FORMA Therapeutics and CRT to discover cancer drugs targeting deubiquitinating enzymes (DUBs)

On July 9, 2013 FORMA Therapeutics and Cancer Research Technology, Ltd. (CRT), the commercialisation company of Cancer Research UK, reported a bold research initiative to discover innovative tools, technologies and therapeutic drug candidates against a variety of protein homeostasis regulators called, deubiquitinating enzymes (DUBs) (Press release, Cancer Research Technology, SEP 9, 2013, View Source [SID1234523253]).

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Under this agreement, FORMA will pair its ultra-efficient drug discovery capabilities with CRT’s expertise in translating academic discoveries through its Discovery Laboratories (CRT-DL) and the exclusive world-class academic network of Cancer Research UK Principal Investigators.

"This initiative with CRT and Cancer Research UK has the potential to significantly accelerate our understanding of the relevant biological applications of DUBs, a key class of enzymes involved in regulating protein homeostasis," said Steven Tregay, Ph.D., President and CEO, FORMA Therapeutics. "We are particularly looking forward to working closely in this initiative with CRT’s Discovery Laboratories and a group of preeminent investigators, who bring critical insights in this area of important biology and have proven track records in basic and translational research."

Keith Blundy, CEO of Cancer Research Technology stated, "Cancer Research UK’s breadth of research combined with CRT-DL’s drug discovery capabilities are a unique platform that has secured the FORMA relationship and will contribute to bringing breakthrough cancer therapeutics to patients."

Protein ubiquitination is involved in many cellular processes and its regulation is controlled in part by DUBs. Ubiquitin "tags" proteins for degradation, and DUBs remove this tag, providing a tool for manipulating protein levels (protein homeostasis) in a cell. Ubiquitin biology is therefore complex and important to a broad range of human diseases. FORMA and CRT-DL will leverage their combined strengths to explore the protease enzymes that regulate ubiquitin-dependent pathways implicated in cancer.

"DUBs represent an attractive area for drug discovery exploration. As key regulators of ubiquitin recycling, processing, proofreading and disassembly, there is a tremendous opportunity to build a franchise of complementary therapeutics targeting the diverse collections of protein complexes," stated Kenneth W. Bair, Ph.D., Chief Scientific Officer and Head of Research and Development for FORMA Therapeutics. Dr. Bair further noted that a tremendous investment is being made by several groups to propel protein homeostasis research and discoveries into the practice of medicine.

As part of this agreement, a collaborative consortium will be formed consisting of FORMATherapeutics Inc. and up to ten FORMA ADDCos (Asset Discovery and Development Company) subsidiaries, Cancer Research Technology – Discovery Laboratories (CRT-DL) and initially five Principal Investigators including:

Professors Michael Clague and Sylvie Urbé – University of Liverpool, Liverpool, UK
Dr. Benedikt Kessler – The University of Oxford, UK
Dr. David Komander – Medical Research Council, Laboratory of Molecular Biology, Cambridge, UK
Dr. Huib Ovaa – Chemical Biology Laboratory, Netherlands Cancer Institute, The Netherlands.
These investigators will focus on furthering the consortium’s understanding of biological and structural insights of DUBs, and assist the discovery teams to ensure the most relevant screening technologies and secondary characterisation assays are deployed for selection of lead candidates. FORMA will provide research funding support and defined compensation payments for DUB-specific ADDCo programs that achieve specified milestones.

Rob Sarisky, Chief Business Officer, FORMA Therapeutics, stated, "We are pleased to have CRT participate as a cornerstone partner in FORMA’s launch of the ADDCo framework. This vehicle allows our not-for-profit collaborators to access a capital efficient engine operating at scale, attain financial returns mirroring their contributions and collectively advance medical science within the framework of a unified team."

Harpal Kumar, Chief Executive of Cancer Research UK, added, "Our research is saving lives. We are making great progress in uncovering the causes of cancer to find better ways to tackle the disease. But there is much still to do and highly collaborative partnerships focused on novel biological pathways to deliver new treatments are urgently needed. This alliance with FORMA allows us to explore a very exciting emerging area of biology to identify and develop potential new cancer drugs that will hopefully benefit patients in the future."

Astex Pharmaceuticals Announces IND Candidate: ASTX727 a Potential Best-in-Class Oral Hypomethylator

On July 8, 2013 Astex Pharmaceuticals reported its plan to submit an Investigational New Drug or IND application to the Food and Drug Administration (FDA) for ASTX727, a novel oral hypomethylating agent (HMA) in the fourth quarter of this year (Press release Astex Pharmaceuticals, JUL 8, 2013, View Source [SID:1234500358]).
ASTX727 is intended as a fixed dose oral combination product consisting of decitabine and E7727, a novel cytidine deaminase inhibitor (CDAi) licensed from Eisai Inc. ASTX727 allows for an efficient oral delivery of decitabine at low doses. Relevant animal studies revealed that the product can result in therapeutic exposures of decitabine at low doses. The profile of E7727 is expected to result in low inter-patient variability across doses of decitabine with little or no gastrointestinal safety issues. Later this year, preclinical data on ASTX727 will be submitted for presentation at a scientific meeting.
Cytidine deaminase (CDA) is an enzyme that is responsible for the degradation of nucleosides, including decitabine and azacitidine. High levels of CDA in the gastrointestinal tract and liver rapidly degrade these nucleosides and prohibit or limit their oral bioavailability. E7727 is a proprietary and patented New Molecular Entity (NME) with a very wide therapeutic margin that inhibits CDA activity. Decitabine can be delivered orally and efficiently absorbed in the gut when it is combined with E7727 due to the inhibition of CDA by E7727. ASTX727 is being developed as a fixed dose oral product that combines E7727 and decitabine. This oral HMA with the potential to be best-in-class will enter clinical development in 2014. Astex has a worldwide license to E7727 from Eisai Inc.

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Comprehensive Summary of Preclinical and Clinical Data for Pacritinib Published in Drugs of the Future

On July 3, 2013 Cell Therapeutics reported that a comprehensive article summarizing preclinical and clinical data for pacritinib, an oral JAK2/FLT3 inhibitor, authored by Srdan Verstovsek, M.D., Ph.D., et al., was published in the journal Drugs of the Future 2013 (Press release CTI BioPharma, JUL 2, 2013, View Source;p=RssLanding&cat=news&id=1835062 [SID:1234500579]). The article reviews the preclinical pharmacology and pharmacokinetics in addition to the safety and efficacy results from the Phase 1 and 2 clinical studies of pacritinib in patients with myelofibrosis and lymphoma.

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The authors conclude that the clinical trials to date support the safety, efficacy and predictable pharmacokinetic profile of pacritinib. The hematological adverse events have been uncommon and no dose reductions for thrombocytopenia were necessary in the Phase 2 studies. In the two studies that enrolled patients with myelofibrosis, pacritinib led to disease response, improvement in splenomegaly (enlargement of the spleen) and lowered white blood cell count, and symptom reduction in patients with and without thrombocytopenia, or low blood cell count.

Pacritinib is currently being evaluated in a randomized Phase 3 clinical trial, known as PERSIST-1, in patients with myelofibrosis. Because of pacritinib’s relative lack of bone marrow suppression, there are no study entry restrictions due to thrombocytopenia or anemia and patients with platelet and red blood cell transfusion dependence are allowed to enroll in the ongoing PERSIST-1 trial. More details on this study can be found at www.clinicaltrials.gov. Pacritinib has orphan drug designation in the United States and Europe.

Regulus has a research collaboration with the Samsung Biomedical Research Institute for testing anti-miR-10b development candidates in specialized preclinical models that mimic human brain cancer (Filing, S-1, Regulus, JUN 26, 2013, View Source [SID:1234503630])

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Human anti-PD-L1/PD-1 Antibodies Exhibit Potent Immune Cell Activation

(Poster Next Generation Protein Therapeutics Summit 2013, Sorrento Therapeutics, JUN 26, 2013, View Source [SID:1234500776])

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