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Opaganib - RedHill Biopharma

Drug Profile

Opaganib - RedHill Biopharma

Alternative Names: ABC 294640; YELIVA

Latest Information Update: 12 May 2020

At a glance

  • Originator Apogee Biotechnology Corporation
  • Developer Apogee Biotechnology Corporation; Medical University of South Carolina; RedHill Biopharma
  • Class Adamantanes; Amides; Anti-inflammatories; Antineoplastics; Antirheumatics; Antivirals; Chlorobenzenes; Pyridines; Small molecules
  • Mechanism of Action Sphingosine kinase inhibitors
  • Orphan Drug Status

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

    Yes - Cholangiocarcinoma
  • New Molecular Entity Yes
  • Available For Licensing Yes - Cancer; Inflammation

Highest Development Phases

  • Phase II Cholangiocarcinoma; Prostate cancer
  • Phase I/II Multiple myeloma
  • Clinical Phase Unknown Cancer; COVID 2019 infections
  • Suspended Liver cancer
  • No development reported Inflammatory bowel diseases; Osteoarthritis; Radiation injuries; Rheumatoid arthritis; Solid tumours

Most Recent Events

  • 08 May 2020 The US FDA approves IND application for opaganib in Pneumonia associated with COVID-2019 infections
  • 30 Apr 2020 Preliminary efficacy data from a clinical trial in COVID-2019 infections released by RedHill Biopharma
  • 21 Apr 2020 RedHill Biopharma plans a phase IIa trial for treatment of patients with COVID-19 infection and Pneumonia in the US (PO)

Development Overview

Introduction

Opaganib is an orally available small molecule inhibitor of sphingosine kinase-2 (SK-2), that is being developed by RedHill Biopharma, for the treatment of cancer, COVID-2019 infections and other inflammatory and gastrointestinal indications. By inhibiting SK-2, opaganib blocks the synthesis of sphingosine 1-phosphate (S1P), a lipid signaling molecule that promotes cancer growth and pathological inflammation. The preclinical data and literature also indicates anti-viral activity of the molecule. The drug was originally developed by Apogee Biotechnology Corporation and was subsequently acquired by RedHill. Clinical development is underway for cancer, including cholangiocarcinoma, hepatocellular carcinoma (liver cancer in the development table), multiple myeloma, prostate cancer and solid tumours in the US. Clinical development for COVID-2019 infections is underway in Israel and planned to extend in the US.

RedHill is pursuing and evaluating multiple clinical programs in oncology, inflammatory and gastrointestinal indications, as well as potential collaboration opportunities with larger pharmaceutical companies to evaluate ABC 204640 as an add-on therapy to their existing oncology treatments.

Preclinical development for inflammatory-bowel-disease, osteoarthritis, radiation-injuries and rheumatoid arthritis was underway in the US. However, no recent reports of development have been identified.

Phase I development for solid tumours was underway in the US. However, no recent reports of development have been identified.

Company Agreements

In September 2016, RedHill Biopharma entered into a research collaboration with Stanford University School of Medicine to evaluate planned phase Ib clinical study to evaluate opaganib as a radioprotectant for prevention of mucositis in head and neck cancer patients undergoing therapeutic radiotherapy. Stanford will evaluate the effect of opaganib on mucositis reduction and tumour control in a murine model of head and neck cancer as part of the collaboration [1] .

In October 2015, RedHill BioPharma announced that National Cancer Institute awarded a Small Business Innovation research (SIBR) grant of US$225 000 to the company to support a preclinical study of opaganib for the treatment of prostate cancer [2] .

National Cancer Institute awarded a Small Business Innovation Research grant of US$2 million to RedHill BioPharma, in September 2015, to support a phase II study of opaganib in patients with multiple myeloma. The grant covers a three year period and was awarded in conjunction with Duke University [3] .

In March 2015, RedHill Biopharma entered into an agreement with Apogee Biotechnology Corporation. Under the terms of the agreement, RedHill acquired the exclusive worldwide rights to the commercialisation, development and addition IP rights of opaganib for all indications. RedHill has agreed to pay $US1.5 million and an additional $US4 million to Apogee as potential milestone payments and royalties [4] .

In August 2011, the US Department of Health and Human Services' Biomedical Advanced Research and Development Authority (BARDA) issued new contracts funds ($US2 million over 2 years), which will be used to conduct preliminary studies of opaganib for reduction of gastrointestinal injury caused by acute radiation exposure [5] .

Key Development Milestones

COVID-2019 infections

In April 2020, the Italian National Institute for Infectious Diseases and Central Italian Ethics Committee (EC) for an expanded access program (EAP) approved the immediate compassionate use of opaganib in patients with COVID-2019 infection in Italy [6] .

In March 2020, RedHill Biopharma reported that based on pre-clinical data and literature indicating potential anti-viral activity, the company is actively pursuing an exploratory program intended to investigate the activity of opaganib and upamostat [see Adis Insight Drug Profile 800021537], individually and in combination with hydroxychloroquine and other compounds in the treatment of COVID-2019 (novel coronavirus) [7] .

In May 2020, the US FDA approved an IND application for a phase IIa trial evaluating opaganib in patients with confirmed moderate-to-severe COVID-2019 infections associated pneumonia [8] [9] . In April 2020, RedHill Biopharma submitted an Investigational New Drug (IND) application to the US FDA for opaganib for the treatment of COVID-19 infections [10] .

As at April 2020, the compassionate use programme for COVID-2019 infections is ongoing in Israel, with first patient dosed with opaganib in addition to standard-of-care hydroxychloroquine as background therapy. In the same month, RedHill Biopharma released efficacy and adverse events data obtained from the trial in COVID-2019 infections. The company announced that six patients have been treated and also reported that two patients safely completed 14 days of opaganib therapy, in April 2020. All six patients analysed were weaned from oxygen and discharged from the hospital. Opaganib has been well tolerated and showed clinical improvement both with and without hydroxychloroquine [8] [11] [12] [13] [6] [14] .

Cholangiocarcinoma

In April 2017, RedHill Biopharma announced that the US FDA has granted opaganib Orphan Drug designation for the treatment of cholangiocarcinoma [15] .

In January 2018, RedHill Biopharma initiated an expanded access program of opaganib for patients with cholangiocarcinoma who do not qualify for participation in ABC-108 study (ABC-108-EA; NCT03414489). In September 2018, RedHill Biopharma announced that a patient enrolled in the US under this programme achieved a confirmed complete response as measured by RECIST criteria [16] .

In December 2017, RedHill Biopharma, in collaboration with Mayo Clinic and The University of Texas MD Anderson Cancer Center, initiated a phase IIa trial investigating ABC 294640 as a monotherapy, for the treatment of patients suffering from advanced, unresectable, intrahepatic, perihilar and extrahepatic cholangiocarcinoma (ABC-108; NCT03377179). The trial intends to enrol approximately 105 patients with no more than two systemic anti-neoplastic therapy, in the US. As at April 2018, first five patients were enrolled in the trial [17] [18] . In September 2018, RedHill Biopharma announced that the ongoing trial met its pre-specified efficacy endpoint of either partial or complete response or stable disease at four months [16] . In March 2020, the company reported that a second arm of the study assessing opaganib in combination with hydroxychloroquine sulfate has been added and recruitment of patients initiated. Redhill Biopharma also plans to add a third arm to the study, evaluating opaganib in combination with upamostat [see Adis Insight Drug Profile 800021537], subject to discussions with the US FDA [7] [19] .

In preclinical studies conducted in patient derived cholangiocarcinoma cell lines, ABC294640 reduced proliferation and survival of the cancer cells by inhibiting STAT3 phosphorylation pathway, by inducing autophagy and by inducing apoptosis. ABC294640 was shown to act synergistically with sorafenib, which resulted in further inhibition of proliferation [20] .

Hepatocellular Carcinoma (HCC)

As of March 2020, RedHill Biopharma completed the enrollment of the full cohort of 39 patients in a phase IIa study evaluating the activity of orally-administered ABC 294640 in advanced cholangiocarcinoma. In September 2019, Apogee Biotechnology and Medical University of South Carolina (MUSC) suspended the phase II trial prior to enrolment as the trial is being rewritten for different disease population. In October 2016, RedHill Biopharma in collaboration with Apogee Biotechnology and MUSC, announced the initiation of the phase IIa trial to evaluate the safety and efficacy of opaganib, in patients with advanced hepatocellular carcinoma (liver cancer in the development table) who have tumour progression following sorafenib treatment in the US(102418; ABC-106; NCT02939807) [21] [22] . The trial is supported by a $US1.8 million grant from the NCI awarded to MUSC (1P01CA203628-01) [23] [24] [25] .

Prostate cancer

In March 2020, Medical University of South Carolina (MUSC) and National Cancer Institute (NCI) initiated a phase II trial to evaluate the efficacy of opaganib in addition to abiraterone and enzalutamide in patients with metastatic castration resistant prostate cancer (mCRPC) (103193; Pro00095537; 1P01CA203628-01; NCT04207255). The non-randomized, open-label trial intends to enroll approximately 60 patients in the US and is supported by a grant awarded by NCI to MUSC [7] [26] .

In August 2015, RedHill Biopharma reported that in early stage and advanced prostate cancer models, oral opaganib disrupted oncogenic signaling including androgen receptor pathways that are deregulated in prostrate cancer. Oral opaganib led to significant inhibition of tumour growth, proliferation, and cell cycle progression also. The study was supported by a grant from the Pennsylvania Department of Health, a Prostate Cancer Foundation Young Investigator award, and a Prostate Cancer Foundation Mazzone Challenge award [27] . National cancer Institute intends to support additional preclinical studies, which will include in vivo and in vitro models of prostate cancer in combination with radiotherapy, to determine the efficacy of opaganib. These preclinical studies will further support the clinical development of the product for the treatment of prostate cancer [2] .

Pneumonia

In April 2020, RedHill Biopharma submitted an IND application of opaganib to the US FDA for the treatment of pneumonia [28] .

Solid tumours

RedHill Biopharma and Apogee completed a dose-escalation phase I trial of opaganib in July 2015, which met the primary endpoint, indicating that it can be safely given to patients with several types of advanced solid tumours, at dosage predicted to have therapeutic activity (NCT01488513; ABC-101). The trial was aimed to establish the dose for phase II trials which are expected to use opaganib alone and in combination with approved anticancer drugs. The trial enrolled 21 patients in the US, most with gastrointestinal cancers, including pancreatic, colorectal and cholangiocarcinoma cancers. Data from this trial will be used to support phase II and phase III trials. As of October 2013, the maximum tolerated dose had not yet been reached. The trial was conducted at the Medical University of South Carolina, and supported by grants from the NCI and the FDA's Office of Orphan Products Development [22] [29] [30] [31] [32] . Final results from the study released by the company in June 2016, showed that the study met its primary and secondary endpoints [24] . In January 2017, the company released additional positive results showing that opaganib may be an effective drug for the treatment of cholangiocarcinoma [33] . In April 2017, the company published results from the trial demonstrating that the drug is well-tolerated and can be safely administered to cancer patients; six of the 21 patients treated in the phase I study had stable disease as their best response and one patient with cholangiocarcinoma developed a partial response. The administration of the drug resulted in a rapid and pronounced decrease in S1P levels over the first 12 hours, with return to baseline at 24 hours, consistent with clearance of the drug [34] .

In November 2010, the US FDA approved an IND for the opaganib for the treatment of cancer. Preclinical data indicated that the compound may have potential in the treatment of breast, colon, lung, liver, kidney and pancreatic cancers [35] .

Other cancers

RedHill Biopharma intends to initiate two phase I/II trials for multiple oncology and inflammatory indications [36] .

The company is planning a phase Ib trial in collaboration with Stanford University School of Medicine to investigate opaganib as a radio-protectant for the prevention of mucositis in head and neck cancer patients undergoing therapeutic radiotherapy in the fourth quarter of 2017. RedHill Biopharma intends to fund the study [37] [38] [33] [1] [2] [39] [40] [41] [42] .

RedHill Biopharma, in collaboration with Apogee Biotechnology and Louisiana State University Health Sciences Center, withdrew a phase Ib/II trial due to lack of recruitment, that was designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of opaganib, administered as oral gelatin capsule, in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), primarily in patients with HIV-related DLBCL (NCT02229981; ABC102). The study was also to determine the maximum tolerated dose of opaganib in this patient population. The trial was initiated in June 2015 and intended to enrol approximately 33 patients in the US. The trial is partly funded by the NCI Small Business Technology Transfer programme (STTR) [43] [44] [39] [45] . In June 2016, RedHill BioPharma had reported that the study was on administrative hold pending consideration of protocol amendment, which was aimed at improving recruitment prospects [24] . The company reported in January 2017, that kaposi sarcoma patients were also to be included in the study [33] .

In May 2019, RedHill Biopharma terminated a phase Ib/II trial of opaganib, due to expiration of National Cancer Institute (NCI) funding of the study, in patients with refractory or relapsed multiple myeloma who had previously received proteasome inhibitors and immunomodulatory drugs (1R44CA199767-01; Pro00062304; NCT02757326). The open-label, dose-escalation trial intended to enrol approxmately 77 patients in the US. The phase Ib portion of the trial was to evaluate safety and determine the maximum tolerated dose, while the phase II portion was to assess overall treatment response rate and overall survival. The trial had received Institutional Review Board (IRB) approval from Duke University (DUHS IRB). The NCI had awarded an SBIR grant of $US2 million to support the trial [46] [47] [48] [24] [20] [49] [29] [3] [50] .

Other indications: In November 2016, RedHill Biopharma and Apogee Biotechnology presented results from non-clinical studies demonstrating the potential anti-tumour and anti-inflammatory effects of opaganib in combination with radiation at the 28th EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium (EORTC-NCI-AACR-2016) [51] [52] .
In October 2013, Apogee Biotechnology Corporation reported that opaganib has demonstrated activity in animal models of inflammatory bowel disease, rheumatoid arthritis and radiation poisoning [31] .

Apogee Biotechnology evaluated the efficacy of opaganib in a rat model of osteoarthritis. Positive data were presented [53] .

Favourable pharmacokinetic and pharmacodynamic data for opaganib for the prevention of liver disorders were presented [54] [55] .

Apogee has synthesised two series of compounds with SK inhibitory activity, of which the lead candidates, opaganib and ABC 747080, have been shown to be orally available, well tolerated in mice and to possess excellent pharmacokinetics [56] .

Financing information

In May 2016, RedHill Biopharma announced that Medical University of South Carolina was awarded with grant of $US1.8 million for a period of five years, by National Cancer Institute (NCI), to support studies on feasibility of targeting sphingolipid metabolism for treatment of variety of solid tumours. Part of the grant will also support a planned phase II trial, for hepatocellular carcinoma [22] .

RedHill Biopharma reported in June 2015 that the development of opaganib has been funded through grants and contracts in excess of $US14 million from the US federal and state government agencies, such as the FDA, Department of Defense (DoD) and the National Institutes of Health (NIH), including the National Cancer Institute and BARDA [44] .

Patent Information

In September 2017, RedHill Biopharma received a Notice of Allowance from the US PTO regarding a patent to Yeliva® and Mesupron [see Adis Insight Drug profile 800021537] covering the use of proprietary investigational compounds in combination with a known antibiotic. The patent covers combination for the potential treatment of cancer, prevention of cancer recurrence or progression and inhibition of growth and proliferation of cancer cells [57] .

RedHill Biopharma submitted a trademark application, in August 2015, to the US Patent and Trademark Office for the new brand name YELIVA™ for opaganib [27] .

In March 2008, Apogee Biotechnology was issued its first patent (7 338 961) entitled "Sphingosine kinase inhibitors". This patent specifically protects the lead development compound, opaganib, and related chemotypes.

Drug Properties & Chemical Synopsis

  • Route of administration PO
  • Formulation Capsule, unspecified
  • Class Adamantanes, Amides, Anti-inflammatories, Antineoplastics, Antirheumatics, Antivirals, Chlorobenzenes, Pyridines, Small molecules
  • Target Sphingosine kinase
  • Mechanism of Action Sphingosine kinase inhibitors
  • WHO ATC code

    A07E (Intestinal Antiinflammatory Agents)

    J05 (Antivirals for Systemic Use)

    L01 (Antineoplastic Agents)

    M01 (Antiinflammatory and Antirheumatic Products)

    V03 (All Other Therapeutic Products)

  • EPhMRA code

    A7E (Intestinal Anti-Inflammatory Agents)

    J5 (Antivirals for Systemic Use)

    L1 (Antineoplastics)

    M1 (Anti-Inflammatory and Anti-Rheumatic Products)

    V3 (All Other Therapeutic Products)

  • Chemical name (7S)-3-(4-chlorophenyl)-N-(pyridin-4-ylmethyl)adamantane-1-carboxamide
  • Molecular formula C23 H25 Cl N2 O
  • SMILES C12(CC3CC(C1)(CC(C3)C2)C(NCC1=CC=NC=C1)=O)C1C=CC(=CC=1)Cl
  • Chemical Structure
  • CAS Registry Number 915385-81-8

Biomarkers Sourced From Trials

Indication Biomarker Function Biomarker Name Number of Trials

bladder cancer

Outcome Measure

sphingosine kinase 2

1

cholangiocarcinoma

Outcome Measure

sphingosine kinase 2

c-Myc

AKT

1

1

1

diffuse large B cell lymphoma

Outcome Measure

Sphingosine 1-phosphate

CD4

1

1

Kaposi's sarcoma

Outcome Measure

Sphingosine 1-phosphate

CD4

1

1

liver cancer

Outcome Measure

sphingosine kinase 2

globotriaosyl lysosphingolipid

1

1

multiple myeloma

Outcome Measure

Syndecan-1

Sphingosine 1-phosphate

MCL1

IL6

c-Myc

1

1

1

1

1

ovarian cancer

Outcome Measure

sphingosine kinase 2

1

pancreatic cancer

Outcome Measure

sphingosine kinase 2

1

solid tumours

Outcome Measure

sphingosine kinase 2

1

Biomarker

Drug Name Biomarker Name Biomarker Function
Opaganib - RedHill Biopharma AKT Outcome Measure
c-Myc Outcome Measure
CD4 Outcome Measure
globotriaosyl lysosphingolipid Outcome Measure
IL6 Outcome Measure
MCL1 Outcome Measure
Sphingosine 1-phosphate Outcome Measure
sphingosine kinase 2 Outcome Measure
Syndecan-1 Outcome Measure
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
COVID 2019 infections compassionate use program; addition to standard-of-care, including hydroxychloroquine background therapy Adjunctive treatment, Combination therapy Clinical Phase Unknown Israel PO / unspecified RedHill Biopharma 06 Apr 2020
Cancer - Combination therapy Clinical Phase Unknown USA PO / Capsule RedHill Biopharma 18 Sep 2017
Cholangiocarcinoma - Inoperable/Unresectable, Late-stage disease, Monotherapy, Second-line therapy or greater Phase II USA PO / unspecified RedHill Biopharma 22 Dec 2017
Cholangiocarcinoma in combination with hydroxychloroquine sulphate Combination therapy, Inoperable/Unresectable, Late-stage disease, Second-line therapy or greater Phase II USA PO / unspecified RedHill Biopharma 13 Mar 2020
Inflammatory bowel diseases - - No development reported (Preclinical) USA PO / unspecified Apogee Biotechnology Corporation 04 Nov 2017
Liver cancer - Late-stage disease, Second-line therapy or greater Suspended (II) USA PO / unspecified Apogee Biotechnology Corporation, RedHill Biopharma, Medical University of South Carolina 12 Sep 2019
Multiple myeloma - Second-line therapy or greater Phase I/II USA PO / unspecified RedHill Biopharma 08 Sep 2016
Osteoarthritis - - No development reported (Preclinical) USA PO / unspecified Apogee Biotechnology Corporation 04 Nov 2017
Prostate cancer in combination with abiraterone and enzalutamide Combination therapy, Hormone refractory, Metastatic disease, Second-line therapy or greater Phase II USA PO / unspecified Medical University of South Carolina 18 Mar 2020
Radiation injuries Gastrointestinal injuries associated with acute radiation syndrome - No development reported (Preclinical) USA PO / unspecified Apogee Biotechnology Corporation 04 Nov 2017
Rheumatoid arthritis - - No development reported (Preclinical) USA PO / unspecified Apogee Biotechnology Corporation 04 Nov 2017
Solid tumours - Late-stage disease No development reported (I) USA PO / Capsule Apogee Biotechnology Corporation 28 Dec 2019

Orphan Status

Indication Patient Segment Country Organisation Event Date
Cholangiocarcinoma - USA RedHill Biopharma 04 Apr 2017

Commercial Information

Involved Organisations

Organisation Involvement Countries
Apogee Biotechnology Corporation Originator USA
RedHill Biopharma Owner World
National Institutes of Health (USA) Funder USA
Biomedical Advanced Research and Development Authority Funder USA
Prostate Cancer Foundation Funder USA
Food and Drug Administration Funder USA
National Cancer Institute (USA) Funder USA
Medical University of South Carolina Collaborator USA
Louisiana State University Health Sciences Center Collaborator USA
Mayo Clinic Collaborator USA
Duke University Collaborator USA
M. D. Anderson Cancer Center Collaborator Usa
Stanford University School of Medicine Collaborator USA

Licensing Availability

Licensing Organisation Available Indication Available Phase Region Date
RedHill Biopharma Cancer, Inflammation Unspecified - 21 Nov 2016

Brand Names

Brand Name Organisations Indications Countries
YELIVA RedHill Biopharma Unspecified USA

Scientific Summary

Pharmacokinetics

The half-time for clearance of opaganib from plasma was determined to be approximately 4 hours in a phase I clinical trial in patients with advanced solid tumours. In addition, through at least the first 3 cohorts, the pharmacokinetics of opaganib were shown to be proportional to the dose of opaganib that was administered. The average Cmax for patients receiving 500 mg was 16.4µm, which was sufficient for anti-cancer efficacy in preclinical models. Patients either received 250 mg four times daily (6 patients), 250 mg twice-daily (4 patients), 500 mg twice-daily (4 patients) or 750 mg twice-daily (3 patients) in the open-label study [31] .

In both combination treatments decreases in ERK phosphorylation and an increase in the phosphorylation of inhibitory site of c-Raf (S259) were observed in both sets of cancer cells. The study evaluated opaganib (a SK2-specific inhibitor) and ABC 294735 (a SK1/SK2 inhibitor), alone and in combination with sorafenib on human pancreatic adenocarcinoma (Bxpc-3) and kidney carcinoma (A- 498) cells in vitro and in vivo [58]

Oral opaganib had dose-proportional peak plasma levels and a t½ value of approximately 8h in rats. At a dose of 50 mg/kg, it had plasma Cmax values of approximately 100, 30 and 15 µmol/L for the parent compound, and its two main metabolites M1 and M2, respectively. Significant levels of opaganib were detected in the liver, kidney, and brain of normal rats, and these were correlated with plasma pharmacokinetics indicating effective biodistribution of the compound. opaganib accumulated at therapeutically effective concentrations in the tumours of mice bearing xenograft of JC mammary adenocarcinoma cells (>50 µg/g or ≅125 µmol/L), and promoted progressive apoptosis in the tumours for at least 5 days [55] .

Adverse Events

In a phase Ib/II trial, administration of opaganib did not show dose-limiting toxicities, in 10 evaluable patients belonging to the phase Ib portion [46] .

Results from a phase I trial in patients with advanced solid tumours showed that treatment with opaganib was safe and well tolerated, with grade 1-2 fatigue and nausea being the most common adverse events. Several patients experienced mild neuropsychiatric symptoms, such as anxiety and mood changes, which were resolved quickly upon discontinuation of study medication. All treatment-related adverse events were rapidly reversible upon dose reduction or study drug removal. The results also showed that opaganib could be safely administered to cancer patients at doses that provide circulating drug levels that are predicted to have therapeutic activity. opaganib caused only a modest decrease in lymphocyte count compared with other S1P receptor-targeting agents such as fingolimod [see Adis Insight drug profile 800006154] and ozanimod [see Adis Insight drug profile 800033563]. The phase I trial enrolled 21 patients with advanced solid tumours [24] [31] [29] [32] .

Adverse events data obtained from a clinial trial in Israel in two of the COVID-19 patients indicated that at doses administered, opaginib was found to be well tolerated with no treatment emergent adverse events [13] [14] .

Pharmacodynamics

Summary

Phase I

Results from a phase I trial that evaluated 21 patients with advanced solid tumours showed that dosing with opaganib rapidly decreased S1P plasma levels over the first 12 hours, with a return to baseline by 24 hours, consistently with drug clearance [24] [29] [32] .

Preclinical studies

ABC treatment arrested elevations of TNF and S1P and reduced histological damage in the small intestines of non-tumour bearing irradiated mice, and significantly increased long-term survival. In tumour models, total body irradiation (1 Gy) caused moderate inhibition of tumour growth in the syngeneic PAN02 and B16 tumour models, but did not show activity against the E0771 tumours. ABC alone demonstrated strong, moderate and no anti-tumor activity in the PAN02, B16 and E0771 models, respectively. Combination of ABC with radiation exerted significant anti-tumour activity in all three models. Use of higher radiation doses (3 Gy) and addition of cisplatin in partially shielded nude mouse models resulted in strong suppression of the growth of both human tumor xenografts (22Rv1 and FaDu). The addition of ABC in the 22Rv1 model did not alter the response to radiation/cisplatin; whereas, this combination showed increased suppression of tumour growth in the FaDu model. C57BL/6 mice were subjected to either total body or partially-shielded irradiation and were treated with ABC alone; radiation alone; or combination of ABC plus radiation. Cisplatin was combined with radiation with or without ABC in the 22Rv1 and FaDu. Syngeneic tumor models comprised C57BL/6 mice implanted with PAN02 (pancreatic), B16 (melanoma) or E0771 (breast) cancer cells; while cross-species xenograft models used NCr nude mice implanted with human 22Rv1 (prostate) or human FaDu (pharynx squamous cell carcinoma) cancer cells [51] .

In vivo testing revealed ABC 29464 plus sorafenib or ABC 294735 plus sorafenib resulted in synergistic cytotoxicity, which was associated with increases in caspases 3/7 activation and apoptotic DNA fragmentation in mice with either Bxpc-3 or A-498 cancer cells. In both combination treatments decreases in ERK phosphorylation and an increase in the phosphorylation of inhibitory site of c-Raf (S259) were observed in both sets of cancer cells. Both opaganib and ABC 294735 delayed tumour growth in both xenograft models without overt toxicity to the animals. Sorafenib co-administration potentiated this growth delay. The study evaluated opaganib (a SK2-specific inhibitor) and ABC 294735 (a SK1/SK2 inhibitor), alone and in combination with sorafenib on human pancreatic adenocarcinoma (Bxpc-3) and kidney carcinoma (A- 498) cells in vitro and in vivo [58] .

Apogee has identified several low molecular weight compounds that potently inhibit sphingosine kinase in close relationship with their anti-proliferative activities [60] .

In preclinical studies, administration of opaganib resulted in a comprehensive inhibition of myeloma tumour growth in vitro and in vivo, in mouse xenograft models. Results have also revealed that sphingosine kinase 2 (SK2) is over-expressed in multiple myeloma cell lines and human multiple myeloma specimens and is critically involved in myeloma cell growth, proliferation and survival [46] .

Following hepatic ischaemia-repefusion (IR), the 7-day survival increased from 28% to 100% in mice treated with opaganib, compared with vehicle treated mice. Additionaly, the changes seen in vehicle-treated mice, 6h after hepatic IR, including increases in ALT, bilirubin, hepatic necrotic cell death, TUNEL-positive apoptotic cells and cleaved caspase-3, were attenuated by 54% to 91% in mice treated with opaganib. Hepatic IR also resulted in mitochondrial depolarisation in 74% of viable hepatocytes, compared with 17% of hepatocytes in opaganib-treated mice [54] .

Treatment with oral opaganib (50 mg/kg bid) for 27 days prevented incapacitance (measured as hind limb weight bearing) in a rat model of osteoarthritis. As weight bearing (%) significantly decreased from 48.8 (day 0) to 41.9 (day 28) following sham oral dosing, these values did not change on day 0 (49.0%) and day 28 (48.8%) in rats receiving opaganib or tramadol treatment. Knee joint histology scores (48 point scale) indicating cartilage and bone destruction were reduced to 24.1 in rats receiving opaganib compared with 30.9 in sham group. There was a significant inverse correlation between histological damage and weight bearing in rats (p=0.036). Moreover, proteoglycan staining in the tibia and femur showed lesser disruption in rats treated with opaganib compared with sham group [53] .

Antimicrobial Activity

Summary

Therapeutic Trials

In a phase Ib/II trial, administration of opaganib showed that out of 10 evaluable patients, two had stable disease for over four months, while one achieved a very good partial response (VGPR). These patients belonged to the phase Ib portion of the trial [46] .

Results from 16 patients, with solid tumours from a phase I trial, assessable for response by RECIST 1.1 criteria showed that, one patient had a partial response with a progression-free survival of 16.9 months, and six patients, including one with metastatic/recurrent bladder cancer, had stable disease with a progression-free survival of between 3.5 and 17.6 months. Of the three patients with cholangiocarcinoma, one had a partial response and the other two had stable disease, one for over a year. In this phase I trial, 21 patients with advanced solid tumours were continuously treated in cycles of 28 days with opaganib, in the absence of disease progression, and tumours were reimaged every two cycles [24] [31] . Additional results from the phase I trial in three cholangiocarcinoma patients showed that one patient had a sustained partial response (Overall Survival (OS) = 20.3 months) and the other two had stable disease (OS = 17.6 and 16.3 months) [33] [32] .

Updated efficacy data obtained from a clinical trial in Israel in six of the COVID-19 patients showed significant improvements following treatment with opaganib with and without hydroxychloroquine including decreased supplemental oxygen requirements, decreased C-reactive protein levels and increased lymphocyte levels. Five of the six patients analysed were weaned from oxygen, and three patients were discharged from the hospital within days of treatment initiation [11] [13] [14] .

Future Events

Expected Date Event Type Description Updated
01 Feb 2020 Trial Update Medical University of South Carolina in collaboration with National Cancer Institute (NCI) plans a phase II trial for Prostate cancer (Combination therapy, Metastatic disease, Hormone refractory) in February 2020 (NCT04207255) (700313102) 18 Mar 2020
31 Dec 2017 Trial Update RedHill plans a phase II trial for Ulcerative colitis in fourth quarter of 2017 [37] 28 Aug 2017
31 Dec 2017 Trial Update RedHill Biopharma plans a phase IIa trial for Cholangicarcinoman fourth quarter of 2017 [37] 27 Dec 2017

Development History

Event Date Update Type Comment
08 May 2020 Regulatory Status The US FDA approves IND application for opaganib in Pneumonia associated with COVID-2019 infections [8] [9] Updated 12 May 2020
30 Apr 2020 Scientific Update Preliminary efficacy data from a clinical trial in COVID-2019 infections released by RedHill Biopharma [11] Updated 30 Apr 2020
21 Apr 2020 Trial Update RedHill Biopharma plans a phase IIa trial for treatment of patients with COVID-19 infection and Pneumonia in the US (PO) [10] Updated 29 Apr 2020
20 Apr 2020 Regulatory Status RedHill Biopharma submits an IND application of opaganib to the US FDA for Pneumonia in USA [28] Updated 29 Apr 2020
17 Apr 2020 Regulatory Status RedHill Biopharma submits an IND application to the FDA for COVID-19 infection in the US [10] Updated 29 Apr 2020
13 Apr 2020 Scientific Update Adverse events and efficacy data from a clinical trial in COVID-2019 infections released by RedHill Biopharma [13] Updated 16 Apr 2020
06 Apr 2020 Phase Change - Clinical Clinical trials in COVID-2019 infections (Adjunctive treatment) in Israel (PO), before April 2020 [6] [13] Updated 13 Apr 2020
06 Apr 2020 Regulatory Status Italian National Institute for Infectious Diseases and Central Italian Ethics Committee approves compassionate use of opaganib for COVID-2019 infections in Italy [6] Updated 13 Apr 2020
06 Apr 2020 Trial Update RedHill Biopharma plans a clinical trial under compassionate use of opaganib for COVID-2019 infections in Italy [6] Updated 13 Apr 2020
13 Mar 2020 Phase Change - II Phase-II clinical trials in Cholangiocarcinoma (Inoperable/Unresectable, Late-stage disease, Second-line therapy or greater, Combination therapy) in USA (PO), before March 2020 (NCT03377179) Updated 18 Mar 2020
13 Mar 2020 Phase Change - Preclinical Preclinical trials in COVID-2019 infections in Israel (PO) [7] Updated 18 Mar 2020
10 Mar 2020 Phase Change - II Phase-II clinical trials in Prostate cancer (Hormone refractory, Combination therapy, Metastatic disease, Second-line therapy or greater) in USA (PO) (NCT04207255) Updated 18 Mar 2020
28 Dec 2019 Phase Change - No development reported No recent reports of development identified for phase-I development in Solid-tumours(Late-stage disease) in USA (PO, Capsule) Updated 28 Dec 2019
20 Dec 2019 Trial Update Medical University of South Carolina in collaboration with National Cancer Institute (NCI) plans a phase II trial for Prostate cancer (Combination therapy, Metastatic disease, Hormone refractory) in February 2020 (NCT04207255) Updated 18 Mar 2020
12 Sep 2019 Phase Change - Suspended(II) Suspended - Phase-II for Liver cancer (Late-stage disease, Second-line therapy or greater) in USA (PO) as the trial is being rewritten for a different disease population (NCT02939807) Updated 17 Sep 2019
16 May 2019 Trial Update RedHill Biopharma Limited terminates a phase I/II trial in Multiple myeloma (Second-line therapy or greater) in USA due to expiration of National Cancer Institute (NCI) funding (PO) (NCT02757326) Updated 28 May 2019
14 Nov 2018 Scientific Update Efficacy and adverse events data from a phase Ib/II trial in Multiple myeloma and pharmacodynamics data from preclinical studies in Cancer released by RedHill Biopharma [46] Updated 21 Nov 2018
24 Jun 2018 Biomarker Update Biomarkers information updated Updated 31 Aug 2018
30 Jan 2018 Trial Update RedHill Biopharma initiates an expanded-access programme for Cholangiocarcinoma in Germany(NCT03414489) Updated 01 Feb 2018
22 Dec 2017 Active Status Review Phase-I development in Solid tumours (Late-stage disease) is ongoing in USA (PO, Capsule) [18] Updated 27 Dec 2017
22 Dec 2017 Phase Change - II Phase-II clinical trials in Cholangiocarcinoma (Late-stage disease, Inoperable/Unresectable, Monotherapy, Second-line therapy or greater) in USA (PO) [18] (NCT03377179) Updated 27 Dec 2017
05 Dec 2017 Trial Update RedHill Biopharma Limited withdraws a phase I/II trial prior to enrolment due to lack of recruitment in Diffuse large B cell lymphoma (Second-line therapy or greater) in USA (PO) (NCT02229981) Updated 20 Dec 2017
04 Nov 2017 Phase Change - No development reported No recent reports of development identified for phase-I development in Solid-tumours(Late-stage disease) in USA (PO, Capsule) Updated 04 Nov 2017
04 Nov 2017 Phase Change - No development reported No recent reports of development identified for preclinical development in Inflammatory-bowel-disease in USA (PO) Updated 04 Nov 2017
04 Nov 2017 Phase Change - No development reported No recent reports of development identified for preclinical development in Osteoarthritis in USA (PO) Updated 04 Nov 2017
04 Nov 2017 Phase Change - No development reported No recent reports of development identified for preclinical development in Radiation-injuries in USA (PO) Updated 04 Nov 2017
04 Nov 2017 Phase Change - No development reported No recent reports of development identified for preclinical development in Rheumatoid-arthritis in USA (PO) Updated 04 Nov 2017
18 Sep 2017 Phase Change - Clinical Clinical trials in Cancer (Combination therapy) in USA (PO) [57] Updated 28 Sep 2017
18 Sep 2017 Patent Information RedHill Biopharma receives patent allowance for Yeliva® and Mesupron in USA [57] Updated 20 Sep 2017
10 Aug 2017 Trial Update RedHill Biopharma plans a phase IIa trial for Cholangicarcinoman fourth quarter of 2017 [37] Updated 27 Dec 2017
10 Aug 2017 Trial Update RedHill plans a phase II trial for Ulcerative colitis in fourth quarter of 2017 [37] Updated 28 Aug 2017
13 Apr 2017 Other Chemical structure information added Updated 13 Apr 2017
04 Apr 2017 Regulatory Status ABC 294640 receives Orphan Drug status for Cholangiocarcinoma in USA [15] Updated 07 Apr 2017
29 Nov 2016 Scientific Update Pharmacodynamics data from preclinical trials in Solid tumours at the 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR-2016) [51] Updated 29 Dec 2016
21 Nov 2016 Licensing Status ABC 294640 is available for licensing as of 21 Nov 2016. www.redhillbio.com [52] Updated 24 Nov 2016
05 Oct 2016 Phase Change - II Phase-II clinical trials in liver cancer (Second-line therapy or greater, Late-stage disease) in USA (PO) [21] Updated 07 Oct 2016
12 Sep 2016 Trial Update RedHill Biopharma plans a phase Ib trial for Mucositis (Prevention) in Israel [1] Updated 14 Sep 2016
08 Sep 2016 Phase Change - I/II Phase-I/II clinical trials in Multiple myeloma (Second-line therapy or greater) in USA (PO) [48] Updated 12 Sep 2016
26 Jul 2016 Trial Update RedHill Biopharmaplans three phase I/II trials for Multiple oncology, inflammatory and gastrointestinal indications [36] Updated 02 Aug 2016
21 Jun 2016 Scientific Update Final positive efficacy and adverse events data from a phase I trial in Solid tumours released by RedHill BioPharma [24] Updated 24 Jun 2016
04 May 2016 Trial Update RedHill Biopharma plans a phase II trial for liver cancer (Second-line therapy or greater, Late-stage disease) [22] Updated 09 May 2016
10 Mar 2016 Phase Change - Preclinical Preclinical trials in Cholangiocarcinoma in USA before March 2016 (PO) [20] Updated 15 Mar 2016
26 Oct 2015 Scientific Update Top-line adverse events and pharmacodynamics data from a phase I trial in Solid tumours (Late-stage disease) released by RedHill Biopharma [29] Updated 29 Oct 2015
22 Oct 2015 Company Involvement RedHill BioPharma receives SBIR grant from National Cancer Institute for ABC 294640 development in Prostate cancer [2] Updated 27 Oct 2015
10 Sep 2015 Trial Update RedHill BioPharma plans a phase II trial for Multiple myeloma (Second-line therapy or greater) in USA [3] Updated 10 Sep 2015
09 Sep 2015 Company Involvement RedHill BioPharma receives SBIR grant from National Cancer Institute for ABC 294640 development in Multiple myeloma [3] Updated 10 Sep 2015
01 Jul 2015 Trial Update RedHill Biopharma completes a phase I trial in Solid tumours (Late-stage disease) in USA (NCT01488513) Updated 03 Sep 2015
07 May 2015 Trial Update RedHill Biopharma plans a phase II trial for Inflammatory-GI diseases and Cancer [41] Updated 06 Jun 2015
31 Mar 2015 Licensing Status RedHill Biopharma acquires ABC 294640 from Apogee Biotechnology Corporation [4] Updated 04 Apr 2015
01 Jan 2015 Phase Change - Preclinical Preclinical trials in Prostate cancer (Hormone refractory) in USA (PO) [27] Updated 07 Sep 2015
01 Dec 2014 Trial Update Apogee Biotechnology completes enrolment in a phase-I clinical trial in Solid tumours (late-stage disease) in USA (PO) (NCT01488513) Updated 17 Jun 2015
15 Oct 2014 Trial Update Apogee Biotechnology Corporation plans a phase I/II trial for Diffuse large B-cell lymphoma in USA (NCT02229981) Updated 15 Oct 2014
01 Oct 2013 Phase Change - Preclinical Preclinical trials in Radiation injuries and rheumatoid arthritis in USA (PO) Updated 09 Oct 2013
01 Oct 2013 Scientific Update Interim efficacy, safety and pharmacokinetics data from a phase I trial in Solid tumours (late-stage disease) released by Apogee Biotechnology Corporation [31] Updated 09 Oct 2013
02 Aug 2011 Phase Change Early research in Radiation injuries in USA (PO) Updated 02 Aug 2011
01 Aug 2011 Phase Change - I Phase-I clinical trials in Solid tumours (late-stage disease) in USA (PO) Updated 18 Jan 2012
11 Nov 2010 Phase Change - Preclinical Preclinical trials in Osteoarthritis in USA (PO) Updated 08 Dec 2010
11 Nov 2010 Scientific Update Pharmacodynamics data from a preclinical study in Rheumatoid arthritis presented at the 74th Annual Scientific Meeting of the American College of Rheumatology and the 45th Annual Meeting of the Association of Rheumatology and Health Professionals (ACR/ARHP-2010) [53] Updated 08 Dec 2010
11 Nov 2010 Regulatory Status US FDA approves IND application for ABC 294640 in Cancer [35] Updated 11 Nov 2010
19 Nov 2009 Scientific Update Pharmacodynamics and pharmacokinetics data from a preclinical trial in Cancer presented at the 21st AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (AACR-NCI-EORTC-2009) [58] Updated 09 Dec 2009
03 Nov 2009 Phase Change - Preclinical Preclinical trials in Liver disorders in USA (unspecified route) Updated 23 Nov 2009
03 Nov 2009 Scientific Update Pharmacodynamics data from a preclinical trial in hepatic ischaemic-reperfusion injury presented at the 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2009) [54] Updated 23 Nov 2009
16 Apr 2008 Scientific Update Preclinical pharmacokinetics data presented at the 99th Annual Meeting of the American Association for Cancer Research (AACR-2008) [55] Updated 30 Apr 2008
18 Nov 2005 Phase Change - Preclinical Preclinical trials in Inflammatory bowel disease in USA (PO) Updated 08 Dec 2005
23 Jul 2003 Phase Change - Preclinical Preclinical trials in Cancer in USA (unspecified route) Updated 23 Jul 2003

References

  1. RedHill Biopharma Announces Research Collaboration with Stanford University for YELIVA(TM).

    Media Release
  2. RedHill Biopharma Announces National Cancer Institute Grant Awarded to Apogee Biotechnology Corp. for YELIVA(TM) (ABC294640) Prostate Cancer Research.

    Media Release
  3. RedHill Biopharma Announces $2 Million National Cancer Institute Grant for YELIVA(TM) (ABC294640) Phase II Study for Multiple Myeloma.

    Media Release
  4. RedHill Biopharma Acquires Phase II First-in-Class Oral Small Molecule SK2 Inhibitor From Apogee Biotech.

    Media Release
  5. BARDA supports development of new drugs to treat radiation injury.

    Media Release
  6. RedHill Biopharma Announces Approval of Compassionate Use of Opaganib for COVID-19 in Italy.

    Media Release
  7. RedHill Biopharma Provides Update on Opaganib (Yeliva(R)).

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  8. Opaganib (ABC294640) successfully treats patients with COVID-19 in Israel, Clinical trial approved in the U.S.

    Media Release
  9. RedHill Biopharma Receives FDA Approval for COVID-19 Clinical Study with Opaganib in the U.S.

    Media Release
  10. IND for COVID-19 with Opaganib Submitted to the FDA by RedHill Biopharma.

    Media Release
  11. Six COVID-19 Patients Treated with RedHills Opaganib Under Compassionate Use Show Objective Clinical Improvement.

    Media Release
  12. Additional Update on COVID-19 Compassionate Use with Opaganib in Israel Provided by RedHill Biopharma.

    Media Release
  13. RedHill Biopharma Provides Initial Update from its Opaganib COVID-19 Compassionate Use Program in Israel.

    Media Release
  14. A trial assessing Opaganib for COVID-19 in Hospitalized patients suffered from moderate-to-severe acute respiratory symptoms related to SARS-CoV-2 infection

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  15. RedHill Biopharma Receives FDA Orphan Drug Designation for YELIVA(R) for the Treatment of Cholangiocarcinoma.

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    Media Release
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    Media Release
  18. RedHill Biopharma Announces Initiation of Phase IIa Study with ABC294640 (YELIVA(R)) for Cholangiocarcinoma at Mayo Clinic and MD Anderson.

    Media Release
  19. A Phase I/IIA Study of ABC294640 Alone and in Combination With Hydroxychloroquine Sulfate in the Treatment of Patients With Advanced, Unresectable Intra-hepatic, Perihilar and Extra-Hepatic Cholangiocarcinoma

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  20. RedHill Biopharma Announces Peer-Reviewed Publication Demonstrating Therapeutic Potential of YELIVA(Tm) in Cholangiocarcinoma Cancer.

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  23. RedHill Biopharma Provides Full-Year 2019 Financial Results and Operational Highlights.

    Media Release
  24. RedHill Biopharma Announces Positive Final Results with Primary and Secondary Endpoints Met in Phase 1 Study with YELIVA(TM) in Advanced Solid Tumors.

    Media Release
  25. A Phase II Study of ABC294640 in Patients With Advanced Hepatocellular Carcinoma Who Have Progressed on Sorafenib

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  26. A Phase II Study of the Addition of Opaganib to Androgen Antagonists in Patients With Prostate Cancer Progression on Enzalutamide or Abiraterone

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  27. RedHill Biopharma Announces Peer-Reviewed Publication Demonstrating Therapeutic Potential of ABC294640 (YELIVA(TM)) in Prostate Cancer.

    Media Release
  28. RedHill Biopharma Announces Agreement with NIAID to Evaluate RHB-107 Against COVID-19.

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  29. RedHill Biopharma Announces Positive Top-line Results from YELIVA(TM) (ABC294640) Phase I Study in Advanced Solid Tumors.

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  30. RedHill Biopharma Announces Last Patient Visit in the Phase I Study With YELIVA(Tm) (ABC294640) for Advanced Solid Tumors.

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  31. Apogee to present phase 1 clinical trial results at the 2013 Molecular Targets and Cancer Therapeutics meeting.

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  35. Apogee Biotechnology Corporation to Launch Phase I Clinical Studies.

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  36. RedHill Biopharma Reports 2016 Second Quarter Financial Results.

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  41. RedHill Biopharma to Host Investor Webcast Forum Following Completion of RHB-105 Dosing in Phase III Study.

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  42. A Phase II study to evaluate ABC294640 as a radioprotectant to prevent mucositis and radiation enhancer in cancer patients undergoing radiotherapy

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    Media Release
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    ctiprofile
  46. RedHill Biopharma Announces Presentation on YELIVA(R) (opaganib) for Multiple Myeloma at EORTC-NCI-AACR Symposium.

    Media Release
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    Media Release
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    Media Release
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    Media Release
  50. A Phase Ib/II Safety and Efficacy Study of ABC294640 in Patients With Refractory or Relapsed Multiple Myeloma Who Have Previously Been Treated With Proteasome Inhibitors and Immunomodulatory Drugs

    ctiprofile
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    Media Release
  53. Fitzpatrick LR, Green C, Maines LW, Smith CD. Experimental Osteoarthritis in Rats Is Attenuated by Treatment with a Selective Inhibitor of Sphingosine Kinase 2. 74th-ACR-45th-ARHP-2010 2010; abstr. 1480.

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  56. French KJ, Smith CD, Zhuang Y, Xia Z, Maines LW, Upson JJ, et al. Development of orally-available inhibitors of sphingosine kinase with anticancer and anti-inflammatory activity. 17th-AACR-NCI-EORTC 2005;248 (plus poster) abstr. C195.

  57. RedHill Biopharma Receives Notice of Allowance for a New U.S. Patent Covering its Combination Therapy for Hard-to-Treat Cancers.

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