The big excitement in Boston biotech today is the news that Acceleron Pharma, Inc, a privately held biotechnology company, has signed a deal with Shire PLC aimed at development and commercialization of Acceleron’s novel protein therapeutics aimed at building muscle, lean body mass and and reducing fat by decreasing signaling through the activin type II B (ActRIIB) receptor. The initial indication is improving muscle volume and function in Duchenne Muscular Dystrophy (DMD) patients, a group which is following these activities with rapt attention. The deal involves a $45 million up front payment and milestone payments of up to $165 for the lead DMD program, and up to an additional $288 million for future programs to treat cancer related bone loss and other indications, and royalty payments on product sales. Shire and Acceleron will jointly collaborate on a worldwide development program to advance the lead product, and Shire will produce commercial supplies of the product for both parties. Acceleron will commercialize the product in the US and Canada, and Shire will commercialize the therapy in the rest of the world.
Acceleron’s novel science is aimed at potentiating or inhibiting signaling of molecules in the TGFβ family by synthesizing circulating decoy receptors which suck up the TGFβ proteins before they can bind to the cell associated receptors. These molecules include the TGFs, the Growth and Differentiation Factor (GDF) family and the Bone Morphogenetic Protein (BMP) family of proteins, all of which use a common battery of multivalent receptors. The lead program is based on Acceleron’s ability to fuse the ActRIIB receptor to part of a human antibody, thereby increasing it’s circulating time in the blood. This fusion product (named ACE-031) binds GDF-8, a protein that inhibits muscle growth. The absence of GDF-8 abolishes the “off” signal to muscle, and allows muscle growth to accelerate and results in an increase in muscle mass. There is a plethora of scientific data demonstrating that decreasing GDF-8 increases muscle mass and function in models of muscular dystrophy, cancer, and corticosteroid induced muscle atrophy. Indeed Acceleron has completed a Phase 1 trial showing ACE-031 increases lean body mass and muscle volume after a single dose in healthy people. Now, a Phase 2 trial is underway in patients with DMD receiving concurrent corticosteroid treatment. The study will characterize the effects of ACE-031 on muscle mass, muscle strength, muscle function, pulmonary function and quality of life. DMD is a debilitating and fatal genetic disorder characterized by the progressive loss of muscle strength and function. Few patients survive past their 20’s when their peripheral muscles have atrophied enough to prevent mobility, and their heart and respiratory muscles weaken and eventually fail. Because this disease has no treatment at this time, in August, the FDA granted Acceleron’s ACE-031 program “fast track” designation enabling expedited review of results. In addition, two weeks later, the FDA granted ACE-031 “orphan drug designation”. Orphan drug designation is granted by the FDA to assist and encourage companies to develop safe and effective therapies for the treatment of rare diseases. Under the Orphan Drug Act, the FDA may provide grant funding towards clinical trial costs, tax advantages, and seven years of market exclusivity in the United States following drug approval by the FDA. This is the area where companies like Shire and Genzyme excel: aiming for severe diseases with no treatment enables faster approval and lowers the safety hurdles substantially. There will certainly be no decade long post-approval safety requirements for ACE-031. This is also the brilliance of Acceleron’s strategy. Certainly the ActRIIB receptor is not specific for GDF-8. Potentially hundreds of proteins will bind to circulating ActRIIB. But as long as there are no life threatening safety signals (and Acceleron’s Phase 1 safety trials were clean) this fact is moot as long as the DMD patient has increased muscle strength and improved quality of life. Perhaps, with a home run, their life expectancy will also increase.
Acceleron has at least 2 other fusion proteins in the pipeline that are outside the deal with Shire. ACE-011 is an immunoglobulin fusion product of the Activin receptor type 2A instead of type2B (ActR2A instead of ActR2B in ACE-031), and appears to increase red blood cell formation and bone formation in murine models of cancer. Although Acceleron must have ideas about which protein ligand they are binding with this circulating receptor, specificity is probably not required, as a careful analysis of these physiologic effects has led Acceleron to target cancer patients with chemotherapy induced anemia and metastatic bone lesions. Another brilliant way to get a new therapeutic on the market in patients with life threatening diseases. Acceleron has completed two safety studies in people and is recruiting three more studies in patients with chemotherapy induced anemia, anemia of end stage renal disease and solid tumors.
ACE-041 is a fusion product of a portion of human immunoglobulin with the activin receptor-like kinase 1 (ALK-1), another multifunctional receptor which appears to bind at least BMP-9 (and BMP-10) and TGFβ and inhibit new blood vessel formation in cell culture experiments and in mice. Again, the potential non-specific effects of using a circulating receptor has led Acceleron to target angiogenesis in cancer patients and they are currently recruiting patients with advanced solid tumors or relapsed/refractory multiple myeloma to test their hypothesis.
Where did Acceleron come from? In the 1980’s and 1990’s Genetics Institute was a widely respected biotechnology company in Cambridge, MA. It achieved it’s impressive reputation by conducting excellent science, which included the cloning, expression and characterization of the TGFβ family of proteins and their receptors. Through a series of unfortunate luck, Genetics Institue was forced to carve a deal with Wyeth to enable funding, and the deal ultimately resulted in Wyeth acquiring Genetics Institute (GI) in toto. For several years, GI was allowed to continue as an independent entity, much as Genentech has been allowed to work under Roche’s management (let’s see how long that lasts), but ultimately the mega-pharmaceutical company couldn’t allow this arrangement to continue. There were many brilliant scientists at GI, but Wyeth couldn’t seem to recognize them, or couldn’t seem to function with these individuals not on a tight leash and complying 100% with big pharma rules. One of these individuals who was responsible in part for the innovative success of GI was John Knopf, who was abruptly dismissed from Wyeth in 2002. Perhaps he was too brilliant for the unimaginative management, more likely he was too independent. He snagged some of the best talent from Wyeth, and his substantial understanding of the TGFβ family enabled him to see that the best way to use these proteins was to alter signaling using soluble receptors. Since 2002, Wyeth, now Pfizer, has continued with a succession of increasingly incompetent management to try and use the plethora of proteins themselves as therapeutics with no success. Knopf and Jasbir Seehra, also from GI, started Acceleron based on the technology of TGFβ receptor fusion proteins to alter signaling, and built an extremely successful brick and mortar (they make all their own proteins), independent, private, and well funded biotech company that commands the respect of all scientists and venture capitalists because of it’s vision, brilliant foresight, and most impressive, its ability to translate great science into innovative therapeutics in record time.