Asana BioSciences, LLC to Provide First Presentation of Pre-Clinical Data on its Novel ERK 1/2 Inhibitor Program at the American Association for Cancer Research Annual Meeting

On April 14, 2016 Asana BioSciences, LLC reported that it will present preclinical data regarding its product candidate, ASN007A, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, being held in New Orleans, Louisiana, from April 16-20, 2016 (Press release, Asana BioSciences, APR 14, 2016, View Source [SID:1234510836]). The presentation details are as follows:

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Abstract Number:
187
Title:
ASN007, a potent ERK 1/2 inhibitor with strong antitumor activity in multiple RAS mutant models
Presenter:
Sanjeeva Reddy, Ph.D., Asana BioSciences
Location:
Section 7, Poster Board Number 12
Date:
Sunday, April 17, 2016
Times:
1:00pm – 5:00pm

ERK kinases play a crucial role in RAS/MAPK pathway, which is upregulated in a wide variety of tumors through mutations in RAS or BRAF genes. ERK inhibitors are expected to treat a wide range of tumors with BRAF, MEK, NRAS, HRAS and KRAS mutations including colorectal, pancreatic, lung, breast, ovarian, melanoma and prostate. In addition, they have potential to overcome resistance to BRAF and MEK inhibitors in patients.

ASN007A is one of the lead compounds from Asana’s ERK 1/2 inhibitor program with low nanomolar IC50 values. It showed strong anti-proliferative activity in both BRAF and RAS mutant cell lines, as well as potent anti-proliferative activity in a number of KRAS, NRAS and HRAS mutant cell lines representing various histological tumor types. It demonstrated strong inhibition of tumor growth in multiple xenograft models in mice and was well tolerated at efficacious doses. Based on its profile in preclinical studies, ASN007A is a potential best-in-class molecule expected to show strong efficacy in BRAF and various RAS mutant cancers.

The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53 independent mechanism.

BCL2 blunts activation of the mitochondrial pathway to apoptosis and high-level expression is required for chronic lymphocytic leukemia (CLL) survival. Venetoclax (ABT-199) is a small molecule selective inhibitor of BCL2 currently in clinical trials for CLL and other malignancies. In conjunction with the phase I first-in-human clinical trial of venetoclax in patients with relapsed or refractory CLL (M12-175), we investigated the mechanism of action of venetoclax in vivo, explored whether in vitro sensitivity assays or BH3 profiling correlated with in vivo responses in patients, and determined whether loss of TP53 function affected responses in vitro and in vivo. In all samples tested, venetoclax induced death of CLL cells in vitro at concentrations achievable in vivo, with cell death evident within four hours. Apoptotic CLL cells were detected in vivo 6 or 24 hours after a single 20mg or 50mg dose in some patients. The extent of mitochondrial depolarisation by a BIM BH3 peptide in vitro was correlated with percentage reduction of CLL in the blood and bone marrow in vivo, while the LC50derived from standard cytotoxicity assays was not. CLL cell death in vitro and the depth of clinical responses were independent of deletion of chromosome 17p,TP53mutation and TP53 function. These data provide direct evidence that venetoclax kills CLL cells in a TP53-independent fashion by inhibition of BCL2 in patients, and support further assessment of BH3 profiling as a predictive biomarker for this drug.
Copyright © 2016 American Society of Hematology (ASH) (Free ASH Whitepaper).

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Notch Receptor-Ligand Engagement Maintains Hematopoietic Stem Cell Quiescence and Niche Retention.

Notch is long recognized as a signaling molecule important for stem cell self-renewal and fate determination. Here, we reveal a novel adhesive role of Notch-ligand engagement in hematopoietic stem and progenitor cells (HSPCs). Using mice with conditional loss of O-fucosylglycans on Notch EGF-like repeats important for the binding of Notch ligands, we report that HSPCs with faulty ligand binding ability display enhanced cycling accompanied by increased egress from the marrow, a phenotype mainly attributed to their reduced adhesion to Notch ligand-expressing stromal cells and osteoblastic cells and their altered occupation in osteoblastic niches. Adhesion to Notch ligand-bearing osteoblastic or stromal cells inhibits wild type but not O-fucosylglycan-deficient HSPC cycling, independent of RBP-JK -mediated canonical Notch signaling. Furthermore, Notch-ligand neutralizing antibodies induce RBP-JK -independent HSPC egress and enhanced HSPC mobilization. We, therefore, conclude that Notch receptor-ligand engagement controls HSPC quiescence and retention in the marrow niche that is dependent on O-fucosylglycans on Notch.
© 2015 AlphaMed Press.

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Versatility of Particulate Carriers: Development of Pharmacodynamically Optimized Drug-Loaded Microparticles for Treatment of Peritoneal Cancer.

Intraperitoneal (IP) chemotherapy confers significant survival benefits in cancer patients. However, several problems, including local toxicity and ineffectiveness against bulky tumors, have prohibited it from becoming a standard-of-care. We have developed drug-loaded, tumor-penetrating microparticles (TPM) to address these problems. TPM comprises two components and uses the versatile PLGA or poly(lacticco-glycolic acid) copolymer to provide tumor-selective adherence and pharmacodynamically optimized fractionated dosing to achieve the desired tumor priming (which promotes particle penetration into tumors) plus immediate and sustained antitumor activity. Preclinical studies show that TPM is less toxic and more effective against several IP metastatic tumors with different characteristics (fast vs. slow growing, porous vs. densely packed structures, wide-spread vs. solitary tumors, early vs. late stage, with or without peritoneal carcinomatosis or ascites), compared to the intravenous paclitaxel/Cremophor micellar solution that has been used off-label in previous IP studies. TPM further requires less frequent dosing. These encouraging preclinical results have motivated the follow-up clinical development of TPM. We are working with National Institutes of Health on the IND-enabling studies.

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Synta and Madrigal Announce Merger Agreement to Create Leading Cardiovascular-Metabolic Diseases and NASH Company

On April 14, 2016 Synta Pharmaceuticals Corp. ("Synta") (NASDAQ:SNTA) and Madrigal Pharmaceuticals, Inc., a privately-held company ("Madrigal"), reported that they have entered into a definitive merger agreement (the "Merger") under which Madrigal will merge with a wholly-owned subsidiary of Synta in an all-stock transaction (Press release, Synta Pharmaceuticals, APR 14, 2016, View Source [SID1234626318]). The Merger will create a company focused on the development of novel small-molecule drugs addressing major unmet needs in cardiovascular-metabolic diseases and non-alcoholic steatohepatitis (NASH). Madrigal’s lead compound, MGL-3196, is a Phase 2-ready once-daily, oral, liver-directed selective thyroid hormone receptor-ß (THR-ß) agonist for the treatment of NASH and heterozygous and homozygous familial hypercholesterolemia (HeFH, HoFH). Upon closing of the transaction, the combined company will be named Madrigal Pharmaceuticals, and Paul A. Friedman, M.D. will become Chairman and Chief Executive Officer.

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Under the terms of the merger agreement, Synta will acquire all outstanding shares of Madrigal in exchange for approximately 253.9 million newly issued shares of Synta common stock. Upon completion of the proposed acquisition, it is anticipated that existing Synta shareholders will own 36.0% of the combined company and Madrigal shareholders will own 64.0% of the combined company. The transaction has been approved by the boards of directors of both companies and the shareholders of Madrigal. The merger is expected to close by the end of the third quarter of 2016, subject to customary closing conditions, including approval of the merger by the shareholders of Synta.

An investor syndicate that includes Bay City Capital, Fred Craves, Ph.D., Founder of Bay City Capital, and SQN LLC, a corporation held by Dr. Friedman and Rebecca Taub, M.D., has committed to invest up to $9 million in Madrigal prior to the closing of the Merger. The combined company intends to use these proceeds, in addition to Synta’s cash balance at the closing of the merger, to fund the development of MGL-3196 through Phase 2 clinical studies in NASH, HeFH and HoFH.

"Following an extensive review of strategic alternatives, Synta’s Board of Directors believes that a merger with Madrigal Pharmaceuticals offers shareholders the most compelling opportunity for enhancing long-term value," said Keith R. Gollust, Chairman of Synta. "Madrigal’s lead compound, MGL-3196, is a selective THR-ß agonist with a unique lipid lowering profile that has been validated through early clinical and preclinical studies. The combined company will be well capitalized with a lead program that offers both a potentially substantial commercial opportunity in NASH, and an efficient clinical development plan with commercial potential in genetic lipid disorders."

"MGL-3196 is designed to specifically target thyroid hormone beta receptors in the liver involved in metabolism and cholesterol regulation, and avoid side effects associated with thyroid hormone receptor activation outside the liver," said Dr. Taub, Founder and Chief Executive Officer of Madrigal. "As a result, and because of MGL-3196’s observed high liver uptake and high ß-selectivity, it has a favorable safety profile and did not show adverse findings observed in chronic animal toxicology studies with a prior thyroid agonist. Madrigal has designed Phase 2 clinical programs to establish proof of concepts in both NASH and FH with data readouts for each program anticipated throughout 2017."

MTS Health Partners, L.P. and ROTH Capital Partners, LLC served as financial advisors, and Mintz, Levin, Cohn, Ferris, Glovsky and Popeo, P.C. served as legal counsel to Synta and Stradling Yocca Carlson & Rauth, P.C. served as legal counsel to Madrigal with respect to the transaction.

Management and Organization
Effective with the signing of the merger agreement, Dr. Friedman has stepped down from Synta’s Board of Directors and will join Madrigal as an executive. Pursuant to the merger agreement, Dr. Friedman, the former Chief Executive Officer of Incyte Pharmaceuticals, will become Chairman and Chief Executive Officer of the combined company. Dr. Taub will assume the newly created role of Chief Medical Officer, Executive Vice President, Research & Development, following the closing of the Merger. Additionally, Marc Schneebaum, the current Chief Financial Officer of Synta, will continue as the Chief Financial Officer of the combined company. The board of directors of the combined company will be comprised of seven directors, including five directors of Madrigal: Dr. Friedman (Chairman); Dr. Taub; Fred Craves, Ph.D.; and two additional directors who will be designated, and one current director of Synta: Keith Gollust. There will also be one additional independent director to be agreed upon by Synta and Madrigal. The corporate headquarters will be located in the Philadelphia area.

About MGL-3196
MGL-3196 is an orally administered, small-molecule ß-selective THR agonist being developed for non-alcoholic steatohepatitis (NASH) and heterozygous and homozygous familial hypercholesterolemia (FH) to lower LDL cholesterol, triglyceride levels and Lp(a). It was designed to specifically target receptors in the liver involved in metabolism and cholesterol regulation, and avoid side effects associated with thyroid hormone receptor activation outside the liver, including those mediated by THR-α receptors. MGL-3196 is a potent regulator of hepatic triglyceride metabolism and cholesterol metabolism. In two week studies in humans MGL-3196 has been shown to reduce lipids: 30% for LDL cholesterol; 28% for non- high density lipoprotein (HDL) cholesterol; 24% for Apolipoprotein B, and up to 60% reduction in triglycerides. NASH in humans is a condition in which thyroid receptor-ß activity is diminished. MGL-3196 reduces lipotoxicity associated with NASH and in NASH preclinical models, MGL-3196 potently reduces hepatic triglycerides and markers of inflammation and fibrosis. MGL-3196, in-licensed from Roche Pharmaceuticals, has completed single, multi-ascending dose and drug interaction studies in humans in which the compound demonstrated a favorable safety profile at all doses tested.

Conference Call and Webcast
Synta and Madrigal will host a conference call and webcast slide presentation at 8:30 AM ET today to discuss the Merger. The conference call and presentation can be accessed by logging on to the "Investors" section of the Synta Pharmaceuticals website, www.syntapharma.com, prior to the event.

The conference call can also be accessed by dialing (855) 451-4851 (U.S.) or (503) 343-6064 (International). The conference ID number for the live call is 91034442. For those unable to join the live call, a replay will be available from 11:30 AM ET on April 14 through 11:59 PM ET on April 28. To access the replay, please dial (855) 859-2056 (U.S.) or (404) 537-3406 (International) and refer to conference ID 91034442.