Clinical Trials

Date: 2016-06-21

Type of information: Results

phase: 1

Announcement: results

Company: Redhill Biopharma (Israel)

Product: Yeliva™ (ABC294640)

Action mechanism:

• enzyme inhibitor/sphingosine kinase-2 (SK2) inhibitor. ABC294640 is a first-in-class, proprietary sphingosine kinase-2 (SK2) selective inhibitor, administered orally, with anti-cancer and anti-inflammatory activities, targeting a number of potential inflammatory, oncology and gastrointestinal indications. By inhibiting the SK2 enzyme, ABC294640 blocks the synthesis of sphingosine 1-phosphate (S1P), a lipid that promotes cancer growth and pathological inflammation. ABC294640 has completed multiple successful pre-clinical studies in inflammatory, GI, radioprotection and oncology models, as well as a Phase I clinical study in cancer patients with advanced solid tumors.
• A Phase I/II study for the treatment of refractory or relapsed multiple myeloma is to be initiated in the coming weeks. The study will be conducted at Duke University Medical Center. 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. A Phase II clinical study to evaluate Yeliva™ as a radioprotectant to prevent mucositis in cancer patients undergoing therapeutic radiotherapy is planned to be initiated in the U.S. during the second half of 2016, subject to regulatory and other conditions. A Phase II study with Yeliva™ for the treatment of advanced hepatocellular carcinoma is planned to be initiated in the third quarter of 2016. The study will be conducted at the MUSC Hollings Cancer Center and additional clinical centers in the U.S. The study is supported by a $1.8 million grant from the NCI awarded to MUSC, intended to support a broad range of studies on the feasibility of targeting sphingolipid metabolism for the treatment of a variety of solid tumor cancers, including the Phase II study with Yeliva™, and will be further supported by additional funding from RedHill.

Disease: advanced solid tumors

Therapeutic area: Cancer - Oncology

Country: USA

Trial details:

• 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™.

Latest news:

• • On June 21, 2016, RedHill Biopharma  announced positive final results from the Phase I study with Yeliva™ (ABC294640) in advanced solid tumors. The Phase I Clinical Study Report (CSR) confirms the positive top-line results previously announced . The final results demonstrated that Yeliva™ 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 biomarker for activity of a sphingolipid-targeted drug. Administration of Yeliva™ 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. In addition, one patient had a prolonged partial remission and several patients had prolonged stabilization of disease. The primary objectives of the study were to identify the maximum tolerated dose (MTD), the dose limiting toxicities (DLTs) and to evaluate the safety of Yeliva™. 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. Several patients experienced mild neuropsychiatric symptoms, such as anxiety and mood changes. These were resolved quickly upon discontinuation of study medication. All treatment-related adverse events were rapidly reversible upon dose reduction or study drug removal. The secondary objectives of the study, to determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties of Yeliva™ and to assess its antitumor activity, were also met. Among the 16 subjects that were assessable for response by RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors), one subject had a partial response with a progression-free survival of 16.9 months, and six subjects 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. Yeliva™was well tolerated over a prolonged period at doses inducing the expected pharmacodynamic effects. Preliminary positive data from the Phase I study was presented by Apogee Biotechnology at the November 2013 Molecular Targets and Cancer Therapeutics meeting.
• • On October 26, 2015, RedHill Biopharma announced positive top-line results from the Phase I study with Yeliva™ (ABC294640) in patients with advanced solid cancers. 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). 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. 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™. 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™ and to assess its antitumor activity, were also met. The results demonstrated that Yeliva™ 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™ 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. A Phase I/II study with Yeliva™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. • On September 1, 2015, RedHill Biopharma announced that the last patient has completed the final scheduled follow-up visit in the Phase I study evaluating Yeliva™ (ABC294640), the Company's orally-administered first-in-class sphingosine kinase-2 (SK2) selective inhibitor, for the treatment of advanced solid tumors (the ABC-101 study). The ABC-101 Phase I study was conducted at the Medical University of South Carolina Hollings Cancer Center and was 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 of Yeliva™ (ABC294640) enrolled 22 patients with advanced solid tumors. The patients were continuously treated with the study drug in the absence of disease progression and evaluated for an additional period of up to one year after discontinuing treatment with Yeliva™ (ABC294640). 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 secondary objectives of the study were to determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties of Yeliva™(ABC294640) and to assess its antitumor activity. The study was supported by grants from the National Cancer Institute (NCI) and the FDA’s Office of Orphan Products Development (OOPD).  The analysis of the study is currently ongoing and top-line results are expected to be announced early in the fourth quarter of 2015. A full analysis and the final Clinical Study Report (CSR) are expected by the end of the year or early 2016.

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