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.

On February 20, 2015 Pfizer reported that the U.S. Food and Drug Administration (FDA) has accepted for priority review a supplemental New Drug Application (sNDA)for RAPAMUNE (sirolimus) for the treatment of lymphangioleiomyomatosis (LAM), a rare, progressive lung disease in women of childbearing age that is often fatal (Press release Pfizer, FEB 20, 2015, View Source [SID:1234501822]). With the Priority Review designation for the sNDA, we anticipate a decision in June of 2015 based on the anticipated Prescription Drug User Fee Act (PDUFA) action date.

“If approved, RAPAMUNE would be the first FDA approved treatment option for patients living with LAM,” said Steve Romano, MD, SVP and head of Global Medicines Development at Pfizer’s Global Innovative Pharmaceuticals Business. “We look forward to continuing to work closely with the FDA throughout the review process.”

The sNDA is based on results from the Multicenter International Lymphangioleiomyomatosis Efficacy and Safety of Sirolimus (MILES) Trial. The MILES Trial included 89 LAM patients with moderate lung impairment who were randomized to receive RAPAMUNE (dose adjusted to 5-15 ng/mL) or placebo for 12 months, followed by a 12 month observation period. In the trial, those treated with RAPAMUNE for one year experienced stabilization of lung function as measured by forced expiratory volume in one second (FEV1). Full results of the MILES Trial were published in the New England Journal of Medicine. The most common adverse events reported during the study were mucositis, diarrhea, nausea, hypercholesterolemia, acneiform rash and swelling in the lower extremities. The adverse drug reactions observed were consistent with the known safety profile of RAPAMUNE in renal transplant patients, with the exception of weight decreased, which was reported at a greater incidence with RAPAMUNE compared to placebo.

“The results of the MILES Trial demonstrated that RAPAMUNE has the potential to stabilize lung decline in patients suffering from LAM,” said Dr. Francis X. McCormack, Director of Pulmonary, Critical Care and Sleep Medicine at the University Of Cincinnati School of Medicine and the lead investigator of the MILES Trial. “We are excited about the FDA’s review of RAPAMUNE and the potential to make this medication available to LAM patients.”

The MILES trial was conducted by Dr. McCormack and conducted within the NIH Rare Lung Diseases Consortium. Pfizer provided study drug and a portion of the funding but had no involvement in the design or conduct of the study. The LAM Foundation assisted with the recruitment of patients and logistics for the study.

“For 20 years, the LAM Foundation has been committed to seeking treatment options for LAM and we are thrilled about the possibility of getting a therapy approved to treat this rare and potentially deadly disease,” said Susan E. Sherman, Executive Director of the LAM Foundation.