Acceleron looks past VEGF in cancer treatment

November 6, 2009 – 4:33 pm by Colette Pilkus

Many cancer treatments being developed in the clinic focus on the VEGF pathway by blocking multiple kinase inhibitors or different proliferative agents simultaneously, which usually leads to serious side effects. But VEGF is just one piece of the tumor angiogenesis puzzle.

Executives with Acceleron Pharma Inc. believe that a need exists for novel angiogenesis inhibitors in cancer that do not have side effects. Toward that end, the company began Phase I human trials with ACE-041, a new drug candidate, that targets members of the TGF-β superfamily of proteins by using the ALK1 receptor.

ACE-041 is a novel angiogenesis inhibitor that binds to and prevents members of the TGF-β superfamily from signaling through the activin receptor-like kinase 1 (ALK1) receptor. Unlike current treatments, ACE-041 prevents angiogenesis by blocking a common, later phase of the blood vessel development process termed vascular maturation.

The company expects ACE-041 to affect tumors that are dependant on vascular supply. “We’re looking at both solid tumors as well as tumors such as multiple myeloma,” says John Knopf, Ph.D., CEO of Acceleron. “We have preclinical data on using multiple myeloma models where we were able to demonstrate a significant inhibition of tumor growth in the bone marrow in these multiple myeloma models.”

In preclinical studies, ACE-041 inhibits blood vessel formation induced by multiple angiogenesis factors, including VEGF and FGF, even though ACE-041 does not bind to these molecules. In several animal models of cancer, administration of ACE-041 inhibits tumor growth and prolongs survival by preventing tumor-induced angiogenesis.

“It’s a breath of fresh air in the angiogenesis area,” Dr. Knopf says. “It’s been a terrific approach and patients has benefited from anti angiogenesis therapy significantly. This is a whole new approach to the process. Instead of focusing on the initial stage, we’re focusing on the next stage, it holds promise to be a significant breakthrough and not just an incremental advance.”

Company executives hope that ACE-041, once approved, will compare favorably with with Genentech’s Avastin. Net U.S. sales of Avastin increased 17% to $2.69 billion in 2008.

“Because it inhibits multiple mediators of angiogenesis, [ACE-041] may be able to be effective as monotherapy,” Dr. Knopf says. “So it may not have to be used in the presence of chemotherapy, as Avastin does in patients. I think as a general statement that many patients develop resistance to Avastin and this is an opportunity to look at a down stream process, which would then provide the patient with an alternative at the very least.”

Tags: Acceleron Pharma, ACE-041, Avastin, VEGF