On October 26, 2015 RedHill Biopharma Ltd. (NASDAQ:RDHL) (TASE:RDHL) ("RedHill" or the "Company"), an Israeli biopharmaceutical company primarily focused on late clinical-stage, proprietary, orally-administered, small molecule drugs for inflammatory and gastrointestinal diseases, including cancer, reported positive top-line results from the Phase I study with YELIVA (ABC294640) in patients with advanced solid cancers (Press release, RedHill Biopharma, OCT 26, 2015, View Source [SID:1234507783]). The study successfully met its primary and secondary endpoints, providing key information about the drug’s safety, toxicities, pharmacokinetics (PK) and pharmacodynamics (PD), supporting the ongoing and planned Phase II studies with YELIVA (ABC294640).
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The top-line results from the Phase I study with YELIVA (ABC294640), demonstrating achievement of primary and secondary endpoints, were provided to RedHill by Apogee Biotechnology Corporation ("Apogee") and remain subject to the completion of an independent review and analysis of the underlying data, including all safety, secondary and other outcome measures, and completion of the clinical study report (CSR), expected by the end of the year or early 2016. Final results of the study will be presented in the appropriate scientific and medical forums following completion of the CSR.
Charles D. Smith, Ph.D., Apogee’s President and CEO, said: "Sphingosine kinase-2 (SK2) is a new potential target for anticancer therapy because it produces sphingosine 1-phosphate (S1P) which regulates cancer cell proliferation and inflammatory pathways. YELIVA (ABC294640), a first-in-class, orally-available inhibitor of SK2, is the only agent in its category in clinical trials. The drug has demonstrated anticancer activity in many preclinical models, and the results from this Phase I study in patients with advanced solid tumors indicate that it can be safely administered to cancer patients at doses that provide circulating drug levels that are predicted to have therapeutic activity."
Terry F. Plasse, MD, RedHill’s Medical Director, said: "We are very pleased with the results from this first-in-man study with YELIVA in advanced solid tumors, which successfully met its primary and secondary objectives. The results demonstrated the safety and tolerability of this novel drug candidate at a pharmacologically active dose, supporting the ongoing and planned Phase II clinical studies with YELIVA. We continue to aggressively pursue development with this promising drug candidate across multiple cancer and inflammatory indications."
The Phase I study, supported by grants from the U.S. National Cancer Institute ("NCI") awarded to the Medical University of South Carolina ("MUSC") and from the U.S. FDA’s Office of Orphan Products Development (OOPD) awarded to Apogee, was conducted at the MUSC Hollings Cancer Center and led by Principal Investigators Melanie Thomas, MD, and Carolyn Britten, MD. The open-label, dose-escalation, pharmacokinetic (PK) and pharmacodynamic (PD) first-in-human Phase I study with YELIVA (ABC294640) treated 21 patients with advanced solid tumors, the majority of which were gastrointestinal cancer patients, including pancreatic, colorectal and cholangiocarcinoma cancers. The patients were continuously treated in cycles of 28 days with the study drug, in the absence of disease progression, and tumors were reimaged every two cycles. Patients were evaluated for an additional period of up to one year after discontinuing treatment with YELIVA (ABC294640). The last patient completed the final scheduled follow-up visit in July 2015.
The primary objectives of the study were to identify the maximum tolerated dose (MTD) and the dose limiting toxicities (DLTs) and to evaluate the safety of YELIVA (ABC294640). The primary objectives were all met and the drug was found to be safe and well tolerated, with grade 1-2 fatigue and nausea being the most common side effects.
The secondary objectives of the study, to determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties of YELIVA (ABC294640) and to assess its antitumor activity, were also met.
The results demonstrated that YELIVA (ABC294640) can be safely administered to cancer patients at doses that provide circulating drug levels that are predicted to have therapeutic activity, based on levels required in preclinical models. The study included the first-ever longitudinal analyses of plasma S1P levels as a potential pharmacodynamic (PD) biomarker for activity of a sphingolipid-targeted drug. The administration of YELIVA (ABC294640) resulted in a rapid and pronounced decrease in S1P levels over the first 12 hours, with return to baseline at 24 hours, which is consistent with clearance of the drug, with several patients having prolonged stabilization of disease.
Multiple preclinical studies previously conducted with YELIVA (ABC294640) in oncology and inflammation models demonstrated the drug’s therapeutic effect, as well as good pharmacokinetics (PK), oral bioavailability and biodistribution (including to the brain), and no hematologic toxicity.
Preliminary positive data from the Phase I study was presented by Apogee at the November 2013 Molecular Targets and Cancer Therapeutics meeting.
A Phase I/II clinical study was recently initiated in the U.S. evaluating YELIVA (ABC294640) in patients with refractory/relapsed diffuse large B-cell lymphoma (DLBCL), primarily in patients with HIV-related DLBCL. The study is being conducted at the Louisiana State University Health Sciences Center (LSUHSC) in New Orleans and is supported by a grant awarded to Apogee from the NCI Small Business Technology Transfer (STTR) program, as well as additional support from RedHill.
A Phase I/II study with YELIVA (ABC294640) for the treatment of refractory or relapsed multiple myeloma is planned to be initiated by early 2016. The study will be conducted at Duke University Medical Center and has received Institutional Review Board (IRB) approval from Duke University Health Sciences (DUHS IRB). The study is supported by a $2 million grant from the NCI Small Business Innovation Research Program (SBIR) awarded to Apogee in conjunction with Duke University, with additional support from RedHill.
RedHill maintains a strong and debt-free balance sheet with approximately $66 million in cash as of the end of July, supporting the ongoing and planned Phase II clinical studies with YELIVA, including a planned Phase II study to evaluate YELIVA as a radioprotectant to prevent mucositis in cancer patients undergoing therapeutic radiotherapy.
The Phase I/II clinical study in patients with refractory/relapsed diffuse large B-cell lymphoma and the Phase I clinical study in cancer patients with advanced solid tumors are registered on www.ClinicalTrials.gov, a web-based service by the U.S. National Institute of Health which provides public access to information on publicly and privately supported clinical studies.
About YELIVA (ABC294640):
YELIVA (ABC294640) is a proprietary, first-in-class, orally-administered, sphingosine kinase-2 (SK2) selective inhibitor with anticancer and anti-inflammatory activities, targeting multiple oncology, inflammatory and gastrointestinal indications. By inhibiting the SK2 enzyme, YELIVA (ABC294640) blocks the synthesis of sphingosine 1-phosphate (S1P), a lipid signaling molecule that promotes cancer growth and pathological inflammation. SK2 is an innovative molecular target for anticancer therapy because of its critical role in catalyzing the formation of S1P, which is known to regulate cell proliferation and activation of inflammatory pathways. YELIVA (ABC294640) was originally developed by U.S.-based Apogee Biotechnology Corp. and completed multiple successful pre-clinical studies in oncology, inflammation, GI, and radioprotection models, as well as the ABC-101 Phase I clinical study in cancer patients with advanced solid tumors. A Phase I/II clinical study evaluating YELIVA (ABC294640) in patients with refractory/relapsed diffuse large B-cell lymphoma (DLBCL) has been initiated in the U.S. The development of YELIVA (ABC294640) was funded to date primarily by grants and contracts from U.S. federal and state government agencies to Apogee Biotechnology Corp., including the U.S. National Cancer Institute, the U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA), the U.S. Department of Defense and the FDA Office of Orphan Products Development.