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  .
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)  .
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   . 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  .
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       .
In April 2017, RedHill Biopharma announced that the US FDA has granted opaganib Orphan Drug designation for the treatment of cholangiocarcinoma  .
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  .
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   . 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  . 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   .
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  .
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)   . The trial is supported by a $US1.8 million grant from the NCI awarded to MUSC (1P01CA203628-01)    .
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   .
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  . 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  .
In April 2020, RedHill Biopharma submitted an IND application of opaganib to the US FDA for the treatment of pneumonia  .
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      . Final results from the study released by the company in June 2016, showed that the study met its primary and secondary endpoints  . In January 2017, the company released additional positive results showing that opaganib may be an effective drug for the treatment of cholangiocarcinoma  . 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  .
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  .
RedHill Biopharma intends to initiate two phase I/II trials for multiple oncology and inflammatory indications  .
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          .
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)     . 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  . The company reported in January 2017, that kaposi sarcoma patients were also to be included in the study  .
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          .
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)   .
In October 2013, Apogee Biotechnology Corporation reported that opaganib has demonstrated activity in animal models of inflammatory bowel disease, rheumatoid arthritis and radiation poisoning  .
Apogee Biotechnology evaluated the efficacy of opaganib in a rat model of osteoarthritis. Positive data were presented  .
Favourable pharmacokinetic and pharmacodynamic data for opaganib for the prevention of liver disorders were presented   .
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  .
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  .
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  .