Discussion
death, HO lesions, epistaxis, grievous injuries, soft-tissue infections, madarosis, heterotopic bone lesion, FOP, deaths, HO, disability
DISEASE, MADAROSIS, EPISTAXIS, EVENTS, PATHOGENESIS
LUMINA-1 assessed the safety and efficacy of garetosmab, an activin A-blocking monoclonal antibody, in patients with FOP. Based on data from a genetic model of FOP in rodentsFlare-ups, while the pathogenesis is not well understood, create a substantial burden for patients with FOP; they are often painful and debilitating and may require the use of corticosteroids in high doses or over prolonged periods of time. Flare-ups were also noted to be reduced by garetosmab, additionally suggesting an activin A mechanism for this phenotype.AEs associated with garetosmab included epistaxis, madarosis and a composite of skin and soft-tissue infections. Investigation of coagulation function and BMP9 levels did not provide definitive insights into the potential mechanisms of epistaxis. These AEs had not been observed in two previous early-phase studies of garetosmab conducted in healthy volunteers (Clinicaltrials.gov identifiers Five fatal events occurred after 8–16 (median, 15) doses during the open-label periods of the study. This number is high for a small study. Each of the deaths was assessed by investigators as being unrelated to treatment and there were no clear patterns to link them with garetosmab nor the mechanism of activin A inhibition. Four out of the five patients who died had particularly advanced disease with high CAJIS scores, while the fifth patient fell down a flight of stairs suffering grievous injuries. While no common pathogenetic mechanism of these deaths could be determined, they occurred during the open-label periods. There are published reports of mortality in FOP; however, there are no published reports of annualized rates of death in this communityLimitations of this phase 2 study in ultra-rare patients with FOP include the relatively small sample size and duration of treatment with a placebo control (28 weeks), before giving all patients garetosmab for the following 28 weeks or longer. The fatalities described above all occurred during the open-label, non-placebo-controlled portion of the study, making definitive assessment of safety and the causality of the deaths highly challenging. With respect to the assessment of the efficacy of garetosmab, the primary placebo-controlled end point, TLA, a reflection of the size and activity of existing HO lesions, was not met. As this was the first prospective, placebo-controlled and systematic application of Together with previously published preclinical data in murine models of FOP, the data generated during LUMINA-1 demonstrate that activin A is a required ligand for HO in FOP and provides strong evidence that inhibition of activin A using garetosmab is a promising disease-modifying therapy with the ability to not only block HO but also reduce the number and severity of painful, soft-tissue inflammatory flare-ups, further alleviating the burden of disease. As the most profound effects were on prevention of new HO lesions, the greatest utility of garetosmab treatment may be early in the course of disease, before substantial disability has accrued. Recently, palovarotene was approved by the US Food and Drug Administration (FDA) for the treatment of FOP.Garetosmab treatment has demonstrated substantial and durable reduction of new heterotopic bone lesion formation and soft-tissue inflammatory flare-ups in adults with FOP. Although a definitive link between garetosmab and the five deaths was not established in this population with advanced disease, the number of deaths was relatively high for this small study; therefore, the benefit–risk profile of garetosmab is currently being further evaluated in the phase 3 OPTIMA trial (