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Avatrombopag - Swedish Orphan Biovitrum

Drug Profile

Avatrombopag - Swedish Orphan Biovitrum

Alternative Names: AKR-501; AKR-501 monomaleate; Avatrombopag maleate; DOPTELET; E-5501; YM-477

Latest Information Update: 02 Oct 2021

At a glance

  • Originator Astellas Pharma
  • Developer Dova Pharmaceuticals; Eisai Co Ltd; Swedish Orphan Biovitrum
  • Class Antithrombotics; Piperazines; Piperidines; Pyridines; Small molecules; Thiazoles
  • Mechanism of Action Thrombopoietin receptor agonists
  • Orphan Drug Status

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

    Yes - Idiopathic thrombocytopenic purpura; Thrombocytopenia
  • New Molecular Entity Yes

Highest Development Phases

  • Marketed Thrombocytopenia
  • Registered Idiopathic thrombocytopenic purpura

Most Recent Events

  • 27 Sep 2021 Biomarkers information updated
  • 16 Sep 2021 Dova Pharmaceuticals plans a phase III trial in Thrombocytopenia in October 2021 (NCT05046327)
  • 12 Mar 2021 Phase-III clinical trials in Thrombocytopenia (In infants, In children, In adolescents) in United Kingdom, Russia (PO) (NCT04516967) (EudraCT2020-003232-24)

Development Overview

Introduction

Avatrombopag is an oral thrombopoietin (TPO) receptor agonist, that has been developed by Dova Pharmaceuticals (a subsidiary of Swedish Orphan Biovitrum), for the once-daily treatment of thrombocytopenia associated with liver disease (TLD), chemotherapy induced thrombocytopenia and idiopathic thrombocytopenic purpura (ITP). The non-peptidyl, small molecule mimetic targets the c-Mpl thrombopoietin cell surface receptor on megakaryocytes, so as to stimulate platelet production. Avatrombopag is launched for the treatment of thrombocytopenia associated with liver disease, in the US and in the UK. Product is approved in Iceland, Norway, Liechtenstein and China. The drug is approved in the US and EU member countries for the treatment of ITP. Clinical development for chemotherapy induced thrombocytopenia and idiopathic thrombocytopenic purpura is ongoing in several countries worldwide.

Avatrombopag was initially developed by MGI PHARMA, which obtained the exclusive development rights from AkaRx (which was formed as a spin-off from Astellas Pharma) in October 2007. However, MGI PHARMA was acquired by Eisai in January 2008 [1] . Subsequently, AkaRx was also acquired by Eisai in January 2010, due to which Eisai gained the exclusive global rights to develop, market and manufacture avatrombopag. In May 2016, Eisai transferred ownership of AkaRx, along with its worldwide rights to avatrombopag to Dova Pharmaceuticals (an affiliate of PBM capital) [2] [3] [4] .

As at January 2021, no recent reports of development had been identified for phase I development in idiopathic thrombocytopenic purpura conducted in the United Kingdom.

In November 2019, Dova Pharmaceuticals has been acquired by Swedish Orphan Biovitrum [5] .

Company Agreements

In June 2019, Dova Pharmaceuticals expanded the marketing agreement with Salix Pharmaceuticals. As per the agreement, from July 2019, Salix will have the exclusive rights to co-promote the chronic liver disease (CLD) indication for Avatrombopag to the hepatology and interventional radiology segments, in addition to gastroenterology, colorectal surgery, and proctology segments. The co promotion agreement has been extended to September 2023. Dova Pharmaceuticals had entered into a marketing agreement with Salix Pharmaceuticals in September 2018, to co-promote avatrombopag in the US. The Salix sales force began selling avatrombopag in mid-October 2018. Pursuant to the agreement, Dova will continue to pay Salix a commission fee based on a percentage of net sales in these specialities. [6] [7]

In March 2018, Dova Pharmaceuticals entered into an agreement through its wholly owned subsidiary, AkaRx, which granted Shanghai Fosun Pharmaceutical the exclusive development and distribution rights of avatrombopag in mainland China and Hong Kong. Additionally, Fosun Pharmaceutical will assist AkaRx with the registration of avatrombopag for the treatment of patients with thrombocytopenia with chronic liver disease, in mainland China and Hong Kong. Fosun Pharmaceutical will also support the development of avatrombopag for expanded indications in these countries. Terms of the transaction included an upfront payment, milestone payments and a fixed transfer price for product supplied. [8]

In March 2016, Eisai entered into a worldwide agreement with one of PBM capital group's affiliates (Dova Pharmaceuticals). Under the agreement, Eisai will transfer ownership of AkaRx, along with all shares and the ownership of avatrombopag, including worldwide rights to develop, market and manufacture avatrombopag. Eisai will receive an upfront payment as well as milestone payments in line with the commercialisation of avatrombopag [4] [9] .

Key Development Milestones

Thrombocytopenia associated with liver disease

In May 2018, Dova Pharmaceuticals launched avatrombopag tablets (DOPTELET®) for the treatment of thrombocytopenia in adult patients with chronic liver disease (CLD) in the US. The approval was based on the data from two phase III (ADAPT-1) and (ADAPT-2) trials (See below) [10] .

In April 2020, the National Medical Products Administration (NMPA) in China approved the use of avatrombopag for the treatment of thrombocytopenia in adults with chronic liver disease (CLD) who are scheduled to undergo a procedure. The approval was based on safety and efficacy data from two global, multicenter, randomised, double-blind, placebo-controlled phase III trials (ADAPT-1 and ADAPT-2) trials (see below) [11] .

The US FDA completed the Priority Review and approved avatrombopag tablets (Doptelet®) for the treatment of low blood thrombocytopenia in adults with chronic liver disease. The approval was based on the consistent safety and efficacy data from two global, multicenter, randomised, double-blind, placebo-controlled phase III trials that met all primary and secondary endpoints (see below) [12] [13] . Earlier in In November 2017, the US FDA had accepted Dova Pharmaceuticals' New Drug Application (NDA) for avatrombopag, and the NDA was granted Priority Review, with a PDUFA goal date of May 21, 2018 [14] . In September 2017, Dova Pharmaceuticals reported the submission of the NDA, seeking approval for avatrombopag for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a procedure, to the US FDA. The NDA submission was supported by data from the ADAPT-1 and ADAPT-2 trials (see below). In both the trials, avatrombopag met the primary and secondary efficacy endpoints with high statistical significance, and demonstrated safety and tolerability which were comparable to placebo [15] .

In October 2020, Swedish Orphan Biovitrum announced the commercial launch of Doptelet® (avatrombopag) in the Europe, with the United Kingdom as the first country for launch for the treatment of thrombocytopenia [16] . In June 2019, Dova Pharmaceuticals reported that the EMA has approved the marketing authorization application (MAA) for avatrombopag, for the treatment of thrombocytopenia in adult patients with chronic liver disease. The approval was based on the data from two global trials double-blind, placebo-controlled trials (See below). The MAA was filed in April 2018 and avatrombopag had received a positive opinion for the treatment of severe thrombocytopenia from the EMA’s human medicines committee (CHMP) in April 2019. The EMA had granted a Standard Review Assessment with a targeted decision date of July 2019 [17] [18] [19] .

In February 2021, Dova Pharmaceuticals initiated a phase IIIb trial to evaluate efficacy, safety, and pharmacokinetics of avatrombopag for the treatment of thrombocytopenia in patients of with immune thrombocytopenia for ≥6 months (NCT04516967; EudraCT2020-003232-24; AVA-PED-301). The randomised, double-blind trial intends to enroll approximately 72 patients, aged from one year to 17 years, in the US, France, Hungary, Germany, Poland, Russia and the UK [20] . Eligible pediatric subjects with platelet counts <30×109/L will enter a 12-week double-blind phase followed by an open-label extension phase up to two years in duration. In March 2021, Swedish Orphan Biovitrum AB announced that the first patient was dosed in the trial [21] .

In March 2019, Dova Pharmaceuticals terminated a phase III trial due to enrolment challenges, that was designed to evaluate the safety and efficacy of avatrombopag in patients with thrombocytopenia scheduled for operations to critical sites or operations with a high risk of bleeding (NCT03326843; AVA-PST320). The trial was initiated in December 2017 and intended to enrol approximately 60 patients in the US [22] [15] [23] .

In October 2017, Dova Pharmaceuticals reported that the ADAPT-1 trial met the primary and secondary efficacy endpoints with high statistical significance (E5501-G000-310; NCT01972529; EudraCT2013-000965-34). Eisai had completed the phase III trial in January 2017, which evaluated the efficacy and tolerability of once-daily oral avatrombopag in patients with thrombocytopenia associated with chronic liver disease undergoing an elective procedure, compared with placebo The randomised, double-blinded trial, that was initiated in February 2014, enrolled 231 patients in the US, Canada, the UK, Italy, Argentina, Australia, Austria, Hungary, Belgium, Brazil, Chile, China, France, Germany, Spain, Portugal, Poland, South Korea, Taiwan and Thailand. The trial was conducted under the Special Protocol Assessment (SPA) with the US FDA. In October 2017, results from the trial were presented at The Liver Meeting 2017: 68th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2017) [24] [25] [3] [4] [26] .

In October 2017, Dova Pharmaceuticals reported that the ADAPT-2 trial met the primary and secondary efficacy endpoints with high statistical significance (E5501-G000-311; JapicCTI-142746; EudraCT2013-000934-36; NCT01976104). Eisai had completed the phase III trial in January 2017, which evaluated the safety and efficacy of once-daily oral avatrombopag in adults with thrombocytopenia associated with chronic liver disease who were undergoing an elective procedure. The randomised, double-blinded trial, that was initiated in November 2013, enrolled 204 patients in the US, Canada, Japan, Australia, Argentina, Brazil, China, Mexico, Israel, France, Italy, the Czech Republic, Belgium, Germany, Spain, Romania and Russia. The trial was conducted under the Special Protocol Assessment (SPA) with the US FDA. In October 2017, results from the trial were presented at The Liver Meeting 2017: 68th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2017) [24] [25] [3] [4] [27] .

Pooled results from the ADAPT-1 and ADAPT-2 phase III trials were presented at the Digestive Disease Week 2018 (DDW-2018) and additional data at the International Liver Congress 2019 (ILC-2109) [28] [29] .

In June 2015, Eisai completed a phase II clinical trial to evaluate the safety, efficacy and pharmacokinetics of once-daily oral avatrombopag in adult patients with thrombocytopenia associated with chronic liver disease (E5501-J081-204; NCT02227693). The randomised, double-blind, placebo-controlled trial was initiated in July 2014 and enrolled 39 patients in Japan [30] .

In May 2014, Eisai completed a randomised, double-blind, placebo-controlled phase II trial to assess the efficacy, safety and pharmacokinetics of avatrombopag in patients with chronic hepatitis C virus-related thrombocytopenia who are candidates for antiviral treatment (E5501-G000-203; NCT01355289; EudraCT2010-024479-20). The trial was initiated in November 2011 and enrolment of 65 patients was completed in May 2013 in the US, Bulgaria and Germany [31] .

A randomised, double-blind, placebo-controlled phase II trial of avatrombopag was initiated in the US in May 2009, in patients with chronic liver diseases and thrombocytopenia (E5501-G000-202; NCT00914927) [32] . Avatrombopag was administered once-daily for up to seven days, prior to patients undergoing elective surgical or diagnostic procedures. The trial enrolled 136 patients in the US, and was completed in January 2012 [33] .

Idiopathic thrombocytopenic purpura (ITP)

In June 2019, the US FDA approved the supplemental New Drug Application (sNDA) of avatrombopag, for the treatment of patients with immune thrombocytopenic purpura, who had an insufficient response to a previous ITP treatments. The sNDA was accepted for review in November 2018 and the Prescription Drug User Fee Act (PDUFA) target action date of 30 June 2019 was assigned by the US FDA. Earlier in September 2018, Dova Pharmaceuticals submitted the supplemental New Drug Application (sNDA) on the basis of the safety and efficacy results from one completed phase III trial (see below). Additionally efficacy data from two phase II ITP trials, as well as data from the two phase III trials, that supported the recent approval of the chronic liver disease (CLD) NDA, formed the basis for this sNDA submission [7] [34] [35] .

In January 2021, European Commission approved avatrombopag for the treatment of immune thrombocytopenic purpura in adult patients refractory to other treatments. In December 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion of avatrombopag for the treatment of primary chronic immune thrombocytopenia (ITP) in adult patients who are refractory to other treatments (e.g. corticosteroids, immunoglobulins). The opinion is now referred to the European Commission for a decision [36] [37] .

In September 2011, the US FDA granted orphan drug designation to avatrombopag for the treatment of Idiopathic thrombocytopenic purpura [38] .

In March 2014, Eisai completed a phase III trial that evaluated the efficacy and safety of avatrombopag plus standard of care in the treatment of idiopathic thrombocytopenia purpura (E5501-G000-302; NCT01438840; EudraCT2011-000830-12). The trial had met its primary and secondary efficacy endpoints with high statistical significance [35] . The randomised, double-blind, placebo-controlled trial was initiated in March 2012 and during the core study, avatrombopag was dosed at 5, 10, 20 or 40mg for 26 weeks. An open-label extension will continue up to 2 years. Enrolment of 49 patients was completed in April 2013 in Greece, Belgium, Bulgaria, Czech Republic, Netherlands, Poland, Slovakia, Ukraine, South Africa, Australia, New Zealand and Singapore. In December 2017, Dova reported that avatrombopag demonstrated superiority to placebo in the trial [39] [40] . In June 2018, clinical data from the trial were presented at 23rd Congress of the European Haematology Association (EHA-2018) [41] . Efficacy data from the core study as well as the extension phase were presented by Dova Pharmaceuticals at the 61st Annual Meeting and Exposition of the American Society of Hematology (ASH-2019). In June 2020, safety and efficacy data from the trial were presented at the 25th Congress of the European Haematology Association (EHA-2020) [42] [43] [44] [45] [46] .

Eisai initiated a randomised, double-blind phase III trial in December 2011, to assess the efficacy and safety of avatrombopag versus eltrombopag, in patients with idiopathic thrombocytopenic purpura; however, in October 2013, the trial was terminated (E5501-G000-305; NCT01433978; EudraCT2011-000831-10). Avatrombopag was to be dosed at 5, 10, 20 or 40mg in a flexible dose design for 26 weeks, and an open-label extension was to be continue up to 2 years. The trial enrolled 350 patients in the US [47] .

In June 2009, Eisai completed a randomised, double-blind phase II trial of orally administered avatrombopag in 64 patients with ITP in the US (AKR-501-CL-003; NCT00441090). The trial evaluated the safety, tolerability and efficacy of avatrombopag, compared with placebo, in patients with ITP. Patients received once-daily dosing of avatrombopag (2.5, 5, 10 or 20mg) or placebo, for 28 days, and underwent weekly evaluation [48] [49] . Patients who completed this trial were enrolled in another randomised, double-blind phase II trial (AKR-501-CL-004; NCT00625443), in which those who met the primary efficacy response criteria in the first trial continued to receive the same blinded study treatment as before, while those who had not met the primary efficacy response criteria received open-label treatment with avatrombopag 10mg/day. The second phase II trial enrolled 53 patients and was completed in October 2009 [50] [51] . Results were reported in June 2011 [52] [53] .

Eisai conducted a phase I trial to evaluate the bioavailability of the third generation formulations of avatrombopag compared with the second generation tablet formulation (E5501-G000-012; NCT01549054). The randomised, open-label, two-part study enrolled 28 healthy volunteers in the UK and was completed in August 2012. However no further development has been reported [54] .

In March 2019, Dova Pharmaceuticals discontinued enrolment in the clinical trial evaluating the treatment of a broader population of patients with thrombocytopenia undergoing surgery (PST) in order to focus on development of avatrombopag for immune thrombocytopenia and chemotherapy-induced thrombocytopenia [22] .

Chemotherapy-induced thrombocytopenia

In December 2019, the US FDA granted Orphan Drug Designation to avatrombopag for the potential treatment of chemotherapy-induced thrombocytopenia [55] [56] .

In December 2020, Dova Pharmaceuticals in colllaboration with Memorial Sloan Kettering Cancer Center withdrew the phase II trial prior to enrolment due to lack of accrual (NCT04437953; 19-483). The study was designed to assess if avatrombopag is an effective treatment for thrombocytopenia in patients with both cancer and a liver disease. The randomized, double-blind, placebo-controlled trial intended to enroll 20 patients in the US [57] .

In June 2018, Dova Pharmaceuticals initiated a phase III trial to evaluate the efficacy and safety of avatrombopag in patients with chemotherapy-induced thrombocytopenia receiving chemotherapy for the treatment of ovarian, non-small cell lung and bladder cancer (AVA-CIT330; EudraCT2018-000023-13; NCT03471078). Evaluation of the efficacy of avatrombopag in proportion of responders is the defined primary endpoint of the trial. In July 2020, the randomised, double-blind, placebo-controlled trial completed enrolment of 122 patients in the US, China, Hungary, Poland Russia, Serbia, and Ukraine [58] . In October 2020, Swedish Orphan Biovitrum AB released topline results from this study [59] .

Healthy volunteers

In September 2016, Eisai completed a three-part phase I trial that assessed the effects of concomitant administration with fluconazole, itraconazole and rifampin on the pharmacokinetics of a single dose of avatrombopag 20mg in healthy volunteers (E5501-A001-019; NCT02809768). The open-label, parallel, non-randomised trial was initiated in April 2016 and enrolled 48 volunteers in the US [60] .

Eisai completed a randomised phase I trial in September 2014 which assessed the pharmacokinetics and pharmacodynamics of single doses of avatrombopag given in fed and fasted states, or fed state, in healthy Japanese and white volunteers (E5501-A001-018; NCT02039076). Avatrombopag was being investigated at doses of 20, 40 and 60mg. The trial was initiated in December 2014, and enrolled 48 volunteers in the US [61] .

Eisai initiated a randomised, crossover phase I trial in January 2013, to assess the pharmacokinetics and pharmacodynamics of single doses of avatrombopag in healthy Japanese male volunteers (E5501-J081-015; NCT01774773). The trial enrolled 15 volunteers and was completed in August 2013 [62] .

Eisai initiated a randomised phase I trial in October 2012, to investigate the inter- and intra-subject pharmacokinetic variability of the to-be-marketed formulation of avatrombopag in healthy volunteers (E5501-A001-017; NCT01759394). volunteers received single 40mg doses in fed and fasted conditions. The trial enrolled 36 volunteers in the US and was completed in March 2013 [63] .

In September 2011, Eisai initiated an open-label, single-sequence, four-treatment period phase I trial to assess the pharmacokinetic and pharmacodynamic interactions between avatrombopag and verapamil, and avatrombopag and cyclosporine, known P-glycoprotein inhibitors, in healthy volunteers (E5501-A001-008; NCT01437384). The trial enrolled 36 volunteers in the US and was completed in March 2012 [64] .

In June 2011, Eisai completed a randomised, four-group, two-period, replicate design phase I trial to assess the within- and between-subject variability in exposure of two lots (P01008ZZA and P01009ZZA) of avatrombopag 20mg tablets, administered as single doses of 40mg, in fed and fasting conditions (E5501-G000-010; NCT01327872). The trial enrolled 84 healthy volunteers in the Netherlands [65] .

Eisai conducted a randomised, open-label phase I trial to assess the relative bioavailability and intra-subject variability of two lots (P01010ZZA and P97001ZZB) of avatrombopag tablets administered twice as single doses to healthy volunteers (E5501-A001-007; NCT01289509). The trial enrolled 42 volunteers in the US and was completed in May 2011 [66] .

Eisai conducted a randomised, double-blind, placebo-controlled phase I trial to evaluate the single-dose pharmacokinetics, pharmacodynamics, safety and tolerability of three dose levels of avatrombopag, followed by a selected dose level for multiple dosing, in healthy Japanese, Chinese and Caucasian volunteers (E5501-A001-006; NCT01251731). The trial enrolled volunteers in the US and was completed in January 2011 [67] .

In June 2010, Eisai completed an open-label, crossover phase I trial to assess the bioavailability of single doses of the avatrombopag old tablet formulation under fasted conditions, and a new tablet formulation administered under fed and fasted conditions in healthy volunteers (E5501-A001-005; NCT01260155). The trial was initiated in January 2010 and enrolled 16 volunteers in the US [68] .

Positive results were demonstrated in a phase I single-and multiple-dose study of avatrombopag in healthy volunteers in the US. The trial was initiated in November 2005 after the completion of $US11.1 million in Series A financing [69] [70] .

Avatrombopag underwent preclinical development in Japan as YM 477 with Astellas Pharma. It has been shown to increase human platelet production in vivo.

Drug Properties & Chemical Synopsis

  • Route of administration PO
  • Formulation Liquid, Suspension, Tablet
  • Class Antithrombotics, Piperazines, Piperidines, Pyridines, Small molecules, Thiazoles
  • Target Thrombopoietin receptor
  • Mechanism of Action Thrombopoietin receptor agonists
  • WHO ATC code

    B02B-X08 (Avatrombopag)

  • EPhMRA code

    B2E (Thrombopoeitin Agonists)

  • Chemical name 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]carbamoyl}pyridin-2-yl)piperidine-4-carboxylic acid
  • Molecular formula C29 H34 Cl2 N6 O3 S2
  • SMILES N1(CCC(CC1)C(=O)O)C1C(=CC(=CN=1)C(NC1SC(=C(N=1)C1=CC(=CS1)Cl)N1CCN(CC1)C1CCCCC1)=O)Cl
  • Chemical Structure
  • CAS Registry Number 570406-98-3

Biomarkers Sourced From Trials

Indication Biomarker Function Biomarker Name Number of Trials

atrial fibrillation

Eligibility Criteria

Factor V

1

chemotherapy-induced damage

Arm Group Description

Thrombopoietin

MPL

1

1

chemotherapy-induced damage

Eligibility Criteria

Prothrombin (PT)

Factor V

1

1

idiopathic thrombocytopenic purpura

Eligibility Criteria

Prothrombin (PT)

myosin, heavy chain 9, non-muscle

Inosine triphosphate

Gastrin (GAS)

Factor V

AT-III

1

1

1

2

7

2

idiopathic thrombocytopenic purpura

Official Title

CYP3A4

CYP2C9

1

1

ischaemic heart disorders

Eligibility Criteria

Factor V

1

liver cirrhosis

Eligibility Criteria

Factor V

C-reactive protein (CRP)

1

1

liver disorders

Eligibility Criteria

Prothrombin (PT)

Factor V

AT-III

1

1

1

paroxysmal supraventricular tachycardia

Eligibility Criteria

Factor V

1

psoriasis

Eligibility Criteria

Factor V

1

rheumatoid arthritis

Eligibility Criteria

Inosine triphosphate

Factor V

AT-III

1

2

1

Sjogren's syndrome

Eligibility Criteria

Inosine triphosphate

Factor V

AT-III

1

1

1

supraventricular tachycardia

Eligibility Criteria

Factor V

1

systemic lupus erythematosus

Eligibility Criteria

Inosine triphosphate

Factor V

AT-III

1

1

1

thrombocytopenia

Arm Group Description

Thrombopoietin

MPL

1

1

thrombocytopenia

Eligibility Criteria

Prothrombin (PT)

Protein C

proline rich protein HaeIII subfamily 2

proline rich protein HaeIII subfamily 1

HFE

Gastrin (GAS)

Factor V

C-reactive protein (CRP)

AT-III

8

1

1

1

1

1

13

1

5

thrombocytopenia

Official Title

CYP3A4

CYP2C9

1

1

thrombocytopenia

Outcome Measure

Prothrombin (PT)

ALT

1

1

Biomarker

Drug Name Biomarker Name Biomarker Function
Avatrombopag - Swedish Orphan Biovitrum ALT Outcome Measure
AT-III Eligibility Criteria
CYP2C9 Official Title
CYP3A4 Official Title
Factor V Eligibility Criteria
Gastrin (GAS) Eligibility Criteria
HFE Eligibility Criteria
Inosine triphosphate Eligibility Criteria
MPL Arm Group Description
myosin, heavy chain 9, non-muscle Eligibility Criteria
proline rich protein HaeIII subfamily 1 Eligibility Criteria
proline rich protein HaeIII subfamily 2 Eligibility Criteria
Protein C Eligibility Criteria
Prothrombin (PT) Eligibility Criteria, Outcome Measure
Thrombopoietin Arm Group Description
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
Idiopathic thrombocytopenic purpura - Treatment-experienced Registered European Union, USA PO / Tablet Swedish Orphan Biovitrum 20 Jan 2021
Idiopathic thrombocytopenic purpura - Treatment-experienced Phase III Australia, New Zealand, Singapore, South Africa, Ukraine PO / Tablet Swedish Orphan Biovitrum 31 Mar 2012
Idiopathic thrombocytopenic purpura P21% powder suspensionLipid-based suspension In volunteers No development reported (I) United Kingdom PO / Suspension Eisai Co Ltd 28 Jan 2021
Idiopathic thrombocytopenic purpura cyclodextrin solution In volunteers No development reported (I) United Kingdom PO / Liquid Eisai Co Ltd 28 Jan 2021
Idiopathic thrombocytopenic purpura 2G In volunteers No development reported (I) United Kingdom PO / Tablet Eisai Co Ltd 28 Jan 2021
Thrombocytopenia Associated with liver disease - Marketed United Kingdom PO / Tablet Dova Pharmaceuticals 04 Nov 2014
Thrombocytopenia Associated with liver disease - Marketed USA PO / Tablet Swedish Orphan Biovitrum 31 May 2018
Thrombocytopenia Associated with liver disease - Registered China, European Union, Iceland, Liechtenstein, Norway PO / Tablet Swedish Orphan Biovitrum 30 Apr 2020
Thrombocytopenia Associated with liver disease - Phase III Argentina, Australia, Brazil, Canada, Chile, Israel, Japan, Mexico, Russia, South Korea, Taiwan, Thailand PO / Tablet Swedish Orphan Biovitrum 20 Mar 2015
Thrombocytopenia - Chemotherapy-induced Phase III China, Hungary, Poland, Russia, Serbia, USA, Ukraine PO / Tablet Swedish Orphan Biovitrum 12 Oct 2018
Thrombocytopenia - In adolescents, In children, In infants Phase III France, Germany, Hungary, Poland, Russia, USA, United Kingdom PO / Tablet Swedish Orphan Biovitrum 12 Mar 2021

Orphan Status

Indication Patient Segment Country Organisation Event Date
Idiopathic thrombocytopenic purpura - USA Swedish Orphan Biovitrum 01 Sep 2011
Thrombocytopenia Chemotherapy-induced USA Swedish Orphan Biovitrum 21 Dec 2019

Commercial Information

Involved Organisations

Organisation Involvement Countries
Astellas Pharma Originator Japan
Swedish Orphan Biovitrum Owner World
Salix Pharmaceuticals Market Licensee USA
Shanghai Fosun Pharmaceutical Licensee China, Hong Kong

Brand Names

Brand Name Organisations Indications Countries
DOPTELET Swedish Orphan Biovitrum Thrombocytopenia China, European Union, USA

Scientific Summary

  • Adverse Events Occasional: Epistaxis; Fatigue; Headache

Adverse Events

Idiopathic thrombocytopenic purpura (ITP)

Phase III

In the phase III, ADAPT-1 and 2 trials, the most common treatment-emergent adverse events (TEAE) were pyrexia, abdominal pain, nausea, fatigue, oedema peripheral and headache, which were similar for placebo and avatrombopag arms in both studies. Most adverse events were mild to moderate in severity. Portal vein thromboses was reported in patients with chronic liver disease and in patients receiving TPO receptor agonists. One treatment-emergent event of portal vein thrombosis was reported in the both studies in an avatrombopag-treated patient (n = 1/430). The thrombotic TEAE occurred with 40mg avatrombopag in cohort 2 in ADAPT2 [77] [24] [26] [27] .

Results from a phase III trial showed that avatrombopag (AVA) was well tolerated in patients (n = 49) with chronic immune thrombocytopenic purpura (ITP). Treatment emergent AEs (TEAEs) were reported by 31 patients (96.9%) in the AVA-treated group compared with 10 patients (58.5%) in the placebo (PBO)-treated group; the incidence of TEAEs, Grade 3/4 TEAEs, and serious AEs were similar in the two treatment groups when adjusted for treatment exposure. The most commonly reported adverse events included headache, contusion, fatigue, petechiae, upper respiratory tract infection, arthralgia, and epistaxis. Five patients had TEAEs leading to study drug dose adjustment in the AVA group, which led to study drug withdrawal for 3 patients [71] [41] [74] [40] .

Avatrombopag was well tolerated in a 28-day, randomised, double-blind, placebo-controlled phase II trial (501-CL-003) in 64 patients with relapsed or refractory chronic ITP. Avatrombopag was dosed once-daily at 2.5, 5, 10 or 20mg. The 53 patients who completed the trial were enrolled into a 24-week extension trial (501-CL-004), in which previous responders (n=25) continued to receive their avatrombopag blinded dose, and previous non-responders (n=28) received open-label 10mg avatrombopag once-daily. Dose was titrated upwards to a maximum dose of 40mg once-daily in non-responders, and the blinded dose plus 20mg once-daily in responders. All 64 patients experienced ≥1 treatment-emergent adverse event (TEAE), but most were mild and transient. The most common TEAEs were fatigue (37.5%), headache (32.8%) and epistaxis (25%). TEAEs resulting in trial discontinuation were reported in 10/64 (15.6%) patients. Serious TEAEs were reported in 12/64 (18.8%) patients; the most common being thrombocytopenia in 5 (7.8%) patients and vomiting in 2 (3.1%) patients. Only 4 events (6.3%) were considered to be treatment-related [52] [53] .

Chemotherapy-induced thrombocytopenia

Top-line results of the randomised, double-blind, placebo-controlled, phase III trial demonstrated that avatrombopag was found to be safe in patients (n = 122) with chemotherapy-induced thrombocytopenia receiving chemotherapy for the treatment of ovarian, non-small cell lung and bladder cancer. The adverse event data for avatrombopag were comparable to that of placebo in the cancer patients receiving myelosuppressive chemotherapy [59] [58] .

Healthy volunteers

Avatrombopag (1-100 mg) was well tolerated in phase I single-and multiple-dose studies in healthy volunteers. No serious drug-related adverse events were observed at any dose [70] .

Pharmacodynamics

Summary

Clinical trials:

A ≥ 50% increase over baseline platelet count was observed in single-and multiple-dose phase I studies of E 5501 in healthy volunteers. A single dose of E 5501 at 100mg resulted in a ≥ 50% increase over baseline platelet count in 5/6 subjects, and in all 6 subjects who received E 5501 at 10 mg for 14 days or 20 mg for 10 days. Dose escalation ceased on day 10 for subjects in the 20 mg treatment group when platelet counts reached ≥ 500 000/mL [70] .

Preclinical studies:

E 5501 dose-dependently increased the production of human platelets in a mouse model. Human hematopoietic stem cells were transplanted into sublethally irradiated NOD/SCID mice, and E 5501 ≤ 3mg/kg/day was administered orally for 14 days. Significant increases in platelet production were seen at doses of E 5501 ≥ 1mg/kg/day, and a 3-fold increase was reached at 3mg/kg/day on day 14. Withdrawal of E 5501 caused the human platelet count to return to the pretreatment level. Expression of an activation-dependent marker, CD62P, was not changed by administration of E 5501, suggesting that the platelets produced by the mice were functional [76] .

Therapeutic Trials

Idiopathic thrombocytopenic purpura

Results from a phase III trial showed that avatrombopag (AVA) was superior to placebo (PBO) in patients (n = 49) with chronic immune thrombocytopenic purpura (ITP). AVA was superior to PBO in the mean cumulative number of weeks with a platelet count ≥50 x 109/L during the 6-month treatment period (93.8), the primary study endpoint (12.4 weeks vs 0 weeks; P < 0.0001). Day 8 platelet responses were also significantly higher for patients who received AVA treatment, 65.6% compared with 0% for PBO (P < 0.0001). Analysis of the previously unreported alternative efficacy endpoints demonstrated a high proportion of AVA-treated patients as responders or complete responders. In the Core Study, a high proportion of AVA patients achieved a platelet count ≥ 50,000/µL relative to PBO by Day 28 (84.4% vs. 0.0%, respectively) and week 26 (87.5% vs. 5.9%). In an integrated analysis of the core study and its extension Phase, 64.7% of PBO patients who rolled-over to AVA in the extension phase also reached the metric equal to AVA. Platelet counts categorised as a complete response, was achieved in a high proportion of patients in the Core Study with 81.3% of patients reaching a platelet count ≥ 100,000/µL at any time by month 6, versus 5.9% with PBO. 53.3% of patients had a PC ≥50,000/µL for at least 4 consecutive weeks, as opposed to 0.0% with placebo. The mean number of weeks of continuous platelet response was 6.5 for AVA versus 0.1 for placebo-treated patients. Across the Core Study and its Extension Phase, 84.4% of patients initially randomised to AVA and 58.8% of those who initially received PBO achieved a complete response at any time. Platelet (Plt) response rates were similar in the core study and extension phase. Durable responders maintained a high rate of Plt response and complete Plt response in the extension phase, providing evidence that AVA-responding patients will continue to respond for extended treatment periods. Additionally, consistent efficacy was noted, as patients in the placebo group who rolled over to active drug demonstrated similar efficacy as AVA-treated patients. AVA-treated patients had substantially higher platelet response and complete platelet response rates than those treated with platelet. Six patients on AVA (42.9%) were able to either reduce or discontinue baseline concomitant corticosteroid. During the extension, patients who received placebo during the core study were switched to AVA, and four additional patients were subsequently able to reduce corticosteroid dose (57.1%).The randomised, double-blind, placebo-controlled trial enrolled 49 patients. At month 6, platelet count ≥30,000/µL at least once or twice during the 6 months on AVA as compared with placebo. The median cumulative number of weeks with a platelet count ≥30,000/µL without requiring rescue treatment was 21.1 for AVA-treated patients and 0.0 for placebo. The median consecutive number of weeks maintaining a platelet count ≥30,000/µL was 11.1 for AVA and 0.0 for placebo. 64.0% of AVA vs. 0.0% of placebo-treated patients experienced a durable platelet response, achieving a platelet count ≥30,000/µL for 6 of the final 8 weeks of the study [42] [43] [44] [45] [46] [71] [41] [74] [40] .

Long-term avatrombopag demonstrated an early and durable platelet response and high responder rates in patients with relapsed or refractory chronic idiopathic thrombocytopenia (cITP). In the 28-day, randomised, double-blind, placebo-controlled phase II trial (501-CL-003) in 64 patients, avatrombopag was dosed once-daily at 2.5, 5, 10 or 20mg. A durable platelet response was achieved in 52.8% of all patients, with the response rate ranging from 35.7% in previous non-responders in the initial trial, up to 72% in previous responders. The Day 28 responder rate was significantly higher in the 20mg dose group than the 2.5mg and placebo groups (80% vs. 13.3% and 0%, respectively).The platelet response rate ranged from ≈60% to 80% at on-therapy visits, and was higher in previous responders than previous non-responders at all assessment timepoints. Among patients using steroid rescue therapy, 54.2% decreased their use by >50%, including 33.3% who discontinued their use permanently. Efficacy was evaluated in the 53 patients who were treated with avatrombopag for an additional 24-weeks in the extension trial (501-CL-004), in which previous responders (n = 25) continued to receive their avatrombopag blinded dose, and previous non-responders (n = 28) received open-label 10mg avatrombopag once-daily. Dose was titrated upwards to a maximum dose of 40mg once-daily in non-responders, and the blinded dose plus 20mg once-daily in responders [52] [53] .

Thrombocytopenia

The phase III, ADAPT-1 trial met its primary and secondary efficacy endpoints with high statistical significance. In patients with low baseline platelet count (<40 x 109/L) in the ADAPT1 study, 66% of avatrombopag patients did not need platelet transfusion or bleeding rescue, compared with 23% on placebo (p<0.0001). Patients with high baseline platelet count (40 to <50 x 109/L) had significantly less need for platelet transfusion or bleeding rescue (88% vs 38%). Avatrombopag was superior to placebo for both secondary endpoints, increasing mean platelet counts on procedure day to 64 x 109/L. The trial enrolled 231 patients with thrombocytopenia associated with chronic liver disease undergoing an elective procedure [24] [26] .

The phase III, ADAPT-2 trial met its primary and secondary efficacy endpoints with high statistical significance. In patients with low baseline platelet count (<40 x 109/L), 69% of avatrombopag patients did not need platelet transfusion or bleeding rescue, compared with 35% on placebo (p<0.0006). Patients with high baseline platelet count (40 to <50 x 109/L) had significantly less need for platelet transfusion or bleeding rescue (89% vs 33%). Avatrombopag was superior to placebo for both secondary endpoints, increasing mean platelet counts on procedure day to 85 x 109/L. The trial enrolled 231 patients with thrombocytopenia associated with chronic liver disease undergoing an elective procedure [24] [27] .

Pooled results:

Pooled results from the ADAPT-1 and ADAPT-2 phase III trials demonstrated that age, gender, race and region of the patients did not impact the efficacy of avatrombopag over placebo in increasing platelet count and reducing platelet transfusions in patients with thrombocytopenia. Avatrombopag showed reduction in platelet transfusion in both cohort 1 and cohort 2 (66.9% and 88%; p< 0.0001) as compared to placebo (28.6% and 35.8%; p< 0.0001). Equal efficacy across various race subgroups were also seen,however the low number of blacks (avatrombopag n = 9, placebo n = 2) or other (avatrombopag n = 8, placebo n = 6) resulted in wider confidence intervals. Additional pooled data from the ADAPT-1 and ADAPT-2 phase III trials demonstrated that avatrombopagwas superior to placebo in increasing platelet counts (PC) and reducing both the proportion of patients requiring a platelet transfusions (PT) or rescue procedure for bleeding, and the proportion achieving a PC ≥ 50 × 10 9 /L by Procedure Day. Efficacy was similar for both end points regardless of splenomegaly status, supporting the consistent efficacy of avatrombopag. For patients with a PC < 40 × 10 9 /L, < 1/10 placebo -treated patient achieved a 9 PC ≥ 50 × 10 /L regardless of splenomegaly status compared to ∼ 7/10 avatrombopag -treated patients. Overall, avatrombopag was superior to placebo in both cohorts in the proportion of patients not requiring a PT or rescue procedure for bleeding (Cohort 1 : p < 0.0001; Cohort 2 : p < 0.0001). Efficacy in meeting the primary end point by splenomegaly (SM) status was generally similar, with a trend of less placebo-treated patients with SM meeting the primary end point. (Cohort 1 : No SM : avatrombopag 67.5%, placebo 27.5%; With SM : avatrombopag 65.1%, placebo 31.8%; Cohort 2 : No SM : avatrombopag 90.0%, placebo 42.9%; With SM: avatrombopag 81.5%, placebo 16.7%) [28] [29] .

Chemotherapy-induced thrombocytopenia

Top-line results of the randomised, double-blind, placebo-controlled, phase III trial in patients (n = 122) with chemotherapy-induced thrombocytopenia receiving chemotherapy for the treatment of ovarian, non-small cell lung and bladder cancer demonstrated that avatrombopag increased platelet counts relative to placebo. The study did not meet the composite primary endpoint of avoiding platelet transfusions, chemotherapy dose reductions by 15% or greater, and chemotherapy dose delays by four days or more. In the intent-to-treat population (full analysis set), 69.5% and 72.5% of avatrombopag and placebo subjects, respectively, were considered responders for the primary endpoint (p = 0.72). In the per-protocol population, 85% and 84.4% of avatrombopag and placebo subjects, respectively, were considered responders for the primary endpoint (p = 0.96) [59] [58] .

Future Events

Expected Date Event Type Description Updated
14 Oct 2021 Trial Update Dova Pharmaceuticals plans a phase III trial in Thrombocytopenia in October 2021 (NCT05046327) (700342772) 22 Sep 2021
31 Dec 2020 Trial Update Dova Pharmaceuticals plans a phase III trial for Thrombocytopenia (In children, in adolescents, Treatment-experienced) in December 2020 (PO) (NCT04516967) (700326814) 25 Feb 2021
31 Jul 2019 Regulatory Status EMA grants a target decision date of July 2019 for Avatrombopag for Thrombocytopenia [19] 27 Jun 2019
16 Jul 2019 Regulatory Status Dova Pharmaceuticals anticipates the commercial launch of Avatrombopag for Idiopathic thrombocytopenic purpura in USA, in mid-July 2019. [7] 02 Jul 2019
30 Jun 2019 Regulatory Status FDA assigns PDUFA action date of (30/06/2019) for avatrombopag Idiopathic thrombocytopenic purpura [34] 02 Jul 2019
30 Sep 2018 Regulatory Status Dova Pharmaceuticals plans to submit a supplemental New Drug Application to the US FDA for Immune thrombocytopenic purpura in the third quarter of 2018 [19] 06 Sep 2018
30 Sep 2018 Regulatory Status Dovo Pharmaceuticals intends to launch avatrombopag in USA in the third quarter of 2018 [72] 10 Jul 2018
30 Jun 2018 Trial Update Dova Pharmaceuticals plans a phase III trial for Thrombocytopenia (Chemotherapy-induced) in the second quarter of 2018 (PO) (NCT03471078) (700291991) [73] 10 Jul 2018
21 May 2018 Regulatory Status FDA assigns PDUFA action date of 21/05/2018 for avatrombopag for Thrombocytopenia in patients with chronic liver disease [14] 22 May 2018
28 Feb 2018 Trial Update Dova Pharmaceuticals plans a phase III trial for Thrombocytopenia in February 2018 (NCT03326843) (700289966) 06 Jan 2018
30 Sep 2017 Regulatory Status Dova announces intention to submit NDA to US FDA for Thrombocytopenia in Q3 2017 [75] 25 Sep 2017

Development History

Event Date Update Type Comment
27 Sep 2021 Biomarker Update Biomarkers information updated Updated 02 Oct 2021
16 Sep 2021 Trial Update Dova Pharmaceuticals plans a phase III trial in Thrombocytopenia in October 2021 (NCT05046327) Updated 22 Sep 2021
12 Mar 2021 Phase Change - III Phase-III clinical trials in Thrombocytopenia (In infants, In children, In adolescents) in United Kingdom, Russia (PO) (NCT04516967) (EudraCT2020-003232-24) [21] Updated 06 Jun 2021
14 Feb 2021 Phase Change - III Phase-III clinical trials in Thrombocytopenia (In children, In adolescents, In infants) in USA (PO) (NCT04516967) (EudraCT2020-003232-24) Updated 25 Feb 2021
03 Feb 2021 Phase Change - III Phase-III clinical trials in Thrombocytopenia (In children, In adolescents, In infants) in Hungary, Germany, France, Poland (PO) (EudraCT2020-003232-24) (NCT04516967) Updated 25 Feb 2021
28 Jan 2021 Phase Change - No development reported No recent reports of development identified for phase-I development in Idiopathic thrombocytopenic purpura(In volunteers) in United Kingdom (PO, Liquid) Updated 28 Jan 2021
28 Jan 2021 Phase Change - No development reported No recent reports of development identified for phase-I development in Idiopathic thrombocytopenic purpura(In volunteers) in United Kingdom (PO, Suspension) Updated 28 Jan 2021
28 Jan 2021 Phase Change - No development reported No recent reports of development identified for phase-I development in Idiopathic thrombocytopenic purpura(In volunteers) in United Kingdom (PO, Tablet) Updated 28 Jan 2021
20 Jan 2021 Phase Change - Registered Registered for Idiopathic thrombocytopenic purpura (Treatment-experienced) in European Union (PO) [36] Updated 22 Jan 2021
11 Dec 2020 Phase Change - Preregistration Preregistration for Idiopathic thrombocytopenic purpura (Treatment-experienced) in European Union (PO) before December 2020 [37] Updated 16 Dec 2020
11 Dec 2020 Regulatory Status The CHMP adopts positive opinion for avatrombopag in Idiopathic thrombocytopenic purpura (Treatment-experienced) in European Union [37] Updated 16 Dec 2020
08 Dec 2020 Trial Update Dova Pharmaceuticals in colllaboration with Memorial Sloan Kettering Cancer Center withdraws phase II trial prior to enrolment for Thrombocytopenia (Chemotherpay-induced) in USA due to lack of accrual (NCT04437953) Updated 18 Dec 2020
09 Oct 2020 Scientific Update Interim efficacy and adverse events data from a phase III trial in Thrombocytopenia released by Swedish Orphan Biovitrum [59] Updated 14 Oct 2020
18 Aug 2020 Trial Update Dova Pharmaceuticals plans a phase III trial for Thrombocytopenia (In children, in adolescents, Treatment-experienced) in December 2020 (PO) (NCT04516967) Updated 25 Feb 2021
20 Jul 2020 Trial Update Swedish Orphan Biovitrum completes enrolment in its phase III trial in Thrombocytopenia (Chemotherapy-induced) in USA, Ukraine, Serbia, Russia, Poland, Hungary and China (PO) after October 2018 (EudraCT2018-000023-13) (NCT03471078) Updated 14 Oct 2020
11 Jun 2020 Scientific Update Efficacy data from a phase III trial in Idiopathic thrombocytopenic purpura presented at the 25th Congress of the European Haematology Association (EHA-2020) [44] [42] Updated 01 Aug 2020
30 Apr 2020 Phase Change - Registered Registered for Thrombocytopenia in China (PO) [11] Updated 05 May 2020
29 Apr 2020 Phase Change - Preregistration Preregistration for Thrombocytopenia in China (PO) before April 2020 [11] Updated 05 May 2020
21 Dec 2019 Regulatory Status Avatrombopag receives Orphan Drug status for Thrombocytopenia (Chemotherapy-induced) in USA [55] [56] Updated 24 Dec 2019
08 Dec 2019 Scientific Update Updated efficacy and adverse events data from a phase III extension study for Idiopathic thrombocytopenic purpura released by Swedish Orphan Biovitrum [71] Updated 12 Dec 2019
07 Dec 2019 Scientific Update Efficacy data from a phase III trial in Idiopathic thrombocytopenic purpura presented at the 61st Annual Meeting and Exposition of the American Society of Hematology (ASH-2019) [46] [45] Updated 20 Dec 2019
10 Nov 2019 Company Involvement Dova Pharmaceuticals has been acquired by Swedish Orphan Biovitrum Updated 20 Nov 2019
27 Jun 2019 Licensing Status Dova Pharmaceuticals expands the marketing agreement with Salix Pharmaceuticals to co-promote Avatrombopag in USA for Thrombocytopenia [7] Updated 02 Jul 2019
27 Jun 2019 Phase Change - Registered Registered for Idiopathic thrombocytopenic purpura (Treatment-experienced) in USA (PO) [7] Updated 02 Jul 2019
27 Jun 2019 Regulatory Status Dova Pharmaceuticals anticipates the commercial launch of Avatrombopag for Idiopathic thrombocytopenic purpura in USA, in mid-July 2019. [7] Updated 02 Jul 2019
25 Jun 2019 Phase Change - Registered Registered for Thrombocytopenia in European Union, Iceland, Norway, Liechtenstein (PO) Updated 27 Jun 2019
26 Apr 2019 Regulatory Status The CHMP recommends approval of Avatrombopag for Thrombocytopenia in the EU [17] Updated 16 May 2019
10 Apr 2019 Scientific Update Pooled efficacy data from a phase III ADAPT 1 and ADAPT 2 trials in Thrombocytopenia presented at the International Liver Congress 2019 (ILC-2019) [28] Updated 19 Sep 2019
05 Mar 2019 Trial Update Dova Pharmaceuticals terminates a phase III trial due to enrolment challenges, the trial was intending to enrol patients with Thrombocytopenia in USA (PO, Tablet) (NCT03326843) Updated 19 Mar 2019
05 Nov 2018 Regulatory Status FDA assigns PDUFA action date of (30/06/2019) for avatrombopag Idiopathic thrombocytopenic purpura [34] Updated 02 Jul 2019
05 Nov 2018 Regulatory Status The US FDA accepts sNDA for avatrombopag for Idiopathic thrombocytopenic purpura for review [34] Updated 09 Nov 2018
12 Oct 2018 Phase Change - III Phase-III clinical trials in Thrombocytopenia (Chemotherapy-induced) in Ukraine, Serbia, Russia, Poland, Hungary and China (PO) after October 2018 (EudraCT2018-000023-13) (NCT03471078) Updated 14 Oct 2020
27 Sep 2018 Licensing Status Dova Pharmaceuticals and Salix Pharmaceuticals agree to co-promote avatrombopag in USA for Thrombocytopenia [6] Updated 04 Oct 2018
04 Sep 2018 Phase Change - Preregistration Preregistration for Idiopathic thrombocytopenic purpura (Treatment-experienced) in USA (PO) [35] Updated 06 Sep 2018
09 Aug 2018 Regulatory Status EMA grants a target decision date of July 2019 for Avatrombopag for Thrombocytopenia [19] Updated 27 Jun 2019
09 Aug 2018 Regulatory Status Dova Pharmaceuticals plans to submit a supplemental New Drug Application to the US FDA for Immune thrombocytopenic purpura in the third quarter of 2018 [19] Updated 06 Sep 2018
09 Aug 2018 Regulatory Status EMA accepts MAA for Avatrombopag for Thrombocytopenia for review [19] Updated 17 Aug 2018
02 Jun 2018 Scientific Update Pooled efficacy data from a phase III ADAPT 1 and ADAPT 2 trials in Thrombocytopenia presented at the Digestive Disease Week 2018 (DDW-2018) [29] Updated 13 Jul 2018
01 Jun 2018 Phase Change - III Phase-III clinical trials in Thrombocytopenia (Chemotherapy-induced) in USA (PO) (NCT03471078) Updated 10 Jul 2018
31 May 2018 Phase Change - Marketed Launched for Thrombocytopenia in USA (PO) [10] Updated 04 Jun 2018
22 May 2018 Active Status Review 9241272- updated Intro, KDM , DevT, FET and HE Updated 22 May 2018
21 May 2018 Phase Change - Registered Registered for Thrombocytopenia in USA (PO) - First global approval [13] Updated 22 May 2018
09 May 2018 Regulatory Status The EMA granted Standard Review Assessment for the MAA filed for Thrombocytopenia in the EU [18] Updated 16 May 2018
27 Apr 2018 Phase Change - Preregistration Preregistration for Thrombocytopenia in European Union (PO) [18] Updated 16 May 2018
19 Mar 2018 Licensing Status Dova Pharmaceuticals grants Shanghai Fosun Pharmaceutical the development and distribution rights of avatrombopag for Thrombocytopenia in China and Hong Kong [8] Updated 22 Mar 2018
15 Feb 2018 Regulatory Status Dovo Pharmaceuticals intends to launch avatrombopag in USA in the third quarter of 2018 [72] Updated 10 Jul 2018
03 Jan 2018 Trial Update Dova Pharmaceuticals plans a phase III trial for Thrombocytopenia (Chemotherapy-induced) in the second quarter of 2018 (PO) (NCT03471078) [73] Updated 10 Jul 2018
22 Dec 2017 Trial Update Dova Pharmaceuticals initiates enrolment in a phase III trial for Thrombocytopenia in USA (PO) (NCT03326843) Updated 06 Jan 2018
14 Dec 2017 Scientific Update Adverse events and efficacy data from a phase III trial in Idiopathic thrombocytopenia purpura presented at the 59th Annual Meeting and Exposition of the American Society of Hematology (ASH-Hem-2017) [74] Updated 03 Jan 2018
27 Nov 2017 Regulatory Status FDA assigns PDUFA action date of 21/05/2018 for avatrombopag for Thrombocytopenia in patients with chronic liver disease [14] Updated 22 May 2018
27 Nov 2017 Regulatory Status The US FDA accepts NDA filing for avatrombopag for Thrombocytopenia with Priority Review [14] Updated 28 Nov 2017
03 Nov 2017 Trial Update Dova Pharmaceuticals plans a phase III trial for Thrombocytopenia in February 2018 (NCT03326843) Updated 06 Jan 2018
23 Oct 2017 Scientific Update Safety and efficacy data from the phase III ADAPT-1 and ADAPT-2 trials in Thrombocytopenia presented at The Liver Meeting 2017: 68th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2017) [24] Updated 23 Nov 2017
22 Sep 2017 Phase Change - Preregistration Preregistration for Thrombocytopenia in USA (PO) [15] Updated 26 Sep 2017
10 Aug 2017 Regulatory Status Dova announces intention to submit NDA to US FDA for Thrombocytopenia in Q3 2017 [75] Updated 25 Sep 2017
06 Jan 2017 Trial Update Dova Pharmaceuticals completes a phase III trial for Thrombocytopenia in USA, Canada, Japan, Australia, Argentina, Brazil, China, Mexico, Israel, France, Italy, the Czech Republic, Belgium, Germany, Spain, Romania and Russia (PO) [3] (NCT01976104) Updated 12 Jan 2017
06 Jan 2017 Trial Update Dova Pharmaceuticals completes a phase III trial for Thrombocytopenia in USA, Canada, United Kingdom, Italy, Argentina, Australia, Austria, Hungary, Belgium, Brazil, Chile, China, France, Germany, Spain, Portugal, Poland, South Korea, Taiwan and Thailand [3] (NCT01972529) Updated 12 Jan 2017
01 Sep 2016 Trial Update Eisai completes a phase I drug-drug interaction trial in Healthy volunteers in USA (PO) (NCT02809768) Updated 12 Jan 2017
17 May 2016 Regulatory Status Eisai and US FDA agree on a Special Protocol Assessment (SPA) for two phase III trials of avatrombopag for Thrombocytopenia associated with liver disease, prior to May 2016 Updated 23 May 2016
01 Apr 2016 Trial Update Eisai initiates a phase I drug-drug interaction trial in Healthy volunteers in USA (PO) (NCT02809768) Updated 23 Jun 2016
30 Mar 2016 Licensing Status Eisai enters agreement with PBM Capital Group for the transfer of worldwide rights of avatrombopag Updated 15 Apr 2016
31 Jul 2015 Active Status Review Avatrombopag is still in phase III development for Idiopathic thrombocytopenic purpura Updated 11 Aug 2015
01 Jun 2015 Trial Update Eisai completes a phase II trial in Thrombocytopenia in Japan (NCT02227693) Updated 07 Jul 2015
20 Mar 2015 Phase Change - III Phase-III clinical trials in Thrombocytopenia (associated with liver disease) in Israel (PO) Updated 11 Aug 2015
04 Nov 2014 Phase Change - Marketed Launched for Thrombocytopenia in United Kingdom (PO) [16] Updated 06 Nov 2020
01 Sep 2014 Trial Update Eisai completes a phase I trial in Healthy volunteers in USA (NCT02039076) Updated 08 Jan 2015
01 Jul 2014 Phase Change - II Phase-II clinical trials in Thrombocytopenia (associated with liver disease) in Japan (PO) (NCT02227693) Updated 15 Oct 2014
27 May 2014 Phase Change - III Phase-III clinical trials in Thrombocytopenia (associated with liver disease) in United Kingdom (PO) Updated 11 Aug 2015
27 May 2014 Phase Change - III Phase-III clinical trials in Thrombocytopenia in Poland (PO) Updated 08 Jan 2015
27 May 2014 Phase Change - III Phase-III clinical trials in Thrombocytopenia (associated with liver disease) in Portugal (PO) (EudraCT2013-000965-34) Updated 07 Oct 2014
22 May 2014 Phase Change - III Phase-III clinical trials in Thrombocytopenia (associated with liver disease) in Asia (PO) Updated 22 May 2014
01 May 2014 Trial Update Eisai completes a phase II trial for Thrombocytopenia (associated with liver disease) in USA, Bulgaria and Germany (NCT01355289) Updated 27 Aug 2014
17 Mar 2014 Phase Change - III Phase-III clinical trials in Thrombocytopenia (associated with liver disease) in Hungary (PO) Updated 22 May 2014
17 Mar 2014 Phase Change - III Phase-III clinical trials in Thrombocytopenia (associated with liver disease) in Austria (PO) Updated 22 May 2014
17 Mar 2014 Phase Change - III Phase-III clinical trials in Thrombocytopenia (associated with liver disease) in Spain (PO) Updated 22 May 2014
01 Mar 2014 Trial Update Eisai completes a phase III trial in Idiopathic thrombocytopenia purpura (Treatment-experienced) in Greece, Belgium, Bulgaria, Czech Republic, Netherlands, Poland, Slovakia, Ukraine, South Africa, Australia, New Zealand and Singapore (NCT01438840) Updated 22 May 2014
01 Feb 2014 Phase Change - III Phase-III clinical trials in Thrombocytopenia (associated with liver disease) in Chile, Brazil, Argentina after February 2014 (PO) (NCT01972529) Updated 01 Apr 2016
01 Feb 2014 Trial Update Avatrombopag initiates enrolment in a phase III trial for Thrombocytopenia (associated with liver disease) in USA and China after February 2014 (PO) (NCT01972529) Updated 01 Apr 2016
01 Feb 2014 Phase Change - III Phase-III clinical trials in Thrombocytopenia in France (PO) Updated 08 Jan 2015
01 Feb 2014 Phase Change - III Phase-III clinical trials in Thrombocytopenia in Taiwan (PO) Updated 08 Jan 2015
01 Feb 2014 Phase Change - III Phase-III clinical trials in Thrombocytopenia in Thailand (PO) Updated 08 Jan 2015
01 Feb 2014 Trial Update Eisai initiates enrolment in a phase III trial for Thrombocytopenia in USA, Belgium and Germany (NCT01972529) Updated 08 Jan 2015
01 Jan 2014 Phase Change - III Phase-III clinical trials in Thrombocytopenia in Australia (PO) Updated 02 Sep 2014
01 Jan 2014 Phase Change - III Phase-III clinical trials in Thrombocytopenia (associated with liver disease) in Italy (PO) Updated 06 Jun 2014
01 Jan 2014 Phase Change - III Phase-III clinical trials in Thrombocytopenia (associated with liver disease) in Canada (PO) Updated 06 Jun 2014
31 Dec 2013 Trial Update Eisai initiates enrolment in a phase I trial in Healthy volunteers in USA (NCT02039076) Updated 28 Jan 2014
30 Nov 2013 Phase Change - III Phase-III clinical trials in Thrombocytopenia (associated with liver disease) in USA (PO) Updated 28 Jan 2014
01 Nov 2013 Phase Change - III Phase-III clinical trials in Thrombocytopenia in Russia (PO) (NCT01976104) after November 2013 Updated 23 Jun 2017
01 Nov 2013 Phase Change - III Phase-III clinical trials in Thrombocytopenia (associated with liver disease) in Mexico and China after November 2013 (PO) (NCT01976104) Updated 01 Apr 2016
01 Nov 2013 Phase Change - III Phase-III clinical trials in Thrombocytopenia (associated with liver disease) in Japan (PO) Updated 11 Aug 2015
01 Nov 2013 Phase Change - III Phase-III clinical trials in Thrombocytopenia in Romania (PO) Updated 09 Jan 2015
01 Nov 2013 Phase Change - III Phase-III clinical trials in Thrombocytopenia (associated with liver disease) in Czech Republic (PO) (NCT01976104) Updated 27 Aug 2014
01 Nov 2013 Phase Change - III Phase-III clinical trials in Thrombocytopenia (associated with liver disease) in Germany and Belgium (PO) (EudraCT 2013-000934-36) Updated 27 Aug 2014
30 Oct 2013 Trial Update Eisai terminates a phase III trial in Idiopathic thrombocytopenic purpura in USA (NCT01433978) Updated 28 Jan 2014
24 Oct 2013 Trial Update Eisai plans phase III trials for Thrombocytopenia (associated with liver disease) in USA and European Union (NCT01972529 & NCT01976104) Updated 13 Nov 2013
31 Aug 2013 Trial Update Eisai completes a phase I trial in Healthy volunteers in Japan (NCT01774773) Updated 14 Feb 2014
16 May 2013 Trial Update Eisai completes enrolment in its phase II trial for Thrombocytopenia (associated with liver disease) in USA, Bulgaria and Germany (NCT01355289) Updated 07 Jun 2013
04 Apr 2013 Trial Update Eisai completes enrolment in its phase III trial for Idiopathic thrombocytopenic purpura (Treatment-experienced) in European Union, Ukraine, South Africa, Australia, New Zealand and Singapore (NCT01438840) Updated 07 Jun 2013
31 Mar 2013 Trial Update Eisai completes a phase I trial in Healthy volunteers in USA (NCT01759394) Updated 05 Jun 2013
21 Jan 2013 Trial Update Eisai completes enrolment in its phase I trial in Healthy volunteers in Japan (NCT01774773) Updated 04 Feb 2013
01 Jan 2013 Phase Change - I Phase-I clinical trials in Thrombocytopenia (In volunteers) in Japan (PO) (NCT01774773) Updated 04 Feb 2013
28 Dec 2012 Trial Update Eisai completes enrolment in a phase I trial in Healthy volunteers in USA (NCT01759394) Updated 24 Jan 2013
31 Oct 2012 Trial Update Eisai initiates enrolment in a phase I trial in Healthy volunteers in USA (NCT01759394) Updated 24 Jan 2013
01 Aug 2012 Trial Update Eisai completes a phase I trial in Healthy volunteers in United Kingdom (NCT01549054) Updated 06 Dec 2012
31 Mar 2012 Trial Update Eisai completes a phase I trial in Healthy volunteers in USA (NCT01437384) Updated 06 Dec 2012
16 Feb 2012 Phase Change - III Phase-III clinical trials in Idiopathic thrombocytopenic purpura (Treatment-experienced) in Australia, Belgium, New Zealand, Netherlands, Bulgaria, Greece, Poland, Singapore, Slovakia and Ukraine (PO) (NCT01438840) Updated 25 May 2018
02 Feb 2012 Phase Change - III Phase-III clinical trials in Idiopathic thrombocytopenic purpura in USA (PO) (NCT01433978) Updated 13 Feb 2012
01 Feb 2012 Phase Change - III Phase-III clinical trials in Idiopathic thrombocytopenic purpura (Treatment-experienced) in South Africa (PO) (NCT01438840) Updated 13 Feb 2012
31 Jan 2012 Trial Update Eisai completes a phase II trial in Thrombocytopenia related to chronic liver disease in USA (NCT00914927) Updated 13 Feb 2012
01 Jan 2012 Phase Change - I Phase-I clinical trials in Idiopathic thrombocytopenic purpura (In volunteers) in United Kingdom (PO, 2G tablet) (NCT01549054) Updated 16 Oct 2014
01 Jan 2012 Phase Change - I Phase-I clinical trials in Idiopathic thrombocytopenic purpura (In volunteers) in United Kingdom (PO, cyclodextrin solution) (NCT01549054) Updated 16 Oct 2014
01 Jan 2012 Phase Change - I Phase-I clinical trials in Idiopathic thrombocytopenic purpura (In volunteers) in United Kingdom (PO, P21% powder and lipid-based suspension) (NCT01549054) Updated 16 Oct 2014
24 Nov 2011 Phase Change - II Phase-II clinical trials in Thrombocytopenia (associated with liver disease) in Bulgaria (PO) (EudraCT2010-024479-20) Updated 07 Jun 2013
24 Nov 2011 Phase Change - II Phase-II clinical trials in Thrombocytopenia (associated with liver disease) in Germany (PO) (EudraCT2010-024479-20) Updated 07 Jun 2013
14 Nov 2011 Trial Update Eisai initiates enrolment in a phase II trial for Thrombocytopenia (associated with Hepatitis C) in USA (NCT01355289) Updated 24 Nov 2011
30 Sep 2011 Trial Update Eisai initiates enrolment in a phase I trial in Healthy volunteers in USA (NCT01437384) Updated 24 Nov 2011
01 Sep 2011 Regulatory Status Avatrombopag - Dova Pharmaceuticals receives Orphan Drug status for Idiopathic thrombocytopenic purpura in USA [38] Updated 25 May 2018
30 Jun 2011 Trial Update Eisai completes a phase I trial in Healthy volunteers in Netherlands (NCT01327872) Updated 22 Mar 2012
12 Jun 2011 Scientific Update Efficacy & adverse events data from a phase II trial in Idiopathic thrombocytopenic purpura presented at the 16th Congress of the European Hematology Association (EHA-2011) [52] Updated 22 Jul 2011
31 May 2011 Trial Update Eisai completes a phase I trial in Healthy volunteers in USA (NCT01289509) Updated 23 Sep 2011
02 Feb 2011 Trial Update Eisai completes enrolment in its phase I trial in Healthy volunteers in USA (NCT01289509) Updated 23 May 2011
01 Feb 2011 Phase Change - I Phase-I clinical trials in Idiopathic thrombocytopenic purpura (In volunteers) in Netherlands (PO) (NCT01327872) Updated 08 Apr 2011
01 Jan 2011 Trial Update Eisai completes a phase I trial in Healthy volunteers in USA (NCT01251731) Updated 23 May 2011
01 Dec 2010 Trial Update Eisai initiates enrolment in its phase I trial in Healthy volunteers in USA (NCT01289509) Updated 25 May 2018
01 Jul 2010 Trial Update Eisai initiates a phase I trial in Healthy volunteers in USA (NCT01251731) Updated 25 May 2018
01 Jun 2010 Trial Update Eisai completes a phase I bioavailability trial in Healthy volunteers in USA (NCT01260155) Updated 25 May 2018
14 May 2010 Trial Update Eisai completes Phase-II trials in Idiopathic thrombocyopenic purpura in USA Updated 20 May 2010
06 Jan 2010 Company Involvement AkaRx has been acquired by Eisai Inc Updated 07 Jan 2010
01 Jan 2010 Trial Update Eisai initiates a phase I bioavailability trial in Healthy volunteers in USA (NCT01260155) Updated 25 May 2018
01 Oct 2009 Trial Update Eisai completes a phase II trial for Idiopathic thrombocytopenic purpura in USA (NCT00625443) Updated 08 Oct 2014
01 Jun 2009 Trial Update Eisai completes a phase II trial for Idiopathic thrombocytopenic purpura in USA (NCT00441090) Updated 08 Oct 2014
01 May 2009 Phase Change - II Phase-II clinical trials in Thrombocytopenia (associated with hepatic disease) in USA (NCT00914927) Updated 19 Feb 2010
29 Jan 2008 Company Involvement MGI Pharma has been acquired by Eisai Updated 31 Jan 2008
12 Oct 2007 Licensing Status Avatrombopag licensed to MGI Pharma worldwide Updated 30 Aug 2007
01 May 2007 Trial Update Eisai initiates enrolment in a rollover phase II trial for Idiopathic thrombocytopenic purpura in USA (NCT00625443) Updated 25 May 2018
27 Feb 2007 Phase Change - II Phase-II clinical trials in Idiopathic thrombocytopenic purpura in USA (PO) (NCT00441090) Updated 19 Feb 2010
08 Jan 2007 Scientific Update Data presented at the 48th Annual Meeting and Exposition of the American Society of Hematology (ASH-2006) added to the adverse events and Haematological disorders pharmacodynamics section [70] Updated 08 Jan 2007
17 Jan 2006 Phase Change - Preclinical Preclinical trials in Thrombocytopenia in Japan (PO) Updated 17 Jan 2006
30 Nov 2005 Company Involvement AkaRx Inc. formed as a spin-off from Astellas Pharma Updated 09 Jan 2007
30 Nov 2005 Phase Change - I Phase-I clinical trials in Thrombocytopenia in USA (PO) Updated 08 Jan 2007

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