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.

On February 23, 2015 Rigel Pharmaceuticals, Inc. (Nasdaq:RIGL) and Bristol-Myers Squibb Company (NYSE:BMY) reported that they have entered into a collaboration agreement for the discovery, development and commercialization of cancer immunotherapies based on Rigel’s extensive portfolio of small molecule TGF beta receptor kinase inhibitors (Press release Bristol-Myers Squibb, FEB 23, 2015, http://news.bms.com/press-release/rd-news/rigel-and-bristol-myers-squibb-announce-research-and-development-collaboration [SID:1234501827]). TGF beta can promote tumor growth, broadly suppress the immune system and increase the ability of tumors to spread in the body. The collaboration will focus on developing a new class of therapeutics aimed at increasing the immune system’s activity against various cancers either as monotherapy or in combination with immune checkpoint inhibitors, including Bristol-Myers Squibb’s Opdivo (nivolumab) and Yervoy (ipilimumab).

Under the terms of the agreement, Bristol-Myers Squibb will obtain exclusive, worldwide rights to develop and commercialize small molecule therapeutics derived from Rigel’s TGF beta library, including, but not limited to, those approved to treat cancer. Bristol-Myers Squibb will pay $30 million upfront and Rigel will be eligible to receive development and regulatory milestones that could total more than $309 million for a successful compound approved in multiple indications. Rigel will also be eligible to receive tiered royalties on the net sales of any products from the collaboration.

“As a company dedicated to leading scientific advances in immuno-oncology, we are committed to exploring the utility of TGF beta inhibition as a potential therapeutic to fight certain cancers,” said Carl Decicco, Ph.D., Head of Discovery, R&D, Bristol-Myers Squibb. “Working with Rigel and having access to their TGF beta receptor kinase inhibitors extends our existing portfolio of immunotherapeutic approaches to include this key mediator of immunosuppression in the tumor microenvironment.”

“This collaboration places our TGF beta receptor kinase inhibitor program into the hands of Bristol-Myers Squibb, a premier immuno-oncology company. Together, we believe TGF beta inhibition may offer novel therapeutic opportunities in oncology treatments,” said Raul Rodriguez, president and chief executive officer of Rigel. “Rigel has focused on immunology, and oncology via numerous partnerships. This collaboration is Rigel’s first in immuno-oncology and is one of the Company’s several programs in this area.”

TGF beta Inhibition

Within the immune system, TGF beta often plays an immunosuppressive role by potently suppressing effector cell proliferation and function while simultaneously promoting differentiation of certain suppressive T-cells. This master regulator is often present within tumor microenvironments and can significantly dampen anti-tumor host immune responses. Current evidence suggests that TGF beta can arise from many sources, including the cancer itself, surrounding cells and infiltrating macrophages.

Developing a drug that inhibits TGF beta signaling in cancer patients has the potential to counteract an important mechanism used by cancers to escape immuno-surveillance, thereby making this signaling pathway an appealing therapeutic target for immuno-oncology related applications.

Rigel has identified a large number of orally bioavailable, potent and selective small molecule inhibitors of TGF beta receptor kinases that have demonstrated in vivo efficacy, in preclinical animal models of cancer, consistent with an immune-mediated mechanism of action.