ACE-031

Also known as: ActRIIB-Fc, Myostatin decoy receptor

Evidence: Clinical

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Overview

Soluble ActRIIB-Fc decoy receptor that binds myostatin and related ligands to increase muscle mass; human trials were halted over bleeding side effects.

ACE-031 is a recombinant fusion of the extracellular domain of activin receptor type IIB with human IgG1-Fc, developed by Acceleron Pharma as a myostatin trap. In a single-ascending-dose phase 1 study, 48 healthy postmenopausal women received 0.02 to 3 mg/kg subcutaneously or placebo; mean t1/2 was 10 to 15 days, and at 3 mg/kg total lean mass rose 3.3% (DXA, p=0.03) and thigh muscle volume 5.1% (MRI, p=0.03) by day 29 (Attie 2013). A randomized placebo-controlled ascending-dose trial then gave 0.5 mg/kg every 4 weeks or 1 mg/kg every 2 weeks subcutaneously to ambulatory boys with Duchenne muscular dystrophy. It was stopped after the second dosing regimen because of epistaxis and telangiectasia, with only non-significant trends on the 6-minute walk test, lean mass and bone density (Campbell 2017). Development was discontinued; nothing was approved.

Benefits

Total lean mass +3.3% and thigh muscle volume +5.1% at day 29 after one 3 mg/kg dose in healthy postmenopausal women (phase 1, n=48); trends toward higher lean mass, bone density and 6-minute walk distance in Duchenne muscular dystrophy (phase 2). Development stopped for bleeding events.

Dosing reference

Research dose: 0.5 mg/kg every 4 weeks or 1 mg/kg every 2 weeks subcutaneously in the phase 2 trial (NCT01099761); 0.02 to 3 mg/kg as a single subcutaneous dose in phase 1
Reconstitution: 2 mL bacteriostatic water
Common vial sizes: 1 mg

Subcutaneous, not intravenous: 0.5 mg/kg every 4 weeks or 1 mg/kg every 2 weeks every 2 to 4 weeks in boys with Duchenne muscular dystrophy, and 0.02 to 3 mg/kg as a single dose in healthy postmenopausal women. Exposure rose linearly with dose and mean t1/2 was 10 to 15 days (Attie 2013). Development was discontinued after the phase 2 trial was stopped for epistaxis and telangiectasia (Campbell 2017). Weight-based dosing, so the mcg dose fields stay null.

Mechanism

ACE-031 is the extracellular domain of activin receptor type IIB fused to human IgG1-Fc. As a soluble decoy it binds myostatin (GDF-8) and other ActRIIB ligands, including activin A and GDF-11, before they reach the receptor, lifting myostatin's brake on muscle growth (Attie 2013; Campbell 2017). Transgenic expression of a dominant-negative ActRIIB in mouse muscle produced muscle-mass increases comparable to myostatin knockouts, which is the preclinical basis for the approach (Lee and McPherron 2001). The bleeding events that stopped development, epistaxis and telangiectasia, are proposed to come from blocking non-myostatin ActRIIB ligands involved in vascular integrity rather than from the muscle effect; the trial report classes them as non-muscle-related adverse events without assigning a mechanism.

Evidence

Clinical: at least one published human trial or an approved drug

In 48 healthy postmenopausal women given one subcutaneous dose of 0.02 to 3 mg/kg or placebo, exposure rose linearly with dose, mean t1/2 was 10 to 15 days, and the 3 mg/kg group gained 3.3% total lean mass (DXA, p=0.03) and 5.1% thigh muscle volume (MRI, p=0.03) by day 29 (Attie et al., 2013)
The main phase 1 adverse event was injection-site erythema; biomarker changes also suggested effects on bone and fat metabolism (Attie et al., 2013)
In ambulatory boys with Duchenne muscular dystrophy dosed 0.5 mg/kg every 4 weeks or 1 mg/kg every 2 weeks subcutaneously, the trial was stopped after the second dosing regimen because of epistaxis and telangiectasia; 6-minute walk, lean mass, bone density and fat mass showed non-significant trends in favour of treatment (Campbell et al., 2017)
Transgenic mice expressing a dominant-negative ActRIIB in skeletal muscle gained muscle mass comparable to myostatin-knockout mice, the preclinical basis for decoy-receptor blockade (Lee and McPherron, 2001)
Human-trial status: one phase 1 and one phase 2 trial published; development was discontinued on safety grounds and no regulator has approved it

References

Side effects

The phase 2 trial in boys with Duchenne muscular dystrophy was stopped after the second dosing regimen because of epistaxis and telangiectasia, and no serious or severe adverse events were recorded before that (Campbell 2017). In the phase 1 single-dose study in 48 healthy postmenopausal women, injection-site erythema was the main adverse event (Attie 2013). Bleeding and dilated surface vessels are the defining safety concern of this compound and the reason development was discontinued. It is not approved for human use.

Storage

Storage: Refrigerate 2-8°C (36-46°F)
Lyophilized: 2+ years at room temp, 3+ years refrigerated
Reconstituted: 28-30 days refrigerated

Pharmacology

Half-life: Mean 10 to 15 days (human, single subcutaneous dose 0.02 to 3 mg/kg; Attie 2013)
Bioavailability: Subcutaneous: AUC and Cmax rose linearly with dose from 0.02 to 3 mg/kg in humans; no absolute bioavailability reported
Molecular weight: 90000 Da
Sequence: ActRIIB extracellular domain fused to IgG1 Fc