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Tuesday, June 21, 2016

RedHill Reports Positive Phase 1 For YELIVA™

On June 21, 2016, RedHill Biopharma (NASDAQ: RDHL) released full results from the company's Phase 1 clinical trial with YELIVA™ (ABC294640) for the treatment of patients with advanced solid tumors. The full clinical study report is consistent with the positive top-line data reported by the company in October 2015. Primary and secondary endpoints were successfully met demonstrating the drug is well tolerated and can be safely administered to cancer patients at predicted therapeutic levels.

Successful Phase 1 Study In The Books

A total of 21 patients with advanced solid tumors were enrolled in the Phase 1 trial. The majority of the subjects had gastrointestinal cancers, including pancreatic, colorectal, and cholangiocarcinoma. The study took place at the Medical University of South Carolina (MUSC) and was supported by grants from the U.S. National Cancer Institute (NCI) awarded to MUSC and from the U.S. FDA's Office of Orphan Products Development (OOPD) awarded to Apogee Biotechnology Corp., the original inventor of the drug. 

RECIST 1.1 data was available for 16 of the 21 subjects. Results show one subject with partial response and six with stable disease. Of the three patients with cholangiocarcinoma, one had a partial response, and the other two had stable disease, one for over a year. The most common side effects were grade 1-2 fatigue and nausea. PK/PD data showed administration of YELIVA™ resulted in a rapid and pronounced decrease in sphingosine 1-phosphate (S1P) levels over the first 12 hours, with a return to baseline at 24 hours, which is consistent with the clearance of the drug. 

A Validated Approach

I just wrote a very detailed article on YELIVA™ last week, so I will not delve into the science or the history of the drug here. However, investors should know that the mechanism of action - downregulation of aberrant sphingosine 1-phosphate (S1P) - is a clinically and commercially validated approach to targeting inflammatory and autoimmune diseases (1). 

In September 2010, Novartis gained U.S. approval for Gilenya® (fingolimod) for the treatment of multiple sclerosis. Fingolimod-phosphate, the active metabolite of Gilenya®, is an S1P receptor modulator that affects immune cell trafficking and activation of innate and adaptive immune response. Gilenya® is thought to arrests lymphocyte egress from secondary lymphoid tissues and reduces neuroinflammation in the nervous system (2). The reduction of inflammation on both the central and peripheral nervous system propagates nerve regeneration via elevation of axonal cAMP and reduction of lysophosphatidic acid (LPA) (3).

In July 2015, Celgene acquired Receptos for $7.2 billion, primarily to add ozanimod, a novel S1P receptor modulator to its pipeline. Ozanimod is currently under late-stage clinical development for the treatment of ulcerative colitis, Crohn's disease, and multiple sclerosis. The ability of ozanimod to sequester lymphocyte subsets in peripheral lymphoid organs, preventing their trafficking to inflamed tissue sites, contributes to the drug's potential utility in autoimmune and inflammatory diseases (4).

However, both fingolimod and ozanimod convey the risk of serious infection, likely due to the drugs' sequestering of lymphocytes. The label for Gilenya® includes warnings for risk of serious infections, including progressive multifocal leukoencephalopathy (PML). YELIVA™, on the other hand, does not sequester lymphocytes. The mechanism to downregulate S1P is through inhibition of sphingosine kinase-2 (SK2), a conserved lipid kinase that catalyzes the phosphorylation of sphingosine to form sphingosine 1-phosphate. RedHill is currently targeting cancer indications with YELIVA™, including both solid tumor and hematological cancers, but the mechanism is one that certainly warrants exploration of inflammatory and autoimmune diseases as well (5).

Next Steps For YELIVA™

RedHill is currently recruiting patients for a Phase 1/2 clinical study (NCT02229981) with YELIVA™ for refractory or relapsed Diffuse Large B-cell Lymphoma (DLBCL). Funding from this program is being supported by a $1.5 million grant awarded by the NCI under the NIH SBIR/STTR program to Apogee in conjunction with the Louisiana State University Health Science Center (LSUHSC). Estimated target enrollment is 33 patients with DLBCL, with the primary analysis focusing on the tolerability of the drug. Secondary evaluations will focus on the preliminary signs of efficacy. The trial is expected to complete in 2017.

Over-expression of S1P is quite common in patients with DLBCL. A team of researchers out of Japan found S1PR1 over-expression in 15.7% of all cases with DLBCL and over half of the cases with primary testicular (PT)-DLBCL (6). The potential to improve response to Rituxan® represents an exciting path forward for YELIVA™ in this indication.

A Phase 1/2 study of YELIVA™ for the treatment of refractory or relapsed Multiple Myeloma (rrMM) will initiate in the coming weeks. The study will take place at Duke University Medical Center and is supported by a $2 million grant awarded to Apogee, in conjunction with Duke University, from the NCI SBIR Program. SK2 is over-expressed in myeloma cells and contributes to myeloma cell survival and proliferation. Data published by MUSC in Blood in 2014 shows that inhibition of SK2 by YELIVA™ effectively inhibited myeloma cell proliferation and induced caspase 3–mediated apoptosis (7). The mechanism of action is down-regulation of c-Myc and Mcl-1, and that there may be a synergistic benefit to combination with a Bcl-2 inhibitor, such as venetoclax (Venclextra™).

Finally, a Phase 2 study with YELIVA™ for the treatment of advanced Hepatocellular Carcinoma (HCC) should be initiated in the third quarter of 2016. The study will take place at the MUSC Hollings Cancer Center, with additional clinical centers in the U.S. The study is supported in part by a $1.8 million grant from the U.S. NCI awarded to MUSC, with additional funding from RedHill. 

The initiation of the Phase 2 HCC study is quite interesting because researchers out of MUSC published data in 2011 showing the antitumor effects of YELIVA™ combined with the multikinase inhibitor, Nexavar® (sorafenib), in mouse models of hepatocellular carcinoma xenografts (8). New data just recently published in Oncotarget show synergistic effects between YELIVA™ and sorafenib in preclinical models of Cholangiocarcinoma (9). Positive Phase 2 data in HCC could spark significant partnering interest in YELIVA™ from big pharma.


Initial clinical funding to date for YELIVA™ has been through non-dilutive grants and awards to partners and universities. I found over a dozen proof-of-concept results in numerous solid tumor and hematological indications. RedHill exited the first quarter with $53.4 million in cash, so management can pursue multiple paths forward with YELIVA™ development. I'm not aware of any other company working on an SK2 inhibitor (per FactSet, June 2016), a mechanism that seems to offer potential synergy with chemotherapies paclitaxel, docetaxel, 5-FU, and cisplatin, along with targeted therapies, including Rituxan® and Nexavar®. I'm particularly interested in the upcoming trials in DLBCL, MM, and HCC.



Why Big Pharma Should Be Interested In RedHill's YELIVA™>> LINK


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