April 1, 2007 (Vol. 27, No. 7)

With a Manufacturing Plant and Novel R&D, the Firm Expects to Rapidly Move into Clinic

Acceleron Pharma (www.acceleronpharma.com) was established in 2003 to develop biotherapeutics for musculoskeletal, metabolic, and cancer-related diseases. The company’s founders not only had novel insights about how to control protein families involved in tissue growth and repair, but they also set up their own in-house GMP-manufacturing facility. “From the start of the company, we have invested in basic biology research and a manufacturing infrastructure,” says Steven Ertel, vp of business development at Acceleron in Cambridge, MA.

Acceleron’s technology platform targets the growth and differentiation factor (GDF) and bone morphogenetic protein (BMP) families, both members of the TGF-beta superfamily. Within these well-studied protein families are potent factors that modulate the growth of various tissues, including bone, muscle, fat, and blood vessels. Acceleron was founded by Wylie Vale at the Salk Institute for Biological Studies in LaJolla, CA, Tom Maniatis at Harvard University, Mark Ptashne at Memorial Sloan-Kettering Cancer Center, Jasbir Seehra, Ph.D., now CSO at Acceleron, and John Knopf, Ph.D., executive vp of corporate development and interim president of Acceleron.

Other companies have tried to create therapies to control the GDF and BMP families by creating ligands that turn up the biological activity of bone and tissue generating factors. This strategy, however, has produced few successful drugs, except for a small number of products that are used locally in spinal fusions or to repair nonunion fractures, where gaps need to be filled between badly damaged bones. These approved drugs have limited application because they do not act systemically and cannot be used to treat diseases such as osteoporosis.

Taking the Brakes Off

Acceleron takes a unique approach to harnessing the powerful GDF/BMP family. In healthy tissue, positive and negative regulators work in balance. In disease states like osteoporosis, negative regulators override positive ones, resulting in a net loss of bone. Rather than directly increasing the positive regulators, Acceleron’s technology instead inhibits the over-abundance of negative regulators of tissue growth. Ertel compares it to an automobile. “Instead of giving it gas, we take off the brakes.” Conversely, in conditions where stimulation of positive regulators leads to problems, such as in obesity or the proliferation of blood vessels that nourish tumors, Acceleron blocks the positive regulators.

Acceleron’s anabolic bone compound is based on the activin receptor type IIA (ActRIIA) fused to the IgG portion of human immunoglobin, creating an Fc receptor fusion protein. Activins, which are involved in many physiological and pathological processes, act through serine/threonine kinases. ActRIIA is the high-affinity natural receptor for activin. “The approach has been successful in preclinical studies,” Ertel says, “and given the extremely high conservation of sequence and function across species within the GDF/BMP families, we are optimistic it will be just as successful in the clinic.”

In the Pipeline

ACE-011, Acceleron’s most advanced drug candidate, began clinical trials in 2006 as a treatment for bone loss. Phase I safety studies are under way in healthy postmenopausal women. Phase II evaluations are planned to start in the summer of 2007. The first indications will be for osteoporosis and bone loss associated with cancer.

Acceleron is studying ACE-031 as a treatment for neuromuscular conditions involving loss of muscle, such as muscular dystrophy and amyotrophic lateral sclerosis. In preclinical studies, it increases muscle mass and strength, offering hope for an entirely new class of biotherapeutic treatments. ACE-031 also could help people who suffer from general physical weakness and frailty associated with aging. “We may be able to significantly improve the clinical condition of these patients by increasing existing muscle mass and strength,” notes Ertel.

On the metabolic side, the company is targeting different kinds of indications, including obesity and diabetes. Preclinical data with ACE-031 show that by increasing muscle tissue, several metabolic functions related to obesity and diabetes, such as blood glucose and insulin levels, also improve.

ACE-041 is in preclinical development to block angiogenesis in tumor cells. Nearly all other antiangiogenesis agents in preclinical and clinical testing act by targeting the VEGF pathway. In contrast, Acceleron created a GDF antagonist that blocks multiple mediators of angiogenesis, including VEGF. In this case, positive regulators of blood vessel growth are inhibited by ACE-041. Acceleron’s approach holds the potential to block angiogenesis even in anti-VEGF resistant tumors.

Internal GMP Manufacturing

By focusing on basic R&D and GMP manufacturing, Acceleron was able to move its first treatment (ACE-011) into Phase I trials in just three years in a capital efficient manner, requiring little outside investment, and retaining worldwide rights. The company manufactures its own Fc fusion proteins in preclinical and clinical quantities. “That’s highly unusual for a company our size,” Ertel points out. The integration of novel scientific insights into a powerful area of biology with expertise in protein engineering separates Acceleron from other companies, he asserts.

The company’s name reflects its mission to create an infrastructure that moves products rapidly into the clinic. Smaller companies without internal manufacturing facilities face expensive and rate-limiting hurdles as they wait for contract manufacturing organizations to produce their proteins. Although Acceleron could potentially increase revenues by offering contract manufacturing services of its own, they have no plans to do so. “We have so many internal programs to advance,” comments Ertel, that “we need all our capacity to make our own products.”

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