On March 10, 2016 Trillium Therapeutics Inc. (Nasdaq:TRIL; TSX: TR) a clinical stage immuno-oncology company developing innovative therapies for the treatment of cancer, reported that it has entered into a collaboration agreement with University Health Network and the Hospital for Sick Children to fund and undertake a research program entitled "SIRPaFc: Translating Genomics Research Into a Novel Cancer Immunotherapy (Filing, 6-K, Trillium Therapeutics, MAR 10, 2016, View Source [SID:1234509472]).

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" Importantly, this project has been approved for funding by Genome Canada under the Genomic Applications Partnership Program (GAPP). In addition, The Ontario Ministry of Research and Innovation is supporting the project with a grant matching Genome Canada’s contribution, providing the collaboration with 3-year budget of approximately $3.4 million.

"Predictive prognostic or pharmacodynamic biomarkers are critical for the development of new therapeutic cancer agents, especially those targeting the immune system," commented Trillium’s Chief Executive Officer, Dr. Niclas Stiernholm. "This new matching funding will allow us to substantially expand our translational research efforts, focusing primarily on acute myeloid leukemia, which is ultimately likely to enhance our clinical programs."

Trillium’s lead program, TTI-621, is currently being tested as a single-agent in patients with relapsed or refractory hematologic malignancies. During the dose escalation phase set to enroll up to 36 subjects, we intend to characterize the safety, tolerability, pharmacokinetics and pharmacodynamics to determine the optimal dose for subsequent enrollment in the expansion phase. In this second part of the trial, we intend to explore the safety and preliminary antitumor activity of TTI-621 at the optimal dose identified in the escalation phase in 12–15 subjects per hematologic malignancy type: indolent B-cell lymphoma, aggressive B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, chronic lymphocytic leukemia, multiple myeloma, acute myeloid leukemia, and myelodysplastic syndrome.

On March 10, 2016 RedHill Biopharma Ltd. (NASDAQ:RDHL) (TASE:RDHL) ("RedHill" or the "Company"), a biopharmaceutical company primarily focused on the development and commercialization of late clinical-stage, proprietary, orally-administered, small molecule drugs for inflammatory and gastrointestinal diseases, including cancer, reported the publication of an article evaluating the therapeutic potential of YELIVA (ABC294640), the Company’s orally-administered first-in-class Sphingosine kinase-2 (SK2) selective inhibitor, in the treatment of cholangiocarcinoma (bile duct cancer) (Press release, RedHill Biopharma, MAR 10, 2016, View Source [SID:1234509463]).

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The article, authored by scientists from the Mayo Clinic Cancer Center, the Hollings Cancer Center at the Medical University of South Carolina and Apogee Biotechnology Corporation ("Apogee"), will be published in Oncotarget and is available online on the journal’s website.

The article[1], entitled "Antitumor effect of the novel sphingosine kinase-2 inhibitor ABC294640 is enhanced by inhibition of autophagy and by sorafenib in human cholangiocarcinoma cells," found that SK2 is overexpressed in multiple human cholangiocarcinoma cell lines, including a patient-derived line. The article describes non-clinical studies conducted with YELIVA (ABC294640) in these cell lines. The results from these studies demonstrated that YELIVA inhibited cancer proliferation and induced apoptosis in these cholangiocarcinoma cancer cells. Furthermore, YELIVA inhibited STAT3 phosphorylation, one of the key signaling pathways regulating cell proliferation and survival, and also induced autophagy. In addition, YELIVA in combination with sorafenib, an FDA-approved multikinase inhibitor for the treatment of hepatocellular carcinoma and renal cell carcinoma (NEXAVAR marketed by Bayer AG), synergistically inhibited the proliferation of cholangiocarcinoma cells.

The authors concluded that these findings provide preliminary insight into the possible use of YELIVA as an anticancer drug for cholangiocarcinoma treatment, as well as novel evidence that SK2 may be a rational therapeutic target in the treatment of this cancer. Additionally, a combination of YELIVA with sorafenib and/or autophagy inhibitors may provide novel strategies for the treatment of cholangiocarcinoma.

Reza Fathi, RedHill’s Senior VP R&D, said: "We are pleased to announce the publication of this important article in a well-respected, peer-reviewed journal. The findings described in this publication provide further insight into the mechanism of the anticancer activities of YELIVA, a novel Sphingosine kinase-2 (SK2) inhibitor, and suggest that YELIVA could potentially be effective in treating cholangiocarcinoma cancer. Notably, it was found that YELIVA inhibited STAT3 phosphorylation, one of the key signaling pathways regulating cholangiocarcinoma cell proliferation and survival. We continue to diligently advance the clinical research of YELIVA for multiple indications. We have initiated a Phase I/II study with YELIVA in patients with refractory/relapsed diffuse large B-cell lymphoma and plan to initiate two additional Phase II studies, for multiple myeloma and radioprotection, during 2016. We are planning additional clinical programs with this novel and promising drug candidate for oncology, inflammatory and gastrointestinal indications."

Charles D. Smith, Ph.D., Apogee’s President and CEO and a co-author of the article, added: "We are pleased that these results provide a rationale for use of YELIVA in a very difficult to treat malignancy. These results further add to the breadth and importance of YELIVA’s mechanism of action studies in multiple human tumors."

Cholangiocarcinoma is a rare cancer that develops in the bile ducts, characterized by its late diagnosis and high mortality rates. Cholangiocarcinoma is the second most common primary liver tumor, accounting for approximately 10-15% of all hepatobiliary malignancies[2]. Although a rare cancer, the incidence and mortality rates of cholangiocarcinoma have been increasing worldwide in the last three decades. The five year survival rates following diagnosis have not increased during this time period, and remain at 10%[3]. Surgery is the only curative treatment option, but only for the minority of patients diagnosed with early-stage disease.

RedHill announced in October 2015 positive top-line results from a Phase I study with YELIVA in patients with advanced solid tumors, the majority of which were gastrointestinal cancer patients, including pancreatic, colorectal and cholangiocarcinoma cancers. Top-line 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 analysis 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 clinical study was initiated in the U.S. evaluating YELIVA in patients with refractory/relapsed diffuse large B-cell lymphoma (DLBCL), including 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. 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.

A Phase I/II study with YELIVA for the treatment of refractory or relapsed multiple myeloma is planned to be initiated in the second quarter of 2016. 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.

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[1] The article was authored by Xiwei Ding, Roongruedee Chaiteerakij, Catherine D. Moser, Hassan Shaleh, Jeffrey Boakye, Gang Chen, Albert Ndzengue, Ying Li, Yanling Zhou, Shengbing Huang, Frank A. Sinicrope, Xiaoping Zou, Melanie B. Thomas, Charles D. Smith, Lewis R. Roberts
[2] A. Bergquist et al. Epidemiology of cholangiocarcinoma, Best Pract Res Clin Gastroenterol. 2015 Apr;29(2):221-32
[3] S. Rizvi and G. J. Gores, Pathogenesis, diagnosis, and management of cholangiocarcinoma, Gastroenterology, vol. 145, no. 6, pp. 1215-1229, 2013.

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 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. A Phase I/II clinical study evaluating YELIVA in patients with refractory/relapsed diffuse large B-cell lymphoma (DLBCL) has been initiated in the U.S. 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.

On March 10, 2016 Ignyta, Inc. (Nasdaq: RXDX), a precision oncology biotechnology company, reported the selection of a recommended Phase 2 dose (RP2D) and initiation of the Phase 1b portion of its Phase 1/1b clinical trial of RXDX-105, the company’s orally available, small molecule multikinase inhibitor with potent activity against such targets as RET and BRAF (Press release, Ignyta, MAR 10, 2016, View Source [SID:1234509455]). The Phase 1b portion of the study utilizes a basket design focusing on patients with solid tumors that contain molecular alterations of RET or BRAF.

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"We are excited to embark on further clinical evaluation of RXDX-105 in selected, molecularly-defined patient populations through this Phase 1b clinical trial expansion," said Pratik Multani, M.D., Chief Medical Officer of Ignyta. "In the now-completed Phase 1 dose escalation and dose finding portion of this clinical study, patients were enrolled without selection for molecular alterations. Given the performance of RXDX-105 in that setting, we now look forward to evaluating this investigational agent at the RP2D in targeted patient populations. We also look forward to providing a clinical data update on this program at an upcoming scientific conference."

About RXDX-105

RXDX-105 is an orally available, small molecule multikinase inhibitor with potent activity against such targets as RET and BRAF.

In November 2015, Ignyta announced interim results from the Phase 1 clinical trial of RXDX-105, which were presented at the 27th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Boston, Massachusetts.

The dose escalation clinical trial was designed to determine the maximum tolerated dose (MTD) and/or RP2D, as well as preliminary anti-cancer activity, of single agent RXDX-105 in patients with advanced or metastatic solid tumors that were not selected based on any molecular alteration.

As of the October 26, 2015, data cut-off for the presentation, the findings showed:

A total of 41 patients with a range of solid tumors were dosed in the clinical trial;
RXDX-105 was well-tolerated;
The MTD and RP2D had not yet been determined;
Pharmacokinetic measurements showed increased exposure with increasing dose, with a half-life compatible with once-daily dosing. Dosing in the fed state appears to further increase exposure;
Exposure was reaching levels expected to be efficacious based on tumor growth inhibition in animal models of RET- and BRAF-driven tumors; and
Tumor regression was observed in six patients treated with 275 mg, including one confirmed partial response (40% reduction) in a patient with non-small cell lung cancer with a KRAS G12C mutation. Two additional patients with thyroid cancer and squamous cell lung cancer exhibited reductions of 20% and 27%, respectively. In patients with tumor regression, there appears to be an exposure/response correlation.

About Ignyta, Inc.

At Ignyta, we fight cancer – a formidable opponent that manifests as thousands of different molecularly defined diseases and takes away millions of lives globally, every year. In this fight, our big hairy audacious goal (BHAG) is not just to shrink tumors but to eradicate residual disease – the source of cancer relapse and recurrence – in precisely defined patient populations by 2030. We will work tirelessly to achieve this BHAG by pursuing an integrated therapeutic (Rx) and companion diagnostic (Dx) strategy for treating cancer patients. Our Rx efforts are focused on discovering, in-licensing or acquiring, then developing and commercializing, molecularly targeted therapies that, sequentially or in combination, are foundational for eradicating residual disease. Our Dx efforts aim to pair these product candidates with biomarker-based companion diagnostics that are designed to precisely identify, at the molecular level, the patients who are most likely to benefit from the therapies we develop. We believe that only through this integrated Rx/Dx approach can we succeed in this fight. For more information, please visit: www.ignyta.com.