Mohammadi, Kusha

Abstract Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder, characterized by progressive heterotopic ossification (HO) and painful soft-tissue inflammatory flare-ups. This was a post hoc analysis from a phase 2 (NCT03188666) trial in which adults with FOP received intravenous anti-activin A antibody garetosmab 10 mg/kg or placebo every 4 wk over 28 wk (Period 1), followed by a 28-wk open-label treatment and extension (Periods 2 and 3). Here we describe flare-ups, their relationship to new HO lesions, and the impact of garetosmab on flare-ups. Volume of new HO lesions was measured by CT. Patient-reported flare-ups were defined by any 2 of the following: new onset of pain, swelling, joint stiffness, decrease in movement, or perceived presence of HO. Flare-ups were experienced by 71% (17/24) of placebo-treated patients, 59% (10/17) of whom developed a new HO lesion irrespective of flare-up location; 24% of flare-ups location-matched new HO lesions. Twenty-nine new HO lesions occurred in the placebo cohort by week 28, of which 12 (41%) occurred in the same location as new or ongoing flare-ups. A higher volume of newly formed heterotopic bone (week 28) occurred in placebo-treated patients who had experienced a prior flare-up vs those without (median [Q1:Q3] of 16.6 [12.0:31.1] vs 3.2 cm3). Garetosmab was previously shown to decrease patient-reported flare-up frequency in Period 1; here, garetosmab reduced the median (Q1:Q3) duration of patient-reported flares (15.0 [6.0:82.0] vs 48.0 [15.0:1.00] d) and the severity of flare-ups vs placebo. Frequency of corticosteroid use was numerically reduced in those treated with garetosmab (40.0%) vs placebo (58.3%). In this analysis, 71% of placebo-treated adults with FOP experienced flare-ups over 28 wk, which were associated with an increased volume of newly formed heterotopic bone. Garetosmab reduced the severity and duration of flare-ups, with effects sustained during the entire trial.

Abstract Disclosure: K.M. Dahir: Consulting Fee; Self; Alexion Pharmaceuticals, Inc., Ultragenyx, Inozyme, AM Pharma. Grant Recipient; Self; Regeneron Pharmaceuticals, Alexion Pharmaceuticals, Inc., AstraZeneca, Ultragenyx. J. McGinniss: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. E. Forleo-Neto: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Mellis: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. R.J. Sanchez: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. M. Di Rocco: Research Investigator; Self; Regeneron Pharmaceuticals, Ipsen. R. Keen: Advisory Board Member; Self; International Clinical Council on FOP and IFOPA Registry. Research Investigator; Self; Ipsen, Regeneron Pharmaceuticals, Clementia. P. Orcel: Research Investigator; Self; Regeneron Pharmaceuticals. C. Roux: Consulting Fee; Self; Alexion Pharmaceuticals, Inc., Amgen Inc. Grant Recipient; Self; Regeneron Pharmaceuticals, Kyowa, Kirin Brewery, Alexion Pharmaceuticals, Inc. J. Tabarkiewicz: Speaker; Self; Merck, Novartis Pharmaceuticals. Other; Self; SoftSystem. J. Bachiller-Corral: Research Investigator; Self; Regeneron Pharmaceuticals. A.M. Cheung: Consulting Fee; Self; Ipsen. Grant Recipient; Self; Ipsen, Incyte, Regeneron Pharmaceuticals. M. Al Mukaddam: Grant Recipient; Self; Ipsen, Clementia, Incyte, Regeneron Pharmaceuticals. K. Mohammadi: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. D. Srinivasan: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. A. Rankin: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. A.N. Economides: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. D. Gonzalez Trotter: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. F.S. Kaplan: Research Investigator; Self; Regeneron Pharmaceuticals, Clementia, Ipsen. M.W. Eekhoff: Grant Recipient; Self; Regeneron Pharmaceuticals, Ipsen, AstraZeneca, IMI, IFOPA. R.J. Pignolo: Grant Recipient; Self; Regeneron Pharmaceuticals, Clementia, Ipsen, Incyte. Background: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare autosomal dominant disorder driven by missense mutations in ACVR1. This results in inappropriate activation by activin-A. FOP is characterized by progressive heterotopic ossification and painful soft tissue inflammatory events known as flare-ups. Garetosmab, an investigational, fully human monoclonal antibody against activin-A, prevents formation of new heterotopic ossification lesions in FOP. Here we describe the impact of garetosmab on flare-up events in the LUMINA-1 study (NCT03188666). Methods: This was a post hoc analysis of phase 2 LUMINA-1, a randomized double-blind placebo-controlled study that evaluated the safety and efficacy of garetosmab 10 mg/kg/every 4 weeks intravenous vs placebo in adult patients with FOP over 28 weeks (Period 1), followed by a 28-week open-label treatment period (Period 2) and subsequent open-label extension (Period 3). Patient-reported flare-ups were collected via a patient diary and severity of symptoms was reported as mild, moderate, or severe. Clinician-reported flare-ups were collected as adverse events. Results: In Period 1, there was a significant reduction in the proportion of patients reporting one or more flare-ups (35% vs 71%, p=0.032) and clinician-reported flare-ups (10% vs 42%, p=0.039) with garetosmab vs placebo, respectively. The overall number of patient-reported flare-ups (13 vs 34) and mean days experiencing new flare-ups (42.6 days vs 65.4 days) were also reduced with garetosmab vs placebo, respectively. Most flare-ups occurred in the back in garetosmab-treated patients, and most flare-ups occurred in the lower extremities and back for those on placebo. Pain was the most frequent symptom among both cohorts. Flare-up associated joint stiffness and severity of flare-up associated symptoms were nominally reduced at both patient and flare-up level of assessment in those treated with garetosmab. No patients reported severe swelling or severe decrease in movement. One patient reported severe pain and joint stiffness in the garetosmab cohort. In Period 2, there were significant reductions in the proportion of patients experiencing flare-ups (68% vs 14%, p=0.0002) and number of patient-reported flares (31 vs 11) among those who crossed over from placebo in Period 1 to garetosmab. Patients who continued on garetosmab through Period 2 maintained a sustained reduction in number of flare-ups (12 vs 6) and proportion of patients experiencing flare-ups (33.3% vs 22.2%). Reductions were maintained through the open-label extension. Conclusions: Patients treated with garetosmab experienced significant and sustained reductions in the frequency, duration, and severity of flare-ups. The ability of garetosmab to reduce flare-up events may provide a clinically meaningful benefit for patients with FOP. Presentation: Sunday, June 18, 2023