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Bristol-Myers Squibb and Five Prime Therapeutics Announce Exclusive Clinical Collaboration to Evaluate the Combination of Investigational Immunotherapies Opdivo (nivolumab) and FPA008 in Six Tumor Types

On November 24, 2014 Bristol-Myers Squibb and Five Prime Therapeutics reported that they have entered into an exclusive clinical collaboration agreement to evaluate the safety, tolerability and preliminary efficacy of combining Opdivo (nivolumab), Bristol-Myers Squibb’s investigational PD-1 (programmed death-1) immune checkpoint inhibitor, with FPA008, Five Prime’s monoclonal antibody that inhibits colony stimulating factor-1 receptor (CSF1R) (Press release Bristol-Myers Squibb, NOV 24, 2014, View Source [SID:1234501008]). The Phase 1a/1b study will evaluate the combination of Opdivo and FPA008 as a potential treatment option for patients with non-small cell lung cancer (NSCLC), melanoma, head and neck cancer, pancreatic cancer, colorectal cancer and malignant glioma. Bristol-Myers Squibb has proposed the name Opdivo, which, if approved by health authorities, will serve as the trademark for nivolumab.

Opdivo and FPA008 are part of a new class of cancer treatments known as immunotherapies that are designed to harness the body’s own immune system to fight cancer. Opdivo is approved in Japan for the treatment of patients with unresectable melanoma, and is being developed in multiple tumor types in more than 50 clinical trials. FPA008, in development as a potential treatment for rheumatoid arthritis (RA) and solid tumors, has initiated dosing for a Phase 1 clinical trial in RA. Preclinical data suggest that combining antibodies targeting PD-1 and CSF1R may lead to an enhanced anti-tumor immune response compared to either approach alone in treating cancer.

“This collaboration supports our strategy to expand the clinical development of Opdivo, including novel combination regimens and across numerous tumor types,” said Michael Giordano, senior vice president, Head of Development, Oncology, Bristol-Myers Squibb. “We are excited to build upon our existing relationship with Five Prime Therapeutics in immuno-oncology, and explore the full potential of Opdivo and FPA008 in multiple tumor types.”

“We are pleased to establish a second collaboration with Bristol-Myers Squibb in the area of immuno-oncology,” said Lewis T. “Rusty” Williams, M.D., Ph.D., president and chief executive officer of Five Prime. “Their vision aligns with our commitment to advancing promising immune-modulating targets, alone or in combination, to create next-generation immunotherapies for cancer patients. We look forward to initiating this study and expanding the development of FPA008 as a potential immunotherapy for these six types of cancer.”

Under the terms of this agreement, Bristol-Myers Squibb will make a one-time payment of $30 million to Five Prime and will be responsible for study costs. Five Prime will conduct the clinical trial, which is expected to begin in 2015. The agreement provides for exclusivity with respect to the development, with a collaborative partner, of combination regimens of anti-PD-1/PDL1 antagonists together with an anti-CSF1R antagonist. Bristol-Myers Squibb will have a time-limited right of first refusal subject to certain conditions if Five Prime wishes to seek a partner for FPA008.

Amgen Announces Termination Of All Amgen-Sponsored Clinical Studies Of Rilotumumab In Advanced Gastric Cancer

On November 24, 2014 Amgen reported the termination of all Amgen-sponsored clinical studies of rilotumumab in advanced gastric cancer, including the Phase 3 RILOMET-1 and RILOMET-2 studies (Press release Amgen, NOV 24, 2014, View Source [SID:1234501006]). Amgen’s decision is based on a planned safety review by the RILOMET-1 independent data monitoring committee that found an increase in the number of deaths in the rilotumumab and chemotherapy treatment arm when compared to the chemotherapy treatment only arm. Protocol-defined futility criteria would likely have been met at the planned interim analysis, scheduled for March 2015. Detailed results of RILOMET-1 will be submitted for presentation and publication.

“While we are disappointed with these results, we will work with lead investigators to further analyze the data in order to help inform future research and therapies in this area,” said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. “There is a high unmet need for new treatments to address advanced gastric cancer, one of the leading causes of cancer death worldwide.”

Amgen is in communication with investigators in rilotumumab studies to coordinate study termination and provide guidance for study subject follow-up.

£50M CRT Pioneer Fund announces investment to develop lung cancer drugs at Cancer Research UK’s Manchester Institute

On November 21, 2014 The Cancer Research Technology Pioneer Fund (CPF) reported a collaboration with the Cancer Research UK Manchester Institute Drug Discovery Unit*, at The University of Manchester, to develop a promising class of drugs called RET inhibitors to treat cancer (Press release, Cancer Research Technology, NOV 21, 2014, View Source [SID1234523219]).

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Cancer Research Technology (CRT), Cancer Research UK’s commercial arm, and the European Investment Fund (EIF) launched the £50M CPF in 2012 to bridge the UK funding gap between cancer drug discovery and early drug development. Sixth Element Capital was appointed to manage the fund.

Today’s investment is the fourth made by the CPF. It will build on research by scientists at Cancer Research UK’s Manchester Institute, enabling them to accelerate the development of RET inhibitors and fund early clinical trials of potential drugs developed through the collaboration.

The RET gene plays a critical role in the development of medullary thyroid cancer. And up to two percent of non-small cell lung adenocarcinomas – originating in the mucus-secreting cells lining the airways – have RET mutations. The goal of the project is to discover novel compounds that will specifically focus on the RET gene in a targeted population of patients.

Ian Miscampbell, managing partner of Sixth Element Capital, said: "We’re delighted to announce the fourth project to be funded by the CRT Pioneer Fund at the Cancer Research UK Manchester Institute and to be collaborating with their world class team. Their expertise in cancer drug discovery and in the genetics of non-small cell lung cancer makes this a very exciting investment for CPF.

"This investment will pave the way for potential new cancer drugs to be taken into Phase I clinical trials. If the first studies are successful we will seek industry partners to further develop and commercialise these drugs."

Dr Donald Ogilvie, head of drug discovery at the Cancer Research UK Manchester Institute at The University of Manchester, said: "We’re extremely pleased to work with the CRT Pioneer Fund to help accelerate progress on the exciting RET inhibitors discovered by Cancer Research UK scientists at our Institute. Lung cancer remains a significant clinical challenge. As part of the Cancer Research UK Centre of Excellence on Lung Cancer, we are determined to deliver new treatments into the clinic for this disease and this programme offers the potential to improve the outlook for cancer patients."

Dr Keith Blundy, chief executive of Cancer Research Technology, said: "It’s fantastic news that CRT’s Pioneer Fund will help accelerate this important research from the lab to a stage where it could potentially benefit patients. It’s absolutely essential that we take steps to bridge the innovation gap in UK drug discovery, so that patients can quickly access the promising new drugs being developed in Cancer Research UK labs and elsewhere around the world."

Blueprint Medicines Unveils New Drug Discovery Program for Patients with
RET Fusions at 26th EORTC-NCI-AACR Symposium

On November 20, 2014 Blueprint Medicines disclosed a new drug discovery program targeting cancers with RET fusions and predicted resistance mutations (Press release, Blueprint Medicines, NOV 20, 2014, View Source [SID:1234508104]). The announcement was made during an oral presentation at the 26th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain, on Blueprint Medicines’ discovery of several novel kinase fusions implicated in cancer and identification of several new cancer indications for known kinase fusions.
"One of the greatest challenges in treating cancer is addressing cancer cells’ ability to become resistant to therapy. Our new drug discovery program uniquely addresses both the activated wild-type form of RET and its predicted resistance mutations, enabling us to potentially develop a transformative therapy for cancer patients with RET fusions," said Christoph Lengauer, PhD, MBA, Chief Scientific Officer of Blueprint Medicines. "With the unveiling of this program, we add another proof point for the productivity of Blueprint Medicines’ team and the differentiation of its kinase-focused drug discovery platform, which combines an innovative target discovery engine with a first-of-its-kind fully-annotated chemical library."
Using proprietary computational tools and techniques, Blueprint Medicines’ scientists identified RET fusions in four of 20 cancer types analyzed, including thyroid, lung, breast and colon cancers, providing a strong rationale for the development of a novel RET inhibitor across multiple patient populations. The identification of RET fusions in colon and breast cancers was one of the novel findings in the research. Combining genomics with structural and cell biology, Blueprint Medicines’ scientists were able to predict future resistance mutations of RET inhibitors currently in clinical studies. Blueprint Medicines’ drug discovery is ongoing.
Blueprint Medicines’ new RET inhibitor program adds to the Company’s existing pipeline, consisting of BLU-285, the first known selective inhibitor of KIT Exon 17 for patients with systemic mastocytosis and gastrointestinal stromal tumors (GIST), and BLU-554, the first known selective FGFR4 inhibitor for patients with hepatocellular carcinoma (HCC). Blueprint Medicines expects to initiate clinical trials for its KIT and FGFR4 programs in 2015.
Fusion genes (or fusions) are known to contribute to the development of cancers. A fusion gene is formed from the abnormal association of two normally separated genes, as a result of a translocation or other chromosomal rearrangements. Fusion genes are proven cancer drug targets, and a number of approved and exploratory drugs target kinase fusions.

OncoSec Medical and the University of Washington Enter Sponsored Research Agreement

On November 20, 2014 OncoSec Medical reported that it has entered into a Sponsored Research Agreement (SRA) with the University of Washington to evaluate the immunologic mechanisms of intratumoral DNA IL-12 electroporation (Press release OncoSec Medical, NOV 20, 2014, View Source [SID:1234500996]).

Dr. I. Nicholas Crispe, MBBS, PhD, a professor in the Department of Immunology at the University of Washington and an expert in liver immunology and tolerance, will serve as the principal investigator. Using a novel liver cell isolation approach, Dr. Crispe has demonstrated that different types of liver cells have the capacity to present antigens, which likely contributes to hepatic immunosuppressive mechanisms. In this SRA, Dr. Crispe will apply these techniques to the B16 melanoma tumor model to not only better understand the systemic mechanisms of intratumoral DNA IL-12 electroporation (ImmunoPulse), but also to potentially identify other molecular targets that might combine with IL-12 to enhance immune response.

Dr. Robert H. Pierce, Chief Scientific Officer of OncoSec Medical, said, "We are excited to embark on this project with Dr. Crispe, who has tremendous expertise in mechanisms of immune tolerance. We believe he will bring fresh insights into tumor immuno-biology from his extensive knowledge of mechanisms of pathogen-induced immuno-subversion."

Dr. Crispe said, "We are focusing on taking the insights we have learned from studies of the basic biology of immune tolerance, and translating them directly to a model of human cancer. Although our initial target is malignant melanoma, we believe it is likely that data from these studies will be directly applicable to other cancers."

Interleukin-12 (IL-12) is a potent inflammatory cytokine that regulates multiple aspects of the immune system; in particular, it initiates both innate and adaptive immune responses. IL-12 is a key driver of the cascade of biological events that ultimately lead to T-cell-specific killing of cancer cells. Moreover, cytokines and chemokines induced by this pathway also increase the recruitment of inflammatory T-cells into tumors.

ImmunoPulse is a proprietary investigational electroporation device that delivers plasmid IL-12 DNA directly into tumors. By locally delivering and expressing IL-12, ImmunoPulse has shown in clinical studies to elicit anti-tumor immune activity, which has led not only to local tumor regression, but also to systemic anti-tumor regression, while mitigating toxicities typically observed with systemic administration of IL-12. Preliminary interim data from OncoSec’s ongoing Phase II study in melanoma provide evidence that local delivery of IL-12 by electroporation increases the production of cytokines such as IFN-γ, resulting in increased expression of genes related to the processes required for cytotoxic CD8+ T cells to recognize and kill cancer cells.