Garetosmab, an inhibitor of activin A, reduces heterotopic ossification and flare-ups in adults with fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial

Abstract

Background: Fibrodysplasia ossificans progressiva (FOP), an ultra-rare disorder caused by mutations in the gene encoding activin A receptor type 1 (ACVR1), is characterized by painful flare-ups and cumulative heterotopic ossification (HO). Garetosmab, a fully-human monoclonal antibody blocking activin A, prevents HO in FOP mice. Methods: LUMINA-1 (NCT03188666) was a phase 2, multi-center, randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, and effects on HO of intravenous (IV) garetosmab 10 mg/kg every 4 weeks (Q4W). Adult patients with FOP were randomized to garetosmab or placebo for 28 weeks (Period 1), followed by an open-label period (Period 2). After Period 2, patients were allowed to stay on garetosmab in an open-label extension. For Period 1, primary endpoints were HO total lesion activity (HO-TLA) by 18F-sodium fluoride positron emission tomography (18F-NaF PET) and HO total lesion volume by computed tomography (CT). The Period 2 primary endpoint compared the number of new lesions in Period 2 versus Period 1. The safety primary endpoint was incidence and severity of TEAEs through the end of the Period 1 at week 28. Findings: Patients (n=44) were randomized to garetosmab (n=20) or placebo (n=24). In Period_1, there was a trend for garetosmab to decrease HO-TLA versus placebo (24.6%; P=0.07), primarily driven by near complete prevention of new lesions (97% decrease by 18F-NaF PET, post-hoc P=0.009; 90% relative reduction by CT, post-hoc P=0.017); flare-ups were significantly reduced (P=0.0005). For placebo patients transitioning to garetosmab in Period 2, no patients developed new HO lesions (0% in Period 2 versus 40.9% in Period_1; P=0.0027) by CT. All 44 patients met primary safety endpoint of at least one TEAE during Period 1. Garetosmab was associated with more adverse events than placebo: mild recurrent epistaxis, madarosis, and skin/soft tissue infections. Overall, the AEs were predominantly mild in severity, with no effect on patients' ability to receive garetosmab. Five deaths (5/44; 11.4%) occurred either in Period 2 or the open-label extension. The deaths were associated with baseline disease severity in some, pre-existing comorbidities in others and occurred following 8-16 doses (median: 15) of garetosmab in the open label/follow-up periods. Interpretation: Garetosmab reduced flare-ups and prevented new HO lesions in FOP patients. Although side effects were mild to moderate, there were a relatively high number of deaths for a small study; the deaths were not related to epistaxis and considered unlikely to be related to garetosmab.

Garetosmab in Fibrodysplasia Ossificans Progressiva: Clinical Pharmacology Results from the Phase 2 LUMINA‐1 Trial

“…Further details of the clinical trial methods and a description of the study population are reported elsewhere. 11…”

“…In the comparative exposure-response safety analyses, the response variables included the following 5 clinically relevant treatment-emergent adverse events (TEAEs) of special interest: acne, composite abscess, composite skin and soft-tissue infection, epistaxis, and folliculitis. 11 For epistaxis, only moderate or severe cases were considered TEAEs of special interest. The incidence of mild cases of epistaxis was reported previously.…”

“…The incidence of mild cases of epistaxis was reported previously. 11 For completeness, the safety variables included 2 additional categories for TEAEs: other AEs of relevance and other skin infections. The TEAEs were expressed as binary outcomes (1 for event vs 0 for no event) or categorical outcomes (TEAE by severity).…”

“…Five deaths occurred in the open-label treatment period and are discussed in detail elsewhere. 11 In this report, we present PK, total activin A, immunogenicity, BMP9 determinations, and comparative exposure-response analyses from the LUMINA-1 trial, and interpret the clinical implications of the results.…”

“…The results of this study showed that garetosmab substantially reduced new heterotopic bone formation (heterotopic ossification lesions) and flare-ups as reported by both physicians and patients. 11 Garetosmab was associated with more adverse events (AEs) than placebo, including epistaxis, madarosis, and skin and soft-tissue infections. Most of these were mild in severity and resolved without medical intervention.…”