AML with an IDH1 mutation, who are >= 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy. The sNDA was accepted and granted priority review. The sNDA was accepted under Real-Time Oncology Review pilot program of the FDA which will allow the agency to access clinical trial data before it is formally submitted. Earlier in January 2019, Agios Pharmaceuticals submitted the sNDA with the US FDA. The submission was supported by results from the untreated AML patients from the phase I dose-escalation and expansion study of ivosidenib in patients with newly diagnosed AML, who are not eligible for standard treatment [20] [21] [22] .

Prior to July 2022, ivosidenib was launched in China for the treatment of patients with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase 1 mutation, after receiving an NDA approval from the National Medical Products Administration (NMPA), in January 2022 (CStone Pharmaceuticals pipeline, July 2022) [23] . Earlier in August 2021, the NMPA of China had accepted the NDA and was considered for priority review [24] .

In December 2023, CStone Pharmaceuticals announced that the Named Patient Program (NPP) for ivosidenib has been launched in Hong Kong, Taiwan, and Singapore [5] .

In May 2023, European commission approved ivosidenib tablets (TIBSOVO®) for the treatment of adult patients with newly diagnosed, IDH1- mutated acute myeloid leukemia (AML) in combination with azacytidine. The approval is based on the results from the AGILE study (see below) [25] . In February 2023, Servier announced that ivosidenib tablets (TIBSOVO®) received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) for the treatment of IDH1-mutated acute myeloid leukemia (AML). The opinion was based on the clinical data from the AGILE (AML) study [26] . In March 2022, Servier had submitted a marketing authorisation application (MAA) to the EMA for ivosidenib tablets (TIBSOVO®) as a first line treatment, in combination with azacitidine, in patients with previously untreated IDH1-mutated acute myeloid leukemia (AML) and not eligible for intensive chemotherapy [27] .

As of December 2021, Servier was discussing with the regulatory health authorities regarding submissions to expand the currently approved indications for ivosidenib in multiple cancers [28] .

In January 2023, CStone Pharmaceuticals completed a phase I bridging registrational study that designed to evaluate the efficacy, safety and pharmacokinetics of ivosidenib (TIBSOVO®) tablet in Chinese patients with IDH1 mutant relapsed or refractory acute myeloid leukaemia (CS3010-101; NCT04176393). The open-label, single-arm study was initiated in November 2019 and enrolled 30 patients in China [29] . In July 2019, the China National Medical Products Administration (NMPA) approved the initiation of this study [30] [31] [32] . In November 2019, CStone Pharmaceuticals dosed the first patient in the study [33] . In August 2021, CStone Pharmaceuticals announced that the study has met its prespecified endpoints. The results demonstrated efficacy and manageable safety of ivosidenib, which were consistent with previously reported data from the global study population. In September 2021, updated results of the trial were presented at the 46th European Society for Medical Oncology Congress (ESMO-2021) [34] [24] .

In June 2019, CStone Pharmaceuticals, through a third party submitted a new drug application to the Taiwan Food and Drug Administration (TFDA) for ivosidenib (TIBSOVO®) for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation. Submissions are based on results from the ongoing phase I dose-escalation and expansion trial [see NCT02074839] [35] .

In March 2019, the US FDA granted breakthrough therapy designation to ivosidenib (TIBSOVO®) in combination with azacitidine for the treatment of newly diagnosed adult patients (75 years or older) with acute myeloid leukaemia with IDH1 mutation [36] .

In December 2016, orphan designation was granted by the European Commission for ivosidenib for the treatment of acute myeloid leukaemia [37] .

In June 2023, Servier intiated a phase III trial to evaluate the safety and efficacy of ivosidenib taken with azacitidine to treat adult patients with acute myeloid leukemia (AML) who are presenting a gene mutation called IDH1 (isocitrate dehydrogenase1 mutation-positive [IDH1m]) and cannot receive treatment with intensive chemotherapy (NCT05907057; DIM-95031-006; EudraCT2022-501709-11). The open-label trial intends to enroll approximately 245 patients in the UK, Australia, Austria, Germany, Netherlands, Sweden may expand to Italy and Spain [38] .

In March 2019, HOVON Foundation initiated phase III HOVON150AML/AMLSG29-18 trial to compare event-free survival (EFS) between ivosidenib or enasidenib [see Adis Insight drug profile 800038591] and placebo in combination with induction therapy and consolidation therapy followed by maintenance therapy in patients with newly diagnosed acute myeloid leukemia (AML) or myedysplastic syndrome EB2 (MDS-EB2) with an IDH1 or IDH2 mutation, eligible for intensive chemotherapy (NCT03839771; EudraCT2018-000451-41; HO150). This multicenter, double-blind, randomised, placebo-controlled study intends to enrol 968 patients in Netherlands, Finland, Lithuania, France, Norway and may expand to Australia, Austria, Belgium, Estonia, Germany, Ireland, Luxembourg, Spain, Sweden and USA [39] [40] .

In October 2020, Agios Pharmaceuticals reported the withdrawal of its European Marketing Authorization Application (MAA) for ivosidenib tablets (TIBSOVO®) for the treatment of patients with relapsed or refractory acute myeloid leukaemia (AML) with an isocitrate dehydrogenase-1 (IDH1) mutation. The decision was based on the feedback from the European Medicine Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) that the available clinical data from the company’s phase I study, did not sufficiently support a positive benefit-risk balance for the proposed indication. Agios Pharmaceuticals is advancing two ongoing phase III randomised, controlled trials evaluating TIBSOVO® combinations in newly diagnosed AML [41] . Earlier, in January 2019, Agios Pharmaceuticals submitted a marketing authorisation application (AMA) to the European Medicines Agency for ivosidenib (TIBSOVO®) for the treatment of adult patients with R/R AML with an IDH1 mutation [22] .

The US FDA granted orphan drug designation to ivosidenib for the treatment of patients with IDH 1 mutant positive AML in June 2015 [42] .

In July 2018, Agios Pharmaceuticals completed an expanded access programme that provided access to ivosidenib monotherapy to patients with relapsed or refractory AML with an IDH1 mutation (AG120-C-010; NCT03245424). The programme was initiated in August 2017 and enrolled patients aged 12 years and older [43] .

In August 2021, Servier Pharmaceuticals reported that the trial met its primary and all key secondary endpoint of event-free survival (EFS). Earlier in June 2017, Agios Pharmaceuticals initiated the phase III AGILE trial to evaluate the efficacy and safety of ivosidenib and azacitidine combination treatment, compared with placebo plus azacitidine in adult patients with previously untreated acute myeloid leukaemia with IDH1 mutation who are considered appropriate candidates for non-intensive therapy (AG120-C-009; NCT03173248; EudraCT2016-004907-30; DRKS00022839; 243-17ff). The primary endpoint is overall survival. The randomised, double-blind, placebo-controlled trial completed enrolment of 146 patients in the US, the UK, Austria, Germany, Japan, France, Netherlands, Scotland, England, Czechia, South Korea, Italy, Canada, Australia, Spain, Russia, Taiwan, Poland, Mexico, Israel, China and Brazil, in June 2021 [30] [44] [45] . In November 2018, Agios Pharmaceuticals reported that the FDA has accepted the event free survival (EFS) as a primary endpoint of the trial [46] . The first patient was dosed in this AGILE trial in China. As of June 2021, enrolment was completed for the trial [30] . In August 2021, Servier Pharmaceuticals released topline efficacy and safety data. In addition, the study halted further enrollment based on the recommendation of the Independent Data Monitoring Committee (IDMC), as a difference of clinical importance was noted between the treatment groups [47] . In December 2021, Servier presented data from the trial at 63rd annual meeting of the American Society of Hematology (ASH-Hem-2021) [48] [28] [49] . In June 2022, Servier Pharmaceuticals presented updated efficacy and adverse events data from a phase III trial at the 58th Annual Meeting of the American Society of Clinical Oncology (ASCO-2022) [50] [51] . In June 2022, Servier Pharmaceuticals presented efficacy data from the trial at the 27th Congress of the European Haematology Association (EHA-2022) [52] [53] . In December 2022, Servier Pharmaceuticals presented results from the trial at the 64th Annual meeting of American Society of Hematology (ASH-2022) [54] [55] . In June 2023, updated efficacy and safety data from the trial were released by the company [56] . In June 2023, updated efficacy and adverse events data from the phase III AGILE trial were presented at the 59th Annual Meeting of the American Society of Clinical Oncology (ASCO-2023) [57] .

In October 2023, Servier initiated a phase I/II trial in Cholangiocarcinoma to investigate the safety, tolerability, and preliminary activity of ivosidenib in combination with nivolumab and ipilimumab in previously treated subjects with nonresectable or metastatic cholangiocarcinoma with an IDH1 mutation (NCT05921760; EudraCT2023-503236-41; CL1-95031-006). The open and parallel trial intends to enrol 92 patients in the US [58] .

In June 2016, Celgene initiated a phase Ib/II study to evaluate the safety and efficacy of oral ivosidenib plus subcutaneous azacitidine, in patients with acute myeloid leukaemia harbouring the isocitrate dehydrogenase 1 (IDH1) mutation and cannot receive intensive induction chemotherapy (AG-221-AML-005; 201464; UKCRN30390; EudraCT2015-003951-23; NCT02677922). The study consists of a phase Ib dose-escalation stage and a phase II randomised stage. The primary endpoint of the phase Ib stage is to determine safety and tolerability and to establish the recommended phase II dose of ivosidenib in combination with azacitidine. The primary endpoint of the phase II stage is to determine the efficacy of the combination of ivosidenib with azacitidine compared with azacitidine alone. Enrolment of 78 patients in the dose-escalation portion and 180 patients in four dose-expansion arms was completed. As at June 2018, phase II part of the trial is underway. Patient recruitment of 258 patients was completed in the US, Canada, Australia, Italy, South Korea, the Netherlands, Spain, France, Germany, Switzerland, the UK and Portugal. Updated data were released by the company in June 2018 [59] . Preliminary safety and efficacy data from the trial were presented at the 59th Annual Meeting of the American Association of Hematology (ASH-Hem-2017) [60] [61] . Additional results from the trial were released by the company [62] . Safety and efficacy results from the phase Ib part of the trial were presented at the 55th Annual Meeting of the American Society of Clinical Oncology [63] . In June 2019, Agios Pharmaceuticals presented interim data of this trial at the 24th Congress of the European Haematology Association (EHA-2019) [64] . In December 2019, results from the study were presented at the 61st Annual Meeting and Exposition of the American Society of Hematology (ASH-2019) [65] .

In June 2023, Agios Pharmaceuticals and Massachusetts General Hospital completed a phase I trial which was designed to evaluate the safety of ivosidenib as maintenance therapy in IDH1 mutated acute myeloid leukaemia, myelodysplasia syndromes and chronic myelomonocytic leukaemia patients (18-123; NCT03564821). The open-label trial was initiated in January 2019 and enrolled 18 patients in the US [66] .

In December 2015, Agios Pharmaceuticals and Celgene initiated a phase Ib trial to investigate the safety of ivosidenib or enasidenib (AG 221) [see Adis Insight drug profile 800038591], in combination with induction therapy and consolidation therapy, in patients with newly diagnosed AML with an IDH1 or IDH2 Mutation (AG120-221-C-001; NCT02632708). The open-label trial will enrol approximately 144 participants in the US, the Netherlands and Germany. Preliminary safety and efficacy data from the trial were presented at the 59th Annual Meeting of the American Association of Hematology (ASH-Hem-2017) [60] . In November 2017, Agios Pharmaceuticals announced initial results of ivosidenib or enasidenib combined with standard induction chemotherapy, wherein the combination was well-tolerated and active in patients with newly diagnosed AML with an IDH1 or IDH2 Mutation [67] [68] [69] . Updated data from the phase I trial were presented at the 60th Annual Meeting of the American Society of Haematology (ASH-2018), in December 2018 [70] . Later, in June 2020, pharmacokinetics and pharmacodynamics data from the trial were presented at the 25th Congress of the European Haematology Association (EHA-2020) [71] . In December 2021, Agios Pharmaceuticals presented the updated results from this trial at 63rd Annual Meeting and Exposition of American Society of Hematology (ASH-Hem-2021) [72]

Agios Pharmaceuticals conducted a single-arm phase I trial to evaluate the impact of ivosidenib on health-related quality of life (HRQoL) in patients with IDH1-mutated relapsed/refractory acute myeloid leukaemia in the US. In June 2018, the company reported that ivosidenib had increased the incremental quality-adjusted life years, largely driven by benefits of adverse event reductions in infections and haematologic disorders, compared with other treatments, and the drug was expected to improve HRQoL in patients [73] .

In March 2018, Agios Pharmaceuticals completed a phase I trial that evaluated the pharmacokinetic, safety, and tolerability of a single 500mg ivosidenib dose in volunteers with mild or moderate hepatic impairment compared to volunteers with normal hepatic function (AG120C012; NCT03282513). The open-label trial was initiated in September 2017, and enrolled 33 volunteers in the US [74] .

In September 2017, Agios Pharmaceutical completed a phase I trial that evaluated the pharmacokinetics and safety of ivosidenib in healthy, adult male Japanese and Caucasian subjects (NCT03071770; AG120C006). The study evaluated three cohorts of a single oral dose of ivosidenib in Japanese and Caucasian subjects. The single-dose, open-label trial was initiated in March 2017, and enrolled 60 volunteers in the US [75] .

In October 2016, Agios Pharmaceuticals completed a phase I trial that assessed the effect of multiple oral doses of itraconazole on the single-dose pharmacokinetics of ivosidenib in healthy volunteers (AG120-C-007; NCT02831972). The open-label, two-period, fixed sequence, parallel, non-randomised trial was initiated in June 2016, and recruited 22 volunteers in the US [76] .

Agios Pharmaceutical initiated a phase I bioavailability trial in June 2015, to evaluate the absorption, metabolism and excretion of radiolabelled AG-120 ([14C]-AG-120) in healthy male volunteers (AG120-C-003; NCT02489513). The open-label trial enrolled eight volunteers in the US, and was completed in October 2015 [77] .

In June 2016, Agios Pharmaceuticals completed a US-based two-part phase I trial, initiated in October 2015, that assessed the effect of food on ivosidenib pharmacokinetics following single oral dose administration in healthy volunteers (AG120-C-004; NCT02579707). PART 1 is an open-label, randomised study that determined the safety and PK parameters of a single 1 000mg oral dose of ivosidenib. The trial recruited 36 volunteers to a fed/fasted or fasted/fed treatment sequence in a 2-period crossover design [78] .

In November 2013, Agios reported that it had completed IND-enabling studies for ivosidenib [79] .

In April 2021, Agios Pharmaceuticals presented preclinical results from ivosidenib in a mutant IDH1 acute myeloid leukaemia patient-derived xenograft model at 112th Annual Meeting of the American Association for Cancer Research (AACR-2021) [80] .

Agios Pharmaceuticals presented preclinical data at the 25th AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (AACR-NCI-EORTC-2013) in October 2013. The data suggested that mutation selective compounds, capable of inhibiting mutant IDH enzymes, were able to correct altered gene expression patterns seen in IDH1/2 mutant AML tumours [81] .

In February 2013, Agios Pharmaceuticals demonstrated that its IDH1 inhibitor blocked the overproduction of 2-HG and its associated cancer causing effects in an IDH1-mutant leukaemia cell model [82] . Further results were published in April 2013, showing the ability of mutant IDH1 to produce 2-HG and impair the growth of patient-derived glioma cells [83] .

Results from preclinical studies demonstrating the direct oncogenic effects of an IDH1 mutation in vivo were published in the journal Nature, in July 2012. Mutation of IDH1 caused elevated levels of the metabolite 2HG, which lead to epigenetic changes commonly seen in AML [84] .

In November 2010, Agios presented in vitro data at the 22nd Symposium on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR-2010). The key findings demonstrated tumour-associated IDH1 somatic mutations result in a gain-of-function which causes the accumulation of 2-HG [85] . Agios also presented early research data at the 101st Annual Meeting of the American Association for Cancer Research (AACR-2010) to support its development of therapeutics targeting IDH1 mutations, in April 2010 [86] .

Cholangiocarcinoma

In April 2023, ivosidenib (TIBSOVO) received approval from the Therapeutic Goods Administration (TGA) for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 (IDH1) R132 mutation after at least one prior line of systemic therapy in Australia [87] .

In August 2021, US FDA approved ivosidenib tablets (TIBSOVO®) for the treatment of adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation [88] . In May 2021, Agios Pharmaceuticals announced that, the US FDA has accepted the supplemental New Drug Application (sNDA) and granted priority review. The sNDA acceptance was supported by data from the ClarIDHy study [see below]. In March 2021, Agios Pharmaceuticals announced the submission of a supplemental New Drug Application (sNDA) to the US FDA [89] [90] .

In May 2023, European commission approved ivosidenib tablets (TIBSOVO®) as monotherapy for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 R132 mutation who were previously treated by at least one prior line of systemic therapy. The approval is based on the results of the ClarIDHy trial (see below) [25] . In February 2023, Servier announced that ivosidenib tablets (TIBSOVO®) received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) for the treatment of IDH1-mutated cholangiocarcinoma. The opinion was based on the clinical data from the ClarIDHy (CCA) study [26] . In March 2022, Servier had submitted a marketing authorisation application (MAA) to the EMA for ivosidenib tablets (TIBSOVO®) in patients with previously treated, locally advanced or metastatic IDH1-mutated cholangiocarcinoma [27] .

In March 2018, orphan designation was granted by the European Commission for ivosidenib for the treatment of biliary tract cancer (cholangiocarcinoma) [91] .

In April 2017, the FDA granted orphan drug designation to ivosidenib for the treatment of cholangiocarcinoma [92] .

In January 2017, Agios Pharmaceuticals announced that the US FDA granted Fast Track designation to ivosidenib for the treatment of patients with previously treated unresectable or metastatic cholangiocarcinoma with an IDH1 mutation [44] .

In April 2022, the Therapeutic Goods Administration granted orphan drug designation to ivosidenib for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 (IDH1) mutation, who were previously treated by at least one prior line of systemic therapy, with a lapse date of 29/10/2022 (Therapeutic Goods Administration, June 2022).

In May 2023, Servier initiated a phase IIIb ProvIDHe trial to evaluate ivosidenib in patients with a pretreated locally advanced or metastatic cholangiocarcinoma (NCT05876754; DIM-95031-002; EudraCT2022-501463-40). The open-label, early access trial intends to enroll approximately 220 patients in the Germany [93] .

In May 2021, Agios Pharmaceuticals completed the phase III ClarIDHy trial that evaluated the safety and efficacy of oral ivosidenib in patients with IDH1 gene-mutated advanced cholangiocarcinoma (AG120-C-005; NCT02989857). This randomised, double-blind, parallel, placebo-controlled trial was initiated in December 2016 and enrolled 187 patients in the US, Germany, France, Italy, South Korea, Spain and the UK [94] . Earlier, in September 2020, Agios Pharmaceuticals announced that the phase III ClarIDHy has met its primary endpoint, demonstrating a statistically significant improvement in progression-free survival (PFS) in patients randomized to ivosidenib compared with placebo patients. The safety profile was also consistent with previously published data. The company presented data from the trial at the European Society for Medical Oncology Congress (ESMO-2019). Agios also announced the publication of results from this trial in the Lancet Oncology. Positive results from the trial were released, in May 2019. In September 2019, efficacy results were released by Agios Pharmaceuticals. Later, in May 2020, additional results from the trial were presented at the 56th Annual Meeting of the American Society of Clinical Oncology (ASCO-2020). In September 2020, updated data was released by Agios Pharmaceuticals. In January 2021, updated efficacy data was released by Agios Pharmaceuticals. In June 2021, results from the trial were presented at the 57th Annual Meeting of the American Society of Clinical Oncology (ASCO-2021) [95] [96] [97] [98] [99] [100] [101] [102] [103] [104] [105] .

In October 2023, Servier initiates a phase II trial to evaluate the efficacy of orally administered ivosidenib in previously treated Japanese patients with nonresectable or metastatic cholangiocarcinoma with an IDH1 mutation (NCT06081829; CL2-95031-008). This open label study is designed to enrol approximately 10 patients in Japan [106] .

Agios pharmaceuticals plans to conduct a randomised phase II study of ivosidenib in IDH1 mutant positive cholangiocarcinoma [67] [107] .

Glioma

In January 2018, the US FDA granted orphan drug designation to ivosidenib for the treatment of glioma [108] .

In November 2023, Agios Pharmaceuticals in collaboration with Bristol-Myers Squibb and University of Pittsburgh Medical Center completed a phase II trial that evaluated the safety, response rate, progression free and overall survival, and summarize safety events of ivosidenib in combination with nivolumab [see Adis Insight drug profile 800022442] in participants with advanced solid tumours (nonresectable or metastatic) or enhancing gliomas (HCC 19-096; NCT04056910). The single group trial was initiated in April 2021 and enrolled 16 patients in the US [109] .

In March 2018, Agios Pharmaceuticals initiated a phase I trial to evaluate the suppression of 2-hydroxyglutarate in IDH-1 mutant gliomas in resected tumour tissue following pre-surgical treatment with ivosidenib or AG 881 [see Adis Insight drug profile 800042899] (AG120-881-C-001; NCT03343197). The randomised, open-label trial is designed to enrol 45 patients in the US [110] . In May 2019, Agios Pharmaceuticals presented safety and efficacy data at the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO-2019) [111] . In November 2019, Agios Pharmaceuticals released results for the trial [112] . In June 2021, results were presented at the 57th Annual Meeting of the American Society of Clinical Oncology (ASCO-2021) [113] . In June 2022, efficacy and adverse events data from the trial were presented at the 58th Annual Meeting of the American Society of Clinical Oncology (ASCO-2022) [114] .

In November 2017, Agios Pharmaceuticals released the preclinical data for ivosidenib and AG 881 [see Adis Insight Drug profile 800042899], in an orthotopic mouse xenograft model of human mIDH1-R132H glioma [115] .

IDH1 inhibitors discovered by Agios showed good potency in a glioblastoma cell line, with a reduction of 2-HG, in a tumour xenograft model [116] .

Myelodysplastic syndrome

In October 2023, Servier received US FDA approval for TIBSOVO® (ivosidenib tablets) in the treatment of patients with isocitrate dehydrogenase 1 (IDH1)-mutated relapsed or refractory (R/R) myelodysplastic syndromes (MDS). The approval was based on the pivotal phase I trial (see below) in myelodysplastic syndrome. In August 2023, Servier announced that US FDA accepted a supplemental New Drug Application (sNDA) and granted priority Review for TIBSOVO® (ivosidenib tablets) in the treatment of patients with isocitrate dehydrogenase 1 (IDH1)-mutated relapsed or refractory (R/R) myelodysplastic syndromes (MDS) [117] [118] [119] .

In December 2019, the US FDA granted breakthrough therapy designation to ivosidenib (TIBSOVO®) in combination with azacitidine for the treatment of relapsed or refractory myelodysplastic syndrome with IDH1 mutation [120] .

In May 2019, Groupe Francophone des Myelodysplasies initiated phase I trial to evaluate efficacy of AG120 (IDH1 inhibitor) in patients With IDH1 Mutated Myelodysplastic Syndrome (NCT03503409, IDIOME-STUDY). The single-arm, multicenter, open trial intends to enrol approximately 68 patients in France. The trial is also expected to be in Italy [121] . In June 2023, Adverse events and efficacy data was released by the company [122]

In March 2014, Agios Pharmaceuticals initiated a pivotal phase I trial to assess the safety, pharmacokinetics, pharmacodynamics and clinical activity of ivosidenib, when administered continuously on days 1 through 28 of a 28-day cycle to patients with relapsed/refractory AML or recurrent/refractory myelodysplastic syndrome (AG120-C-001; NCT02074839). IDH1 mutation was identified or confirmed using the Abbott RealTime™ IDH1 assay. The co-primary endpoints are the incidence of adverse events and the maximum tolerated dose or recommended phase II dose. The open-label, dose-escalation recruited 266 patients in the US and France. In June 2015, Agios presented data from 57 evaluable patients at the 20th Congress of the European Haematology Association (EHA-2015), which showed a reduction in plasma levels of oncometabolite 2-hydroxglutarate (2-HG) in the patients. In November 2016, additional data were presented at the 58th Annual Meeting and Exposition of the American Society of Hematology (ASH-Hem-2016). In December 2017, Agios Pharmaceuticals released the primary efficacy and safety data of the trial. In May 2018 and June 2018, Agios Pharmaceuticals data were presented at the 54th Annual Meeting of American Society of Clinical Oncology (ASCO-2018) and the 23rd Congress of the European Haematology Association (EHA-2018), respectively. In July 2018, Agios released additional data from the trial showing durable responses as a monotherapy that can help patients achieve and maintain transfusion independence. In December 2018, the updated were presented at the 60th American Society of Haematology Annual Meeting (ASH-2018). In June 2019, data presented at the 24th Congress of the European Haematology Association (EHA-2019) showed that ivosidenib monotherapy was well tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed mIDH1 (mutant IDH1 protein). In June 2020, data from the trial were presented at the 25th Congress of the European Haematology Association (EHA-2020). Later, in December 2020, updated data from the trial was presented at the 62nd Annual Meeting and Exposition of the American Society of Hematology (ASH-2020). In June 2023, updated efficacy and safety data from the trial were released by the company [56] [123] [124] [125] [126] [17] [103] [127] [67] [104] [128] [129] [130] [131] [132] [133] [134] [135] [136] .

Solid tumours

In January 2024, Institut de Recherches Internationales Servier completed phase I trial which evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-120 in advanced solid tumors, including glioma, that harbor an IDH1 mutation (NCT02073994; AG120-C-002). The open label trial was initiated in March 2014 and enrolled approximately 174 patients in the US and France [137] . Results from the trial were released in November 2016 [138] [139] . In June 2017, the company presented results for the same at the 53rd Annual Meeting of American Society of Clinical Oncology (ASCO-2017) [140] . In June 2017, the company released interim safety and efficacy results of the trial [115] . Data from this trial were presented at the 54th Annual Meeting of the American Society of Clinical Oncology (ASC0-2018) [141] [137] . In June 2023, the company presented updated efficacy and safety data from the trial at the 59th Annual Meeting of the American Society of Clinical Oncology (ASC0-2023) [142] .

Labelling information

The approved label of ivosidenib contains a black box warning for differentiation syndrome [17] .

Patent Information

As of January 2018, Agios Pharmaceuticals owned approximately 10 issued US patents, 10 issued foreign patents, 20 pending US patent applications, 270 pending foreign patent applications in a number of jurisdictions, and 10 pending PCT patent applications, directed to its isocitrate dehydrogenase (IDH) mutant product candidates. These patents will be valid till at least 2033 to 2034 [143] .

Drug Properties & Chemical Synopsis

  • Route of administration PO
  • Formulation Tablet, unspecified
  • Class Antineoplastics, Cyclobutanes, Nitriles, Pyridines, Pyrrolidines, Small molecules
  • Target Isocitrate dehydrogenase 1
  • Mechanism of Action Isocitrate dehydrogenase 1 inhibitors
  • WHO ATC code

    L01X-X62 (Ivosidenib)

  • EPhMRA code

    L1X9 (All other antineoplastics)

  • Chemical name (2S)-N-[(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl]-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide
  • Molecular formula C28 H22 Cl F3 N6 O3
  • SMILES N1(C(CCC1=O)C(=O)N(C1C=NC=C(C=1)F)C(C(=O)NC1CC(C1)(F)F)C1C(=CC=CC=1)Cl)C1C=C(C=CN=1)C#N
  • Chemical Structure
  • CAS Registry Number 1448347-49-6

Biomarkers Sourced From Trials

Indication Biomarker Function Biomarker Name Number of Trials

acute myeloid leukaemia

Arm Group Label

IDH2

IDH1

1

1

acute myeloid leukaemia

Outcome Measure

Tumor Mutational Burden

Isocitric acid

IDH1

B-cell lymphoma 2 (Bcl-2)

2-Hydroxyglutarate

1

2

3

1

2

acute myeloid leukaemia

Brief Title

IDH2

IDH1

2

12

acute myeloid leukaemia

Arm Group Description

TET2

RUNX1

runt-related transcription factor 1; translocated to, 1 (cyclin D-related)

p53 (tumor protein p53)

Nucleophosmin

MYH11

IDH2

IDH1

FLT3

core-binding factor, beta subunit

1

1

1

1

1

1

3

3

1

1

acute myeloid leukaemia

Detailed Description

Tumor Mutational Burden

PD-L1/CD274

Interferon Gamma (IFNg)

IDH1

CYP2D7

CYP2D6

1

1

1

6

1

1

acute myeloid leukaemia

Eligibility Criteria

UGT1A1

UDP glucuronosyltransferase family 1 member A8

UDP glucuronosyltransferase family 1 member A4

UDP glucuronosyltransferase family 1 member A10

UDP glucuronosyltransferase 1 family, polypeptide A7

UDP glucuronosyltransferase 1 family, polypeptide A6

retinoic acid receptor, alpha

Pyruvic acid

protease, serine 27

promyelocytic leukemia

PML-RARA fusion

platelet-activating factor acetylhydrolase 1b, regulatory subunit 1 (45kDa)

MHC class I antigen HLA-A heavy chain (HLA-A)

L-Aspartic acid

jagged 1

Isocitric acid

IDH2

IDH1

HLA-A

FLT3

FANCB

DNA (cytosine-5-)-methyltransferase 3 beta

cytochrome P450 family 2 subfamily C member 8

cytochrome P450 family 2 subfamily B member 6

CYP3A4

CYP2D7

CYP2D6

CYP1A2

Creatinine

Bilirubin

BCR-ABL / Philadelphia Chromosome

AXL receptor tyrosine kinase

ASXL1

ALT

Alkaline phosphatase (ALPL)

4

4

4

4

4

4

1

1

2

1

3

1

1

2

1

2

4

15

1

2

2

1

1

1

1

1

1

1

2

2

1

1

1

2

1

acute myeloid leukaemia

Official Title

Isocitric acid

IDH2

IDH1

B-cell lymphoma 2 (Bcl-2)

1

4

13

1

acute myeloid leukaemia

Brief Summary

Isocitric acid

IDH2

IDH1

3

3

11

astrocytoma

Brief Title

IDH1

1

astrocytoma

Detailed Description

IDH1

1

astrocytoma

Eligibility Criteria

IDH1

ATRX

2

1

astrocytoma

Official Title

IDH1

2

astrocytoma

Brief Summary

IDH1

2-Hydroxyglutarate

2

1

cholangiocarcinoma

Brief Title

IDH1

2

cholangiocarcinoma

Detailed Description

IDH1

Fibroblast growth factor receptor 2 (FGFR2)

CYP2D7

CYP2D6

1

1

1

1

cholangiocarcinoma

Eligibility Criteria

IDH1

Fibroblast growth factor receptor 2 (FGFR2)

CYP2D7

CYP2D6

3

1

1

1

cholangiocarcinoma

Official Title

IDH1

2

cholangiocarcinoma

Brief Summary

IDH1

2

chondrosarcoma

Brief Summary

IDH1

2

chondrosarcoma

Brief Title

IDH1

2

chondrosarcoma

Eligibility Criteria

IDH1

2

chondrosarcoma

Official Title

IDH1

2

chronic myeloid leukaemia

Arm Group Label

IDH2

IDH1

1

1

chronic myeloid leukaemia

Outcome Measure

IDH2

IDH1

1

1

chronic myeloid leukaemia

Arm Group Description

IDH2

IDH1

1

1

chronic myeloid leukaemia

Detailed Description

IDH2

IDH1

1

1

chronic myeloid leukaemia

Eligibility Criteria

protease, serine 27

proline rich protein BstNI subfamily 1

IDH2

IDH1

Breakpoint cluster region protein (BCR/NY-REN-26)

1

1

1

1

1

chronic myelomonocytic leukaemia

Outcome Measure

Tumor Mutational Burden

Isocitric acid

IDH1

2-Hydroxyglutarate

1

1

1

1

chronic myelomonocytic leukaemia

Brief Title

IDH1

1

chronic myelomonocytic leukaemia

Detailed Description

IDH1

1

chronic myelomonocytic leukaemia

Eligibility Criteria

MHC class I antigen HLA-A heavy chain (HLA-A)

IDH1

HLA-A

1

1

1

chronic myelomonocytic leukaemia

Official Title

IDH1

1

chronic myelomonocytic leukaemia

Brief Summary

IDH1

1

CNS cancer

Brief Summary

IDH1

1

CNS cancer

Brief Title

IDH1

1

CNS cancer

Detailed Description

IDH1

1

CNS cancer

Official Title

IDH1

1

essential thrombocythaemia

Arm Group Label

IDH2

IDH1

1

1

essential thrombocythaemia

Outcome Measure

IDH2

IDH1

1

1

essential thrombocythaemia

Arm Group Description

IDH2

IDH1

1

1

essential thrombocythaemia

Detailed Description

IDH2

IDH1

1

1

essential thrombocythaemia

Eligibility Criteria

protease, serine 27

proline rich protein BstNI subfamily 1

IDH2

IDH1

Breakpoint cluster region protein (BCR/NY-REN-26)

1

1

1

1

1

glioma

Brief Title

IDH1

2

glioma

Detailed Description

IDH1

CYP2D7

CYP2D6

2

1

1

glioma

Eligibility Criteria

IDH1

CYP2D7

CYP2D6

ATRX

3

1

1

1

glioma

Official Title

IDH1

3

glioma

Brief Summary

IDH1

2-Hydroxyglutarate

2

1

haematological malignancies

Outcome Measure

IDH1

B-cell lymphoma 2 (Bcl-2)

1

1

haematological malignancies

Brief Title

IDH1

2

haematological malignancies

Detailed Description

IDH1

1

haematological malignancies

Eligibility Criteria

protease, serine 27

IDH1

1

2

haematological malignancies

Official Title

IDH1

B-cell lymphoma 2 (Bcl-2)

2

1

haematological malignancies

Brief Summary

IDH1

2

lymphoma

Brief Summary

IDH1

1

lymphoma

Brief Title

IDH1

1

lymphoma

Detailed Description

IDH1

1

lymphoma

Official Title

IDH1

1

myelodysplastic syndromes

Arm Group Label

IDH2

IDH1

2

2

myelodysplastic syndromes

Outcome Measure

Tumor Mutational Burden

Isocitric acid

IDH2

IDH1

B-cell lymphoma 2 (Bcl-2)

2-Hydroxyglutarate

1

1

1

3

1

1

myelodysplastic syndromes

Brief Title

IDH2

IDH1

1

8

myelodysplastic syndromes

Arm Group Description

IDH2

IDH1

2

2

myelodysplastic syndromes

Detailed Description

Tumor Mutational Burden

PD-L1/CD274

Interferon Gamma (IFNg)

IDH2

IDH1

CYP2D7

CYP2D6

1

1

1

1

7

1

1

myelodysplastic syndromes

Eligibility Criteria

UGT1A1

UDP glucuronosyltransferase family 1 member A8

UDP glucuronosyltransferase family 1 member A4

UDP glucuronosyltransferase family 1 member A10

UDP glucuronosyltransferase 1 family, polypeptide A6

retinoic acid receptor, alpha

Pyruvic acid

protease, serine 27

promyelocytic leukemia

proline rich protein BstNI subfamily 1

MHC class I antigen HLA-A heavy chain (HLA-A)

L-Aspartic acid

IDH2

IDH1

HLA-A

FLT3

DNA (cytosine-5-)-methyltransferase 3 beta

cytochrome P450 family 2 subfamily C member 8

cytochrome P450 family 2 subfamily B member 6

CYP3A4

CYP2D7

CYP2D6

CYP1A2

Creatinine

Breakpoint cluster region protein (BCR/NY-REN-26)

Bilirubin

ALT

2

2

2

2

2

1

1

2

1

1

1

1

2

9

1

1

1

1

1

1

1

1

1

2

1

1

1

myelodysplastic syndromes

Official Title

IDH2

IDH1

B-cell lymphoma 2 (Bcl-2)

1

8

1

myelodysplastic syndromes

Brief Summary

Isocitric acid

IDH2

IDH1

1

1

7

myelodysplasticsyndromes

Eligibility Criteria

UDP glucuronosyltransferase 1 family, polypeptide A7

2

myelofibrosis

Arm Group Label

IDH2

IDH1

1

1

myelofibrosis

Outcome Measure

IDH2

IDH1

1

1

myelofibrosis

Arm Group Description

IDH2

IDH1

1

1

myelofibrosis

Detailed Description

IDH2

IDH1

1

1

myelofibrosis

Eligibility Criteria

protease, serine 27

proline rich protein BstNI subfamily 1

IDH2

IDH1

Breakpoint cluster region protein (BCR/NY-REN-26)

1

1

1

1

1

myeloproliferative disorders

Arm Group Label

IDH2

IDH1

1

1

myeloproliferative disorders

Outcome Measure

IDH2

IDH1

1

1

myeloproliferative disorders

Brief Title

IDH1

1

myeloproliferative disorders

Arm Group Description

IDH2

IDH1

1

1

myeloproliferative disorders

Detailed Description

IDH2

IDH1

1

2

myeloproliferative disorders

Eligibility Criteria

UGT1A1

UDP glucuronosyltransferase family 1 member A8

UDP glucuronosyltransferase family 1 member A4

UDP glucuronosyltransferase family 1 member A10

UDP glucuronosyltransferase 1 family, polypeptide A7

UDP glucuronosyltransferase 1 family, polypeptide A6

Pyruvic acid

protease, serine 27

proline rich protein BstNI subfamily 1

L-Aspartic acid

IDH2

IDH1

DNA (cytosine-5-)-methyltransferase 3 beta

cytochrome P450 family 2 subfamily C member 8

cytochrome P450 family 2 subfamily B member 6

CYP3A4

CYP1A2

Creatinine

Breakpoint cluster region protein (BCR/NY-REN-26)

ALT

1

1

1

1

1

1

1

1

1

1

1

2

1

1

1

1

1

1

1

1

myeloproliferative disorders

Official Title

IDH1

1

neuroblastoma

Brief Summary

IDH1

1

neuroblastoma

Brief Title

IDH1

1

neuroblastoma

Detailed Description

IDH1

1

neuroblastoma

Official Title

IDH1

1

oligodendroglioma

Brief Title

IDH1

1

oligodendroglioma

Detailed Description

IDH1

1

oligodendroglioma

Eligibility Criteria

IDH1

ATRX

2

1

oligodendroglioma

Official Title

IDH1

2

oligodendroglioma

Brief Summary

IDH1

2-Hydroxyglutarate

2

1

pancytopenia

Outcome Measure

IDH1

1

pancytopenia

Brief Title

IDH1

1

pancytopenia

Eligibility Criteria

IDH1

1

pancytopenia

Official Title

IDH1

1

pancytopenia

Brief Summary

IDH1

1

polycythaemia vera

Arm Group Label

IDH2

IDH1

1

1

polycythaemia vera

Outcome Measure

IDH2

IDH1

1

1

polycythaemia vera

Arm Group Description

IDH2

IDH1

1

1

polycythaemia vera

Detailed Description

IDH2

IDH1

1

1

polycythaemia vera

Eligibility Criteria

protease, serine 27

proline rich protein BstNI subfamily 1

IDH2

IDH1

Breakpoint cluster region protein (BCR/NY-REN-26)

1

1

1

1

1

solid tumours

Brief Title

IDH1

3

solid tumours

Detailed Description

IDH1

CYP2D7

CYP2D6

2

1

1

solid tumours

Eligibility Criteria

IDH1

CYP2D7

CYP2D6

2

1

1

solid tumours

Official Title

IDH1

3

solid tumours

Brief Summary

IDH1

2

thrombocytopenia

Outcome Measure

IDH1

1

thrombocytopenia

Brief Title

IDH1

1

thrombocytopenia

Eligibility Criteria

IDH1

1

thrombocytopenia

Official Title

IDH1

1

thrombocytopenia

Brief Summary

IDH1

1

Biomarker

Drug Name Biomarker Name Biomarker Function
Ivosidenib - Servier 2-Hydroxyglutarate Brief Summary, Outcome Measure
Alkaline phosphatase (ALPL) Eligibility Criteria
ALT Eligibility Criteria
ASRGL1 Arm Group Description
ASXL1 Eligibility Criteria
ATRX Eligibility Criteria
AXL receptor tyrosine kinase Eligibility Criteria
B-cell lymphoma 2 (Bcl-2) Official Title, Outcome Measure
BCR-ABL / Philadelphia Chromosome Eligibility Criteria
Bilirubin Eligibility Criteria
Breakpoint cluster region protein (BCR/NY-REN-26) Eligibility Criteria
CA125 ovarian cancer antigen (MUC16) Eligibility Criteria
caudal type homeobox 2 Eligibility Criteria
CD45 (leukocyte common antigen) Eligibility Criteria
chromosome 17 open reading frame 97 Eligibility Criteria
component of oligomeric golgi complex 8 Outcome Measure
core-binding factor, beta subunit Arm Group Description
Creatinine Eligibility Criteria
CYP1A2 Eligibility Criteria
CYP2D6 Detailed Description, Eligibility Criteria
CYP2D7 Detailed Description, Eligibility Criteria
CYP3A4 Eligibility Criteria
cytochrome P450 family 2 subfamily B member 6 Eligibility Criteria
cytochrome P450 family 2 subfamily C member 8 Eligibility Criteria
Cytokeratin 20 Eligibility Criteria
dermcidin Eligibility Criteria
DNA (cytosine-5-)-methyltransferase 3 beta Eligibility Criteria
FANCB Eligibility Criteria
Fibroblast growth factor receptor 2 (FGFR2) Detailed Description, Eligibility Criteria
FLT3 Arm Group Description, Eligibility Criteria
HLA-A Eligibility Criteria
HLA-B Eligibility Criteria
IDH1 Arm Group Description, Arm Group Label, Brief Summary, Brief Title, Detailed Description, Eligibility Criteria, Official Title, Outcome Measure
IDH2 Arm Group Description, Arm Group Label, Brief Summary, Brief Title, Detailed Description, Eligibility Criteria, Official Title, Outcome Measure
Interferon Gamma (IFNg) Detailed Description
Isocitric acid Brief Summary, Eligibility Criteria, Official Title, Outcome Measure
jagged 1 Eligibility Criteria
keratin 7 Eligibility Criteria
L-Aspartic acid Eligibility Criteria
major histocompatibility complex, class I, C Eligibility Criteria
major histocompatibility complex, class II, DR beta 1 Eligibility Criteria
MHC class I antigen HLA-A heavy chain (HLA-A) Eligibility Criteria
MYH11 Arm Group Description
NK2 homeobox 1 Eligibility Criteria
Nucleophosmin Arm Group Description
opioid receptor delta 1 Outcome Measure
p53 (tumor protein p53) Arm Group Description
PD-L1/CD274 Detailed Description
PIF1 5'-to-3' DNA helicase Eligibility Criteria
platelet-activating factor acetylhydrolase 1b, regulatory subunit 1 (45kDa) Eligibility Criteria
PML-RARA fusion Eligibility Criteria
proline rich protein BstNI subfamily 1 Eligibility Criteria
promyelocytic leukemia Eligibility Criteria
protease, serine 27 Eligibility Criteria
PSA Eligibility Criteria
Pyruvic acid Eligibility Criteria
retinoic acid receptor, alpha Eligibility Criteria
RNA binding motif protein 45 Eligibility Criteria
runt-related transcription factor 1; translocated to, 1 (cyclin D-related) Arm Group Description
RUNX1 Arm Group Description
TET2 Arm Group Description
TTF1 Eligibility Criteria
Tumor Mutational Burden Detailed Description, Outcome Measure
UDP glucuronosyltransferase 1 family, polypeptide A6 Eligibility Criteria
UDP glucuronosyltransferase 1 family, polypeptide A7 Eligibility Criteria
UDP glucuronosyltransferase family 1 member A10 Eligibility Criteria
UDP glucuronosyltransferase family 1 member A4 Eligibility Criteria
UDP glucuronosyltransferase family 1 member A8 Eligibility Criteria
UGT1A1 Eligibility Criteria
For more detail, check out BiomarkerBase: the leading source of information about biomarkers used in drug development and diagnostic tests, tracking a comprehensive list of biomarker uses worldwide by over 800 companies

Development Status

Summary Table

Indication Qualifier Patient Segment Phase Countries Route / Formulation Developers Event Date
Acute myeloid leukaemia relapsed or refractory AML with an IDH1 mutation Second-line therapy or greater Marketed China PO / Tablet CStone Pharmaceuticals 01 Jul 2022
Acute myeloid leukaemia In patients with an IDH1 mutation who are not eligible for standard therapy First-line therapy, In adults, In the elderly, Monotherapy, Newly diagnosed Marketed USA PO / Tablet Agios Pharmaceuticals 03 May 2019
Acute myeloid leukaemia in combination with azacitidine Combination therapy, First-line therapy Marketed USA PO / unspecified Agios Pharmaceuticals 26 May 2022
Acute myeloid leukaemia with an IDH1 mutation Second-line therapy or greater Marketed USA PO / Tablet Agios Pharmaceuticals 02 Aug 2018
Acute myeloid leukaemia in combination with azacitidine; in untreated IDH1-mutated AML and not eligible for intensive chemotherapy Combination therapy, First-line therapy Registered European Union, Iceland, Liechtenstein, Norway PO / unspecified Agios Pharmaceuticals 10 May 2023
Acute myeloid leukaemia in patients with IDH1 mutation Monotherapy, Second-line therapy or greater Preregistration Taiwan PO / unspecified CStone Pharmaceuticals 02 Jun 2019
Acute myeloid leukaemia in combination with azacitidine; in patients with IDH1 or IDH2 Mutation in combination with azacitidine Combination therapy, First-line therapy Phase III Brazil, Canada, China, Israel, Mexico, Russia, South Korea, Taiwan PO / unspecified Agios Pharmaceuticals 19 Jul 2019
Acute myeloid leukaemia with an IDH1 mutation First-line therapy, In adults, In the elderly, Newly diagnosed Phase III Finland, France, Lithuania, Norway PO / Tablet HOVON Foundation 01 Mar 2019
Acute myeloid leukaemia in combination with azacitidine; in patients with IDH1 or IDH2 Mutation Combination therapy, First-line therapy, In adults Phase III Australia, United Kingdom PO / unspecified Agios Pharmaceuticals 01 Jun 2018
Acute myeloid leukaemia with an IDH1 mutation Combination therapy, First-line therapy, In adults, In the elderly Phase III Netherlands PO / Tablet HOVON Foundation 01 Mar 2019
Acute myeloid leukaemia - Combination therapy, First-line therapy Phase III England, Japan, Scotland PO / Tablet Agios Pharmaceuticals 01 Jun 2017
Acute myeloid leukaemia in combination with azacitidine Combination therapy, Second-line therapy or greater Phase III Czech Republic PO / unspecified Agios Pharmaceuticals 20 Jun 2017
Acute myeloid leukaemia - Combination therapy, First-line therapy, In adults Phase III Austria, Germany, Sweden PO / Tablet Servier 14 Jun 2023
Acute myeloid leukaemia in combination with azacitidine; in patients with IDH1 or IDH2 Mutation Combination therapy, First-line therapy Phase I/II Switzerland PO / unspecified Agios Pharmaceuticals 08 Mar 2017
Acute myeloid leukaemia with an IDH1 genetic mutation Second-line therapy or greater No development reported (I) France PO / unspecified Agios Pharmaceuticals 28 Jul 2020
Acute myeloid leukaemia - In adults, Second-line therapy or greater Preregistration Submission Withdrawal European Union PO / Tablet Agios Pharmaceuticals 16 Oct 2020
Cholangiocarcinoma in IDH1 mutation positive patients Inoperable/Unresectable, Late-stage disease, Metastatic disease, Second-line therapy or greater Marketed USA PO / Tablet Agios Pharmaceuticals 25 Aug 2021
Cholangiocarcinoma - Late-stage disease, Metastatic disease, Second-line therapy or greater Registered Australia PO / Tablet Servier 06 Apr 2023
Cholangiocarcinoma previously treated, locally advanced or metastatic IDH1-mutated cholangiocarcinoma Late-stage disease, Metastatic disease, Second-line therapy or greater Registered European Union, Iceland, Liechtenstein, Norway PO / unspecified Agios Pharmaceuticals 10 May 2023
Cholangiocarcinoma - Inoperable/Unresectable, Late-stage disease, Metastatic disease, Second-line therapy or greater Phase III Germany PO / Tablet Servier 03 May 2023
Cholangiocarcinoma - Inoperable/Unresectable, Late-stage disease, Metastatic disease, Second-line therapy or greater Phase III South Korea, United Kingdom PO / unspecified Agios Pharmaceuticals 01 Dec 2016
Cholangiocarcinoma IDH1 Mutation Inoperable/Unresectable, Late-stage disease, Metastatic disease, Second-line therapy or greater Phase II Japan PO / Tablet Servier 10 Oct 2023
Glioma In combination with nivolumabSolid tumours with an IDH1 genetic mutation Combination therapy, Late-stage disease Phase II USA PO / unspecified Agios Pharmaceuticals, University of Pittsburgh Medical Center, Bristol-Myers Squibb 14 Apr 2021
Glioma with an IDH1 genetic mutation Late-stage disease, Second-line therapy or greater No development reported (I) France PO / unspecified Agios Pharmaceuticals 28 Jul 2020
Glioma - Recurrent No development reported (I) USA PO / unspecified Agios Pharmaceuticals 28 Jul 2020
Myelodysplastic syndromes with an IDH1 genetic mutation Recurrent, Second-line therapy or greater Marketed USA PO / unspecified Agios Pharmaceuticals 24 Oct 2023
Myelodysplastic syndromes with an IDH1 mutationwith excess blasts-2 First-line therapy, In adults, In the elderly, Newly diagnosed Phase III Finland, France, Lithuania, Netherlands, Norway PO / Tablet HOVON Foundation 01 Mar 2019
Myelodysplastic syndromes with an IDH1 genetic mutation Recurrent, Second-line therapy or greater No development reported (I) France PO / unspecified Agios Pharmaceuticals 28 Jul 2020
Solid tumours In combination with nivolumabSolid tumours with an IDH1 genetic mutation Combination therapy, Inoperable/Unresectable, Late-stage disease, Metastatic disease Phase II USA PO / unspecified Agios Pharmaceuticals, University of Pittsburgh Medical Center, Bristol-Myers Squibb 14 Apr 2021
Solid tumours with an IDH1 genetic mutation Late-stage disease, Second-line therapy or greater No development reported (I) France PO / unspecified Agios Pharmaceuticals 28 Jul 2020

Priority Development Status

Type Region Indication
Breakthrough Therapy USA Acute myeloid leukaemia; Myelodysplastic syndromes

Orphan Status

Indication Patient Segment Country Organisation Event Date
Acute myeloid leukaemia - European Union Agios Pharmaceuticals 12 Dec 2016
Acute myeloid leukaemia - USA Agios Pharmaceuticals 09 Jun 2015
Cholangiocarcinoma - USA Agios Pharmaceuticals 26 Apr 2017
Cholangiocarcinoma - Australia Servier 29 Apr 2022
Cholangiocarcinoma - European Union Agios Pharmaceuticals 21 Mar 2018
Glioma - USA Agios Pharmaceuticals 05 Jan 2018

Commercial Information

Involved Organisations

Organisation Involvement Countries
Agios Pharmaceuticals Originator USA
Servier Owner World
HOVON Foundation Collaborator Netherlands
Thermo Fisher Scientific Collaborator USA
Bristol-Myers Squibb Collaborator USA
University of Pittsburgh Medical Center Collaborator USA

Brand Names

Brand Name Organisations Indications Countries
Tuoshuvo Servier Acute myeloid leukaemia European Union
TIBSOVO Servier, Agios Pharmaceuticals Cholangiocarcinoma, Acute myeloid leukaemia, Myelodysplastic syndromes Australia, USA
Tosuvo Servier Acute myeloid leukaemia USA
Tuoshuwo Servier Cholangiocarcinoma, Acute myeloid leukaemia Australia, China, USA

Scientific Summary

  • Adverse Events Occasional: Anaemia; Constipation; Diarrhoea; Dizziness; Fatigue; Febrile neutropenia; Fever; Hypokalaemia; Insomnia; Nausea; Neutropenia; Sepsis; Thrombocytopenia; Vomiting

Pharmacokinetics

Updated results from a phase I study in mIDH1 advanced solid tumours including cholangiocarcinoma showed rapid absorption, good oral exposure and a bi-exponential decline in plasma levels of ivosidenib post single and multiple dose administration. The mean terminal half-life was 40–102 hours. Steady state was achieved within 14 days, along with a moderate accumulation (1.5- to 1.7-fold for AUC at 500 mg QD) in plasma ivosidenib exposure. Ivosidenib exposure and Ivosidenib clearance were unaffected by intrinsic factors and mild/moderate renal impairment, mild hepatic impairment, and concomitant administration of weak CYP3A4 inhibitors/inducers, respectively. The results were reported from 168 patients [141] [150] [137] .

In a phase I trial, in 258 evaluable patients, ivosidenib was readily absorbed, following a single and multiple dose administration, with a median Tmax of three hours. Drug concentration reduced bi-exponentially, after peaking, with a mean terminal half-life of 72–138 hours, after a single dose. Dose-exposure nonlinearity from 300 to 1200 mg QD suggested that doubling of the dose would achieve an approximately 30% increase in area-under-the-curve (AUC). Within 14 days, steady state (SS) was reached. Following administration of a 500 mg QD dose, moderate accumulation was observed, with mean AUC and Cmax accumulation ratios of 1.9- and 1.46-fold. Intrinsic patient factors or concomitant administration of weak CYP3A4 inhibitors/inducers did not affect drug clearance. However, moderate/strong CYP3A4 inhibitors lowered clearance and enhanced drug SS exposure (AUC0-24hr by ~56%; Cmax by ~47%). A plateau was reached by plasma 2-HG reduction within 14 days of dosing, after multiple doses of 500 mg QD, and was reduced by ≥90% over the range of ivosidenib SS AUC, in patients with newly diagnosed and relapsed/refractory AML, irrespective of IDH1-R132 mutation type [132] [136] .

In a phase trial, treatment with vorasidenib and ivosidenib showed brain penetrance, with mean brain:plasma ratios of 3.16 (vorasidenib 10 mg), 1.74 (vorasidenib 50 mg), 0.13 (TIBSOVO® 250 mg) and 0.10 (TIBSOVO® 500 mg). The trial enrolled 49 patients with glioma [112] [110] .

Results from a phase I trial in patients with newly diagnosed AML with an IDH1 or IDH2 mutation demonstrated that treatment with ivosidenib or enasidenib in combiantion with intensive induction and consolidation chemotherapy exhibited similar pharmacokinetic profile to those estimated in previous studies, and appeared to be similar across the combination cohorts. Ivosidenib and enasidenib were rapidly absorbed, with median peak plasma concentrations at 4 hours following single and multiple doses. Exposure at steady state was higher than after a single dose, with mean estimated accumulation ratios of 2.4 and 8.3 using the area under the plasma concentration-time curve from time 0 to 24 hours and 1.7 and 6.3 using the maximum observed plasma concentration respectively, following 14 days of QD dosing [69] [71]

Results of the phase I bridging registrational trial of ivosidenib in Chinese patients with IDH1 mutant relapsed or refractory acute myeloid leukaemia showed that in prespecified nine evaluable patients, the Cmax (4730 ng/mL) was reached 3.98 h after single-dose administration and AUC0-24 was 62100 ng*h/mL. Systemic exposure parameters demonstrated moderate to high variability. 30 patients were treated, with 17 remaining on treatment [34] [29] .

Adverse Events

Phase III

Final results of the global phase III ClarIDHy trial in patients with previously treated unresectable or metastatic cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation demonstrated that ivosidenib (IVO) was well tolerated. Common all-grade treatment emergent adverse events (TEAEs, = 15%) in the IVO arm: nausea 41%, diarrhea 35%, fatigue 31%, cough 25%, abdominal pain 24%, decreased appetite 24%, ascites 23%, vomiting 23%, anemia 18%, and constipation 15%. Grade = 3 TEAEs were reported in 50% of IVO patients vs 37% of placebo (PBO) patients, with grade = 3 treatment-related AEs in 7% of IVO patients vs 0% in PBO. 7% of IVO patients experienced an AE leading to treatment discontinuation vs 9% of PBO patients. There were no treatment-related deaths. Previous trial results showed that ivosidenib treatment displayed a safety profile consistent with earlier phase I data from patients with IDH1 mutant solid tumours. Less than third of patients experienced serious AEs in either arm (30% of 121 who received ivosidenib versus 22% of 59 patients who received placebo), with the most common being ascites (9% total ivosidenib versus 7% placebo). TEAEs leading to discontinuation were more common with placebo compared with total ivosidenib (8.5% versus 5.8%). TEAEs leading to dose reductions (2.6% versus 0%) and interruptions (26.3% versus 16.9%) were more common with total ivosidenib relative to placebo. The most common TEAEs of any grade for total ivosidenib were nausea (36%), diarrhoea (31%) and fatigue (26%). Patients randomized to placebo experienced a significantly greater decline in physical functioning from baseline compared to patients randomized to ivosidenib on the first day of their second 28-day treatment cycle [95] [99] [98] [100] [94] .

Updated results from the phase III AGILE trial ivosidenib in combination with azacitidine demonstrated a safety profile consistent with previously published data. There were fewer neutropenic fever events (27.8% vs 33.8%) and infections (34.7% vs 51.4%) with ivosidenib in combination with azacitidine than with azacitidine plus placebo. Treatment-emergent adverse events led to discontinuation of ivosidenib in combination with azacitidine or azacitidine plus placebo in 26.4% and 25.7% of patients, respectively [57] [56] . Previous result from a phase III AGILE study showed fewer adverse events of febrile neutropenia (28.2% vs 34.2%) and infections (28.2% vs 49.3%) were reported in the IVO+AZA arm compared to the PBO+AZA arm [51] . Results from the phase III AGILE study showed that, administration of ivosidenib in combination with azacytidine found to be safe and well tolerated. Common all-grade adverse events (AEs) occurring in more than 20 percent of patients receiving TIBSOVO in combination with azacitidine vs. placebo plus azacitidine were nausea (42.3% vs. 38.4%), vomiting (40.8% vs 26.0%), diarrhea (35.2% vs 35.6%), pyrexia (33.8% vs 39.7%), anemia (31.0% vs 28.8%), febrile neutropenia (28.2% vs 34.2%), thrombocytopenia (28.2% vs 20.5%), neutropenia (28.2% vs 16.4%), constipation (26.8% vs 52.1%) and pneumonia (23.9% vs 31.5%). Sixty-six (93.0%) patients receiving combination vs 69 (94.5%) patients receiving placebo experienced a grade ≥ 3 AE. Common grade ≥ 3 AEs occurred in > 20% of patients who received combination vs placebo included febrile neutropenia (28.2% vs 34.2%), anemia (25.4% vs 26.0%), thrombocytopenia (23.9% vs 20.5%), and pneumonia (22.5% vs 28.8%). Frequency of all-grade differentiation syndrome (DS) as assessed by investigators was 14.1% with combination vs 8.2% with placebo, and that of grade ≥ 3 DS was 4.2% with combination vs 4.1% with placebo. In a phase III (AGILE study) in patients with previously untreated IDH1-mutated acute myeloid leukemia (AML), administration of ivosidenib in combination with azacitidine compared to azacitidine in combination with placebo was safe and well-tolerated [48] [28] [47] [45]

Phase I/II:

In the phase Ib portion of a phase Ib/II trial, first line therapy with ivosidenib in combination with azacitidine was well tolerated in patients with acute myeloid leukaemia. In phase Ib part of the trial, the most common adverse events included nausea (61%, n=14), anaemia (52%, n=12) and thrombocytopenia (48%, n=11). The most common Grade 3-4 AEs included anaemia (44%) thrombocytopenia (44%, n=10 each), and febrile neutropenia (39%, n=9). IDH differentiation syndrome was reported in three patients. Mean neutrophil and platelet counts were maintained near or above thresholds for CR with partial hematologic recovery (CRh) while on study treatment with ivosidenib and azacitidine [62] [59] [60] . Evaluable 12 patient showed, ≥30% patients showed AEs thrombocytopenia (65%), nausea (61%), diarrhoea (57%), anaemia (52%), constipation (52%), febrile neutropenia (39%), pyrexia (39%), vomiting (35%), fatigue (35%), hypokalaemia (35%), dizziness (35%), insomnia (35%), and neutropenia (30%). Grade 3/4 AEs were thrombocytopenia (61%), anaemia (44%), febrile neutropenia (39%), neutropenia (26%), sepsis (22%), and ECG QT prolonged (13%). AEs of special interest included ECG QT prolonged (26%), IDH differentiation syndrome (17%), and leukocytosis (13%) [63] [64] [61] .

Phase I

Updated data from phase I study in in IDH1-mutated relapsed/refractory Myelodysplastic Syndromes showed that overall, treatment-related adverse events (TRAEs) were consistent with the known safety profile of TIBSOVO. Among 19 patients included in the safety analysis set, TRAEs occurred in eight (42.1%) patients, including a grade 1 QTc interval increase in one (5.3%) patient, grade 3 fatigue in one patient, and grade 3 hyponatremia in one patient, none of which led to discontinuation with treatment [122] [136] . Updated data from phase I study, ivosidenib as a single agent was tolerable in patients (n = 16) with mIDH1 relapsed/refractory myelodysplastic syndrome (R/R MDS). Study was discontinued by 11 (69%), including 6 for disease progression, 1 for allogeneic stem cell transplantation, and 1 owing to an adverse event (AE) of sepsis (the only fatal AE; reported by investigator as not related to IVO). In earlier data from 12 myelodysplastic syndrome (MDS) patients the most common adverse events (AEs) were back pain and fatigue (n=4, 33.3% each) and anaemia, decreased appetite, diarrhoea, dyspnea, hypokalaemia, pruritus, and rash (n=4 each, 33.3%) occurred in 20% of patients. The most reported AEs were in grade one or two and reported as unrelated to treatment. No AEs led to any permanent discontinuation of treatment. Grade 2 IDH differentiation syndrome (IDH-DS) was observed in 1 of 12 patients. Electrocardiogram QT prolonged was reported in 2 of 12 patients (17%; grade 1 in 1 patient and grade 2 in 1 patient [114] [135] . Ivosidenib exhibited a favourable safety profile in patients with advanced haematologic malignancies in a phase I study. Most of the patients exhibited mild to moderate adverse events, of which the most common were diarrhoea, nausea, fatigue and pyrexia. Thirty-five serious adverse events and majority of these were disease related. Four cases of leukocytosis were observed. Thirteen deaths were reported, but none were considered to be related to ivosidenib. Updated data from 78 evaluable patients, most commonly reported adverse events were diarrhea, fatigue, and nausea; the most common grade ≥3 AEs (≥15%) were febrile neutropenia, anaemia, leukocytosis and pneumonia. The most common serious AEs were febrile neutropenia (16.7%) and pneumonia (12.8%) [130] [104] . Updated results from phase I trial in 258 patients ivosidenib demonstrated well tolerability and a favourable safety profile. The most common adverse events (AEs) regardless of causality were diarrhoea (33.5%), leucocytosis (31.3%), nausea (31.3%), fatigue (28.5%), febrile neutropenia (29.1%) and electrocardiogram QT prolongation (25.7%). Majority of these AEs were grade 1–2 and unrelated to treatment. IDH differentiation syndrome (IDH-DS) was reported in 19 of 179 (10.6%) patients, including grade ≥3 IDH-DS in 9 (5.0%). Study drug was held owing to IDH-DS in six patients (3.4%), and no instances of IDH-DS led to dose reduction, permanent treatment discontinuation, or death. Dose reduction was done in two patients and held in 13 patients (for any grade of ECG QT prolongation) [134] [133] . In the trial, 19% (34/179) of patients treated with ivosidenib experienced differentiation syndrome. Ivosidenib-treated patients showed QTc interval prolongation and Guillain-Barré Syndrome. The most common adverse reactions (≥20%) of any grade were fatigue, leucocytosis, arthralgia, diarrhoea, dyspnoea, oedema, nausea, mucositis, electrocardiogram QT prolonged, rash, pyrexia, cough and constipation. Differentiation syndrome (10%), leucocytosis (10%) and electrocardiogram QT prolonged (7%) were the most frequent serious adverse reactions (≥5%) observed [17] . Primary analysis of 125 patients in relapsed or refractory acute myeloid leukaemia (R/R AML) observed 8% AEs reported grade 3 leucocytosis, which was managed with hydroxyurea, and no cases were fatal. Grade 3 QT prolongation was reported in 8%. Ivosidenib was reduced in one patient and held in five patients (for any grade of QT prolongation), and no cases were grade 4 or fatal. IDH-differentiation syndrome (IDH-DS) was reported 9.6%, and was managed with corticosteroids and diuretics, none were grade 4 or fatal [131] . Interim results of the trial showed that the majority of adverse events reported by investigators were mild to moderate, with the most common regardless of causality being fatigue, nausea, diarrhoea, pyrexia and peripheral oedema. Fifty-three patients experienced at least one serious adverse event (SAE), the majority being disease related. The maximum tolerated dose was not reached. The recommended phase II dose was 500mg once daily, which is being studied in the ongoing expansion phase of the trial. Nine patients discontinued from the study due to death, including one reported as possibly related to ivosidenib. All cause mortality at 30 and 60 days were 12% and 21%, respectively. Data were reported from safety analysis conducted for all 78 treated patients and 34 untreated patients [151] . Ivosidenib was well tolerated and induced durable remissions in patients with poor-prognosis mIDH1 newly diagnosed AML (n=34). As of Nov 02, 2018, 7/34 (21%) patients remained on treatment; 3 (9%) patients discontinued treatment for allogeneic stem cell transplant. Median duration of IVO exposure was 4.3 mo (range 0.3–40.9). AEs of any grade and causality in ≥25% of patients were diarrhoea (53%), fatigue (47%), nausea (38%), decreased appetite (35%), leukocytosis, anemia, thrombocytopenia, peripheral oedema (all 26%). Most were grade 1–2 and unrelated to treatment. Data indicated that 6/34 patients (18%) exhibited IDH differentiation syndrome (DS), which was grade ≥3 in 3 patients (9%). Ivosidenib treatment was withheld due to DS in 3 patients. QT prolongation was seen in 6 pateints (18%) [126] [148] . Phase I trial data from 34 patients with untreated AML (nine from dose-escalation and 25 from expansion) and an IDH1 mutation demonstrated consistent safety profile with previously reported data for all 258 patients. The most common adverse events (AEs) in untreated AML patients were diarrhoea (52.9%), fatigue (44.1%), nausea (38.2%), decreased appetite (32.4%), leucocytosis (26.5%), anaemia (26.5%) and edema peripheral (26.5%). Grade 3 ECG QT prolongation was reported in 8.8% patients, 17.6% reported IDH-differentiation syndrome (IDH-DS), which was later managed with corticosteroids and diuretics. Grade 3 leucocytosis was reported in 3% of patients. No AEs lead to any permanent treatment discontinuations or deaths [135] .

Updated results of a phase I study in patients (n = 13) with progressive low grade isocitrate dehydrogenase-1 mutant (IDH1m) glioma showed that the drug was safe and well-tolerated. The most frequent treatment emergent AEs (in > 4 pts; mostly grade 1/2) were diarrhea (n = 5) and nausea (n = 5). Six patients experienced grade ≥3 AEs. Three pts experienced serious AEs (none considered related to treatment). There were no discontinuations, dose reductions or deaths due to AEs [142] . Earlier results of the dose expansion cohort of the phase I study in patients (n = 35) with progressive low grade isocitrate dehydrogenase-1 mutant (IDH1m) glioma demonstrated that ivosidenib was well-tolerated with no dose limiting toxicities, and a favourable safety profile in glioma patients. The majority of adverse events (AEs) reported were mild to moderate, and the most common AEs included headache, diarrhoea, nausea and vomiting. There were five patients with serious adverse events (SAEs), but all were deemed unrelated to study treatment [115] . Interim results of patients (n = 73) with IDH1 mutant positive cholangiocarcinoma, was safe and well-tolerated with the favourable safety profile observed. Dose limiting toxicities or treatment-related deaths were not reported. Two patients experienced drug related AEs as fatigue (n=1) and blood alkaline phosphatase increases (n=1), at the dose level of 500 mg. While at the dose level of 1200 mg, two patients experienced drug-related AEs as fatigue (n=1) and blood phosphorous decreases (n=1). One grade two, possibly drug-related AE of worsening leg cramps was observed, for which dose reduction was done for the patient. Interim results of patients (n = 66) with IDH-1 mutant positive glioma and chondrosarcoma showed that the adverse events reported were mild to moderate in nature and commonly observed were headache, nausea, diarrhoea, decreased appetite, QT-prolongation, fatigue and vomiting. There were 11 patients with serious adverse events none of them were drug related and one case of serious adverse event hypophosphataemia was considered to be possibly related to the treatment [140] [138] [137] .

Updated data from the phase I trial demonstrated that the as of 16-Jan-2020, 2 patients assigned to start enasidenib on day 8 had an ongoing adverse event or died on day 8, and therefore never received enasidenib and were not included in the efficacy analysis. Ivosidenib or enasidenib combined with induction and consolidation were well tolerated. Median durations of follow-up were 21.2 and 23.7 months for ivosidenib and enasidenib, respectively. For patients who entered maintenance, median duration of active maintenance was 13.8 and 11.0 months for ivosidenib and enasidenib respectively. Of patients who achieved CR, 7/42 (16.7%) of those treated with ivosidenib and 7/51 (13.7%) of those treated with enasidenib experienced relapse or death. Overall survival. Updated data from the phase I trial indicated that the most common grade 3 or higher adverse events in the ivosidenib arm were isocitrate dehydrogenase (IDH) differentiation syndrome in 3% (2/60) patients, QT interval prolongation in 2% (1/60) patients and increased blood bilirubin in 7% (4/60) patients. The 30-day and 60-day mortality rate was 5% and 8%, respectively. In a phase I trial first line therapy with ivosidenib in combination with standard induction chemotherapy in patients with acute myeloid leukaemia was well tolerated. In the ivosidenib arm, the most common grade 3 or higher non-haematologic adverse events during the induction period were febrile neutropenia (60%), blood bilirubin increased (9%), hypertension (9%), colitis (9%), increased alanine aminotransferase (9%) and increased aspartate aminotransferase (9%). The 30 and 60-day mortality rates were both 6%, and there were no dose-limiting toxicities. The median time to absolute neutrophil count (ANC) recovery (>500/µL) was 28.5 days (95% CI: 27 -34). Median time to platelet recovery (>50,000/µL) was 28 days (95% CI: 26 - 34). The open-label, non-randomized trial enrolled 60 patients with newly diagnosed acute myeloid leukaemia in the ivosidenib treatment arm [60] [69] [72]

Results from a phase I trial, demonstrated all grade treatment emergent adverse events which included diarrhoea (36%), hypocalcemia and constipation (each 20%), anaemia, hyperglycemia, pruritus, headache and nausea (each 16%), and hypokalaemia and fatigue (each 12%), in glioma patients treated with ivosidenib and vorasidenib. As per the updated data from 49 patients, diarrhoea (29.2%), fatigue (29.2%) and nausea (29.2%) were the most common adverse events (AE) occurring in >25% of patients in the vorasidenib arm. Where as headache (32%), diarrhoea (28%) and anaemia (28%) were the most common AE occurring in ivosidenib arm. Transaminase elevations including one grade III transaminase elevation at 50 mg daily which resolved with dose interruption was observed in 8.3% of patients on vorasidenib arm. Grade III or higher events were noted in six (25.0%) vorasidenib patients and four (16.0%) ivosidenib patients, with the majority related to postoperative complications. No treatment discontinuation was noted due to an AE [112] [111] [110] .

Results of the phase I bridging registrational trial of ivosidenib in Chinese patients with IDH1 mutant relapsed or refractory acute myeloid leukaemia showed that ivosidenib was well tolerated. All patients reported treatment-emergent adverse events (TEAEs). Grade =3 TEAEs occurred in 26 (86.7%) patients, most commonly platelet count decreased (36.7%), neutrophil count decreased (33.3%) and anaemia (33.3%). %). Two fatal TEAEs occurred in 2 (6.7%) patients, with neither related to ivosidenib. Serious AEs were reported in 18 (60.0%) patients [34] [29] .

Pharmacodynamics

Summary

Phase I/II

In the phase Ib part of a phase Ib/II trial, which evaluated first line therapy with ivosidenib in combination with azacitidine in patients with acute myeloid leukaemia, IDH1 mutation clearance was observed in 7 of 21 patients [59] [61] .

Phase I:

Data from the phase I trial for ivosidenib, conducted in patients with IDH1 mutant positive cholangiocarcinoma, showed morphologic changes suggestive of cellular differentiation which is consistent with the proposed mechanism of action of the drug [140] . Additional data demonstrated that post multiple dosing, plasma 2-HG (oncometabolite D-2-hydroxyglutarate) levels were reduced (up to 98.4% inhibition, achieving levels similar to those in healthy volunteers) and tumour biopsy 2-HG levels were also substantially reduced (by up to 99.9%) at all dose levels tested. No significant pretreatment elevation of plasma 2-HG was observed in glioma patients. The 500 mg QD dose resulted in the largest magnitude of 2-HG inhibition relative to other dose levels. The results were reported from 168 patients [141] [150] [138] [137] .

In the phase I dose-escalation and expansion study in patients with relapsed or refractory acute myeloid leukaemia (R/R AML) and an isocitrate dehydrogenase-1 (IDH1) mutation, clearance of IDH1 mutation was observed in 23% (11/47) of patients with R/R AML who achieved CR or CRh and had molecular data available, including 28% (10/36) of patients with CR and 1/11 patients with CRh. Preliminary data suggest that R/R AML patients with IDH1-mutation clearance in bone marrow mononuclear cells who have achieved CR/CRh have prolonged remission durations and overall survival versus those without IDH1-mutation clearance [133] [136] .

Results from a phase I trial in patients with newly diagnosed AML with an IDH1 or IDH2 mutation demonstrated that treatment with ivosidenib or enasidenib in combiantion with intensive induction and consolidation chemotherapy exhibited similar pharmacodynamic profile across the combination cohorts. The plasma 2-HG concentrations were elevated at baseline and decreased after both single and multiple doses of ivosidenib or enasidenib. After multiple doses, mean trough plasma 2-HG concentrations decreased to within the range observed in healthy volunteers (up to 99% inhibition), and 2-HG inhibition was maintained throughout continued ivosidenib or enasidenib. Mean trough bone marrow 2-HG concentrations also decreased (up to 99% inhibition) after multiple dosing [69] [71]

In a phase I trial oral administration of ivosidenib (IVO) and vorasidenib (VOR) lowered 2-hydroxyglutarate (2-HG) in patients with glioma, compared with untreated patients. Mean brain to plasma ratio was reported to be 0.16 for IVO, 2.4 for VOR. Tumour 2-HG was reported to be 10μg/mL for IVO pts and 6.8μg/mL for VOR pts with -93% and -95% CI, respectively. IVO and VOR showed mean percent reduction in 2-HG (95% CI) as 92.6% (76.1, 97.6) and 91.1% (72.0, 97.0), respectively. Optimal 2-HG suppression (post-treatment 2-HG below the upper limit of 2-HG levels in a reference set of 15 wild-type IDH samples) was observed in 23 of 40 patients, including 9 (90%) patients receiving VOR 50 mg QD and 6 (50%) receiving IVO 500 mg QD. Those with optimal 2-HG suppression (n = 21) showed upregulation of neural differentiation-related gene expression, but downregulation of stemness-related gene expression, vs those with suboptimal 2-HG suppression (post-treatment 2-HG above upper limit of IDH 2-HG levels; n=17; p=0.01). Results showed a 2-fold decrease in Ki-67–positive cells in samples with optimal 2-HG suppression (mean 2.7%; n = 22) vs those with suboptimal suppression (5.8%; n = 16; p=0.05) and a 2-fold increase in mean 5-hydroxymethylcytosine (5hmC) levels in samples with optimal (0.36%; n = 17) vs suboptimal 2-HG suppression (0.2%; n = 15; p=0.05), suggesting reversal of TET2 inhibition. It showed an increased mean CD3+ and CD8+ tumour-infiltrating lymphocyte levels in samples with optimal (1.05% [CD3]/0.22% [CD8]; n = 22) vs suboptimal 2-HG suppression (0.44% [CD3]/0.07% [CD8]; n = 16; p=0.05). Optimal 2-HG suppression was associated with upregulation of gene expression related to type I interferon signaling and antigen presentation (p=0.01). The trial enrolled 49 patients with glioma [113] [112] [110] .

Preclinical studies

In an orthotopic mouse xenograft model of human mIDH1-R132H glioma, preclinical data demonstrated that ivosidenib and AG 881 [see Adis Insight Drug profile 800042899] suppress the oncometabolite D-2-hydroxyglutarate (2-HG). In an orthotopic tumour mouse models, treatment with ivosidenib resulted in 85% maximal 2-HG inhibition and treatment with AG-881 resulted in >98% inhibition of 2-HG levels at the doses explored. Neither ivosidenib and AG 881 delayed the therapeutic effect of concomitant or sequenced radiation therapy [115] .

In vitro

studies showed that mutant-isocitrate dehydrogenase (IDH) specific enzyme inhibitors reversed hypermethylation of histones and DNA, and induced cellular differentiation in IDH mutant cell lines and primary acute myeloid leukaemia (AML) patient samples with IDH1/2 mutations [81] .

The in vitro results demonstrated that isocitrate dehydrogenase 1 (IDH1) mutations result in a gain-of-function which causes the accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). IDH1-mutated human glioma samples showed a higher level of 2HG compared with wild type bearing tumours [85] .

Data showed that a mutation of IDH1 results in a reduced affinity for isocitrate and increases the affinity for α-ketoglutarate, thereby preferentially catalyzing a reduction to the oncometabolite 2HG [86] .

Results from early research studies showed that 2-hydroxyglutarate (2-HG) cancer-causing effects were reversed by an isocitrate dehydrogenase-1 (IDH1) inhibitor in an IDH1-mutant leukaemia cell model. Follow treatment with the IDH1 inhibitor the mutant IDH1 transformed cells lost the ability to rapidly proliferate in the absence of exogenous growth factors, and reverted to their previous state [82] .

In preclinical settings, ivosidenib reduced the overall tumour burden and increased overall survival of syngeneic allografts of intrahepatic cholangiocaarcinoma (ICCs) derived from the genetically engineered mouse models (GEMM). The treatment led to induction of mature hepatocyte lineage markers and immune stimulatory interferon signaling, a reduction of tumour produced 2-HG >85% and an increased recruitment of CD8+ T cells to the tumors and strong PD-L1 upregulation, compared with vehicle control [145] .

Preclinical results showed that, ivosidenib+azacitidine combination led to a > 99% reduction in hCD45+ cells within the bone marrow and undetectable disease in the peripheral blood of 7/10 mice by week 10. Similar results were observed with ivosidenib and venetoclax treated animal bone marrow (99% reduction in hCD45+ cells) and undetectable disease was observed in 8/10 mice by week 10. Also, each combination was well tolerated by the mice. The observed disease control with either combination in the animals was greater than any of the three single agents alone [80] .

Therapeutic Trials

Phase III

Final results of the global phase III ClarIDHy trial in patients with previously treated unresectable or metastatic cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation demonstrated that ivosidenib resulted in a favourable overall survival (OS) trend vs placebo (PBO) despite a high rate of crossover. Coupled with statistical improvement in progression-free survival (PFS), ivosidenib treatment demonstrated clinical benefit. OS data were mature, with 79% OS events in IVO arm and 82% in PBO. Median OS (mOS) was 10.3 months for IVO (n = 126) and 7.5 months for PBO (n = 61) (HR = 0.79; 95% CI 0.56–1.12; one-sided p = 0.093). The rank-preserving structural failure time (RPSFT)-adjusted mOS was 5.1 months for PBO (HR = 0.49; 95% CI 0.34–0.70; p < 0.0001). In the phase III ClarIDHy trial (n=185 patients; 124 in ivosidenib - IVO arm and 61 in placebo - PBO arm), the primary endpoint was met, when ivosidenib treatment led to a statistically significant improvement in progression-free survival (PFS), per independent radiology review, as compared with placebo-treated patients. Results demonstrated a statistically significant improvement in progression-free survival (PFS) by independent radiology review of 2.7 months among patients randomised to ivosidenib compared with 1.4 months among placebo patients (hazard ratio [HR] 0.37; 95% CI [0.25, 0.54], p<0.001). PFS benefits were observed across all subgroups analysed. The estimated PFS rate was 32% at six months and 22% at 12 months for patients randomised to ivosidenib, while no patients randomized to placebo were free from progression beyond these timepoints as of the data cut-off. In the ivosidenib arm, 2% of patients achieved a partial response and 51% had stable disease, compared to 28% with stable disease in the placebo arm. A consistent trend in improved OS was observed in patients treated with ivosidenib tablets, compared with those randomised to placebo arm, but was not statistically significant. Median overall survival (OS) was 10.3 months for patients randomised to ivosidenib compared to 7.5 months for placebo patients (HR=0.79; 95% CI [0.56, 1.12], one sided p=0.093). Using the rank-preserving structural failure time (RPSFT) method to reconstruct the survival curve for the placebo subjects as if they never crossed over to ivosidenib, the median OS with placebo adjusts to 5.1 months (HR=0.49; 95% CI [0.34, 0.70], one sided p<0.001). Additional results from the trial demonstrated a median PFS of 2.7 months for IVO versus 1.4 months for placebo. Longitudinal analysis with biomarker data also demonstrated isocitrate dehydrogenase 1 (IDH1)-MC in plasma from 10 IVO-treated patients with PFS ≥2.7 months (n = 36) versus 0 patients with PFS < 2.7 months (n = 40). No IDH1-MC was observed in patients treated with placebo, irrespective of response (n = 49) [95] [96] [97] [102] [99] [98] [100] [94] .

In the phase III AGILE trial, ivosidenib in combination with azacitidine demonstrated the median overall survival of Tuoshuvo® combined with azacitidine was extended to 29.3 months, and further confirmed the effect of Tuoshuwo® as the first-line treatment of newly diagnosed acute myeloid leukemia (AML). Continued to benefit a three-fold improvement in median Overall Survival (24 months) compared with azacitidine plus placebo (7.9 months) as a first-line treatment for IDH1-mutated AML (HR: 0.44; p = 0.0005). In long-term follow-up data as of June 2022, at a median follow-up of 28.6 months, median OS was 29.3 months (95% CI 13.2, not reached) for TIBSOVO in combination with azacitidine vs 7.9 months (95% CI 4.1, 11.3) for placebo plus azacitidine (HR 0.42 [0.27, 0.65]; 1-sided p < 0.0001). At 24 months, OS rates were 53.1% with ivosidenib in combination with azacitidine, compared to 17.4% with azacitidine plus placebo. At 12 months, OS rates were 62.9% with ivosidenib in combination with azacytidine, compared to 38.3% with azacitidine plus placebo. In the ivosidenib in combination with azacitidine arm, hemoglobin levels steadily increased from baseline and then stabilized week 3 (3.99 x 109/L) and week 4 (4.36 x 109/L); mean platelet count recovered from baseline values as early as week 8 and remained stable through week 80 (171.9 x 109/L); and mean neutrophil counts rapidly increased from baseline to weeks 3 and 4 and then stabilized to within the normal range. Conversion from baseline transfusion dependence (red blood cell and/or platelet transfusion dependence) to post-baseline transfusion independence was significantly higher with ivosidenib in combination with azacytidine, compared with azacitidine plus placebo (53.8% vs 17.1%, respectively; 1-sided p = 0.0004) [57] [56] . Previous results from the phase III AGILE trial demonstrated that the median number of baseline mutations was 3 (range 1 - 10). Suppression of all baseline non-DTA (DNMT3A / TET2 / ASXL1) mutations to below the LOD (“mutation clearance”) was observed in 28 patients, including 22/34 (65%) patients who achieved CR/CRh. Overall, emerging mutations were identified in 22/46 (48%) patients (median 2 emerging mutations; range 1-6). 2/46 (4%) patients had emerging mutations in IDH2, but discontinued treatment due to adverse events and stable disease, respectively. No second-site IDH1 mutations were observed across any response category. Longitudinal samples were available for 8/10 (80%) patients who discontinued treatment due to relapse (RL) following an objective response (4 CR, 2 CRh, 1 CRi, 1 MLFS). Emerging mutations were detected in 6/8 (75%) of RL patients. Genes with emerging mutations recurrently associated with RL included ASXL1, FLT3, RUNX1, and TET2 (2 patients each). The IDH1 mutation was not detected at RL in 6/8 (75%) patients. Among the two RLs that occurred in the absence of emerging mutations, one was associated with expansion of a baseline FLT3-ITD subclone, and one was not associated with any new emerging or expanding mutations [55] . Updated results from the phase III AGILE trial of ivosidenib (IVO) plus azacitidine (AZA) in adult patients with previously untreated acute myeloid leukaemia (AML) with IDH1 mutation demonstrated that, IVO in combination with azacytidine showed deep, durable remissions associated with clearance of IDH1-mutated AML, with no second-site IDH1 mutations observed to date amongst the patients enrolled in the IVO plus azacitidine study arm with both baseline and longitudinal DNA sequencing available (46/72 patients) [54] . Results from the study demonstrated that IVO (Ivosidenib)+AZA (azacytidine) arm reported maintained or improved health-related quality of life (HRQoL) from cycle 5 through to cycle 19 compared with placebo+AZA arm. At first, there was an initial decline in HRQoL in both the arms for ~4 months, consistent with time to response, and which was generally not clinically meaningful. IVO+AZA was associated with preserved or improved HRQoL compared to baseline. EORTC QLQ-C30 subscales with clinically meaningful improvements from baseline at most timepoints from C5 to C19 in the IVO+AZA arm included GHS/QoL, fatigue, pain and appetite loss. In contrast, there were also few clinically meaningful improvements from baseline in placebo+AZA patients. GHS/QoL scores were significantly improved (p≤0.05) for IVO+AZA versus placebo+AZA. Likewise, improvements in EORTC QLQ-C30 fatigue, appetite loss, nausea and vomiting, diarrhea, cognitive functioning and social functioning favored IVO+AZA over placebo+AZA at multiple timepoints [52] . Earlier, results in the IVO (Ivosidenib)+AZA (azacitidine) and placebo+ AZA arms demonstrated that 4.2% and 5.5% of patients, respectively, received concomitant granulocyte colony-stimulating factor. Hemoglobin levels steadily increased from baseline at a similar rate in both treatment arms. Mean platelet count recovered from baseline values in the IVO+AZA and placebo+ AZA arms (71.0 and 92.6 x 109/L, respectively) as early as week 9 of treatment (171.1 and 155.1 x 109/L, respectively) and continued to steadily increase thereafter in the treated population. In patients receiving IVO+AZA, mean neutrophil counts rapidly increased from baseline (0.99 x 109/L) to week 2 (2.05 x 109/L) and week 5 (4.07 x 109/L), and then generally stabilized to within the normal range to study end (last available cycle value; ~2.0 x 109/L). Mean neutrophil counts initially declined with placebo+ AZA before slowly recovering to near-normal levels after 36-40 weeks. The increased blood counts were accompanied by a rapid decrease in the mean Bone marrow (BM) blast percentage from 54.8% at baseline to 12.0% and 7.2% at week 9 and 17, respectively, in IVO+AZA treated patients and were maintained for 149 weeks. The decline in BM blasts was slower in the placebo+ AZA arm (53.7%, 34.6% and 19.6% at baseline, week 9 and week 17, respectively). Among patients who were RBC/platelet transfusion-dependent at baseline (~54.0% in both groups), 46.2% in the IVO+AZA group achieved RBC/platelet transfusion independence compared with 17.5% in the placebo+ AZA arm (1-sided p=0.0032) [53] . In updated result from a phase III Agile trial of ivosidenib (IVO) plus azacitidine (AZA) 47 patients were treated with IVO+AZA and 32 patients with PBO+AZA demonstrated IDH1-MC in 21/35 (60%) IVO+AZA patients achieved CR/CRh vs 4/11 (36%) PBO+AZA patients. In CR/CRh pts with time points available after IDH1-MC, suppression of the mIDH1 was durable and IDH1-MC maintained in all subsequent samples in 17/17 (100%) IVO+AZA treated patients and 1/3 (33%) PBO+AZA patients. Further analysis of baseline co-mutations on 120 pts (IVO+AZA: n = 58; PBO+AZA: n = 62) showed that DNMT3A, SRSF2, and RUNX1 were the most frequent in both treatment arms. Importantly, comparison of CR/CRh and non CR/CRh responses by cohort did not identify any single gene or pathway associated with an inferior outcome in IVO+AZA pts compared to PBO+AZA pts (p < 0.05, Fisher’s Exact test). Several genes (DNMT3A, RUNX1, SRSF2, STAG2) and pathways (Differentiation, Epigenetics, Splicing) were associated with improved outcomes with IVO+AZA, including the RTK pathway, which was previously reported to be associated with primary resistance to IVO monotherapy [50] . Earlier result from a phase III Agile trial of ivosidenib (IVO) plus azacitidine (AZA) showed that the haemoglobin levels steadily increased from baseline at a similar rate in both treatment arms (IVO+AZA and PBO+AZA). Mean platelet count recovered from baseline values in the IVO+AZA and PBO+AZA arms (71.0 and 92.6 x 109/L, respectively) as early as week 9 of treatment (171.1 and 155.1 x 109/L, respectively) and continued to steadily increase thereafter in the treated population. In patients receiving IVO+AZA, mean neutrophil counts rapidly increased from baseline (0.99 x 109/L) to week 2 (2.05 x 109/L) and week 5 (4.07 x 109/L), and then generally stabilized to within the normal range to study end (last available cycle value; ̃2.0 x 109/L). Mean neutrophil counts initially declined with PBO+AZA before slowly recovering to near-normal levels after 36-40 weeks. The increased blood counts were accompanied by a rapid decrease in the mean BM blast percentage from 54.8% at baseline to 12.0% and 7.2% at week 9 and 17, respectively, in IVO+AZA treated patients and were maintained for 149 weeks. The decline in BM blasts was slower in the PBO+AZA arm (53.7%, 34.6% and 19.6% at baseline, week 9 and week 17, respectively). Among patients who were RBC/platelet transfusion-dependent at baseline (̃54.0% in both groups), 46.2% in the IVO+AZA group achieved RBC/platelet transfusion independence compared with 17.5% in the PBO+AZA arm (1-sided p = 0.0032). This sub-analysis demonstrated a rapidly improved recovery of blood counts and a reduced dependence on RBC and/or platelet transfusion [51] . Data from the phase III AGILE study ivosidenib tablets in combination with azacitidine compared to azacitidine in combination with placebo demonstrated significant improvements in complete remission rate, complete remission and complete remission with partial hematologic recovery rate and objective response rate. A statistically significant improvement in EFS (hazard ratio [HR] = 0.33, 95% CI 0.16, 0.69, 1-sided P = 0.0011). A statistically significant improvement in event-free survival (EFS) (hazard ratio [HR] = 0.35 [95% CI 0.17, 0.72], 2-sided p-value = 0.0038) and overall survival (OS) (HR = 0.44 [95% CI 0.27, 0.73]; 2-sided p = 0.0010). In addition, the combination of TIBSOVO with azacitidine showed a statistically significant improvement in OS (HR = 0.44 [95% CI 0.27, 0.73]; 1-sided P = 0.0005), with a median OS of 24.0 months in the ivosidenib + azacitidine arm vs 7.9 months in the placebo + azacitidine arm. Complete remission (CR) rate was 47.2% (n=34/72; 95% CI 35.3%, 59.3%) for TIBSOVO in combination with azacitidine vs. 14.9% (n=11/74; 95% CI 7.7%, 25.0%) for placebo plus azacitidine (p < 0.0001). CR + complete remission with partial hematologic recovery rate (CR + CRh rate) was 52.8% (n=38/72; 95% CI 40.7%, 64.7%) for TIBSOVO in combination with azacitidine vs. 17.6% (n=13/74; 95% CI 9.7%, 28.2%) for placebo plus azacitidine (p < 0.0001). Objective response rate (ORR) was 62.5% (n=45/72; 95% CI 50.3%, 73.6%) for TIBSOVO in combination with azacitidine vs. 18.9% (n=14/74; 95% CI 10.7%, 29.7%) for placebo plus azacitidine (p < 0.0001). The CR rate by 24 weeks for combination vs placebo was 37.5% and 10.8%, respectively. All reported P-values are 1-sided. In a phase III (AGILE study), treatment with TIBSOVO in combination with azacitidine compared to azacitidine in combination with placebo demonstrated a statistically significant improvement in EFS. Additionally, the trial met all of its key secondary endpoints, including complete remission rate (CR rate), overall survival (OS), CR and complete remission with partial hematologic recovery rate (CRh rate) and objective response rate (ORR) [48] [28] [47] [45] .

Phase I/II:

Results from the study demonstrated higher clinical response with molecular remissions. The overall response rate was 78% (18/23 patients): CR 61% (14/23), CR with incomplete hematologic or platelet recovery 9% (2/23), and morphologic leukemia-free state 9% (2/23). Complete remission (CR) plus CR with partial hematologic recovery (CR+CRh) rate was 70% (16/23). CR/CRh was achieved in newly diagnosed AML patients who typically have a poor prognosis, or did not achieve a CR/CRh response to single-agent IVO therapy. IDH1-MC in BMMCs was observed in 13/14 (93%) CR/CRh patients by NGS and in 11/16 (69%) by digital PCR. Utilizing the 2-log more sensitive digital PCR assay specific to mIDH1, there was strong concordance in the mIDH1 VAF observed in BMMCs and PBMCs (Pearson correlation coefficient [r]=0.919) with 12/16 (75%) CR/CRh patients achieving MC in PBMCs, and 11/12 (92%) achieving MC in both BMMCs and PBMCs. These IDH1-MC rates are higher than those previously observed in IC-ineligible ND AML patients treated with single agent IVO. All mutations were cleared in 11/14 (79%) patients, apart from mutations in the DTA (DNMT3A/TET2/ASXL1) genes typically associated with clonal hematopoiesis and the mutations in the DTA genes were cleared in 2/5 (40%) CR/CRh patients. Orthogonal evaluation of the depth of these remissions by flow cytometry found that 10/12 (83%) CR/CRh pts achieved measurable residual disease (MRD) negativity [65] . In the phase Ib part of a phase Ib/II trial, the first line therapy with ivosidenib, in combination with azacitidine, in patients with acute myeloid leukaemia, demonstrated efficacy in 78% patients (18/23) with a response. The combined complete response/complete response with incomplete haematologic or platelet recovery (CR)/CRi/CRp rate was 65% (15/23), including CR in 57% (13 of 23 patients) and CRi/CRp in 22% (5 of 23 patients). The median time to first response was 1.8 months and the median time to best response was 3.6 months. The median duration of complete response as well as CR with partial haematologic recovery (CRh) was not reached. The 12-month survival rate was 82%. The median duration of follow-up was 9.5 months. Patients who achieved a CR, IDH1 mutation clearance was observed in nine of 13 patients with available bone marrow mononuclear cells (BMMCs) and 10 of 13 patients with available peripheral blood mononuclear cells (PBMCs) as quantified by a sensitive digital PCR assay with lower limit of sensitivity for mutant IDH1 of 0.02-0.04% [62] [59] [60] . Updated efficacy results from the phase Ib part of the trial demonstrated ORR of 78% (n = 18), CR of 57%, CRi/CRpof 13%, and MLFS of 9%. CR+CRh rate was 70% (n = 16). At the time of data cut off, median response duration was not reached. Median time to CR was 3.5 months (0.8-6.0) and to response it was 1.7 months (0.7-3.8) [64] [63] [61] .

Phase I:

Updated results of a phase I trial of ivosidenib in patients (n = 13) with progressive low grade isocitrate dehydrogenase-1 mutant (IDH1m) glioma demonstrated an ORR of 23.1%. Median duration of response was 42.5 months (range: 25.8-51.8 months). One patient with a base of the skull lesion achieved a CR (1200 mg IVO QD), two achieved PR (one 500 mg and one 1200 mg IVO QD), seven had SD (five received ≥500 mg IVO QD) and two had PD (both received ≥500 mg IVO QD). All responses occurred after > 2 years on treatment. Median PFS was 7.4 months (95% CI: 2.0-61.3) [142] . Earlier results of the dose expansion cohort of the phase I study of ivosidenib in patients (n = 35) with progressive low grade isocitrate dehydrogenase-1 mutant (IDH1m) glioma showed that the treatment with TIBSOVO resulted in durable remissions, including complete response in nearly 40% of patients. In the efficacy analysis set (n=18), a complete remission (CR) rate of 38.9% and overall response rate (ORR) of 83.3% were documented in patients. In addition, the median time to CR was 1.87 months. At the time of data cutoff, the median duration of CR had not been reached and the median overall survival was 35.7 months . Additionally, of the nine patients who were transfusion dependent with red blood cells or platelets at baseline, 66.7% (n=6) became independent of transfusions during any =56-day post-baseline period. Further, of the nine patients who were transfusion independent with red blood cells or platelets at baseline, 77.8% (n=7) maintained transfusion independence during any =56-day post-baseline period [122] . Earlier data showed durable stable disease and reduction of tumour growth rates observed for patients with low grade glioma, median treatment duration of 16 months (range 1.4 – 27.1 months), with 51% (18/35) of patients remaining on treatment. A daily dose of 500 mg ivosidenib was selected as the expansion dose. The median progression free survival (PFS) for all non-enhancing patients was 13 months, the median PFS for Grade 2 patients (n = 24) was not reached. For patients in the expansion arm (n=24), the average six-month tumour growth was 24% prior to treatment and 11% following treatment with ivosidenib [115] . Treatment of ivosidenib, in patients (n = 73) with IDH1 mutant positive cholangiocarcinoma showed partial response in four patients (5%), at the dose level of 300 mg and 500 mg. Stable disease was demonstrated in 41 patients (56%). The progression free survival observed at six (PFS6) and 12 months (PFS12) were 38.5% and 20.7% respectively. The median progression free survival (PFS) was 3.8 months (95% CI 3.6, 7.3) [140] . Interim results of patients (n = 66) with IDH-1 mutant positive glioma and chondrosarcoma, ivosidenib showed 63% patients with stable disease including 27 patients with non-enhancing disease. The volumetric analysis conducted centrally demonstrated stabilisation or a decrease in tumour growth rate, compared to the pretreatment rate, in 64% (n=14 of 22) of glioma patients with non-enhancing disease receiving ivosidenib. The three-month progression free survival rate observed was 58% [138] [137] .

Updated data from a phase I dose escalation study, of 179 patients with R/R AML who received ivosidenib in the study, 57 (31.8%) achieved complete response (CR)/CR with partial hematologic recovery (CRh). Of these, 13 patients (22.8% of responders, 7.3% of cohort) achieved exceptional response, defined as a duration of CR/CRh response (DOCRCRh) without hematopoietic stem cell transplantation of more than 12 months, and eight (14.0% of responders, 4.5% of cohort) had a DOCRCRh of more than two years. The 13 exceptional responders all achieved a complete response, with a median DOCRCRh of 43 months. No patient with DOCRCRh > 32 months relapsed. Clinical and molecular characteristics among patients who achieved an exceptional response included a low mutational burden, lack of receptor tyrosine kinase (RTK) pathway mutations and canonical AML drivers, and co-occurrence of mutations associated with clonal hematopoiesis appear to be associated with exceptional response [56] . In previous data from the phase I trial, ivosidenib as a single agent induced durable remissions and transfusion independence in patients with mIDH1 relapsed/refractory myelodysplastic syndrome (R/R MDS). Complete response was achieved by 7/16 patients (CR, 44%; 95% CI, 20%, 70%). Partial response, marrow CR was achieved by one patient (6%), five patients (31%), respectively. This resulted in ORR of 81% (95% CI, 54%, 96%). Hematologic improvement in ≥1 lineages was achieved by 11/16 (69%) patients. The Kaplan-Meier estimate of duration of CR+PR at 12 months was 60%. 3 patients experienced CRs lasting 24.0, 63.7, and 65.4 months, which remain ongoing. 5/7 patients (71%) who were transfusion dependent at baseline became independent of red blood cell or platelet transfusions for 56 or more consecutive days on treatment. In earlier data from the phase I AG120-C-001, in a cohort of newly diagnosed patients with AML with IDH1 (n = 28), ivosidenib demonstrated durable responses. IVO treated patients showed a longer survival than historical control (HC), with HRs ranging from 0.43–0.73. The 95% CI upper bounds were noted to be 1, except for one sensitivity analysis. When compared to non-IC RWD patients (n=65), the survival benefit of IVO was observed to be more pronounced, with significant prolonged survival in the unmatched IVO population (n=157) (median 8.8 vs 3.8 months; unadjusted HR 0.55). Matched results demonstrated a consistent benefit with HRs of 0.26–0.57, and all analyses except one sensitivity analysis had a 95% CI upper bound of 1. IVO OS was noted to be lower when compared to IC RWD patients (n=61) (unadjusted median 8.8 vs 10.8 months; unadjusted HR 1.69). In addition, IVO was associated with an increased CR in comparison to non-IC RWD patients (n=65) (21.7% vs 7.7%; unadjusted odds ratio [OR] 3.32) and a lower CR compared to IC RWD patients (n=61) (21.7% vs 47.5%; unadjusted OR 0.31). Earlier results showed complete remission plus complete remission with partial hematologic improvement (CR+CRh) rate was 42.9% (95% CI: 24.5, 62.8). The CR rate was 28.6% (95% CI 13.2, 48.7) and the CRh rate was 14.3% (95% CI 4.0, 32.7). Median durations of CR and CR+CRh were not determined, with 41.7% patients, who achieved CR or CRh remaining onivosidenib treatment (treatment duration range: 20.3 to 40.9 months). Almost 58.3% patients, who achieved CR or CRh were in remission at 1 year after receiving treatment. For patients, who achieved a CR or CRh, the median time to best response of CR or CRh was 2.8 months (range, 1.9 to 12.9 months). Among the 17 patients, who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, seven patients became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 11 patients who were independent of both RBC and platelet transfusions at baseline, six patients remained transfusion independent during any 56-day post-baseline period [114] [20] . In subgroup of patients with mIDH1 AML who proceeded to haematopoeitic cell transplant (HCT) after treatment with ivosidenib, last reported responses prior to HCT were 50.0% CR, 22.2% CRi/CRp, 11.1% morphological leukemia-free state (MLFS) 5.6% relapse, and 11.1% with response not evaluable. Survival rates were reported to be 77.8% and 50.0% six - and 12-months post-HCT; median relapse-free survival post HCT was 7.3 months (range 2.6–not estimable [NE]). Median overall survival (OS) from start of ivosidenib was 16.8 months (95% CI 9.2, NE) for HCT patients vs 9.0 month (95% CI 7.1, 10.2) in the entire study cohort; median follow-up time was 33.2 months (range 3.2–41.9). of the eight HCT patients censored for OS, five are in remission, two relapsed and are in survival follow-up, and one was lost to follow-up. Among the 43 patients who achieved CR as best response, median OS was NE (95% CI 9.1, NE) for the 12 CR patients who underwent HCT vs 20.5 mo (95% CI 16.4, NE) for the 31 CR patients who did not undergo HCT. mIDH1 was undetectable in 1/18 (6%) patients; 4/18 (22%) patients had reduction below 1% VAF at the last assessment prior to HCT [124] . Updated data from the dose-escalation and expansion study demonstrated an overall response rate (ORR) of 41.9% (75 of 179 patients) and a combined complete remission (CR) and CR with partial haematologic recovery (CRh) rate of 31.8% [95% CI 25.1, 39.2]. The CR rate was found to be 24% (43 of 179 patients) [95% CI 18.0, 31.0] and the CRh rate was found to be 7.8% (14 of 179 patients). Median duration of response was 10.1 months [95% CI 6.5, 22.2] for patients who achieved a CR, 8.2 months [95% CI 5.6, 12.0] for patients who achieved a CR/CRh and 6.5 months [95% CI 5.5, 10.1] for all patients who responded to treatment. Median time to first response was 1.9 months (0.8-4.7) for all patients who responded and median time to CR/CRh was 2.0 months [95% CI 0.9, 5.6]. Transfusion independence was observed across all patients in all response categories, where all patients became independent of platelet transfusions and 88.2% became independent of RBC transfusions during any 56-day post baseline period [134] [133] . Ivosidenib showed CR+CRh rate of 32.8% (57 of 174 patients) (95% CI: 25.8, 40.3), a CR rate of 24.7% (43 of 174 patients) (95% CI 18.5, 31.8) and a CRh rate of 8% (14 of 174 patients) (95% CI 4.5, 13.1). Median duration of CR+CRh was 8.2 months (95% CI: range 5.6, 12 months). The median time to best response of CR or CRh was 2.0 months (range, 0.9 to 5.6 months) for patients who achieved a CR or CRh. Of the 110 patients who were dependent on RBC and/or platelet transfusions at baseline, 41 (37.3%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. During any 56-day post-baseline period, of the 64 patients who were independent of both RBC and platelet transfusions at baseline, 38 (59.4%) remained transfusion independent. Post ivosidenib treatment, 21/174 patients (12%) went on to stem cell transplant [17] . Earlier analysis of 125 patients had demonstrated a CR and CRh rate of 30.4% [95% CI 22.5, 39.3], and an ORR of 41.6% (52/125 patients). The CR rate was 21.6% (27/125 patients) [95% CI 14.7, 29.8] and the CRh rate was 8.8% (11/125 patients). Median duration of response was 9.3 months [95% CI 5.6, 18.3] for patients who achieved a CR, 8.2 months [95% CI 5.5, 12.0] for patients who achieved a CR/CRh and 6.5 months [95% CI 4.6, 9.3] for all patients who responded. Median time to first response was 1.9 months (0.8-4.7) for all patients who responded, median time to CR was 2.8 months (0.9-8.3) for patients who achieved a CR, and median time to CR/CRh was 2.7 months (0.9-5.6) for patients who achieved a CR/CRh. OS was 9.3 months [95% CI 3.7, 10.8] for non-CR/CRh responders, 3.9 months [95% CI 2.8, 5.8] for non-responders and 8.8 months [95% CI 6.7, 10.2] overall. In patients who were transfusion dependent at baseline and achieved a CR, 100% became independent of platelet transfusions and 84.6% became independent of RBC transfusions [131] . Interim results of 78 patients demonstrated an ORR of 38% (30/78), including 14 complete remissions, eight CRs with incomplete neutrophil recovery or platelet recovery (CRi/CRp), six marrow CR (mCR)/morphologic leukemia-free state (MLFS) and two partial remissions (PR). Of the 63 patients with relapsed/refractory AML, 21 (33%) achieved an objective response, including 10 (16%) CRs, eight CRi/CRp, two MLFS and one PR. Responses were durable, with a median response duration of 10.2 months (3.7- not estimable (NE)) overall and 6.5 months (3.7-NE) in the subset of patients with R/R AML. Median duration of treatment was 3.2 months (ranging from 0.1 to 24.2 months). Further, IDH1 mutation clearance (IDH1-MC) was observed in 36% of CRs (5 of 14) and 4% of non-CRs (2 of 53). IDH1-MC was enriched in patients achieving CR (p-value = 0.003). The median time to mutational clearance was 2.7 months (ranging from 1.1 to 3.8 months). Updated data from the phase I trial in 34 patients with newly diagnosed AML with an IDH1 mutation demostrated a complete remission (CR) rate of 30% (95% CI 16%, 49%), complete remission (CR) + CR with incomplete hematologic or platelet recovery (CR+CRh) rate of 42% (95% CI 26%, 61%), and overall response rate (ORR) of 55% (95% CI 36%, 72%). CR, CR+CRh, and overall response for 12-month response durations were 78%, 62%, and 63%, respectively. Data indicated that 43% of the patients (n=21), who were transfusion dependent at baseline, became transfusion independent for ≥56 consecutive days on treatment. IDH1 mutation clearance was observed in 64% (9/14) of patients with untreated AML who achieved CR or CRh, including 50% (5/10) of patients with CR and 100% (4/4) of patients with CRh. Later, it was reported that ivosidenib monotherapy showed prolonged OS and increased CR rates vs standard of care therapies. Median OS was 8.1 months (mo) (95% CI: 5.7, 9.8) with ivosidenib, compared with 2.9 mo (95% CI: 1.9, 4.5) in the historical control patients. The hazard ratio for OS was 0.396 (95% CI: 0.279, 0.562), strongly in favour of ivosidenib (p < 0.0001). There was clear and early separation of the ivosidenib and hazard ratio Kaplan–Meier curves, reflecting the early and sustained benefit of ivosidenib treatment in this setting. Six- and 12-mo survival rates in the ivosidenib cohort were 57.7% (95% CI: 48.2, 67.2) and 35.0% (95% CI: 25.7, 44.3), respectively, representing improvements versus 6- and 12-mo survival rates in the historical control cohort of 29.1% (95% CI: 17.4, 40.8) and 10.8% (95% CI: 2.7, 18.9), respectively. The ivosidenib cohort also demonstrated higher rates of CR than the historical control cohort, with an observed CR rate of 18.3% (95% CI: 11.6, 26.9), compared with 7.0% (95% CI: 1.5, 19.1). Updated data from phase I dose-escalation and expansion study in 12 myelodysplastic syndrome (MDS) patients. Of the 12 patients with MDS, five achieved CR (41.7%) [95% CI (15.2%, 72.3%)], one achieved a partial response (PR) (8.3%) and five achieved marrow CR (mCR) (41.7%), resulting in an ORR of 91.7% [95% CI (61.5%, 99.8%)]. The percentages of patients who remained in CR and response at 12 months were 60.0% and 61.4%, respectively.Among the five patients who were transfusion dependent at baseline, four became transfusion independent for at least 56 days on treatment [135] . [123] [130] [104] [151] [126] [135] [148] [125] [136] .

Updated data from the phase I trial demonstrated that the as of 16-Jan-2020, ivosidenib or enasidenib in combination with induction and consolidation therapy have shown acceptable safety profiles, with =80% CR+CRi/CRp remission rates in patients with AML. With over 21 months of follow-up, overall survival rates were high, with 12-month survival probabilities of 75% for both the ivosidenib and enasidenib treated patients. The clinical benefit of adding ivosidenib or enasidenib to induction, consolidation, and maintenance therapy for patients with newly diagnosed AML. Among the 60 ivosidenib treated patients, a response of complete remission (CR), CR with incomplete hematologic recovery (CRi), or CR with incomplete platelet recovery (CRp) was achieved in 37/42 (88.1%) patients with AML and in 10/18 (55.6%) patients with sAML. Among the 91 enasidenib treated patients, a response of CR, CRi, or CRp was achieved in 45/56 (80.4%) patients with AML and in 22/35 (62.9%) patients with sAML. Best overall response was reported. Patients achieving CR, CRi, or CRp who had available samples were analyzed for mutation clearance and MRD negativity. In those treated with ivosidenib, the mutation was cleared in 16/41 (39.0%) patients, and 16/20 (80.0%) were considered MRD negative. In those treated with enasidenib , the mutation was cleared in 15/64 (23.4%) patients, and 10/16 (62.5%) were MRD negative. Updated data from the phase I trial in patients with acute myeloid leukaemia indicated that ivosidenib in combination with standard induction chemotherapy achieved an overall best response of CR+CRi/CRp in 80% (39/49) efficacy evaluable patients. The CR+CRi/CRp rate was 91% (31/34) and 53% (8/15) for de novo and secondary acute myeloid leukaemia (sAML) patients, respectively. Elimination of measurable residual disease (MRD) by flow cytometry was observed in 88% (15/17) patients, from a subset of patients achieving a CR or CRi/CRp. Isocitrate dehydrogenase-1 (IDH1) mutation clearance by digital PCR was achieved in 41% (12/29) patients, whose best response was CR or CRi/CRp. At the time of cut-off, the probability of survival at one-year was 79%. The median time to absolute neutrophil count (ANC) recovery (>500/µL) and the median time to platelet recovery (>50,000/µL)from induction therapy (n=38) was 28 days (95% CI 28, 30) and 28 days (95% CI 27, 30), respectively. In a phase I trial, which evaluated first line therapy with ivosidenib in combination with standard induction chemotherapy in patients with acute myeloid leukaemia, overall complete response (CR) and complete response with incomplete neutrophil or platelet recovery (CRi/CRp) rate was 77%. The CR+CRi/CRp rate for newly diagnosed patients was 91% and 44% for secondary acute myeloid leukaemia patients [60] [69] [72]

In a phase I trial, as per the results from 42 evaluable patients, among patients treated post-operatively with 50 mg vorasidenib, four patients (31%) showed objective tumour responses (two achieved a partial response and two achieved a minor response) according to the investigator by Response Assessment in Neuro-Oncology for low-grade glioma (RANO-LGG). From patients treated post-operatively with 500 mg ivosidenib, four patients (31%) achieved confirmed responses (two achieved a partial response and two achieved a minor response) according to the investigator by RANO-LGG. Stable disease was experienced by 15 patients treated with vorasidenib and 16 patients treated with ivosidenib, resulting in disease control rates of 90% and 95% respectively [112] [111] [110] .

Results of the phase I bridging registrational trial in Chinese patients with IDH1 mutant relapsed or refractory acute myeloid leukaemia showed that ivosidenib induced durable remissions with clinical benefits. The complete remission (CR) + CR with partial haematologic recovery (CRh) rate was 30.0% [9/30; 95% CI: 14.7–49.4%], with all nine patients achieving CR. Median duration of CR+CRh was not reached (range: 0.03 – 10.09 months) and median time to CR+CRh was 2.79 months (range: 1.0–6.5). Objective response rate (ORR) was 36.7% [11/30; 95% CI: 19.9–56.1%]. One (3.3%) patient received haematopoietic stem cell transplantation after achieving CR. Transfusion independence was achieved in 7/18 patients (38.9%) and maintained in 8/12 patients (66.7%) [34] [29] .

Future Events

Expected Date Event Type Description Updated
01 Apr 2024 Trial Update Servier plans the phase III CHONQUER trial for Chondrosarcoma (Late-stage disease, Metastatic disease, First-line therapy, Second-line therapy or greater) (PO, Tablet, once daily), in April 2024 (NCT06127407) (700368830) 20 Nov 2023
31 Dec 2023 Regulatory Status CStone Pharmaceuticals announces intention to launch ivosidenib in China in 2023 [147] 01 Jul 2022
31 Oct 2023 Trial Update Servier plans a phase II trial for Cholangiocarcinoma (Inoperable/Unresectable, Metastatic-disease, Second-line therapy or greater) (PO) in October 2023 (NCT06081829) 21 Dec 2023
31 Aug 2023 Trial Update Servier plans a phase I/II trial in Cholangiocarcinoma (Combination therapy, Metastatic disease, Unresectable/Inoperable) in August 2023 (NCT05921760; EudraCT2023-503236-41; CL1-95031-006) 05 Dec 2023
30 Jun 2021 Regulatory Status Cstone intends to submit NDA in China by the first half of 2021 [146] 01 Jul 2022
31 Mar 2021 Regulatory Status Agios pharmaceuticals announces intention to submit sNDA to US FDA for Cholangiocarcinoma (Second-line therapy or greater) in the first quarter of 2021 [144] 03 Mar 2021
31 Dec 2020 Regulatory Status Cstone expects Marketing approval in Taiwan for treatment of adult patients with R/R AML containing an isocitrate dehydrogenase-1 mutation in 2020 [146] 02 Apr 2020
21 Jun 2019 Regulatory Status FDA assigns PDUFA action date of 21/06/2019 for ivosidenib for Acute myeloid leukaemia (First-line therapy, Monotherapy, Newly diagnosed) [21] 30 Nov 2019
31 Jan 2019 Regulatory Status Agios Pharmaceuticals plans to submit sNDA to the US FDA for IDH1m positive Acute myeloid leukaemia by the end of January 2019 [46] 30 Nov 2019
31 Dec 2018 Trial Update Agios Pharmaceuticals plans a phase III HOVON 150 trial for Acute myeloid leukaemia with an IDH1 or IDH2 mutation (First-line therapy, Newly diagnosed, Combination therapy) in the fourth quarter of 2018 (700304761) [46] 17 Apr 2020
31 Dec 2018 Regulatory Status Agios Pharmaceuticals plans to launch ivosidenib for Acute myeloid leukaemia in the US in the second half of 2018 [149] 06 Aug 2018
31 Dec 2018 Regulatory Status Agios Pharmaceuticals plans to submit a MAA to the European Medicines Agency for ivosidenib for Acute myeloid leukaemia in the fourth quarter of 2018 [149] 30 Nov 2019
21 Aug 2018 Regulatory Status FDA assigns PDUFA action date of 21/08/2018 for ivosidenib for Acute myeloid leukaemia (Second-line therapy or greater) [18] 24 Jul 2018
31 Jul 2018 Trial Update Massachusetts General Hospital and Agios Pharmaceuticals plan a phase I trial for Acute myeloid leukaemia, Myelodysplastic syndromes and Chronic myelomonocytic leukaemia (Maintenance therapy) in USA (NCT03564821) (700297026) 28 Jan 2019
30 Jun 2018 Trial Update Agios Pharmaceuticals plans a perioperative window trial for Glioma (Recurrent) in USA in the first half of 2018 (NCT03343197) (700290581) [115] 19 Mar 2018
31 Dec 2017 Regulatory Status Agios Pharmaceuticals announces intention to submit NDA to the US FDA for IDH1m positive Acute myeloid leukaemia (Second-line therapy or greater) by the end of 2017 [92] 28 Jun 2018
30 Sep 2017 Trial Update Agios Pharmaceuticals plans a phase I trial in Healthy volunteers in USA (PO) (NCT03282513) 05 Oct 2017
30 Jun 2017 Trial Update Agios Pharmaceuticals plans to initiate the phase III AGILE trial in Acute myeloid leukaemia (First-line therapy, Combination therapy) (PO) (NCT03173248) 29 Jun 2017
31 Mar 2017 Trial Update Agios Pharmaceutical plans a phase I trial in Healthy volunteers in USA (NCT03071770) 11 Apr 2017

Development History

Event Date Update Type Comment
04 Jan 2024 Trial Update Institut de Recherches Internationales Servier completes a phase I trial in Solid tumours (Late-stage disease, Second-line therapy or greater) in the US and France (NCT02073994) Updated 23 Feb 2024
21 Dec 2023 Licensing Status Servier acquires Ivosidenib from CStone Pharmaceuticals in China, Hong Kong, Macau, Taiwan and Singapore [5] Updated 04 Jan 2024
21 Dec 2023 Licensing Status Ivosidenib is no longer licensed to CStone Pharmaceuticals in China, Hong Kong, Macau, Taiwan and Singapore [5] Updated 03 Jan 2024
21 Dec 2023 Regulatory Status Ivosidenib launched under Named Patient Program in Hong Kong, Taiwan, and Singapore [5] Updated 03 Jan 2024
13 Nov 2023 Trial Update Agios Pharmaceuticals in collaboration with Bristol-Myers Squibb and University of Pittsburgh Medical Center completes a phase II trial in Solid tumours (Late-stage disease, Combination therapy, Metastatic disease, Inoperable/Unresectable) and Glioma (Combination therapy, Late-stage disease) in USA (PO) (NCT04056910) Updated 12 Dec 2023
13 Nov 2023 Trial Update Servier plans the phase III CHONQUER trial for Chondrosarcoma (Late-stage disease, Metastatic disease, First-line therapy, Second-line therapy or greater) (PO, Tablet, once daily), in April 2024 (NCT06127407) Updated 20 Nov 2023
24 Oct 2023 Phase Change - Marketed Launched for Myelodysplastic syndromes (Recurrent, Second-line therapy or greater) in USA (PO) [118] Updated 07 Dec 2023
24 Oct 2023 Phase Change - Registered Registered for Myelodysplastic syndromes (Recurrent, Second-line therapy or greater) in USA (PO) [118] Updated 26 Oct 2023
23 Oct 2023 Trial Update Servier initiates a phase I/II trial in Cholangiocarcinoma (Combination therapy, Metastatic disease, Unresectable/Inoperable) in USA (NCT05921760; EudraCT2023-503236-41). Updated 05 Dec 2023
13 Oct 2023 Trial Update Servier plans a phase II trial for Cholangiocarcinoma (Inoperable/Unresectable, Metastatic-disease, Second-line therapy or greater) (PO) in October 2023 (NCT06081829) Updated 21 Dec 2023
10 Oct 2023 Phase Change - II Phase-II clinical trials in Cholangiocarcinoma (Metastatic disease, Inoperable/Unresectable, Second-line therapy or greater, Late-stage disease) in Japan (PO) (NCT06081829) Updated 21 Dec 2023
15 Aug 2023 Phase Change - Preregistration Preregistration for Myelodysplastic syndromes (Recurrent, Second-line therapy or greater) in USA (PO) [119] Updated 18 Aug 2023
15 Aug 2023 Regulatory Status Ivosidenib receives priority review status for Myelodysplastic syndrome in USA [119] Updated 18 Aug 2023
27 Jun 2023 Trial Update Servier plans a phase I/II trial in Cholangiocarcinoma (Combination therapy, Metastatic disease, Unresectable/Inoperable) in August 2023 (NCT05921760; EudraCT2023-503236-41; CL1-95031-006) Updated 05 Dec 2023
15 Jun 2023 Trial Update Servier plans a phase IIIb trial for Acute myeloid leukemia (Combination therapy, In adults, First-line therapy) in UK, Australia, Austria, Germany, Netherlands, Sweden, Italy and Spain (PO, Tablet) (NCT05907057) Updated 21 Jun 2023
14 Jun 2023 Phase Change - III Phase-III clinical trials in Acute myeloid leukaemia (In adults, Combination therapy, First-line therapy) in Sweden, Germany, Austria, Australia, United Kingdom, Germany, Netherlands, Sweden, Italy and Spain (PO)(NCT05907057) Updated 28 Jul 2023
14 Jun 2023 Trial Update Servier initiates enrolment in a phase III trials in Acute myeloid leukaemia (In adults, Combination therapy, First-line therapy) in Australia, United Kingdom, Germany, Netherlands, Sweden, Italy and Spain (PO)(NCT05907057) Updated 28 Jul 2023
09 Jun 2023 Scientific Update Efficacy and adverse events data from a phase I trial in Myelodysplastic Syndromes released by Servier [122] Updated 16 Jun 2023
06 Jun 2023 Trial Update Agios Pharmaceuticals completes a phase I trial in Acute myeloid leukemia, Myelodysplastic syndromes and Chronic myelomonocytic leukemia (as Maintenance therapy) in USA (NCT03564821) Updated 10 Nov 2023
05 Jun 2023 Scientific Update Updated efficacy and adverse events data from the phase III AGILE trial in Acute myeloid leukemia released by Servier [56] Updated 10 Jun 2023
05 Jun 2023 Scientific Update Updated efficacy data from a phase I expansion trial in Acute myeloid leukaemia released by Servier [56] Updated 10 Jun 2023
02 Jun 2023 Scientific Update Updated efficacy and adverse events data from a phase I trial in Solid tumours presented at the 59th Annual Meeting of the American Society of Clinical Oncology (ASCO-2023) [142] Updated 07 Jul 2023
02 Jun 2023 Scientific Update Updated efficacy and adverse events data from the phase III AGILE trial in Acute myeloid leukemia presented at the 59th Annual Meeting of the American Society of Clinical Oncology (ASCO-2023) [57] Updated 03 Jul 2023
10 May 2023 Phase Change - Registered Registered for Acute myeloid leukaemia (Combination therapy, First-line therapy) in European Union (PO) [25] Updated 17 May 2023
10 May 2023 Phase Change - Registered Registered for Acute myeloid leukaemia (Combination therapy, First-line therapy) in Iceland (PO) [25] Updated 17 May 2023
10 May 2023 Phase Change - Registered Registered for Acute myeloid leukaemia (Combination therapy, First-line therapy) in Liechtenstein (PO) [25] Updated 17 May 2023
10 May 2023 Phase Change - Registered Registered for Acute myeloid leukaemia (Combination therapy, First-line therapy) in Norway (PO) [25] Updated 17 May 2023
10 May 2023 Phase Change - Registered Registered for Cholangiocarcinoma (Late-stage disease, Metastatic disease, Second-line therapy or greater) in European Union (PO) [25] Updated 17 May 2023
10 May 2023 Phase Change - Registered Registered for Cholangiocarcinoma (Late-stage disease, Metastatic disease, Second-line therapy or greater) in Iceland (PO) [25] Updated 17 May 2023
10 May 2023 Phase Change - Registered Registered for Cholangiocarcinoma (Late-stage disease, Metastatic disease, Second-line therapy or greater) in Liechtenstein (PO) [25] Updated 17 May 2023
10 May 2023 Phase Change - Registered Registered for Cholangiocarcinoma (Late-stage disease, Metastatic disease, Second-line therapy or greater) in Norway (PO) [25] Updated 17 May 2023
03 May 2023 Phase Change - III Phase-IIIb clinical trials in Cholangiocarcinoma (Inoperable/Unresectable, Late-stage disease, Metastatic disease, Second-line therapy or greater) in Germany (PO) (NCT05876754) Updated 30 May 2023
06 Apr 2023 Phase Change - Registered Registered for Cholangiocarcinoma (Late-stage disease, Metastatic disease, Second-line therapy or greater) in Australia (PO) [87] Updated 03 May 2023
15 Mar 2023 Regulatory Status CStone Pharmaceuticals anticipates MAA approval in for the first-line treatment of AML and cholangiocarcinoma with IDH1 mutations in EU in 2023 Updated 24 Mar 2023
01 Mar 2023 Regulatory Status CStone announces intention to submit new drug applications for ivosidenib in Hong Kong, Taiwan, and Singapore Updated 03 Mar 2023
24 Feb 2023 Regulatory Status CHMP of the EMA issues positive opinion recommending approval of ivosidenib for IDH1-mutated Acute myeloid leukemia (AML) in European Union [26] Updated 28 Feb 2023
24 Feb 2023 Regulatory Status CHMP of the EMA issues positive opinion recommending approval of ivosidenib for IDH1-mutated Cholangiocarcinoma in European Union [26] Updated 28 Feb 2023
18 Jan 2023 Trial Update CStone Pharmaceuticals completes a phase I trial in Acute myeloid leukaemia (Second-line therapy or greater) in China (PO) (NCT04176393) Updated 23 Feb 2023
10 Dec 2022 Scientific Update Updated efficacy data from a phase III AGILE trial in Acute myeloid leukaemia presented at 64rd Annual Meeting of the American Society of Hematology (ASH-2022) [54] [55] Updated 20 Dec 2022
01 Jul 2022 Phase Change - Marketed Launched for Acute myeloid leukaemia (Second-line therapy or greater) in China (PO) (CStone Pharmaceuticals pipeline, July 2022) Updated 01 Jul 2022
09 Jun 2022 Scientific Update Efficacy data from a phase III AGILE trial in Acute myeloid leukaemia presented at the 27th Congress of the European Haematology Association (EHA-2022) [53] Updated 01 Aug 2022
09 Jun 2022 Scientific Update Efficacy data from a phase III AGILE trial in Acute myeloid leukaemia presented at the 27th Congress of the European Haematology Association (EHA-2022) [52] Updated 01 Aug 2022
03 Jun 2022 Scientific Update Updated efficacy and adverse events data from a phase III trial in Acute myeloid leukemia presented at the 58th Annual Meeting of the American Society of Clinical Oncology (ASCO-2022) [50] Updated 09 Jul 2022
03 Jun 2022 Scientific Update Updated efficacy and adverse events data from a phase III trial in Acute myeloid leukemia presented at the 58th Annual Meeting of the American Society of Clinical Oncology (ASCO-2022) [51] Updated 29 Jun 2022
03 Jun 2022 Scientific Update Updated efficacy and adverse events data from a phase I trial in Acute myeloid leukaemia and Myelodysplastic syndromes presented at the 58th Annual Meeting of the American Society of Clinical Oncology (ASCO-2022) [114] Updated 29 Jun 2022
26 May 2022 Phase Change - Marketed Launched for Acute myeloid leukaemia (Combination therapy, First-line therapy) in USA (PO) [14] Updated 01 Jun 2022
25 May 2022 Phase Change - Registered Registered for Acute myeloid leukaemia (Combination therapy, First-line therapy) in USA (PO) [14] Updated 30 May 2022
29 Apr 2022 Regulatory Status Ivosidenib - Servier receives Orphan Drug status for Cholangiocarcinoma in Australia (Therapeutic Goods Administration, June 2022) Updated 06 Jun 2022
10 Mar 2022 Phase Change - Preregistration Preregistration for Acute myeloid leukaemia (Combination therapy, First-line therapy) in European Union (PO) [27] Updated 14 Mar 2022
10 Mar 2022 Phase Change - Preregistration Preregistration for Cholangiocarcinoma (Late-stage disease, Metastatic disease, Second-line therapy or greater) in European Union (PO) [27] Updated 14 Mar 2022
07 Mar 2022 Phase Change - Preregistration Preregistration for Acute myeloid leukaemia (Combination therapy, First-line therapy) in USA (PO) [15] Updated 25 Mar 2022
07 Mar 2022 Regulatory Status Ivosidenib receives priority review status for Acute myeloid leukaemia (Combination therapy, First-line therapy) in USA (PO) [15] Updated 25 Mar 2022
31 Jan 2022 Phase Change - Registered Registered for Acute myeloid leukaemia (Second-line therapy or greater) in China (PO) [23] Updated 01 Jul 2022
11 Dec 2021 Scientific Update Efficacy and adverse events data from a phase I trial in Acute myeloid leukaemia presented at the 63rd Annual Meeting and Exposition of American Society of Hematology (ASH-Hem-2021) [72] Updated 21 Jan 2022
11 Dec 2021 Regulatory Status Servier Pharmaceuticals plans to discuss with Health authorities regarding regulatory submissions to expand the approved indications for ivosidenib [28] Updated 14 Dec 2021
11 Dec 2021 Scientific Update Safety and efficacy data from the phase III AGILE trial in Acute myeloid leukaemia presented at 63rd annual meeting of the American Society of Hematology (ASH-Hem-2021) [28] [48] Updated 14 Dec 2021
01 Oct 2021 Biomarker Update Biomarkers information updated Updated 02 Oct 2021
16 Sep 2021 Scientific Update Efficacy, safety, and pharmacokinetics data from a phase I trial in acute myeloid leukaemia presented at the 46th European Society for Medical Oncology Congress (ESMO-2021) [34] Updated 01 Dec 2021
25 Aug 2021 Phase Change - Marketed Launched for Cholangiocarcinoma (Inoperable/Unresectable, Late-stage disease, Metastatic disease, Second-line therapy or greater) in USA (PO) [88] Updated 27 Aug 2021
03 Aug 2021 Phase Change - Preregistration Preregistration for Acute myeloid leukaemia (Second-line therapy or greater) in China (PO) [24] Updated 09 Aug 2021
03 Aug 2021 Regulatory Status Ivosidenib receives priority review status for Acute myeloid leukemia in China [24] Updated 06 Aug 2021
03 Aug 2021 Regulatory Status National Medical Products Administration (NMPA) of China accepts NDA for ivosidenib for Acute myeloid leukaemia for review [24] Updated 06 Aug 2021
03 Aug 2021 Scientific Update Efficacy and safety data of a phase III (AGILE study) in Acute myeloid leukemia released by Servier [47] Updated 03 Aug 2021
03 Aug 2021 Trial Update Servier halted enrollment in a phase III (AGILE study) in Acute myeloid leukemia based on the recommendation of the Independent Data Monitoring Committee (IDMC) [47] Updated 03 Aug 2021
04 Jun 2021 Scientific Update Final efficacy and adverse events data from phase III ClarIDHy trial for Cholangiocarcinoma presented at the 57th Annual Meeting of the American Society of Clinical Oncology (ASCO-2021) [95] Updated 17 Jul 2021
04 Jun 2021 Scientific Update Phamacodynamics data from a phase I trial in Glioma presented at the the 57th Annual Meeting of the American Society of Clinical Oncology (ASCO-2021) [113] Updated 12 Jul 2021
01 Jun 2021 Trial Update Agios Pharmaceuticals completes enrolment in phase III trials in Acute myeloid leukaemia (Combination therapy, First-line therapy) in Australia, Austria, Brazil, Canada, China, Czech Republic, England, France, Germany, Israel, Italy, Japan, Mexico, Netherlands, Poland, Russia, Scotland, South Korea, Spain, Taiwan, UK, USA (PO) (EudraCT2016-004907-30) (NCT03173248) Updated 19 Jun 2021
17 May 2021 Trial Update Agios Pharmaceuticals completes the phase III ClarIDHy trial for Cholangiocarcinoma (Late-stage disease, Inoperable/Unresectable, Metastatic disease, Second-line therapy or greater) in United Kingdom, Germany, Spain, South Korea, Italy, Italy, France (PO) (NCT02989857) Updated 20 Oct 2021
05 May 2021 Regulatory Status The US FDA accepts sNDA for ivosidenib for Cholangiocarcinoma (Inoperable/Unresectable, Late-stage disease, Metastatic disease, Second-line therapy or greater) and grants priority review [89] Updated 07 May 2021
14 Apr 2021 Phase Change - II Phase-II clinical trials in Glioma (Combination therapy, Late-stage disease) in USA (PO) (NCT04056910) Updated 19 Apr 2021
14 Apr 2021 Phase Change - II Phase-II clinical trials in Solid tumours (Late-stage disease, Combination therapy, Metastatic disease, Inoperable/Unresectable) in USA (PO) (NCT04056910) Updated 19 Apr 2021
10 Apr 2021 Scientific Update Pharmacodynamic data from a preclinical trial in Acute myeloid leukaemia at 112th Annual Meeting of the American Association for Cancer Research (AACR-2021) [80] Updated 19 Jun 2021
01 Apr 2021 Licensing Status Servier aquires oncology portfolio from Agios Pharmaceuticals [1] Updated 06 Apr 2021
01 Mar 2021 Phase Change - Preregistration Preregistration for Cholangiocarcinoma (Inoperable/Unresectable, Late-stage disease, Metastatic disease, Second-line therapy or greater) in USA (PO) [90] Updated 03 Mar 2021
01 Mar 2021 Regulatory Status Agios Pharmaceuticals requests Priority review for Cholangiocarcinoma from the US FDA [90] Updated 03 Mar 2021
17 Jan 2021 Scientific Update Efficacy data from phase III ClarIDHy trial for Cholangiocarcinoma released by Agios Pharmaceuticals [96] Updated 24 Jan 2021
21 Dec 2020 Licensing Status Servier enters into purchase agreement to aquire oncology portfolio from Agios Pharmaceuticals [2] Updated 24 Dec 2020
05 Dec 2020 Scientific Update Updated efficacy data from a phase I trial in Acute myeloid leukaemia presented at the 62nd Annual Meeting and Exposition of the American Society of Hematology (ASH-2020) [123] Updated 05 Jan 2021
16 Oct 2020 Phase Change - Preregistration-Submission Withdrawal Regulatory submission withdrawn for Acute myeloid leukaemia (Second-line therapy or greater, In adults) in European Union (PO) [41] Updated 22 Apr 2021
16 Oct 2020 Regulatory Status Agios Pharmaceuticals anticipates regulatory approvals in Acute myeloid leukaemia in USA and European Union [41] Updated 20 Oct 2020
16 Oct 2020 Regulatory Status Agios Pharmaceuticals withdraws the European Marketing Authorization Application for Acute myeloid leukaemia (In adults, Second-line therapy or greater) in European Union [41] Updated 20 Oct 2020
21 Sep 2020 Scientific Update Updated efficacy data from the phase III ClarIDHy trial in Cholangiocarcinoma released by Agios Pharmaceuticals [97] Updated 23 Sep 2020
30 Jul 2020 Regulatory Status Agios pharmaceuticals announces intention to submit sNDA to US FDA for Cholangiocarcinoma (Second-line therapy or greater) in the first quarter of 2021 [144] Updated 03 Mar 2021
28 Jul 2020 Phase Change - No development reported No recent reports of development identified for phase-I development in Acute-myeloid-leukaemia(Second-line therapy or greater) in France (PO) Updated 28 Jul 2020
28 Jul 2020 Phase Change - No development reported No recent reports of development identified for phase-I development in Glioma(Late-stage disease, Second-line therapy or greater) in France (PO) Updated 28 Jul 2020
28 Jul 2020 Phase Change - No development reported No recent reports of development identified for phase-I development in Glioma(Late-stage disease, Second-line therapy or greater) in USA (PO) Updated 28 Jul 2020
28 Jul 2020 Phase Change - No development reported No recent reports of development identified for phase-I development in Glioma(Recurrent) in USA (PO) Updated 28 Jul 2020
28 Jul 2020 Phase Change - No development reported No recent reports of development identified for phase-I development in Myelodysplastic-syndromes(Recurrent, Second-line therapy or greater) in France (PO) Updated 28 Jul 2020
28 Jul 2020 Phase Change - No development reported No recent reports of development identified for phase-I development in Myelodysplastic-syndromes(Recurrent, Second-line therapy or greater) in USA (PO) Updated 28 Jul 2020
28 Jul 2020 Phase Change - No development reported No recent reports of development identified for phase-I development in Solid-tumours(Late-stage disease, Second-line therapy or greater) in France (PO) Updated 28 Jul 2020
28 Jul 2020 Phase Change - No development reported No recent reports of development identified for phase-I development in Solid-tumours(Late-stage disease, Second-line therapy or greater) in USA (PO) Updated 28 Jul 2020
22 Jun 2020 Scientific Update Data from preclinical studies in Intrahepatic cholangiocarcinoma presented at the 111th Annual Meeting of the American Association for Cancer Research-II (AACR-2020) [145] Updated 19 Jul 2020
11 Jun 2020 Scientific Update Pharmacokinetics and pharmacodynamics data from a phase I trial in Acute myeloid leukaemia presented at the 25th Congress of the European Haematology Association (EHA-2020) [71] Updated 08 Aug 2020
11 Jun 2020 Scientific Update Efficacy data from a phase I trial in Acute myeloid leukaemia presented at the 25th Congress of the European Haematology Association (EHA-2020) [125] [124] Updated 02 Aug 2020
29 May 2020 Scientific Update Efficacy data from the phase III ClarIDHy trial in Cholangiocarcinoma presented at the 56th Annual Meeting of the American Society of Clinical Oncology (ASCO-2020) [102] Updated 20 Jun 2020
26 Mar 2020 Regulatory Status Cstone intends to submit NDA in China by the first half of 2021 [146] Updated 01 Jul 2022
26 Mar 2020 Regulatory Status Cstone expects Marketing approval in Taiwan for treatment of adult patients with R/R AML containing an isocitrate dehydrogenase-1 mutation in 2020 [146] Updated 02 Apr 2020
23 Jan 2020 Regulatory Status CStone Pharmaceuticals announces intention to launch ivosidenib in China in 2023 [147] Updated 01 Jul 2022
18 Dec 2019 Regulatory Status Ivosidenib - Agios Pharmaceuticals receives Breakthrough Therapy status for Myelodysplastic syndromes in USA [120] Updated 24 Dec 2019
07 Dec 2019 Scientific Update Efficacy data from a phase I/II trial in Acute myeloid leukaemia presented at the 61st Annual Meeting and Exposition of the American Society of Hematology [65] Updated 14 Dec 2019
22 Nov 2019 Scientific Update Adverse events, pharmacokinetic, phamacodynamics and efficacy data from a phase I trial in Glioma released by Agios Pharmaceuticals [112] Updated 04 Dec 2019
12 Nov 2019 Phase Change - I Phase-I clinical trials in Acute myeloid leukaemia (Second-line therapy or greater) in China (PO) (NCT04176393) [33] Updated 30 Nov 2019
30 Sep 2019 Scientific Update Positive efficacy and adverse events data from the phase III ClarIDHy trial in Cholangiocarcinoma released by Agios Pharmaceuticals [98] Updated 10 Oct 2019
22 Jul 2019 Regulatory Status National drug administration approves a phase I trial of ivosidenib for acute myeloid leukaemia in China [32] Updated 24 Jul 2019
22 Jul 2019 Trial Update Cornerstone Pharmaceuticals plans a phase I trial for Acute myeloid leukaemia (Second-line therapy or greater) in China [32] Updated 24 Jul 2019
19 Jul 2019 Phase Change - III Phase-III clinical trials in Acute myeloid leukaemia (Combination therapy, First-line therapy) in China (PO) [30] (NCT03173248) Updated 19 Aug 2019
18 Jul 2019 Trial Update HOVON Foundation plans a phase III trial to compare ivosidenib or enasidenib for Acute myeloid leukemia or Myelodysplastic syndrome (Newly diagnosed, First-line therapy) in Australia (ACTRN12619001031156p) Updated 09 Mar 2020
13 Jun 2019 Scientific Update Efficacy and adverse events data from a phase I trial in Acute myeloid leukaemia presented at the 24th Congress of the European Haematology Association (EHA-2019) [126] [64] Updated 04 Sep 2019
02 Jun 2019 Phase Change - Preregistration Preregistration for Acute myeloid leukaemia (Monotherapy, Second-line therapy or greater) in Taiwan (PO) [35] Updated 06 Jun 2019
31 May 2019 Scientific Update Safety and efficacy data from phase I/II in Acute myeloid leukaemia (Combination therapy, First-line therapy, Newly diagnosed) was presented at the 55th Annual Meeting of the American Society of Clinical Oncology [63] Updated 09 Jun 2019
31 May 2019 Scientific Update Updated safety and efficacy data from a phase I trial in Acute myeloid leukemia presented at the 55th Annual Meeting of American Society of Clinical Oncology (ASCO-2019) [148] Updated 08 Jun 2019
31 May 2019 Scientific Update Adverse events and efficacy data from a phase I trial in Glioma presented at the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO-2019) [111] Updated 03 Jun 2019
23 May 2019 Scientific Update Positive efficacy and adverse events data from the phase III ClarIDHy trial in Cholangiocarcinoma released by Agios Pharmaceuticals [100] Updated 27 May 2019
03 May 2019 Phase Change - Marketed Launched for Acute myeloid leukaemia (First-line therapy, In the elderly, Monotherapy, Newly diagnosed, In adults) in USA (PO) [20] Updated 10 May 2019
02 May 2019 Phase Change - Registered Registered for Acute myeloid leukaemia (First-line therapy, Monotherapy, Newly diagnosed, In adults, In the elderly) in USA (PO) [20] Updated 10 May 2019
02 May 2019 Scientific Update Updated efficacy data from the phase I trial in Acute myeloid leukaemia released by Agios Pharmaceuticals [20] Updated 10 May 2019
26 Mar 2019 Regulatory Status Ivosidenib receives Breakthrough Therapy status for Acute myeloid leukaemia (Newly diagnosed, First-line therapy, Combination therapy) in USA [36] Updated 29 Mar 2019
01 Mar 2019 Phase Change - III Phase-III clinical trials in Acute myeloid leukaemia (In the elderly, In adults, Newly diagnosed, First-line therapy) in Norway, France, Lithuania, Finland, Netherlands (PO) (NCT03839771) (EudraCT2018-000451-41) Updated 09 Mar 2020
01 Mar 2019 Phase Change - III Phase-III clinical trials in Myelodysplastic syndromes (In adults, In the elderly, Newly diagnosed, First-line therapy) in Norway, Finland, Lithuania, France, Netherlands (PO) (NCT03839771) (EudraCT2018-000451-41) Updated 09 Mar 2020
25 Feb 2019 Scientific Update Efficacy and adverse events data from a phase I/II trial in Acute myeloid leukaemia released by Agios Pharmaceuticals [62] Updated 28 Feb 2019
20 Feb 2019 Regulatory Status FDA assigns PDUFA action date of 21/06/2019 for ivosidenib for Acute myeloid leukaemia (First-line therapy, Monotherapy, Newly diagnosed) [21] Updated 30 Nov 2019
20 Feb 2019 Regulatory Status The US FDA grants priority review for ivosidenib in Acute myeloid leukaemia (First-line therapy, Monotherapy, Newly diagnosed) [21] Updated 25 Feb 2019
20 Feb 2019 Regulatory Status The US FDA accepts supplemental NDA for ivosidenib for Acute myeloid leukaemia (First-line therapy, Monotherapy, Newly diagnosed) for priority review [21] Updated 22 Feb 2019
14 Feb 2019 Trial Update Agios Pharmaceuticals completes enrolment in the phase III ClarIDHy trial for Cholangiocarcinoma (Late-stage disease, Inoperable/Unresectable, Metastatic disease, Second-line therapy or greater) in USA, France, Italy, South Korea, Spain and the UK (PO) (NCT02989857) [101] Updated 20 Feb 2019
16 Jan 2019 Trial Update Agios Pharmaceuticals initiates a phase I trial for Acute myeloid leukemia, Myelodysplastic syndromes and Chronic myelomonocytic leukemia (as Maintenance therapy) in USA (NCT03564821) Updated 28 Jan 2019
07 Jan 2019 Phase Change - Preregistration Preregistration for Acute myeloid leukaemia (Monotherapy, Newly diagnosed, First-line therapy) in USA (PO) [22] Updated 14 Jan 2019
07 Jan 2019 Phase Change - Preregistration Preregistration for Acute myeloid leukaemia (Second-line therapy or greater, In adults) in European Union (PO) [22] Updated 14 Jan 2019
04 Dec 2018 Scientific Update Updated efficacy and adverse events data from a phase I trial in Acute myeloid leukaemia presented at the 60th American Society of Haematology Annual Meeting (ASH-2018) [135] Updated 05 Dec 2018
03 Dec 2018 Scientific Update Updated efficacy and adverse events data from the phase I trial in Acute myeloid leukaemia presented at the 60th Annual Meeting of the American Society of Haematology (ASH-2018) [70] Updated 05 Dec 2018
01 Nov 2018 Trial Update Agios Pharmaceuticals plans a phase III HOVON 150 trial for Acute myeloid leukaemia with an IDH1 or IDH2 mutation (First-line therapy, Newly diagnosed, Combination therapy) in the fourth quarter of 2018 [46] Updated 17 Apr 2020
01 Nov 2018 Regulatory Status Agios Pharmaceuticals plans to submit sNDA to the US FDA for IDH1m positive Acute myeloid leukaemia by the end of January 2019 [46] Updated 30 Nov 2019
02 Aug 2018 Phase Change - Marketed Launched for Acute myeloid leukaemia (Second-line therapy or greater) in USA (PO) prior to August 2018 [16] Updated 06 Aug 2018
31 Jul 2018 Active Status Review Phase-I development in Acute-myeloid-leukaemia (Second-line therapy or greater) and Myelodysplastic-syndromes (Recurrent, Second-line therapy or greater) is underway in France and USA (NCT02074839) Updated 31 Jul 2018
31 Jul 2018 Active Status Review Phase-I development in Glioma (Recurrent) is ongoing in USA (PO) (NCT03343197) Updated 31 Jul 2018
31 Jul 2018 Active Status Review Phase-I development in Solid tumours (Late-stage disease, Second-line therapy or greater) is ongoing in USA and France (PO) (NCT02073994) Updated 31 Jul 2018
20 Jul 2018 Trial Update Agios Pharmaceuticals completes an expanded-access programme for Acute myeloid leukaemia (Monotherapy, Second-line therapy or greater, In children, In adolescents, In adults, In the elderly) (PO) (NCT03245424) Updated 07 Aug 2018
20 Jul 2018 Phase Change - Registered Registered for Acute myeloid leukaemia (Second-line therapy or greater) in USA (PO) - First Global Approval [17] Updated 24 Jul 2018
20 Jul 2018 Scientific Update Updated efficacy and adverse events data from a phase I trial in Acute myeloid leukaemia released by Agios Pharmaceuticals [17] Updated 24 Jul 2018
28 Jun 2018 Trial Update Massachusetts General Hospital and Agios Pharmaceuticals plan a phase I trial for Acute myeloid leukaemia, Myelodysplastic syndromes and Chronic myelomonocytic leukaemia (Maintenance therapy) in USA (NCT03564821) Updated 28 Jan 2019
26 Jun 2018 Licensing Status Agios and CStone Pharmaceuticals enter into an exclusive collaboration and licensing agreement to develop and commercialize ivosidenib in China, Hong Kong, Macau and Taiwan [4] Updated 06 Aug 2018
26 Jun 2018 Licensing Status Ivosidenib licensed to CStone Pharmaceuticals in China, Hong Kong, Macau and Taiwan [4] Updated 29 Jun 2018
14 Jun 2018 Scientific Update Efficacy and adverse events data from a phase I trial in Acute myeloid leukaemia presented at the 23rd Congress of the European Haematology Association (EHA-2018) [134] Updated 16 Jul 2018
14 Jun 2018 Trial Update Agios Pharmaceuticals initiates a phase I trial for Acute myeloid leukaemia (Refractory metastatic disease) in USA (PO), prior to June 2018 [73] Updated 16 Jul 2018
04 Jun 2018 Scientific Update Updated efficacy, safety and pharmacodynamics data from a phase I trial in Acute myeloid leukaemia released by Agios Pharmaceuticals [59] Updated 11 Jun 2018
02 Jun 2018 Scientific Update Updated efficacy, safety and pharmacodynamics data from a phase I trial in Acute myeloid leukaemia presented at the Annual Meeting of American Society of Clinical Oncology (ASCO-2018) [133] Updated 06 Jun 2018
01 Jun 2018 Scientific Update Pharmacokinetics data from a phase I trial in Acute myeloid leukaemia presented at the 54th Annual Meeting of the American Society of Clinical Oncology [132] Updated 29 Jun 2018
01 Jun 2018 Scientific Update Pharmacokinetics and pharmacodynamics data from a phase I trial in Solid tumours presented at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO-2018) [141] Updated 28 Jun 2018
31 Mar 2018 Trial Update Agios Pharmaceuticals completes a phase I trial in Healthy volunteers in USA (PO) (NCT03282513) Updated 11 May 2018
21 Mar 2018 Regulatory Status Ivosidenib - Servier receives Orphan Drug status for Cholangiocarcinoma in European Union [91] Updated 23 Aug 2022
15 Feb 2018 Regulatory Status FDA assigns PDUFA action date of 21/08/2018 for ivosidenib for Acute myeloid leukaemia (Second-line therapy or greater) [18] Updated 24 Jul 2018
15 Feb 2018 Regulatory Status US FDA accepts NDA for ivosidenib for Acute myeloid leukaemia (Second-line therapy or greater) for review [18] Updated 20 Feb 2018
15 Feb 2018 Regulatory Status US FDA grants priority review for ivosidenib for Acute myeloid leukaemia (Second-line therapy or greater) for review [18] Updated 20 Feb 2018
14 Feb 2018 Patent Information Agios Pharmaceuticals has issued patents and pending patents covering IDH mutant product candidates, including ivosidenib, in countries worldwide [143] Updated 20 Mar 2018
08 Jan 2018 Regulatory Status Agios Pharmaceuticals plans to submit a MAA to the European Medicines Agency for ivosidenib for Acute myeloid leukaemia in the fourth quarter of 2018 [149] Updated 30 Nov 2019
08 Jan 2018 Regulatory Status Agios Pharmaceuticals plans to launch ivosidenib for Acute myeloid leukaemia in the US in the second half of 2018 [149] Updated 06 Aug 2018
05 Jan 2018 Regulatory Status Ivosidenib - Agios Pharmaceuticals receives Orphan Drug status for Glioma in USA [108] Updated 24 Jul 2018
26 Dec 2017 Phase Change - Preregistration Preregistration for Acute myeloid leukaemia (Second-line therapy or greater) in USA (PO) [19] Updated 28 Dec 2017
26 Dec 2017 Regulatory Status Agios requests priority review for ivosidenib's NDA for Acute myeloid leukaemia (Second-line therapy or greater) to the US FDA [19] Updated 28 Dec 2017
11 Dec 2017 Scientific Update Safety and efficacy data from a phase I trial in Acute myeloid leukaemia presented at the 59th Annual Meeting of the American Society of Haematology (ASH-2017) [60] Updated 18 Dec 2017
11 Dec 2017 Scientific Update Safety and efficacy data from a phase Ib/II trial in Acute myeloid leukaemia presented at the 59th Annual Meeting of the American Society of Haematology (ASH-2017) [60] Updated 18 Dec 2017
11 Dec 2017 Scientific Update Interim efficacy and adverse events data from a phase I/II trial in Acute myeloid leukaemia released by Agios Pharmaceuticals [131] Updated 14 Dec 2017
11 Dec 2017 Trial Update Agios Pharmaceuticals completes enrolment in its phase I/II trial for Acute myeloid leukaemia (Combination therapy, First-line therapy) in Australia, Canada, Italy, South Korea, Netherlands, Spain, France, Germany, Switzerland, United Kingdom, Portugal and USA (PO) before December 2017 [131] Updated 14 Dec 2017
17 Nov 2017 Trial Update Agios Pharmaceuticals plans a perioperative window trial for Glioma (Recurrent) in USA in the first half of 2018 (NCT03343197) [115] Updated 19 Mar 2018
17 Nov 2017 Scientific Update Interim efficacy and adverse events data from a phase I trial in Solid tumours released by Agios Pharmaceuticals [115] Updated 23 Nov 2017
17 Nov 2017 Scientific Update Pharmacodynamics data from a preclinical trial in Glioma released by Agios Pharmaceuticals [115] Updated 23 Nov 2017
22 Sep 2017 Trial Update Agios Pharmaceuticals plans a phase I trial in Healthy volunteers in USA (PO) (NCT03282513) Updated 05 Oct 2017
06 Sep 2017 Trial Update Agios Pharmaceutical completes a phase I trial in Healthy volunteers in USA (PO) (NCT03071770) Updated 24 Jan 2018
01 Sep 2017 Trial Update Agios Pharmaceuticals initiates enrolment in a phase I trial in Healthy volunteers in USA (PO) (NCT03282513) Updated 05 Oct 2017
07 Aug 2017 Trial Update Agios Pharmaceuticals initiates an expanded-access programme for Acute myeloid leukaemia (Monotherapy, Second-line therapy or greater, In children, In adolescents, In adults, In the elderly) (PO) (NCT03245424) Updated 16 Aug 2017
21 Jul 2017 Trial Update Agios Pharmaceuticals initiates enrolment in a phase I trial in Acute myeloid leukaemia (Combination therapy, First-line therapy) in Netherlands, Germany before July 2017 (NCT02632708) Updated 07 Nov 2017
30 Jun 2017 Trial Update Agios Pharmaceuticals completes enrolment in its phase I trial for Solid tumours (Late-stage disease, Second-line therapy or greater) in USA and France (NCT02073994) Updated 28 Jun 2018
20 Jun 2017 Phase Change - III Phase-III clinical trials in Acute myeloid leukaemia (Combination therapy, Second-line therapy or greater) in Czech Republic (PO) after June 2017 (NCT03173248) Updated 24 Jul 2018
15 Jun 2017 Trial Update Agios Pharmaceuticals plans to initiate the phase III AGILE trial in Acute myeloid leukaemia (First-line therapy, Combination therapy) (PO) (NCT03173248) Updated 29 Jun 2017
03 Jun 2017 Scientific Update Updated adverse events, efficacy and pharmacodynamics data from a phase I trial in Solid tumours presented at the Annual Meeting of American Society of Clinical Oncology (ASCO-2017) [140] Updated 12 Jun 2017
02 Jun 2017 Scientific Update Pharmacokinetics and pharmacodynamics data from a phase I trial in Solid tumours and Glioma presented at the 53rd Annual Meeting of the American Society of Clinical Oncology (ASCO-2017) [150] Updated 18 Jul 2017
01 Jun 2017 Phase Change - III Phase-III clinical trials in Acute myeloid leukaemia (Combination therapy, First-line therapy) in Scotland, England, Japan, Austria, Germany (PO) (NCT03173248) Updated 19 Jun 2021
01 Jun 2017 Phase Change - III Phase-III clinical trials in Acute myeloid leukaemia (Combination therapy, First-line therapy) in United Kingdom, France, Netherlands, South Korea, Italy, Canada, Australia, Spain, Russia, Taiwan, Poland, Mexico, Israel, Brazil (PO) (NCT03173248) Updated 28 Jun 2018
01 Jun 2017 Phase Change - III Phase-III clinical trials in Acute myeloid leukaemia (Combination therapy, First-line therapy) in USA (PO) (NCT03173248) Updated 29 Jun 2017
04 May 2017 Regulatory Status Agios Pharmaceuticals announces intention to submit NDA to the US FDA for IDH1m positive Acute myeloid leukaemia (Second-line therapy or greater) by the end of 2017 [92] Updated 28 Jun 2018
26 Apr 2017 Regulatory Status Ivosidenib receives Orphan Drug status for Cholangiocarcinoma in USA [92] Updated 30 May 2017
17 Apr 2017 Other Chemical structure information added Updated 17 Apr 2017
02 Apr 2017 Trial Update Agios Pharmaceutical initiates enrolment in a phase I trial in Healthy volunteers in USA (NCT03071770) Updated 11 Apr 2017
09 Mar 2017 Trial Update Agios Pharmaceutical plans a phase I trial in Healthy volunteers in USA (NCT03071770) Updated 11 Apr 2017
08 Mar 2017 Phase Change - I/II Phase-I/II clinical trials in Acute myeloid leukaemia (Combination therapy, First-line therapy) in Switzerland, Germany and France (PO) before March 2017 (NCT02677922) Updated 08 Mar 2017
09 Jan 2017 Regulatory Status AG 120 receives Fast Track designation for Cholangiocarcinoma [PO] in USA [44] Updated 02 Feb 2017
09 Jan 2017 Trial Update Agios Pharmaceuticals plans a phase III trial for Acute myeloid leukaemia (Combination therapy) [44] Updated 01 Feb 2017
31 Dec 2016 Phase Change - III Phase-III clinical trials in Cholangiocarcinoma (Late-stage disease, Inoperable/Unresectable, Metastatic disease, Second-line therapy or greater) in USA (PO) in December 2016 (9210051; NCT02989857) Updated 02 Feb 2017
12 Dec 2016 Regulatory Status Ivosidenib - Servier receives Orphan Drug status for Acute myeloid leukaemia in European Union [37] Updated 23 Aug 2022
09 Dec 2016 Trial Update Agios Pharmaceuticals plans the phase III ClarIDHy trial for Cholangiocarcinoma (Late-stage disease, Inoperable/Unresectable, Metastatic disease, Second-line therapy or greater) in USA (PO) (NCT02989857) Updated 15 Dec 2016
05 Dec 2016 Phase Change Investigation in Cholangiocarcinoma in USA (PO) before December 2016 Updated 15 Dec 2016
05 Dec 2016 Scientific Update Efficacy and adverse events data from a phase I trial in presented at the American Society of Hematology Annual Meeting and Exposition (ASH-2016) [151] Updated 13 Dec 2016
01 Dec 2016 Phase Change - III Phase-III clinical trials in Cholangiocarcinoma (Late-stage disease, Metastatic disease, Second-line therapy or greater, Inoperable/Unresectable) in Germany (PO) after December 2016 (NCT02989857) Updated 20 Oct 2021
01 Dec 2016 Phase Change - III Phase-III clinical trials in Cholangiocarcinoma (Late-stage disease, Inoperable/Unresectable, Metastatic disease, Second-line therapy or greater) in United Kingdom, Spain, South Korea, Italy, Italy, France (PO) after December 2016 (NCT02989857) Updated 24 Jul 2018
21 Nov 2016 Scientific Update Safety and efficacy data from a phase II trial in Haematological malignancies presented at the 58th Annual Meeting and Exposition of the American Society of Hematology (ASH-2016) [130] Updated 09 Mar 2017
18 Nov 2016 Scientific Update Efficacy, pharmacodynamics and adverse events data from a phase I trial in Solid tumours released by Agios Pharmaceuticals [138] Updated 24 Nov 2016
03 Nov 2016 Regulatory Status Agios Pharmaceuticals announces intention to submit NDA for Acute myeloid leukaemia to the US FDA in 2017 [103] Updated 08 Nov 2016
01 Oct 2016 Trial Update Agios Pharmaceuticals completes a phase I drug-drug interaction trial in Healthy volunteers in USA (PO) (NCT02831972) Updated 10 Feb 2017
30 Jun 2016 Trial Update Agios Pharmaceuticals completes a phase I trial in Healthy volunteers in USA (NCT02579707) Updated 09 Dec 2016
03 Jun 2016 Phase Change - I/II Phase-I/II clinical trials in Acute myeloid leukaemia (Combination therapy, First-line therapy) in Portugal (PO) (NCT02677922) Updated 12 Jun 2017
01 Jun 2016 Phase Change - I/II Phase-I/II clinical trials in Acute myeloid leukaemia (Combination therapy, First-line therapy) in Italy, South Korea, Netherlands, United Kingdom (PO) (NCT02677922) after June 2016 Updated 10 Feb 2017
01 Jun 2016 Phase Change - I/II Phase-I/II clinical trials in Acute myeloid leukaemia (Combination therapy, First-line therapy) in Canada and Australia (PO) (NCT02677922) Updated 13 Dec 2016
01 Jun 2016 Phase Change - I/II Phase-I/II clinical trials in Acute myeloid leukaemia (First-line therapy, Combination therapy) in Spain (PO) after June 2016 (NCT02677922) Updated 09 Nov 2016
01 Jun 2016 Trial Update Agios Pharmaceuticals initiates a phase I drug-drug interaction trial in Healthy volunteers in USA (PO) (NCT02831972) Updated 15 Jul 2016
01 Jun 2016 Phase Change - I/II Phase-I/II clinical trials in Acute myeloid leukaemia (Combination therapy, First-line therapy) in USA (PO) (NCT02677922) Updated 04 Apr 2016
17 May 2016 Licensing Status Agios retains its option for worldwide development and commercialisation rights for AG 120, under the terms of the collaboration with Celgene [6] Updated 30 May 2016
05 May 2016 Trial Update Agios Pharmaceuticals plans a phase II trial in Cholangiocarcinoma in USA [67] Updated 11 May 2016
05 Feb 2016 Trial Update Celgene plans a phase Ib/II trial in Acute myeloid leukaemia (Combination therapy, Newly-diagnosed, First-line therapy) in USA (NCT02677922) Updated 26 Feb 2016
01 Dec 2015 Phase Change - I Phase-I clinical trials in Acute myeloid leukaemia (Combination therapy, First-line therapy) in USA (PO) (NCT02632708) Updated 30 Dec 2015
01 Oct 2015 Trial Update Agios Pharmaceuticals completes a phase I trial in Healthy volunteers in USA (NCT02489513) Updated 21 Dec 2015
01 Oct 2015 Trial Update Agios Pharmaceuticals initiates a phase I pharmacokinetics trial in Healthy volunteers in USA (PO) (NCT02579707) Updated 26 Oct 2015
08 Jul 2015 Trial Update Agios Pharmaceuticals initiates enrolment in a phase I trial in Healthy volunteers in USA (NCT02489513) Updated 08 Jul 2015
20 Jun 2015 Scientific Update Efficacy and adverse events data from a phase I trial in Haematoligic malignancies presented at the 20th Congress of the European Haematology Association (EHA-2015) [104] Updated 20 Jun 2015
12 Jun 2015 Trial Update Agios Pharmaceuticals plans a phase III trial for Acute myeloid leukaemia in USA [104] Updated 08 Jul 2015
12 Jun 2015 Trial Update Agios Pharmaceuticals plans clinical trials in Acute myeloid leukaemia and Haematologic malignancies (Combination therapy, First-line therapy) in USA [104] Updated 08 Jul 2015
09 Jun 2015 Regulatory Status AG 120 receives Orphan Drug status for Acute myeloid leukaemia in USA [42] Updated 11 Jun 2015
29 Aug 2014 Phase Change - I Phase-I clinical trials in Glioma (Late-stage disease, Second-line therapy or greater) in France (PO) Updated 30 Sep 2014
29 Aug 2014 Phase Change - I Phase-I clinical trials in Solid tumours (Late-stage disease, Second-line therapy or greater) in France (PO) Updated 30 Sep 2014
04 Aug 2014 Phase Change - I Phase-I clinical trials in Acute myeloid leukaemia (Second-line therapy or greater) in France (PO) (NCT02074839) Updated 30 Sep 2014
04 Aug 2014 Phase Change - I Phase-I clinical trials in Myelodysplastic syndromes (Recurrent, Second-line therapy or greater) in France (PO) Updated 30 Sep 2014
13 Jun 2014 Licensing Status AG 120 licensed to exclusively to Celgene outside USA for Haematological malignancies, including Acute myeloid leukaemia [7] Updated 17 Aug 2015
14 Mar 2014 Phase Change - I Phase-I clinical trials in Glioma (Recurrent) in USA (PO) (NCT03343197) Updated 19 Mar 2018
10 Mar 2014 Phase Change - I Phase-I clinical trials in Acute myeloid leukaemia and Myelodysplastic syndromes (recrurrent, second-line therapy or greater) in USA (PO) (NCT02074839) Updated 12 Mar 2014
28 Feb 2014 Phase Change - I Phase-I clinical trials in Glioma (late-stage disease, second-line therapy or greater) in USA (PO) (NCT02073994) Updated 14 Mar 2014
28 Feb 2014 Phase Change - I Phase-I clinical trials in Solid tumours (late-stage disease, second-line therapy or greater) in USA (PO) (NCT02073994) Updated 14 Mar 2014
03 Feb 2014 Licensing Status Agios exercises its option for US development and commercialisation rights for the IDH1 programme, including AG 120, under the terms of the collaboration with Celgene [12] Updated 12 Mar 2014
11 Dec 2013 Licensing Status Agios Pharmaceuticals and Celgene Corporation extend their collaboration until 2015 [9] Updated 12 Mar 2014
21 Oct 2013 Scientific Update Pharmacodynamics data from a preclinical study in Acute myeloid leukaemia presented at the 25th AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (AACR-NCI-EORTC-2013) [81] Updated 12 Mar 2014
14 Feb 2013 Scientific Update Pharmacodynamics data from preclinical trials in Acute myleoid leukaemia released by Agios Pharmaceuticals [82] Updated 12 Mar 2014
05 Oct 2011 Licensing Status Agios and Celgene extend their collaboration until 2014 [10] Updated 12 Mar 2014
16 Nov 2010 Scientific Update Pharmacodynamics data from early research presented at the 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR-2010) [85] Updated 12 Mar 2014
17 Apr 2010 Scientific Update Pharmacodynamics data from early research presented at the 101st Annual Meeting of the American Association for Cancer Research (AACR-2010) [86] Updated 12 Mar 2014
15 Apr 2010 Licensing Status Agios Pharmaceuticals and Celgene Corporation agree to co-develop therapeutics targeting cancer metabolism, including AG 120 [13] Updated 12 Mar 2014
15 Apr 2010 Phase Change Early research in Haematological malignancies in USA (PO) Updated 12 Mar 2014
15 Apr 2010 Phase Change Early research in Solid tumours in USA (PO) [13] Updated 12 Mar 2014

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  44. Agios Announces Key Upcoming Milestones to Support Evolution to a Commercial Stage Biopharmaceutical Company in 2017.

    Media Release
  45. A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of AG-120 in Combination With Azacitidine in Subjects ≥ 18 Years of Age With Previously Untreated Acute Myeloid Leukemia With an IDH1 Mutation

    ctiprofile
  46. Agios Reports Third Quarter 2018 Financial Results.

    Media Release
  47. Servier Announces Positive Topline Data from the Global Phase 3 Study of TIBSOVO(Rm) (ivosidenib tablets) in Combination with Azacitidine in Patients with Previously Untreated IDH1-mutated Acute Myeloid Leukemia.

    Media Release
  48. Montesinos P, Recher C, Vives S, Zarzycka E, Wang J, Bertani G, et al. AGILE: A Global, Randomized, Double-Blind, Phase 3 Study of Ivosidenib + Azacitidine Versus Placebo + Azacitidine in Patients with Newly Diagnosed Acute Myeloid Leukemia with an IDH1 Mutation. ASH-Hem-2021 2021; abstr. 697.

    Available from: URL: https://ash.confex.com/ash/2021/webprogram/Paper147805.html
  49. Servier Group Reports Financial Year 2020/2021 Annual Results, R&D Strategy and Pipeline.

    Media Release
  50. De Botton S, Choe S, Marchione DM, Montesinos P, Recher C, Polo SV, et al. Molecular characterization of clinical response in patients with newly diagnosed acute myeloid leukemia treated with ivosidenib + azacitidine compared to placebo + azacitidine. ASCO-2022 2022; abstr. 7019.

    Available from: URL: https://meetings.asco.org//abstracts-presentations/208264
  51. Dohner H, Montesinos P, Polo SV, Zarzycka E, Wang J, Bertani G, et al. Hematologic improvements with ivosidenib + azacitidine compared to placebo + azacitidine in patients with newly diagnosed acute myeloid leukemia. ASCO-2022 2022; abstr. 7042.

    Available from: URL: https://meetings.asco.org//abstracts-presentations/208205
  52. Schuh A, de Botton S, Recher C, Polo SV, Zarzycka E, Wang J, et al. Changes in Health-Related Quality of Life in Patients with Newly-Diagnosed Acute Myeloid Leukemia Receiving Ivosidenib + Azacitidine or Placebo + Azacitidine. EHA-2022 2022; abstr. P556.

    Available from: URL: https://library.ehaweb.org/eha/2022/eha2022-congress/357420/andre.schuh.changes.in.health-related.quality.of.life.in.patients.with.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D2233%2Aot_id%3D26840%2Amarker%3D1769%2Afeatured%3D17676
  53. Dohner H, Montesinos P, Polo SV, Zarzycka E, Wang J, Bertani G, et al. Hematologic Improvements with Ivosidenib + Azacitidine Compared with Placebo + Azacitidine in Patients with Newly-Diagnosed Acute Myeloid Leukemia. EHA-2022 2022; abstr. P557.

    Available from: URL: https://link.adisinsight.com/c8DLm
  54. Servier Presents Patient Follow Up Data from the Phase 3 AGILE Study at ASH 2022.

    Media Release
  55. Dohner H, Marchione DM, Choe S, Montesinos P, Recher C, Vives S, et al. Molecular Characterization of Clinical Response and Relapse in Patients with IDH1m ND-AML Treated with Ivo+AZA in the AGILE Study . ASH-Hem-2022 2022; abstr. 223.

    Available from: URL: https://ash.confex.com/ash/2022/webprogram/Paper159473.html
  56. Servier Bolsters Position as the Leader in Mutant IDH Inhibition with Positive New IDH1-Mutated Acute Myeloid Leukemia Data at ASCO.

    Media Release
  57. De Botton S, Montesinos P, Polo SV, Zarzycka E, Wang J, Riva M, et al. Updated efficacy and safety data from the AGILE study in patients with newly diagnosed acute myeloid leukemia treated with ivosidenib + azacitidine compared to placebo + azacitidine. ASCO-2023 2023; abstr. 7012.

    Available from: URL: https://meetings.asco.org/abstracts-presentations/220059
  58. A Phase 1/2, Safety Lead-in and Dose Expansion, Open-label, Multicenter Trial Investigating the Safety, Tolerability, and Preliminary Activity of Ivosidenib in Combination With Nivolumab and Ipilimumab in Previously Treated Subjects With Nonresectable or Metastatic Cholangiocarcinoma With an IDH1 Mutation

    ctiprofile
  59. New Data from Phase 1 Study of Ivosidenib or Enasidenib in Combination with Azacitidine Demonstrate Robust Responses and a Well Tolerated Safety Profile in Newly Diagnosed IDHm AML Patients.

    Media Release
  60. Data from Phase 1 Studies of Ivosidenib or Enasidenib in Combination with Full Doses of Standard of Care Chemotherapy Demonstrate Tolerability and Preliminary Clinical Activity in Newly Diagnosed AML Patients With an IDH Mutation.

    Media Release
  61. A Phase 1b/2 Open-label, Randomized Study of 2 Combinations of Isocitrate Dehydrogenase (IDH) Mutant Targeted Therapies Plus Azacitidine: Oral AG-120 Plus Subcutaneous Azacitidine and Oral AG-221 Plus SC Azacitidine in Subjects With Newly Diagnosed Acute Myeloid Leukemia Harboring an IDH1 or an IDH2 Mutation, Respectively, Who Are Not Candidates to Receive Intensive Induction Chemotherapy

    ctiprofile
  62. Agios Reports Updated Data from Phase 1 Study of Ivosidenib in Combination with Azacitidine Demonstrating Deep and Durable Responses in Newly Diagnosed IDH1 Mutant Acute Myeloid Leukemia (AML) Patients.

    Media Release
  63. Dinardo CD, Stein AS, Stein EM, Fathi AT, Frankfurt O, Schuh AC, et al. Mutant IDH1 inhibitor ivosidenib (IVO; AG-120) in combination with azacitidine (AZA) for newly diagnosed acute myeloid leukemia (ND AML). ASCO-2019 2019; abstr. 7011.

    Available from: URL: http://abstracts.asco.org/239/AbstView_239_253047.html
  64. DiNardo CD, Stein AS, Stein EM, Fathi AT, Frankfurt O, Schuh AC, et al. Mutant Idh1 Inhibitor Ivosidenib (Ag-120) in Combination with Azacitidine for Newly Diagnosed Acute Myeloid Leukemia. EHA-2019 2019; abstr. PS1023.

    Available from: URL: https://library.ehaweb.org/eha/2019/24th/266640/courtney.d.dinardo.mutant.idh1.inhibitor.ivosidenib.28ag-12029.in.combination.html?f=listing%3D3%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D1550
  65. Daigle SR, Choe S, Quek L, DiNardo CD, Stein A, Stein EM, et al. High Rate of IDH1 Mutation Clearance and Measurable Residual Disease Negativity in Patients with IDH1-Mutant Newly Diagnosed Acute Myeloid Leukemia Treated with Ivosidenib (AG-120) and Azacitidine. ASH-Hem-2019 2019; abstr. 2706.

    Available from: URL: https://ash.confex.com/ash/2019/webprogram/Paper122590.html
  66. A Phase 1 Study of IDH1 Inhibition Using Ivosidenib as Maintenance Therapy for IDH1-mutant Myeloid Neoplasms Following Allogeneic Stem Cell Transplantation

    ctiprofile
  67. Agios Reports First Quarter 2016 Financial Results.

    Media Release
  68. Agios to Present New Data from PKR and IDH Programs at the 2017 ASH Annual Meeting.

    Media Release
  69. A Phase 1, Multicenter, Open-Label, Safety Study of AG-120 or AG-221 in Combination With Induction Therapy and Consolidation Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia With an IDH1 and/or IDH2 Mutation

    ctiprofile
  70. Agios Announces Updated Data from Phase 1 Study of Ivosidenib or Enasidenib in Combination with Standard Induction and Consolidation Chemotherapy in Newly Diagnosed AML Patients With an IDH Mutation.

    Media Release
  71. Chen Y, Yin F, Hua L, Almon C, Nabhan S, Cooper M, et al. Pharmacokinetic/Pharmacodynamic Evaluation of Ivosidenib or Enasidenib Combined with Intensive Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed Idh1/2-Mutant Aml. EHA-2020 2020; abstr. EP620.

    Available from: URL: http://link.adisinsight.com/Gy7z4
  72. Stein EM, DiNardo CD, Fathi AT, Mims AS, Savona MR, Stein AS, et al. Updated Survival and Response Analyses from a Phase 1 Study of Ivosidenib or Enasidenib Combined with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML with an IDH1 or IDH2 Mutation. ASH-Hem-2021 2021; abstr. 1276.

    Available from: URL: https://ash.confex.com/ash/2021/webprogram/Paper146507.html
  73. Wehler E, Storm M, Kowal S, Campbell C, Boscoe A. A Health State Utility Model Estimating the Impact of Ivosidenib on Quality of Life in Patients with Relapsed/Refractory Acute Myeloid Leukemia. EHA-2018 2018; abstr. PS1442.

    Available from: URL: https://learningcenter.ehaweb.org/eha/2018/stockholm/215730/michael.storm.a.health.state.utility.model.estimating.the.impact.of.ivosidenib.html?f=menu=6*ce_id=1346*ot_id=19069*media=3*marker=167
  74. A Phase 1, Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of AG-120 (Ivosidenib) in Subjects With Mild or Moderate Hepatic Impairment or Normal Hepatic Function

    ctiprofile
  75. A Phase 1, Single-Dose, Open-Label Trial to Evaluate the Pharmacokinetics and Safety of AG-120 in Healthy Male Japanese Subjects Relative to Healthy Male Caucasian Subjects

    ctiprofile
  76. An Open-Label, 2-Period, Fixed Sequence Study to Determine the Effect of Multiple Oral Doses of Itraconazole on the Single Dose Pharmacokinetics of AG 120 in Healthy Adult Subjects

    ctiprofile
  77. A Phase 1, Open-label Study to Investigate the Absorption, Metabolism, and Excretion of [14C]-AG-120 Following Single Oral Dose Administration in Healthy Male Subjects

    ctiprofile
  78. A Phase 1, Open-Label, Randomized, 2-Period Crossover Study To Evaluate The Effect Of Food On AG-120 Pharmacokinetics Following Single Oral Dose Administration To Healthy Subjects

    ctiprofile
  79. Agios Pharmaceuticals Reports Third Quarter 2013 Financial Results.

    Media Release
  80. Investigations into rational combination approaches with ivosidenib in a mutant IDH1 acute myeloid leukemia patient-derived xenograft model. Internet-Doc 2021;.

    Available from: URL:
  81. Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, et al. IDH mutations and tumorigenicity. 25th-AACR-NCI-EORTC-2013 2013; abstr. PL02-04.

    Available from: URL: http://www.abstractsonline.com/plan/ViewAbstract.aspx?mID=3429&sKey=9f83c53e-be1a-4e4e-807c-82d68d1e52ba&cKey=208877ce-ad89-45cc-9242-7dc17d070b5a&mKey=18fa2242-fd0d-4689-82a0-e4d68ac8a74a
  82. New Publication in Science Shows That Agios IDH1 Inhibitor Can Reverse Cancer-Causing Effects of Oncometabolite 2-HG in Leukemia Model.

    Media Release
  83. Agios Publishes Two Articles in Science Demonstrating the Effects of Mutant IDH1 and IDH2 Inhibitors in Primary Tumor Models.

    Media Release
  84. Nature Publication from Agios Scientists and Co-founder Reinforces Link Between Key Metabolic Enzyme IDH and Cancer.

    Media Release
  85. Jin S, Dang L, Gross S, Driggers E, Yen K, Bittinger M, et al. Cancer-associated IDH1 and IDH2 mutations: therapeutic opportunities. 22nd-EORTC-NCI-AACR-2010 2010; abstr. 160.

    Available from: URL: http://www.ecco-org.eu
  86. Fantin VR, Gross S, Cairns RA, Minden MD, Driggers EM, Jang HG, et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in AML with IDH1/2 mutations. 101st-AACR-2010 2010; abstr. 5452.

    Available from: URL: http://www.abstractsonline.com
  87. Servier Announces FDA Approval of TIBSOVO(R)(ivosidenib tablets) in IDH1-Mutated Cholangiocarcinoma.

    Media Release
  88. Servier Announces FDA Filing Acceptance and Priority Review for TIBSOVO(Rm) (ivosidenib tablets) in IDH1-mutated Cholangiocarcinoma.

    Media Release
  89. Agios Submits Supplemental New Drug Application to FDA for TIBSOVO(Rm) (ivosidenib tablets) for Patients with Previously Treated IDH1-Mutant Cholangiocarcinoma.

    Media Release
  90. Public summary of opinion on orphan designation - Ivosidenib for the treatment of biliary tract cancer. Internet-Doc 2022;.

    Available from: URL: https://www.ema.europa.eu/en/documents/orphan-designation/eu/3/18/1994-public-summary-opinion-orphan-designation-ivosidenib-treatment-biliary-tract-cancer_en.pdf
  91. Agios Reports First Quarter 2017 Financial Results.

    Media Release
  92. An Open-Label Early Access Phase 3b Study of Ivosidenib in Patients With a Pretreated Locally Advanced or Metastatic Cholangiocarcinoma

    ctiprofile
  93. A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-controlled Study of AG-120 in Previously-treated Subjects With Nonresectable or Metastatic Cholangiocarcinoma With an IDH1 Mutation

    ctiprofile
  94. Abou-Alfa GK, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, et al. Final results from ClarIDHy, a global, phase 3, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation. ASCO-2021 2021; abstr. 4069.

    Available from: URL: https://meetinglibrary.asco.org/record/197183/abstract
  95. Agios Presents Final Data from Phase 3 ClarIDHy Study of TIBSOVO(R) (ivosidenib tablets) in Patients with Previously Treated IDH1-Mutant Cholangiocarcinoma.

    Media Release
  96. Agios Announces Final Overall Survival Data from Phase 3 ClarIDHy Study of TIBSOVO(Rm) (ivosidenib tablets) in Previously Treated IDH1-Mutant Cholangiocarcinoma Patients.

    Media Release
  97. Data from Agios Phase 3 ClarIDHy Trial of TIBSOVO(Rm) Demonstrates Significant Improvement in Progression Free Survival (PFS) Compared to Placebo in Previously Treated IDH1 Mutant Cholangiocarcinoma Patients.

    Media Release
  98. Agios Announces Publication of TIBSOVO(R) Phase 3 Data in The Lancet Oncology Demonstrating Significant Improvement in Progression-Free Survival Compared to Placebo in Previously Treated IDH1-Mutant Cholangiocarcinoma Patients.

    Media Release
  99. Cstone partner Agios Announces the Phase 3 ClarIDHy Trial of TIBSOVO (ivosidenib) Achieved its Primary Endpoint.

    Media Release
  100. Agios Reports Fourth Quarter and Full Year 2018 Financial Results.

    Media Release
  101. Aguado E, Abou-Alfa GK, Zhu AX, Macarulla T, Fan B, Nejad P, et al. IDH1 mutation detection in plasma circulating tumor DNA (ctDNA) and association with clinical response in patients with advanced intrahepatic cholangiocarcinoma (IHC) from the phase III ClarIDHy study. ASCO-2020 2020; abstr. 4576.

    Available from: URL: https://meetinglibrary.asco.org/record/186563/abstract
  102. Agios Reports Third Quarter 2016 Financial Results and Reviews Recent Progress in IDH and PKR Development Programs.

    Media Release
  103. Agios Announces New Data from Ongoing Phase 1 Trial of AG-120 Showing Durable Clinical Activity in Patients with Advanced Hematologic Malignancies.

    Media Release
  104. Thermo Fisher Scientific Signs Development Agreement with Agios Pharmaceuticals for Next-Generation Sequencing Oncology Companion Diagnostic in Cholangiocarcinoma.

    Media Release
  105. A Phase 2, Open-label, Multicenter Study of Orally Administered Ivosidenib in Previously Treated Japanese Subjects With Nonresectable or Metastatic Cholangiocarcinoma With an IDH1 Mutation

    ctiprofile
  106. A randomized Phase II study of AG-120 in IDH1 mutant positive cholangiocarcinoma

    ctiprofile
  107. ivosidenib - ODD glioma. Internet-Doc 2018;.

    Available from: URL: https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=637718
  108. Phase II Study of IDH1 Inhibitor Ivosidenib and Nivolumab in IDH1 Mutant Gliomas and Advanced Solid Tumors

    ctiprofile
  109. A Phase 1, Multicenter, Randomized, Controlled, Open-Label, Perioperative Study of AG-120 and AG-881 in Subjects With Recurrent, Non-Enhancing, IDH1 Mutant, Low Grade Glioma

    ctiprofile
  110. Mellinghoff IK, Cloughesy TF, Wen PY, Taylor JW, Maher EA, Arrillaga I, et al. A phase I, open label, perioperative study of AG-120 and AG-881 in recurrent IDH1 mutant, low-grade glioma: Results from cohort 1. ASCO-2019 2019; abstr. 2003.

    Available from: URL: http://abstracts.asco.org/239/AbstView_239_251465.html
  111. Agios Presents New Pharmacodynamic and Response Data from Both Cohorts of the Perioperative Study of Vorasidenib and TIBSOVO(Rm) (ivosidenib) in Patients with IDH1 Mutant Positive Low-Grade Glioma.

    Media Release
  112. Lu M, Cloughesy TF, Wen PY, Tassinari A, Choe S, Zhu D, et al. Impact of mutant IDH (mIDH) inhibition on DNA hydroxymethylation, tumor cell function, and tumor immune microenvironment (TIME) in resected mIDH1 lower-grade glioma (LGG). ASCO-2021 2021; abstr. 2008.

    Available from: URL: https://meetinglibrary.asco.org/record/195934/abstract
  113. Sallman DA, Foran JM, Watts JM, Stein E, De Botton S, Fathi AT, et al. Ivosidenib in patients with IDH1-mutant relapsed/refractory myelodysplastic syndrome (R/R MDS): Updated enrollment and results of a phase 1 dose-escalation and expansion substudy. ASCO-2022 2022; abstr. 7053.

    Available from: URL: https://link.adisinsight.com/Lr9i4
  114. Agios Presents Updated Phase 1 Data from Dose Expansion Cohort of Ivosidenib (AG-120) in Patients with IDH1 Mutant Positive Glioma.

    Media Release
  115. Agios Publication Identifies First Potent Inhibitors of Mutant IDH1 that Lower Tumor Oncometabolite

    Media Release
  116. Servier Announces FDA Approval of TIBSOVO(Rm) (ivosidenib tablets) for the Treatment of IDH1-Mutated Relapsed or Refractory (R/R) Myelodysplastic Syndromes (MDS).

    Media Release
  117. FDA Approves New Therapy for Rare Form of Blood Cancers Called Myelodysplastic Syndromes.

    Media Release
  118. Servier Announces FDA Filing Acceptance and Priority Review for TIBSOVO(Rm) (ivosidenib tablets) in the Treatment of IDH1-mutated Relapsed or Refractory (R/R) Myelodysplastic Syndromes (MDS).

    Media Release
  119. Cornerstone Pharmaceutical Partners Announces TIBSOVO(R) (ivosidenib) Approved by U.S. FDA Breakthrough Therapy for Adult Patients with Relapsed or Refractory Myelodysplastic Syndrome with IDH1 Mutation.

    Media Release
  120. A Single-arm Phase II Multicenter Study of IDH1 (AG 120) Inhibitor in Patients With IDH1 Mutated Myelodysplastic Syndrome

    ctiprofile
  121. Servier Presents Updated Results for TIBSOVO(Rm) (ivosidenib tablets) in IDH1-mutated Relapsed/Refractory Myelodysplastic Syndromes at the 2023 European Hematology Association (EHA) Congress.

    Media Release
  122. Paschka P, Dombret H, Thomas X, Recher C, Chantepie S, Fernandez PM, et al. Ivosidenib Improves Overall Survival Relative to Standard Therapies in Relapsed or Refractory Mutant IDH1 AML: Results from Matched Comparisons to Historical Controls. ASH-Hem-2020 2020; abstr. 625.

    Available from: URL: https://ash.confex.com/ash/2020/webprogram/Paper136957.html
  123. DiNardo CD, Stein EM, Pigneux A, Altman JK, Collins R, Erba HP, et al. Ivosidenib (Ivo) Prior to Hematopoietic Cell Transplant for Patients with Idh1-Mutant Relapsed or Refractory Acute Myeloid Leukemia (R/R Aml). EHA-2020 2020; abstr. EP577.

    Available from: URL: http://link.adisinsight.com/c8M5H
  124. Paschka P, Dombret H, Thomas X, Recher C, Chantepie S, Montesinos P, et al. Ivosidenib Improves Overall Survival Relative to Standard Therapies in Relapsed or Refractory Mutant Idh1 Aml: Results from Matched Comparisons to Historical Controls. EHA-2020 2020; abstr. EP540.

    Available from: URL: http://link.adisinsight.com/w2GMg
  125. Roboz GJ, DiNardo CD, Stein EM, de Botton S, Mims AS, Prince GT, et al. Ivosidenib (Ag-120) Induces Durable Remissions and Transfusion Independence in Patients with Idh1-Mutant Newly-Diagnosed Aml: Updated Results from a Phase 1 Dose Escalation and Expansion Study. EHA-2019 2019; abstr. PS1025.

    Available from: URL: https://library.ehaweb.org/eha/2019/24th/266642/gail.j.roboz.ivosidenib.28ag-12029.induces.durable.remissions.and.transfusion.html?f=listing%3D3%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D1550
  126. Agios Reports Second Quarter 2016 Financial Results.

    Media Release
  127. Agios Announces Enrollment of First Patient in Phase 1 Study of AG-120 in Advanced Hematologic Malignancies with an IDH1 Mutation.

    Media Release
  128. Agios Pharmaceuticals to Present Clinical Data from AG-120 Ongoing Phase 1 Study in Hematologic Malignancies at EORTC-NCI-AACR 2014.

    Media Release
  129. DiNardo CD, de Botton S, Stein EM, Roboz GJ, Swords RT, Pollyea DA, et al. Determination of IDH1 Mutational Burden and Clearance Via Next-Generation Sequencing in Patients with IDH1 Mutation-Positive Hematologic Malignancies Receiving AG-120, a First-in-Class Inhibitor of Mutant IDH1. ASH-Hem-2016 2016; abstr. 1070.

    Available from: URL: http://www.bloodjournal.org/content/128/22/1070
  130. New Data from Ivosidenib Phase 1 Dose-Escalation and Expansion Trial Demonstrate Durable Responses in Patients with IDH1m Relapsed or Refractory AML.

    Media Release
  131. Dai D, Dinardo CD, Stein E, de Botton S, Attar EC, Liu H, et al. Clinical pharmacokinetics/pharmacodynamics (PK/PD) of ivosidenib in patients with IDH1-mutant advanced hematologic malignancies from a phase 1 study. ASCO-2018 2018; abstr. 2581.

    Available from: URL: http://abstracts.asco.org/214/AbstView_214_214385.html
  132. Updated Data from Ivosidenib Phase 1 Dose-Escalation and Expansion Trial in IDH1m Relapsed or Refractory AML Continue to Show Durable Responses as a Single Agent.

    Media Release
  133. Pollyea DA, DiNardo CD, de Botton S, Stein EM, Roboz GJ, Mims AS, et al. Ivosidenib (Ag-120) in Mutant Idh1 Relapsed/Refractory Acute Myeloid Leukemia: Results of a Phase 1 Study. EHA-2018 2018; abstr. S1560.

    Available from: URL: http://link.adisinsight.com/Rq6i5
  134. Agios Presents Updated Data from the Ivosidenib Phase 1 Dose-Escalation and Expansion Trial in IDH1 Mutant Positive Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Ineligible for Standard Treatment and Myelodysplastic Syndrome (MDS).

    Media Release
  135. A Phase I, Multicenter, Open-Label, Dose-Escalation and Expansion, Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Orally Administered AG-120 in Subjects With Advanced Hematologic Malignancies With an IDH1 Mutation

    ctiprofile
  136. A Phase 1, Multicenter, Open-Label, Dose-Escalation and Expansion, Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Orally Administered AG-120 in Subjects With Advanced Solid Tumors, Including Glioma, With an IDH1 Mutation

    ctiprofile
  137. Agios Announces Phase 1 Data from Dose Expansion Cohorts of AG-120 in Patients with IDH1 Mutant Positive Glioma and Chondrosarcoma.

    Media Release
  138. Agios Enrolls First Patient in Phase 1 Study of AG-120 in Advanced Solid Tumors with an IDH1 Mutation.

    Media Release
  139. Agios Presents Phase 1 Data from Dose-Escalation and Expansion Cohorts of AG-120 (Ivosidenib) in Patients with Previously Treated IDH1 Mutant Positive Cholangiocarcinoma.

    Media Release
  140. Fan B, Mellinghoff IK, Wen PY, Pandya SS, Jiang L, Liu G, et al. Pharmacokinetics/pharmacodynamics (PK/PD) of ivosidenib in patients with IDH1-mutant advanced solid tumors from a phase 1 study. ASCO-2018 2018; abstr. 2577.

    Available from: URL: http://abstracts.asco.org/214/AbstView_214_211401.html
  141. Tap WD, Cote GM, Burris HA, Gore L, Beeram M, Conley AP, et al. Phase I study of the mutant IDH1 inhibitor ivosidenib: Long-term safety and clinical activity in patients with conventional chondrosarcoma. ASCO-2023 2023; abstr. 11532.

    Available from: URL: https://meetings.asco.org/abstracts-presentations/220636
  142. Agios Pharmaceuticals Form 10-K, February 2018. Internet-Doc 2018;.

    Available from: URL: https://www.sec.gov/Archives/edgar/data/1439222/000143922218000004/agio-123117x10k.htm
  143. Agios Reports Business Highlights and Second Quarter 2020 Financial Results.

    Media Release
  144. Wu M-J, Shi L, Dubrot J, Hudson C, Merritt J, Adil R, et al. The mutant IDH1 inhibitor ivosidenib promotes tumor cell differentiation and anti-tumor immunity in intrahepatic cholangiocarcinoma. AACR-II-2020 2020; abstr. 1810 / 10.

    Available from: URL: https://www.abstractsonline.com/pp8/#!/9045/presentation/5096
  145. CStone Pharmaceuticals Reports 2019 Annual Financial Results.

    Media Release
  146. CStone successfully hosted the first U.S. R&D Day in New York.

    Media Release
  147. Roboz GJ, Dinardo CD, Stein EM, de Botton S, Mims AS, Prince GT, et al. Ivosidenib (IVO; AG-120) in IDH1-mutant newly-diagnosed acute myeloid leukemia (ND AML): Updated results from a phase 1 study. ASCO-2019 2019; abstr. 7028.

    Available from: URL: http://abstracts.asco.org/239/AbstView_239_253977.html
  148. Agios Outlines Key 2018 Priorities Expanding Clinical and Research Programs to Drive Long Term Value.

    Media Release
  149. Fan B, Goyal L, Lowery MA, Pandya SS, Manyak E, Le K, et al. Pharmacokinetic/pharmacodynamic (PK/PD) profile of AG-120 in patients with IDH1-mutant cholangiocarcinoma from a phase 1 study of advanced solid tumors. ASCO-2017 2017; abstr. 4082.

    Available from: URL: http://abstracts.asco.org/199/AbstView_199_182082.html
  150. Agios Announces New Clinical Data from Dose-Escalation Portion of Phase 1 Trial of Single Agent AG-120 Showing Durable Molecular Responses in Patients with Advanced Hematologic Malignancies.

    Media Release
  151. Agios Reports Third Quarter 2017 Financial Results.

    Media Release
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