Acceleron Presents Preliminary ACE-031 Results from a Phase 1 Multiple Ascending Dose Study in Healthy Volunteers
Cambridge, Mass. October 13, 2010 Acceleron Pharma, Inc., a biopharmaceutical company developing novel therapeutics that modulate the growth of cells and tissues including muscle, bone, fat, red blood cells and the vasculature, today announced preliminary results from a Phase 1b study to assess the safety, tolerability and pharmacodynamic (PD) activity of ACE-031 following multiple ascending doses in healthy postmenopausal volunteers. ACE-031 is an investigational protein therapeutic designed to build muscle and increase strength by blocking proteins that inhibit muscle growth. In the trial, ACE-031 was generally well-tolerated with rapid and sustained effects on muscle, bone and fat. Preliminary results from this randomized, placebo-controlled study were presented at the 15th International Congress of the World Muscle Society in Kumamoto, Japan.
The ACE-031 Phase 1b study (A031-02) randomized 60 healthy postmenopausal women in 6 cohorts of 10 subjects each to receive ACE-031 or placebo (8:2) at dose levels ranging from 0.1 to 3 mg/kg given by subcutaneous injection every two or four weeks for a total of three or two doses, respectively, over a four week period. Subjects were followed for 12 weeks after their last dose. Lean mass (measured by DXA scans) and muscle volume of the thigh (assessed by MRI scans) were obtained at baseline and weeks 5, 8 and 16. Other PD endpoints included biomarkers of bone formation, bone resorption and fat metabolism, and measures of muscle strength and function. Although this safety study was not powered to assess statistically significant changes in these PD endpoints, multiple exploratory statistical analyses were performed on the data presented at the meeting. For a more detailed description of the study design, visit clinicaltrials.gov and query study identifier NCT00952887.
The preliminary results of this multiple dose study in healthy volunteers confirm and expand upon the encouraging results observed previously in the single dose study of ACE-031, said Matthew Sherman, MD, Chief Medical Officer of Acceleron. These data are encouraging as we continue the development of ACE-031 in the ongoing Phase 2 study in patients with Duchenne Muscular Dystrophy.
Summary of Preliminary ACE-031 Phase 1b Study Results:
Safety, Tolerability and Pharmacokinetics: ACE-031 was generally well tolerated at all dose levels. The most common adverse events (AEs) included injection site reactions, headaches and nosebleeds. The majority of AEs were mild and transient. ACE-031 had a half-life of approximately 12 days, supportive of dosing every 2-4 weeks.
Lean Mass: Mean total body lean mass measured by DXA at day 36 increased by 5.2% from baseline in the group receiving ACE-031 at 1 mg/kg every 2 weeks. This was statistically significant compared to the 0.4% increase in the placebo group (p=0.008) and was sustained through day 57. Significant increases were also seen at doses of 2 and 3 mg/kg every 4 weeks.
Muscle Volume: Mean thigh muscle volume measured by MRI at day 36 increased by 4.1% from baseline in the group receiving ACE-031 at 1 mg/kg every 2 weeks compared to 1.1% in the placebo group (p=0.012). Significant increases were also seen at 2 mg/kg given every 4 weeks. No statistically significant changes were observed in grip strength or functional tests in this healthy volunteer safety study.
Bone Density: ACE-031 therapy led to a rapid and significant increase in a biomarker of bone formation (BSAP) and decrease in a biomarker of bone resorption (CTX) versus placebo. Consistent with these effects, lumbar spine bone mineral density by DXA increased up to 3.4% in the 2 mg/kg every 4 week group from baseline to day 113, compared with a decrease of 1.5% in the placebo group (p=0.001).
Fat: ACE-031 treatment led to significantly altered biomarkers of fat metabolism (increased adiponectin and decreased leptin) by day 8. Total body fat mass measured by DXA decreased up to 8.2% from baseline at day 113 in the 3 mg/kg every 4 week group compared with an increase of 0.5% in the placebo group (p=0.024).
ACE-031 is an investigational protein therapeutic designed to build muscle and increase strength by inhibiting signaling through a cell surface receptor called activin receptor type IIB (ActRIIB). ACE-031 is a recombinant fusion protein that is produced by joining a portion of the human ActRIIB receptor to a portion of a human antibody. This creates a freely circulating, decoy version of ActRIIB which interferes with proteins, such as GDF-8 (myostatin), that normally limit the growth and regeneration of muscle by binding to and activating endogenous ActRIIB. Recent preclinical and clinical studies with ACE-031 suggest that blocking signaling through ActRIIB may be a way to increase muscle mass and improve muscle strength and function. In a range of animal models of muscle disease, including models of muscular dystrophy, muscle loss related to corticosteroid treatment, androgen deprivation or advanced age, ACE-031 increased muscle mass, strength and physical function. Unlike the mutation-specific RNA-based therapeutics in clinical development for Duchenne Muscular Dystrophy (DMD), ACE-031 could potentially benefit patients with DMD, irrespective of the underlying genetic mutation. ACE-031 is being developed in collaboration with Shire.