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.

10-Q/A [Amend] – Quarterly report [Sections 13 or 15(d)]

(Filing, 10-K, TapImmune, 2015, APR 14, 2016, View Source [SID:1234510877])

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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.

Autophagy protects ovarian cancer-associated fibroblasts against oxidative stress.

RNA-Seq and gene set enrichment anylysis revealed that ovarian cancer associated fibroblasts (CAFs) are mitotically active compared with normal fibroblasts (NFs). Cellular senescence is observed in CAFs treated with H2O2 as shown by elevated SA-β-gal activity and p21 (WAF1/Cip1) protein levels. Reactive oxygen species (ROS) production and p21 (WAF1/Cip1) elevation may account for H2O2-induced CAFs cell cycle arrest in S phase. Blockage of autophagy can increase ROS production in CAFs, leading to cell cycle arrest in S phase, cell proliferation inhibition and enhanced sensitivity to H2O2-induced cell death. ROS scavenger NAC can reduce ROS production and thus restore cell viability. Lactate dehydrogenase A (LDHA), monocarboxylic acid transporter 4 (MCT4) and superoxide dismutase 2 (SOD2) were up-regulated in CAFs compared with NFs. There was relatively high lactate content in CAFs than in NFs. Blockage of autophagy decreased LDHA, MCT4 and SOD2 protein levels in CAFs that might enhance ROS production. Blockage of autophagy can sensitize CAFs to chemotherapeutic drug cisplatin, implicating that autophagy might possess clinical utility as an attractive target for ovarian cancer treatment in the future.

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PharmaMar Announces Presentations at American Association for Cancer Research (AACR) Annual Meeting 2016

On April, 14 2016. PharmaMar (MSE:PHM) reported four poster presentations at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) annual meeting, taking place in New Orleans, April 16-20th 2016 (Press release, PharmaMar, APR 14, 2016, View Source [SID:1234510832]). The presentations are based on the latest data obtained on the company’s compounds of marine origin, lurbinectedin, plitidepsin and PM184. Under the heading "Delivering Cures Through Cancer Science", oncologists and investigators from around the world will interchange knowhow and reinforce the links between research and the advancements in patient care.

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PharmaMar will present results from three molecules that are presently under clinical investigation in different types of solid and hematological tumors. Each one of these compounds has a very different mechanism of action. Apart from its direct activity on tumor cells, lurbinectedin (PM1183) also attacks the microenvironment, rendering tumor growth unfeasible. Plitidepsin (Aplidin), targets the eEF1A2 protein, and finally PM184 disrupts the tumor’s blood vessels, causing a reduction in the supply of both nutrients and oxygen to the tumor cells.

"At PharmaMar we have a commitment to the identification of new and novel mechanisms of action from marine compounds that can provide a step forward in the treatment of patients with cancer," explains Carmen Cuevas, Ph.D., R&D Director from the Oncology Business Unit at PharmaMar. "The results that we will present at scientific congresses such as the AACR (Free AACR Whitepaper) show that we are on right path and that we can count on a robust pipeline that will provide new methods for attacking tumor cells." 2
Presentation details are as follows:

PM1183 (lurbinectedin)
PM1183 is compound under clinical investigation, inhibitor of the RNA polymerase II enzyme. It is essential for the transcription process, inhibiting tumor growth, and resulting in tumor death. The antitumor efficacy of PM1183 is being investigated in various types of solid tumors.

Lurbinectedin reduces tumor-associated macrophages and the production of inflammatory cytokines, chemokines and angiogenic factors in preclinical models (abstract No 1284). Paola Allavena et al. Poster presentation, section 18, Monday April 18th, 8:00 am – 12:00 am.

This proves that part of lurbinectedin’s antitumor activity is due to its antiproliferative activity in monocytes and tumor associated macrophages, cells that are essential in the inflammatory microenvironment. Lurbinectedin inhibits transcription, therefore, the production of cytokines and angiogenic factors by these cells. Tumor growth is unfeasible, even when the tumor cells are resistant to the compound.

Lurbinectedin specifically targets transcription in cancer cells, triggering DNA breaks and degradation of phosphorylated Pol II (Abstract No 3039). Gema Santamaría-Nuñez et al. Poster presentation, section 17, Tuesday April 19th , 8:00 am-12:00 am.
Lurbinectedin (PM1183) binds to the DNA in the CG rich regions surrounding the promoter of genes, inhibiting transcription activity. The mechanism involves the ubiquitination and degradation by proteasome of the RNA polymerase II (pol II). The degradation of pol II is directly related to the appearance of DNA damage and the induction of cell death through apoptosis.

Plitidepsin (Aplidin)
Plitidepsin is an antitumor drug of marine origin, at the investigational phase for hematological tumors, including a phase Ib study in relapsed and refractory Multiple Myeloma, in triple combination with bortezomib and dexamethasone, along with a phase II study in Relapsed and Refractory Angioimmunoblastic T-cell Lymphoma. Recently, positive results have been seen in pivotal study in combination with dexamethasone in patients with Multiple Myeloma. 3

Plitidepsin targets the GTP-bound form of eEF1A2 in cancer cells (Abstract No 3015). Alejandro Losada et al. Poster presentation, section 17, Tuesday April 19th, 8:00am-12:00am.

This confirms that the protein eEF1A2 is Aplidin’s pharmacological target. This protein has numerous functions within the tumor cell, some of which have a marked oncogenic character. This assay delves into the peculiarities of the direct interaction of Aplidin with purified GTP bound eEF1A2.

PM184
PM184 is an inhibitor of tubulin polymerization. It is at the clinical development stage for solid tumors, including a Phase II trial in hormone-receptor positive, HER2-negative, locally advanced and/or metastatic breast cancer.

Anti-angiogenic properties of PM184 (Abstract No 3066). Carlos M. Galmarini et al. Poster presentation, section 25, Tuesday April 19th, 8:00am-12:00am.

The tumor cells rapidly growth, needing the supply of a large quantity of nutrients. One of the paths for the treatment of cancer at the moment is to disrupt the blood cells within the tumor, or to stop the development of new cells, cutting the supply of nutrients and oxygen to the tumor cells. Adding to its capacity to specifically eliminate tumor cells, PM184 has shown itself to have a strong intratumor vascular disrupting activity, inhibiting in this extraordinarily effective way, human transplanted tumors in mice.