On February 23, 2015 Novartis reported that the US Food and Drug Administration (FDA) has approved Farydak (panobinostat, previously known as LBH589) capsules in combination with bortezomib and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior regimens, including bortezomib and an immunomodulatory (IMiD) agent (Press release Novartis, FEB 23, 2015, View Source [SID:1234501839]).

“Farydak represents an exciting agent with a new mechanism of action that is part of a promising class of drugs in this setting,” said study investigator Paul Richardson, MD, Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute. “Importantly, Farydak has been shown to improve progression-free survival in relapsed multiple myeloma patients who have received at least two prior regimens, including bortezomib and an IMiD, which is an area of particular unmet medical need.”

Farydak has been shown to extend the progression-free survival (PFS) benefit of the standard-of-care therapy in this patient population. Farydak is approved under accelerated approval based on PFS. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. The FDA’s accelerated approval program gives patients access to treatments for serious or life-threatening illnesses that provide meaningful therapeutic benefit over existing treatments. The FDA has approved a risk evaluation and mitigation strategy (REMS) for Farydak. The REMS program serves to inform and educate healthcare professionals about the risks that may be associated with Farydak treatment.

This FDA approval is based on efficacy and safety data in a pre-specified subgroup analysis of 193 patients who had received prior treatment with both bortezomib and an IMiD during the Phase III, randomized, double-blind, placebo-controlled, multicenter global registration trial, called PANORAMA-1 (PANobinostat ORAl in Multiple MyelomA). The trial found that the median PFS benefit increased in Farydak patients who had received prior treatment with both bortezomib and an IMiD (10.6 months; n=94), as compared to the placebo arm (5.8 months; n=99) (hazard ratio=0.52 [95% confidence interval (CI): 0.36, 0.76]).

The most common adverse reactions (incidence >= 20%) in clinical studies are diarrhea, fatigue, nausea, peripheral edema, decreased appetite, pyrexia and vomiting. The most common non-hematologic laboratory abnormalities (incidence >= 40%) are hypophosphatemia, hypokalemia, hyponatremia and increased creatinine. The most common hematologic laboratory abnormalities (incidence >= 60%) are thrombocytopenia, lymphopenia, leukopenia, neutropenia and anemia. Farydak can cause fatal and serious toxicities including severe diarrhea and cardiac toxicities. Severe diarrhea occurred in 25% of Farydak-treated patients. Severe and fatal cardiac ischemic events, including severe arrhythmias and ECG changes have occurred in patients receiving Farydak. Serious adverse events (SAEs) occurred in 60% of patients treated with Farydak, bortezomib and dexamethasone compared to 42% of patients in the control arm. The most frequent (>= 5%) treatment-emergent SAEs reported for patients treated with Farydak were pneumonia (18%), diarrhea (11%), thrombocytopenia (7%), fatigue (6%) and sepsis (6%). Additional serious adverse reactions included hemorrhage, myelosuppression, infections, hepatotoxicity and embryo-fetal toxicity.

“Novartis is committed to developing innovative first-in-class therapies for patients who need treatment options,” said Bruno Strigini, President, Novartis Oncology. “Farydak represents a new drug class in multiple myeloma, providing these patients with an important treatment approach for this difficult-to-treat cancer.”

Farydak is the first histone deacetylase (HDAC) inhibitor available to patients with multiple myeloma. As an HDAC inhibitor, its epigenetic activity may help to restore cell function in multiple myeloma.

Additional regulatory submissions for Farydak are being reviewed by health authorities worldwide.

On February 23, 2015 NGM Biopharmaceuticals and Merck reported that they have entered into a multi-year collaboration to research, discover, develop and commercialize novel biologic therapies across a wide range of therapeutic areas (Press release Merck & Co, FEB 23, 2015, View Source [SID:1234501835]). This agreement will become effective upon the expiration of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act.

“We are very pleased to establish this alliance with Merck, which will be transformational for NGM, providing us with the resources and flexibility to pursue our ambitious research and development goals while preserving our unique drug discovery culture,” said William J. Rieflin, Chief Executive Officer of NGM. “We look forward to working with Merck to generate a robust pipeline of therapies with the potential to make a significant difference in the lives of patients.”

“NGM has developed a uniquely powerful research program that has permitted identification of novel, and quite consequential, pathways for metabolic regulation,” said Dr. Roger M. Perlmutter, President of Merck Research Laboratories. “Through this new collaboration, we hope to apply Merck’s well-established translational capabilities to advance innovative biologics that address the needs of patients suffering from diabetes, metabolic dysregulation, and malignancy.”

The collaboration includes multiple drug candidates currently in preclinical development at NGM, including NP201, which is being evaluated for the treatment of diabetes, obesity and nonalcoholic steatohepatitis (NASH). NGM will lead the research and development of the existing preclinical candidates and have the autonomy to identify and pursue other discovery stage programs at its discretion. Merck will have the option to license all resulting NGM programs following human proof of concept trials. If Merck exercises this option, Merck will lead global product development and commercialization for the resulting products, if approved.

Under the terms of the agreement, Merck will make an upfront payment to NGM of $94 million and will purchase a 15 percent equity stake in NGM for $106 million at a price per share that represents a 20 percent premium to NGM’s most recent financing. Merck will commit up to $250 million to fund all of NGM’s efforts under the initial five-year term of the collaboration, with the potential for additional funding if certain conditions are met.

Prior to Merck initiating a Phase 3 study for a licensed program, NGM may elect to either receive milestone and royalty payments or, in certain cases, to co-fund development and participate in a global cost and revenue share arrangement of up to 50 percent. The agreement also provides NGM with the option to participate in the co-promotion of any co-funded program in the United States. Merck will have the option to extend the research agreement for two additional two-year terms.

“This collaboration brings together our biology-driven research and development product platform with Merck’s late-stage development and commercialization expertise, while also enabling NGM to explore exciting new drug targets,” commented Dr. Jin-Long Chen, Founder and Chief Scientific Officer of NGM. “Both companies’ commitment to scientific excellence and willingness to creatively combine our strengths was key to establishing this relationship.”

NGM’s lead program, NGM282, currently in clinical development for primary biliary cirrhosis (PBC) and NASH, as well as programs that are the focus of NGM’s pre-existing collaboration agreements, are not subject to the option under the Merck collaboration.

On February 23, 2015 Foundation Medicine and H3 Biomedicine reported a multi-year collaboration for the discovery and development of precision medicines in oncology (Press release Foundation Medicine, FEB 23, 2015, View Source [SID:1234501833]). The collaboration marries Foundation Medicine’s comprehensive genomic knowledgebase of more than 35,000 genomic profiles, FoundationCORE, with H3 Biomedicine’s drug discovery engine and computational biology platform. The approach aims to identify potential drug targets based on the unique genomic dependencies of individual cancers, rapidly accelerate clinical development, and lead to the commercialization of new, safe and effective precision medicines for individuals living with cancer.

“Large-scale genomic data sets are the key to identifying actionable targets and addressing the multitude of difficult-to-treat cancers,” said Markus Warmuth, M.D., president and chief executive officer of H3 Biomedicine. “More than ever before, we in cancer drug development have the benefit of an ever-growing arsenal of genomic information including publicly available data sets that inform validation of targets, development of therapies and translation from bench to bedside. In this regard, we believe Foundation Medicine offers one of the most comprehensive cancer genomics knowledgebases available. This collaborative effort will further empower our state-of-the-art discovery engines to deliver novel first-in-class medicines and improve our clinical development strategies by accessing a wealth of clinically annotated, genomic information at least in part derived from later-stage and metastatic cancers.”

“This collaboration with H3 Biomedicine shows how Foundation Medicine is creating value through FoundationCORE,” said Michael J. Pellini, M.D., president and chief executive officer of Foundation Medicine. “Recent scientific advances identifying the unique molecular drivers of cancer are elucidating new approaches to targeted drug development. FoundationCORE, our unique and rapidly growing genomic knowledgebase, can provide valuable insights for our life sciences partners and help them accelerate and increase the probability of success for clinical development of new targeted therapies for patients with cancer.”

Under the terms of the agreement, H3 Biomedicine will pay Foundation Medicine a technology access fee for identification of target concepts arising from FoundationCORE and success milestones for selection, validation, clinical progression, and commercialization of products developed from the program. In addition, Foundation Medicine is eligible to receive royalties on sales of any products resulting from the collaboration.

On February 23, 2015 Celldex Therapeutics reported that the U.S. Food and Drug Administration (FDA) has granted rindopepimut (Rintega) Breakthrough Therapy Designation for the treatment of adult patients with EGFRvIII-positive glioblastoma (GBM) (Press release Celldex Therapeutics, FEB 23, 2015, View Source [SID:1234501831]).

This application was based on data from the Phase 2 ReACT study in recurrent GBM, the Phase 2 ACT III study in newly diagnosed GBM and additional supportive Phase 2 studies. An international Phase 3 study of rindopepimut, called ACT IV, in newly diagnosed GBM completed enrollment (n=745) in December of 2014.

“The FDA’s decision to grant Breakthrough Designation underscores rindopepimut’s therapeutic potential for patients with glioblastoma,” said Anthony Marucci, Co-founder, President and Chief Executive Officer of Celldex Therapeutics. “These patients have extremely limited treatment options, with only three new drugs approved in more than twenty years. Emerging clinical data suggests that rindopepimut may offer an improvement over existing standard of care for EGFRvIII-positive patients. With continued positive data, we look forward to working closely with the FDA to support potential approval of rindopepimut as expeditiously as possible.”

According to the FDA, Breakthrough Therapy Designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. The criteria for Breakthrough Therapy Designation require preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy.

Rindopepimut (Rintega) is an investigational immunotherapy that targets the tumor specific oncogene EGFRvIII. Patients with EGFRvIII-positive glioblastoma typically have a worse prognosis than the overall glioblastoma population, including poor long term survival.

On February 23, 2015 Bristol-Myers Squibb Company (NYSE: BMY) and Flexus Biosciences reported the companies have signed a definitive agreement under which Bristol-Myers Squibb will acquire all of the outstanding capital stock of Flexus, a privately held biotechnology company focused on the discovery and development of novel anti-cancer therapeutics (Press release Bristol-Myers Squibb, FEB 23, 2015, View Source [SID:1234501828]). The transaction has a potential total consideration of $1.25 billion, including $800 million upfront and development milestones that, upon achievement, could total up to $450 million. The transaction has been approved by the boards of directors of both companies and by the stockholders of Flexus.

The acquisition will give Bristol-Myers Squibb full rights to F001287, Flexus’ lead preclinical small molecule IDO1-inhibitor targeted for IND filing in the second half of 2015. In addition, Bristol-Myers Squibb will acquire Flexus’ IDO/TDO discovery program which includes its IDO-selective, IDO/TDO dual and TDO-selective compound libraries. A newly formed entity established by the current shareholders of Flexus will retain, from and after the closing, all non-IDO/TDO assets of Flexus including those related to Flexus’ Phase 1 FLT3 and CDK4/6 inhibitor, its earlier stage small-molecule Treg cancer immunotherapy programs, and its current personnel and facilities.

“Bristol-Myers Squibb is committed to leading scientific advances in immuno-oncology and our acquisition of Flexus will expand our innovative pipeline with an important approach to enhancing immune responses in cancer,” said Francis Cuss, MB BChir, FRCP, executive vice president and chief scientific officer, Bristol-Myers Squibb. “With the addition of a potentially best-in-class IDO1 inhibitor and the broad IDO/TDO programs, Bristol-Myers Squibb will accelerate its ability to explore numerous immunotherapeutic approaches across tumor types, including combinations with our biologic checkpoint and co-stimulatory agents that target different and complementary pathways.”

“Bristol Myers Squibb is a recognized leader in the cancer immunotherapy field, and we are delighted with the opportunity to have their organization advance the development of our potentially best-in-class IDO/TDO inhibitors and to bring more innovative cancer immunotherapies to patients,” said Terry Rosen, Ph.D., Chief Executive Officer of Flexus Biosciences. “With the consummation of this acquisition, we will continue to advance our oncology and immuno-oncology pipeline of Agents for Reversal of Tumor Immunosuppression (ARTIS) in the newly created spin-off, with the strong support of our committed group of investors.”

Bristol-Myers Squibb and Flexus anticipate the transaction will close during the first quarter of 2015. Closing of the transaction is subject to customary closing conditions, including clearance under the Hart-Scott-Rodino Antitrust Improvements Act.

Citi acted as exclusive advisor to Flexus on the transaction and Gunderson Dettmer acted as legal counsel. Kirkland & Ellis LLP is serving as legal advisor to Bristol-Myers Squibb in connection with the transaction.

About IDO/TDO

IDO and TDO are enzymes expressed by many tumor cells and cells in the surrounding microenvironment that suppress T-cell function by producing a potent immunosuppressive factor, kynurenine, thus inhibiting the immune system from identifying and destroying certain types of tumors. IDO/TDO inhibitors reduce kynurenine production enabling the immune system to attack tumors more effectively. Given the immuno-modulatory effects of IDO/TDO inhibitors, strong scientific rationale supports exploring combination regimens with immunotherapies where synergistic activity may enhance long-term survival benefits for patients.