Author: [email protected]

A Phase 1, Multi-Center, Open-Label, Dose-Escalation Study of 131I-CLR1404 in Subjects with Relapsed or Refractory Advanced Solid Malignancies.

This study explores the imaging and therapeutic properties of a novel radiopharmaceutical, (131)I-CLR1404. Phase 1a data demonstrated safety and tumor localization by SPECT-CT. This 1b study assessed safety, imaging characteristics, and possible antineoplastic properties and provided further proof-of-concept of phospholipid ether analogues’ retention within tumors. A total of 10 patients received (131)I-CLR1404 in an adaptive dose-escalation design. Imaging characteristics were consistent with prior studies, showing tumor uptake in primary tumors and metastases. At doses of 31.25 mCi/m(2) and greater, DLTs were thrombocytopenia and neutropenia. Disease-specific studies are underway to identify cancers most likely to benefit from (131)I-CLR1404 monotherapy.

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Targeting HIV-1 Env gp140 to LOX-1 Elicits Immune Responses in Rhesus Macaques.

Improved antigenicity against HIV-1 envelope (Env) protein is needed to elicit vaccine-induced protective immunity in humans. Here we describe the first tests in non-human primates (NHPs) of Env gp140 protein fused to a humanized anti-LOX-1 recombinant antibody for delivering Env directly to LOX-1-bearing antigen presenting cells, especially dendritic cells (DC). LOX-1, or 1ectin-like oxidized low-density lipoprotein (LDL) receptor-1, is expressed on various antigen presenting cells and endothelial cells, and is involved in promoting humoral immune responses. The anti-LOX-1 Env gp140 fusion protein was tested for priming immune responses and boosting responses in animals primed with replication competent NYVAC-KC Env gp140 vaccinia virus. Anti-LOX-1 Env gp140 vaccination elicited robust cellular and humoral responses when used for either priming or boosting immunity. Co-administration with Poly ICLC, a TLR3 agonist, was superior to GLA, a TLR4 agonist. Both CD4+ and CD8+ Env-specific T cell responses were elicited by anti-LOX-1 Env gp140, but in particular the CD4+ T cells were multifunctional and directed to multiple epitopes. Serum IgG and IgA antibody responses induced by anti-LOX-1 Env gp140 against various gp140 domains were cross-reactive across HIV-1 clades; however, the sera neutralized only HIV-1 bearing sequences most similar to the clade C 96ZM651 Env gp140 carried by the anti-LOX-1 vehicle. These data, as well as the safety of this protein vaccine, justify further exploration of this DC-targeting vaccine approach for protective immunity against HIV-1.

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OSE Pharma and Effimune announce the signing of the Merger Treaty to create OSE Immunotherapeutics

On April 15, 2016 OSE Pharma (ISIN : FR0012127173 ; Mnemo : OSE), an immuno-oncology company with a specific immunotherapy activating T lymphocytes, currently in a registration Phase 3 study, and Effimune, a biotech company specialized in immune regulation with clinical applications in autoimmunity, transplantation and immune-oncology, reported the signing of the Merger Treaty to create OSE Immunotherapeutics, a player in the field of activation and regulation immunotherapy (Press release, OSE Immunotherapeutics, APR 15, 2016, View Source [SID1234519634]). The terms of the merger will be submitted for approval to the shareholders of the two companies during the next General Meetings.

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The Merger Treaty, signed following announcement of the merger project on February 24, 2016, confirms the terms of the proposed transaction. The merger will be submitted for approval to the shareholders during both companies’ General Meetings which will be convened o n May 30, 2016 for Effimune and on May 31, 2016 for OSE Pharma.

After completion of the merger, the shareholders of OSE Pharma will hold approximately 71% of the capital of the merged entity and the shareholders of Effimune will own approximately 29%. The agreement will take the form of a merger by OSE Pharma of Effimune at the end of which the shareholders of Effimune will receive 1.93 newly issued share s of OSE Pharma (corresp onding to an issuing of approximately 4 million OSE Pharma new shares) in exchange for each 1 held share of Effimune.

To reflect the change in company profile brought by the merger, it is expected that OSE Pharma will be renamed "OSE Immunotherapeutics", and the headquarters will be transferred from Paris (France) to Nantes (France), reflecting Effimune ’s strong academic establishment.

A Merger Prospectus (Document E) registered by the "Autorité des Marchés Financiers" (French stock exchange market regula tor) and other detail ed information regarding the characteristics and terms of the merger will be soon provided to the shareholders of OSE Pharma and Effimune, according to the legal and regulatory provisions. Any decision to join in the merger must be based on the full documentation regarding this intended merger, especially on the Merger Treaty posted this day on the website of the two companies, and on the Merger Prospectus which will be registered (Document E) by the "Autorité des Marchés Financiers" and published before the Extraordinary General Meetings of the two companies.

ARIAD Presents Updated Phase 1/2 Clinical Data on Brigatinib in Patients with ALK+ Non-Small Cell Lung Cancer

On April 15, 2016 ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) reported updated clinical data on its investigational tyrosine kinase inhibitor, brigatinib, in patients with advanced malignancies, including anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC), from an ongoing Phase 1/2 trial (Press release, Ariad, APR 15, 2016, View Source [SID:1234510870]).

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This report includes updated data on the brigatinib safety profile and pharmacokinetics (PK) from all patients treated in the trial, with a focus on brigatinib clinical activity in patients with ALK+ NSCLC, including those with intracranial CNS metastases at study entry. The report also details overall survival outcomes of patients in the study.

The updated results were presented at the 6th European Lung Cancer Conference (ELCC) being held in Geneva, Switzerland.

Phase 1/2 Study

The data presented at ELCC include pharmacokinetics and safety analyses on all patients in the trial (n=137) and efficacy analyses on patients with ALK+ NSCLC (n=79). The presentation is based on patient data as of February 2015 with a median time on treatment for ALK+ NSCLC patients of 12.6 months (range, 0.03 – 35.5+ months). Patient enrollment in the trial is complete, with the last patient enrolled in July 2014. The primary endpoint in the Phase 2 portion of the trial is overall response rate. Secondary endpoints include safety and tolerability, pharmacokinetic parameters, progression free survival, and overall survival.

"The updated data from the Phase 1/2 trial of brigatinib show a one year overall survival rate of 100 percent in crizotinib-naive patients, and 81 percent in patients with prior crizotinib treatment," stated Rafael Rosell, M.D., Director, Cancer Biology & Precision Medicine Program Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital in Barcelona, Spain. "In addition, the new data show predictable pharmacokinetics, with drug exposure increasing proportionally with dose. The Phase 1/2 trial has provided important long-term follow-up data on the safety and efficacy of this promising drug candidate."

Key Data Update from Study

Anti-tumor Activity – ALK+ NSCLC Patients:

Of the 70 evaluable ALK+ NSCLC patients with prior crizotinib therapy treated with brigatinib, median progression-free survival (PFS) was 13.4 months. Median PFS was not yet reached in ALK+ NSCLC patients who were crizotinib-naive (n=8).

The "waterfall plot" analysis demonstrated tumor shrinkage in nearly all evaluable ALK+ NSCLC patients, with 25 patients experiencing 100% shrinkage of the target lesion.

Of the eight evaluable TKI-naive ALK+ NSCLC patients treated with brigatinib, all demonstrated an objective response (100%), including three complete responses. Seven responses were confirmed.

Of the 70 evaluable ALK+ NSCLC patients with prior crizotinib therapy treated with brigatinib, 50 (71%) demonstrated an objective response, including four complete responses. Forty-three responses were confirmed.

The one-year overall survival (OS) rate in ALK+ NSCLC crizotinib-naive patients (n=8) was 100 percent and the projected two-year OS is also estimated to be 100 percent. Of the 71 ALK+ NSCLC patients who received prior treatment with crizotinib, the one-year OS was estimated to be 81 percent with projected two-year OS estimated to be 71 percent.

An evaluation of the efficacy of brigatinib in ALK+ NSCLC patients with intracranial CNS metastases at baseline was also included in the ELCC presentation. In an independent central review of brain magnetic resonance imaging (MRI) scans, 50 of 79 ALK+ NSCLC patients were identified to have intracranial CNS metastases at baseline.

Of these 50 patients, 17 had measurable intracranial CNS metastases (15 evaluable), and 33 patients had only non-measurable intracranial CNS metastases (31 evaluable).

8 of 15 (53%) patients with measurable intracranial CNS metastases had at least 30% reduction in intracranial target lesion diameter, and 11 of 33 (33%) with only non-measurable intracranial CNS metastases had complete disappearance of intracranial lesions.

Median intracranial PFS for evaluable ALK+ NSCLC patients with intracranial CNS metastases at baseline was 15.6 months.
Pharmacokinetics:

The brigatinib plasma steady-state parameters increased proportionally with dose over the dose range of 60 to 240 mg once daily.
The geometric mean average plasma concentrations of brigatinib at steady state at 90 mg once daily and 180 mg once daily exceed the IC50 values for native ALK and all clinically relevant ALK resistance mutants tested.

Safety and Tolerability – All Patients Enrolled:

The most common treatment-emergent adverse events (TEAEs; ≥ 30%), regardless of treatment relationship, were nausea (52%), fatigue (42%), diarrhea (40%), headache (33%), and cough (32%).

TEAEs, grade 3 or higher, occurring in three or more patients were increased lipase (9%), dyspnea (7%), hypertension (5%), hypoxia (5%), neoplasm progression (5%), pneumonia (5%), increased amylase (4%), fatigue (4%), and pulmonary embolism (≥3%).

Serious AEs, all causality, occurring in three or more patients were dyspnea (7%), pneumonia (6%), hypoxia (5%), neoplasm progression (5%), pulmonary embolism (3%), malignant pericardial effusion (2%), and pyrexia (2%).

A subset of pulmonary events, including dyspnea, hypoxia, pneumonia and/or pneumonitis, often with radiographic findings of linear or ground-glass pulmonary opacities, were observed in 8% (11/137) of patients within 7 days of dosing. The incidence of these early-onset pulmonary events was lower with a starting dose of 90 mg (1/50 patients, 2%) vs. 180 mg (6/44 patients, 14%). In addition, no early-onset pulmonary events were observed after dose escalation in the 32 patients started at 90 mg and escalated to 180 mg after seven days.

"As we continue to study brigatinib in the ongoing Phase 1/2 trial, the pivotal Phase 2 ALTA trial and the new Phase 3 ALTA 1L trial in the front-line setting, we are encouraged by the potential of this targeted drug candidate for patients with ALK positive NSCLC and are looking forward to an NDA submission later this year," stated Timothy P. Clackson, Ph.D., president of research and development and chief scientific officer at ARIAD. "The safety, PK and efficacy results reported with this update provide the potential for differentiation of brigatinib in the crizotinib-resistant patient population."

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.