ACE-011 (Bone Growth)

ACE-011, the lead product in Acceleron’s bone program, is being developed for bone disease associated with multiple myeloma and other cancers. ACE-011 works by inhibiting activin, a negative regulator of bone mass, thereby freeing the body to rebuild bone mass and strength.

Activin Inhibits Bone Formation and Drives Bone Resorption

There are natural checks and balances in many processes in the human body, including the process that maintains healthy bone tissue. Activin, a member of the GDF protein family, works as a negative regulator of bone mass. Activin prevents new bone formation by having both stimulatory effects on osteoclasts (bone resorbing cells) and inhibitory effects on osteoblasts (bone forming cells). The net result is decreased bone mineral density (BMD) and strength (see figure):

ACE-011: A Decoy Activin Receptor

ACE-011 was specifically developed to inhibit activin, and thereby free the body to add new, healthy bone mass to skeleton weakened by disease. ACE-011 is a biotherapeutic based on the activin receptor type IIA (ActRIIA), which is the natural high affinity receptor for activin. Acceleron scientists have engineered the product to combine the portion of ActRIIA that binds tightly to activin along with a component of an antibody molecule. This allows ACE-011 to circulate freely throughout the body (see figure)

Inhibiting the Inhibitor: Using ACE-011 to Grow New Bone

ACE-011 acts as a decoy receptor and binds activin before it is able to bind with ActRIIA on the surface of bone tissue cells. The prevention of activin signaling allows normal bone formation processes to occur, and the net result of treatment with ACE-011 is increased bone mineral density and strength (see figure):

The growth of new bone stimulated by ACE-011 has the potential to improve not only bone mass, but bone quality as well. Factors which affect the underlying structure of bone, such as geometry, bone turnover, damage accumulation, and mineralization, are as important as increasing bone mineral density (BMD) in preventing fractures. In several animal models of bone loss, ACE-011 has demonstrated both increased BMD as well as improved bone architecture and mechanical strength (see figure below):

In addition, in a Phase 1 clinical study in healthy post-menopausal women, ACE-011 showed an encouraging safety profile, increased bone formation biomarkers and decreased bone resorption biomarkers.

Clinical Importance of ACE-011

Skeletal morbidity in multiple myeloma and other cancers causes significant loss of physical function and quality of life. The current standard of care is anti-resorptive therapy with intravenously administered bisphosphonates. These anti-resorptive agents decrease the rate of bone resorption, but do not lead to the formation of new, high-quality bone. Furthermore, despite treatment, many patients continue to experience severe bone pain, fractures and spinal compressions. The use of a bone forming agent, such as ACE-011, has the potential to significantly improve the bone health of these patients.

Acceleron is developing ACE-011 to treat cancer-related bone loss caused by:

Multiple Myeloma
Bone Metastases of Solid Tumors
Cancer Treatments

ACE-011 has completed Phase I clinical development and will enter Phase II clinical trials this year.

See Publications and Presentations on ACE-011