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RedHill Biopharma Announces Phase Ib/II Study with YELIVA™ Initiated for Multiple Myeloma at a Leading U.S. Academic Medical Center

On September 8, 2016 RedHill Biopharma Ltd. (NASDAQ:RDHL) (TASE:RDHL) ("RedHill" or the "Company"), a biopharmaceutical company primarily focused on development and commercialization of late clinical-stage, proprietary, orally-administered, small molecule drugs for gastrointestinal and inflammatory diseases and cancer, reported that a Phase Ib/II clinical study evaluating YELIVA (ABC294640) in patients with refractory or relapsed multiple myeloma has been initiated (Press release, RedHill Biopharma, SEP 8, 2016, View Source [SID1234515006]).

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The open-label, dose escalation Phase Ib/II study is being conducted at Duke University Medical Center and will enroll up to 77 patients with refractory or relapsed multiple myeloma who have previously been treated with proteasome inhibitors and immunomodulatory drugs.

Dr. Yubin Kang, MD, Associate Professor in the Division of Hematologic Malignancies and Cellular Therapy in the Department of Medicine at Duke University School of Medicine, is the lead investigator for the study.

The study is supported by a $2 million grant from the National Cancer Institute (NCI) Small Business Innovation Research Program (SBIR) awarded to Apogee Biotechnology Corp. (Apogee), in conjunction with Duke University, with additional support from RedHill.

YELIVA is a proprietary, first-in-class, orally-administered, sphingosine kinase-2 (SK2) selective inhibitor with anti-cancer and anti-inflammatory activities. By inhibiting the SK2 enzyme, YELIVA blocks the synthesis of sphingosine 1-phosphate (S1P), a lipid signaling molecule that promotes cancer growth and pathological inflammation.

RedHill is pursuing with YELIVA multiple clinical programs in oncology, inflammatory and gastrointestinal indications.

"We are very pleased that this study with YELIVA has been initiated at Duke University. Award of the NCI funding to support the study and the interest in the product by a major research university confirms the potential promise of YELIVA in this serious, chronic disease," said Terry Plasse, MD, RedHill’s Medical Director. "The clinical study follows a successful preclinical study demonstrating that sphingosine kinase-2 is overexpressed in multiple myeloma cell lines and in human specimens, and that its inhibition may fight the disease. This is the second Phase I/II study initiated with YELIVA. We expect to initiate additional clinical studies in the coming months, including studies in advanced hepatocellular carcinoma and prevention of mucositis in head and neck cancer patients undergoing therapeutic radiotherapy. Given YELIVA’s unique mechanism of action, we continue to evaluate its therapeutic potential for multiple oncology, inflammatory and gastrointestinal indications, as a single agent and in combination with other oncology drugs."

The primary objectives of the first portion of the study (Phase Ib) are to assess safety and determine the maximum tolerated dose (MTD) in refractory or relapsed multiple myeloma patients. Secondary objectives include assessment of antitumor activity and determination of the pharmacokinetic (PK) and pharmacodynamic (PD) properties of YELIVA in this group of patients. The Phase Ib will be conducted at Duke University Division of Hematologic Malignancies and Cellular Therapy.

The primary objectives of the second portion of the study (Phase II) are to assess the overall treatment response rate and overall survival. Secondary objectives include evaluating the treatment response to YELIVA in patients with refractory or relapsed multiple myeloma after three cycles of treatment and evaluation of pharmacodynamic markers. The Phase II portion will be conducted at multiple sites and will be managed by the Duke Cancer Network.

Results from the Phase I study with YELIVA in patients with advanced solid tumors confirmed that the study, conducted at the Medical University of South Carolina (MUSC), successfully met its primary and secondary endpoints, demonstrating that the drug is well-tolerated and can be safely administered to cancer patients at doses that provide circulating drug levels that are predicted to have therapeutic activity.

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.

A Phase II study with YELIVA for the treatment of advanced hepatocellular carcinoma is planned to be initiated in the coming weeks. The study will be conducted at MUSC Hollings Cancer Center and additional clinical centers in the U.S. It is supported by a $1.8 million grant from the NCI awarded to MUSC, intended to fund 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.

A clinical study to evaluate YELIVA as a radioprotectant for prevention of mucositis in head and neck cancer patients undergoing therapeutic radiotherapy is also planned.

A Phase I/II clinical study evaluating YELIVA in patients with refractory/relapsed diffuse large B-cell lymphoma (DLBCL) was initiated at the Louisiana State University Health Sciences Center (LSUHSC) in New Orleans in June 2015 and is expected to resume later this year following administrative hold and pending a protocol amendment aimed at improving overall recruitment. The study is supported by a grant awarded to Apogee from the NCI, as well as additional support from RedHill.

The studies with YELIVA (ABC294640) 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 Multiple Myeloma:
Multiple myeloma is a malignant plasma cell disorder which is usually not curable1. Symptomatic multiple myeloma is characterized by a clonal proliferation of plasma cells preceding clinical findings that include bone lesions, fractures, anemia, renal failure and hypercalcemia2. Approximately 30,000 new cases of multiple myeloma are expected to be diagnosed in the U.S. in 2016, accounting for 1.8% of all cancers. The 5-year survival rate of myeloma is estimated at 48.5% and approximately 95,000 people are living with myeloma in the United States3. The risk of multiple myeloma increases as people age. Most patients diagnosed with this cancer are at least 65 years old4, making treatment with the most effective therapies problematic. The worldwide sales of multiple myeloma therapies are estimated to exceed $12 billion in 20165.

About YELIVA (ABC294640):
YELIVA (ABC294640) is a Phase II-stage, proprietary, first-in-class, orally-administered, sphingosine kinase-2 (SK2) selective inhibitor with anticancer and anti-inflammatory activities. RedHill is pursuing with YELIVA multiple clinical programs in oncology, inflammatory and gastrointestinal indications. By inhibiting the SK2 enzyme, YELIVA 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 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. The development of YELIVA was funded to date primarily by grants and contracts from U.S. federal and state government agencies awarded 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.

8-K – Current report

On September 8, 2016 The Food and Drug Administration ("FDA") has notified Clovis Oncology, Inc. (the "Company") that FDA is not currently planning to hold an advisory committee meeting to discuss the Company’s New Drug Application for rucaparib (Filing, 8-K, Clovis Oncology, SEP 8, 2016, View Source [SID:1234515002]). As previously announced by the Company, FDA has accepted the Company’s NDA for accelerated approval of rucaparib and granted priority review status to the application with a Prescription Drug User Fee Act (PDUFA) date of February 23, 2017.

GTx Achieves Stage 1 Milestone in Phase 2 Clinical Trial of Enobosarm in ER+/AR+ Breast Cancer

On September 8, 2016 GTx, Inc. (Nasdaq: GTXI) reported the achievement of the Stage 1 milestone for the 9 mg cohort of its Phase 2 clinical trial of enobosarm (GTx-024) to treat women with advanced, estrogen receptor positive (ER+), androgen receptor positive (AR+) breast cancer (Press release, GTx, SEP 8, 2016, View Source [SID:1234514999]). A pre-defined number of patients demonstrated clinical benefit per protocol to allow the clinical trial to advance to the second and final stage of the trial (Stage 2). GTx also expects to provide an update on Stage 1 of the second dosing cohort (18 mg) in the clinical trial once there are sufficient evaluable patients to assess clinical benefit in this cohort. The Company anticipates reporting Stage 1 data from the clinical trial in the fourth quarter of 2016.

"The demonstration of clinical benefit among a pre-defined number of evaluable patients in Stage 1 of the 9 mg cohort of our ER+/AR+ breast cancer study represents an important milestone for GTx since we have met the protocol specified success criteria to continue with enrollment in Stage 2 of this cohort," said Robert J. Wills, Ph.D., Executive Chairman of GTx. "We believe enobosarm may provide a new hormonal approach for the treatment of estrogen receptor positive breast cancer and may delay the need for chemotherapy in these women."

About the Phase 2 Clinical Trial in ER+/AR+ Breast Cancer

The open-label, multi-center, multinational Phase 2 clinical trial (NCT02463032) will assess the efficacy and safety of orally administered enobosarm in up to 88 evaluable patients with metastatic or locally advanced, ER+/AR+ breast cancer. Patients will receive orally-administered enobosarm (9 mg or 18 mg) daily for up to 24 months. The two cohorts in the trial will be treated independently for the purpose of assessing efficacy. The first stage of evaluation will be assessed among the first 18 evaluable patients for each cohort. If at least 3 of 18 patients achieve clinical benefit at week 24, then the trial will proceed to the second stage of enrollment for that cohort to assess clinical benefit in a total of 44 evaluable patients per arm. Clinical benefit is defined as a complete response, partial response, or stable disease, as measured by Response Evaluation Criteria in Solid Tumors (RECIST) at 24 weeks. The lead investigator for the trial is Dr. Beth Overmoyer from the Dana Farber Cancer Institute and the Harvard Medical School.

About enobosarm

Enobosarm, a selective androgen receptor modulator (SARM), has been evaluated in 24 completed or ongoing clinical trials enrolling over 1,500 subjects, of which approximately 1000 subjects were treated with enobosarm at doses ranging from 0.1 mg to 100 mg. At all evaluated dose levels, enobosarm was observed to be generally safe and well tolerated.

Previously, enobosarm 9 mg has been tested in a Phase 2, proof of concept clinical trial of 22 postmenopausal women with ER+ metastatic breast cancer who have previously responded to endocrine therapy. 17 of the 22 patients were confirmed to be AR+, and 6 of those 17 patients demonstrated clinical benefit at six months. In total, 7 patients (one patient with indeterminate AR status) achieved clinical benefit at six months. The results also demonstrated that, after a median duration on study of 81 days, 41 percent of all patients (9/22) achieved clinical benefit as best response and also had increased PSA which appears to be an indicator of AR activity. Enobosarm was well tolerated. The most common adverse events reported were pain, fatigue, nausea, hot flash/night sweats, and arthralgia.

About ER+/AR+ Breast Cancer

Breast cancer is the most commonly diagnosed cancer in women, and one in eight women will develop invasive breast cancer in their lifetime. In 2012, 1.7 million women world-wide were diagnosed with breast cancer, and there were 6.3 million women alive who had been diagnosed with breast cancer in the previous five years. Clinical assessment of breast cancer provides for routine characterization of receptor status, including the presence or absence of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) in the tumor tissue. Receptor status is used to assess metastatic potential as well as to guide treatment decisions. The majority of breast cancers are considered hormone receptor positive (expressing ER or progesterone receptor). Approximately 70 percent of women in the U.S. with breast cancer have ER+ tumors, and 75 to 90 percent of these cancers are also AR+.

Estrogen promotes the growth of breast cancers that are hormone receptor positive. Therefore, treatment is directed at blocking the effects of estrogen on the breast cancer either through blocking the estrogen receptor or minimizing the production of estrogen. This endocrine therapy is the cornerstone of treatment for the majority of women with hormone receptor positive advanced breast cancer and is the preferred initial treatment over alternative approaches such as chemotherapy, due to its efficacy and favorable safety profile. Patients who respond to one endocrine therapy are likely to respond to subsequent hormonal therapies. Therefore, the standard of care for women with hormone receptor positive breast cancer typically involves the sequencing of endocrine agents until intolerance or development of resistance occurs, or metastatic progression necessitates a transition to chemotherapy.

Enobosarm may offer an alternate hormonal approach for the treatment of endocrine sensitive advanced breast cancer prior to the introduction of chemotherapy.

Sutro Marks Important Progress — Receives Two Milestone Payments from Celgene

On September 7, 2016 Sutro Biopharma reported that it has received two milestone payments from drug discovery and development partner Celgene Corporation (Celgene) for achievements in preclinical development and manufacturing under the company’s 2014 immuno-oncology collaboration with Celgene (Press release, Sutro Biopharma, SEP 7, 2016, View Source [SID1234516952]). Financial terms of the milestones are not being disclosed.

These payments support acceleration of Sutro’s pipeline from the late-stage preclinical phase into clinical development, as well as expansion of the company’s cell-free manufacturing capability. The payments fall under a September 2014 collaboration agreement in which Celgene paid Sutro $95 million, including an equity investment, and agreed to pay up to an additional $75 million for research and manufacturing milestones during an initial research phase.

"These milestone payments recognize the significant advances we have made toward developing and manufacturing best-in-class, multispecific antibodies and antibody drug conjugates (ADCs) using our proprietary platform," said Sutro’s CEO, Bill Newell.

Expanded Manufacturing capabilities have the potential to accelerate clinical development
Unlike conventional cell-based expression systems, Sutro’s technology isolates a cell’s protein production machinery into a cell-free extract, Xtract CF, that includes all the necessary biochemical components for energy production, transcription and translation. Xtract CF and Xtract CF+ are used in the Xpress CF and Xpress CF+ platforms to support cell-free biochemical protein synthesis by the addition of the specific DNA sequence for the desired protein. This process is capable of producing single proteins at gram per liter yields in eight to ten hours at large scale, unconstrained by cellular structures and their limitations.

Sutro’s GMP-compliant manufacturing facility in San Carlos, California, is built to maximize the speed and efficiency of cell-free extract and protein production. The Xtract CF and Xtract CF+ processes enable manufacture of cell-free extract through a continuous multi-day process, which in turn can drive the Xpress CF and Xpress CF+ reactions at scale. At full production capacity, the San Carlos manufacturing facility will be able to produce sufficient quantities of protein to support the early clinical development pipeline for Sutro and its collaboration partners.

The Sutro-Celgene three-year collaboration focuses on the discovery and development of multispecific antibodies and ADCs aimed at immuno-oncology therapeutics. Celgene has an option to extend the collaboration beyond the initial research term in exchange for an additional payment. Sutro is also eligible to receive additional clinical development and regulatory approval milestones for each compound selected by Celgene under the collaboration, as well as tiered royalties based on annual net sales of licensed products. Beginning in September 2016 through the end of the collaboration (as extended), Celgene will have the exclusive option to acquire Sutro based on a pre-specified valuation procedure, including rights to all Sutro-owned programs at that time.

Fate Therapeutics and Memorial Sloan Kettering Cancer Center Launch Partnership for Development of Off-the-Shelf T-Cell Immunotherapies

On September 7, 2016 Fate Therapeutics, Inc. (NASDAQ:FATE), a biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, reported a partnership with Memorial Sloan Kettering Cancer Center for the development of off-the-shelf T-cell product candidates using engineered pluripotent cell lines (Press release, Fate Therapeutics, SEP 7, 2016, View Source [SID:1234515009]). Research and development activities under the multi-year collaboration will be led by Michel Sadelain, M.D., Ph.D., Director of the Center for Cell Engineering and the Stephen and Barbara Friedman Chair at Memorial Sloan Kettering Cancer Center.

"This partnership brings together Memorial Sloan Kettering’s excellence in the manufacture and delivery of cell-based immunotherapies, and our established expertise in pluripotent cell generation, engineering and differentiation," said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. "Together, we are at the forefront of an off-the-shelf paradigm shift, seeking to broaden patient access to revolutionary T-cell immunotherapies through a renewable, robust and standardized product approach."

"Engineering therapeutic attributes into pluripotent cell lines, such as antigen specificity, lack of alloreactivity, enhanced persistence and histocompatibility, is a breakthrough approach to renewably generate potent T-cell immunotherapies," said Dr. Sadelain. "This unique approach offers the prospect for off-the-shelf delivery of T-cell immunotherapies with enhanced safety and therapeutic potential at the scale necessary to serve significant numbers of patients."

The collaboration unites research, preclinical development and manufacturing work currently being conducted independently at Fate Therapeutics and Memorial Sloan Kettering to accelerate the clinical translation of T-cell product candidates derived from engineered pluripotent cells. Collectively, the groups have amassed significant and complementary expertise necessary to deliver off-the-shelf T-cell immunotherapies, including the engineering, maintenance and expansion of induced pluripotent cell lines and the scalable generation of T cells with enhanced safety profiles and effector functions.

In connection with the partnership, Fate Therapeutics has exclusively licensed from Memorial Sloan Kettering foundational intellectual property covering induced pluripotent cell-derived immune cells, including T cells and NK cells derived from pluripotent cells engineered with chimeric antigen receptors, for human therapeutic use. Additionally, Fate Therapeutics maintains an option to exclusively license intellectual property arising from all research and development activities under the collaboration.

Off-the-Shelf Immunotherapy Opportunity
Cellular immunotherapies are poised to transform the treatment of cancer and immunological conditions. However, cellular immunotherapies currently undergoing clinical investigation are patient-specific and their delivery requires the extraction, engineering, expansion and re-introduction of each individual patient’s T cells. This multi-step manufacturing process is logistically challenging and complex, and significant hurdles remain to ensure that patient-specific T-cell immunotherapies can be efficiently and consistently manufactured, and safely and reliably delivered, at the scale necessary to support broad patient access and wide-spread commercialization.

Induced pluripotent cells possess the unique dual properties of self-renewal and differentiation potential into all cell types of the body including T cells. Similar to master cell lines used for the manufacture of monoclonal antibodies, engineered pluripotent cell lines can repeatedly deliver clonal populations of T cells with broad histocompatibility and enhanced effector functions. These highly-stable pluripotent cell lines have the potential to serve as a renewable cell source for the consistent manufacture of homogeneous populations of effector cells for the treatment of many thousands of patients.

Exclusive License & Development Plan
Through the three-year collaboration, the group aims to leapfrog the field’s current patient-specific approach to T-cell immunotherapy. Over the last decade, Fate Therapeutics has developed a proprietary, patent-protected platform to efficiently generate, genetically engineer, isolate and bank pluripotent cell lines. Memorial Sloan Kettering is leading the field in generating pluripotent cell-derived, tumor-targeting T cells that are capable of profound tumor clearance in vivo. The scientific teams will combine forces to create pluripotent cell lines that have been engineered for enhanced antigen specificity and functionality, optimize T-cell differentiation protocols, and clinically translate off-the-shelf engineered T-cell product candidates.

New Subsidiary Formed
Fate Therapeutics has also launched a new venture company, Tfinity Therapeutics, Inc., which will focus exclusively on the advancement of off-the-shelf T-cell immunotherapies across a wide range of diseases using Fate’s proprietary, patent-protected pluripotent cell platform. Fate Therapeutics has an intellectual property portfolio consisting of over 60 issued patents and 90 pending patent applications, which are owned or exclusively licensed by Fate Therapeutics, that cover compositions and methods critical for deriving, engineering, maintaining and differentiating induced pluripotent cells. Tfinity Therapeutics is a majority-owned subsidiary of Fate Therapeutics, and holds an option to license from Fate Therapeutics intellectual property covering pluripotent cell-derived T-cell immunotherapies.