Mukaddam, Mona Al

ABSTRACT Fibrodysplasia ossificans progressiva (FOP) is an ultra‐rare, severely disabling genetic disorder of progressive heterotopic ossification (HO). The single‐arm, open‐label, phase 3 MOVE trial (NCT03312634) assessed efficacy and safety of palovarotene, a selective retinoic acid receptor gamma agonist, in patients with FOP. Findings were compared with FOP natural history study (NHS; NCT02322255) participants untreated beyond standard of care. Patients aged ≥4 years received palovarotene once daily (chronic: 5 mg; flare‐up: 20 mg for 4 weeks, then 10 mg for ≥8 weeks; weight‐adjusted if skeletally immature). The primary endpoint was annualized change in new HO volume versus NHS participants (by low‐dose whole‐body computed tomography [WBCT]), analyzed using a Bayesian compound Poisson model (BcPM) with square‐root transformation. Twelve‐month interim analyses met futility criteria; dosing was paused. An independent Data Monitoring Committee recommended trial continuation. Post hoc 18‐month interim analyses utilized BcPM with square‐root transformation and HO data collapsed to equalize MOVE and NHS visit schedules, BcPM without transformation, and weighted linear mixed‐effects (wLME) models, alongside prespecified analysis. Safety was assessed throughout. Eighteen‐month interim analyses included 97 MOVE and 101 NHS individuals with post‐baseline WBCT. BcPM analyses without transformation showed 99.4% probability of any reduction in new HO with palovarotene versus NHS participants (with transformation: 65.4%). Mean annualized new HO volume was 60% lower in MOVE versus the NHS. wLME results were similar (54% reduction fitted; nominal p = 0.039). All palovarotene‐treated patients reported ≥1 adverse event (AE); 97.0% reported ≥1 retinoid‐associated AE; 29.3% reported ≥1 serious AE, including premature physeal closure (PPC)/epiphyseal disorder in 21/57 (36.8%) patients aged <14 years. Post hoc computational analyses using WBCT showed decreased vertebral bone mineral density, content, and strength, and increased vertebral fracture risk in palovarotene‐treated patients. Thus, post hoc analyses showed evidence for efficacy of palovarotene in reducing new HO in FOP, but high risk of PPC in skeletally immature patients. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

AbstractGenetic variants are vital in informing clinical phenotypes, aiding physical diagnosis, guiding genetic counseling, understanding the molecular basis of disease, and potentially stimulating drug development. Here we describe two families with an ultrarare ACVR1 gain‐of‐function pathogenic variant (codon 375, Arginine > Proline; ACVR1R375P) responsible for a mild nonclassic fibrodysplasia ossificans progressiva (FOP) phenotype. Both families include people with the ultrarare ACVR1R375P variant who exhibit features of FOP while other individuals currently do not express any clinical signs of FOP. Thus, the mild ACVR1R375P variant greatly expands the scope and understanding of this rare disorder.

Abstract Background: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, autosomal dominant disorder driven by mutations in ACVR1 that render it responsive to Activin A. FOP is characterized by progressive heterotopic ossification (HO) and distressing inflammatory events called “flare-ups.” Flare-ups can precede new HO; however, limited prospective data exists on this phenomenon. Garetosmab (GAR), an investigational human monoclonal antibody against Activin A, blocks formation of new HO in FOP. Methods: This is a post-hoc analysis of LUMINA-1 (NCT03188666) a phase 2, randomized, double-blind, placebo-controlled study, which evaluated the safety and efficacy of GAR (10 mg/kg/week IV) versus placebo (PBO) in adult patients with FOP over 28 weeks. Patient-reported flare-ups were collected via a patient diary and severity level was reported as mild, moderate or severe. Clinician-reported flare-ups were collected as adverse events in the trial. HO lesions were imaged by 18F-NaF positron emission tomography (PET) and whole-body low-dose X-ray computed tomography (CT). Results: There was a two-fold higher proportion of patients who reported one or more flare-ups on PBO 17/24 (71%) compared with GAR 7/20 (35%). Clinicians reported a four-fold higher proportion of patients experiencing one or more flare-ups on PBO 10/24 (42%) compared with GAR 2/20 (10%). Overall rates of flare-up events were two-fold higher on PBO vs. GAR (1.4 vs. 0.65 events/patient/28 weeks) for patient-reported events and eight-fold higher on PBO vs. GAR by clinician report (0.83 vs. 0.10 events/patient/28 weeks). Most flare-ups occurred on the extremities and back; pain was the most commonly reported symptom. Patient-reported flare-ups on PBO were more frequently reported as severe (29.4%) compared with GAR (7.7%). Among subjects with at least 12 weeks of follow-up from start of patient-reported flare-up, development of new HO near the site was 5/27 (18.5%) on PBO and (0%) on GAR. Of all new HO lesions, 41% on PBO and 0% on GAR occurred with spatial and temporal relation to flare-up. Conclusions: Approximately two-thirds of patients on PBO reported flare-ups over 28 weeks. GAR was associated with reductions in frequency and severity of flare-ups. Fewer than 20% of patient-reported flare-ups were associated with new HO, indicating frequent discordance of these phenomena, and compatible with previous reports. GAR’s ability to reduce patient- and clinician-reported flare-ups, as well as new HO lesions may provide an important therapeutic option.

Abstract Background Genetic contributors to cardiac arrhythmias often found in cardiovascular conduction pathway and channel proteins. However, genes outside of these categories can contribute to cardiovascular conduction abnormalities. Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by large volumes heterotopic ossification caused by a highly recurrent R206H mutation in the ACVR1/Alk2 gene. This mutation produces an abnormal activation of the bone morphogenetic pathway (BMP) pathway in response to Activin A. Prior studies suggested an increased risk of cardiopulmonary complications in FOP1. We examined patients in a Natural History Study (NHS) of FOP (NCT02322255) to better understand their cardiovascular risk. Methods The NHS is an ongoing 3 year international multi-center cross-sectional study of 114 patients with FOP (ages 4–56 years) genetically verified to have the AVCR1 R206H mutation. Patients at baseline and 12 months were assessed by electrocardiogram (ECG). Abnormal lead placements were excluded. ECG readings were assessed in a central ECG laboratory. Results At baseline, 45.3% (48/106) of ECGs showed conduction abnormalities. The majority of these abnormalities were classified as nonspecific intraventricular conduction delay (37.7% of all ECGs). For patients &gt; 18 years old, 22.7% (10/44) had conduction abnormalities, which was significantly higher than previously reported in the healthy population (5.9%; n=3978)2 (proportional t-test; p&lt;0.00001). FOP patients &lt; 18 years of age also had an extremely high prevalence of conduction abnormalities (60.3%, 38/61). The NHS 12-month follow up data showed similar prevalence. The high frequency of conduction abnormalities did not correlate with the presence of chest wall deformities or scoliosis, abnormal pulmonary function test results, increased cumulative analog joint involvement scale (CAJIS) scores, or abnormal echocardiograms. Conclusions Our results show that some patients with FOP may have subclinical conduction abnormalities. These ECG changes appear to be independent of chest wall deformities or scoliosis, although ectopic bone may make ECG measurement in FOP patients challenging. Though there is no reported association of FOP with clinically significant heart block to date and clinical implications for cardiovascular risk remain unclear, knowledge about these ECG changes may be important for planning clinical care and clinical trials of investigational agents in patients with FOP. Further studies of how the AVCR1 R206H activating mutation and BMP signaling changes cardiac conduction are needed to better understand the mechanistic link. References (1)Hingorani et al. Indian J Med Res. 2012; 135:322–330 (2)Kussmaul et al. Clinical Orthopaedic Related Research. 1998; 346:104–109

Abstract Background: FOP is an ultra-rare, severely disabling genetic disorder characterized by episodic flare-ups and heterotopic ossification (HO) leading to restricted movement, physical disability, and early death. FOP may initially be misdiagnosed in ~90% of individuals leading to unnecessary and often harmful interventions. Patients with FOP are diagnosed and managed by multiple specialties, including endocrinologists. Data from an ongoing, prospective, longitudinal, global, natural history study (NCT02322255) were used to investigate the progression of FOP, HO formation, and impact on physical functioning over time. We present results from the first 12 months of the 3-year study. Methods: Males and females with FOP and a documented ACVR1 R206H mutation participated. HO volume was assessed by low-dose whole body computed tomography (WBCT) scan, excluding the head. All imaging was interpreted at a blinded, central laboratory using pre-specified procedures. Functional outcomes were evaluated using the Cumulative Analogue Joint Involvement Scale (CAJIS; for each joint: score=0 represents &lt;10% involvement, score=1 represents 10–90% involvement, and score=2 represents &gt;90% ankylosed across 15 major joints; total score range 0 to 30 [higher scores indicate more severe mobility limitations]) and the FOP Physical Function Questionnaire (FOP-PFQ; percent total score). Changes from Baseline at Month 12 were evaluated for new HO volume, CAJIS, and FOP-PFQ. Results: Of 114 participants (pts) with Baseline data, 99 (4 to 56 years at enrollment; mean 17 years of age; 56% male) also had a Month 12 assessment. A total of 93 pts had evaluable WBCT scans at Baseline and Month 12 and were included in the HO analysis. In total, 40% (37/93) of pts had new HO over 12 months; the mean volume of new HO in these pts was 57,706 mm3 (SD=100,079 mm3; median=20,753 mm3; range: 522 to 438,826 mm3). Of the pts with new HO, 65% (24/37) reported at least one flare-up (mean rate of 2.3 flare-ups/year). Over 12 months, 60% (56/93) of pts did not have new HO; 43% (24/56) of them reported at least one flare-up (mean rate of 1.8 flare-ups/year). Mean changes from Baseline in CAJIS and FOP-PFQ were minimal: CAJIS: 0.6 (SD=2.4; median=1.0; n=99) and FOP-PFQ: 4.4% (SD=11.2; median=3.7%; n=90); and were similar across pts with or without new HO. Conclusions: In participants with FOP, although deterioration of physical function is expected over a patient’s lifetime, CAJIS and FOP-PFQ scores did not worsen significantly in the relative short-term of this study. However, HO volume, quantified by WBCT, increased over the course of 12 months. These results show that measuring HO may be a viable way to monitor changes in FOP over short periods of time.

Clinical trials for orphan diseases are critical for developing effective therapies. One such condition, fibrodysplasia ossificans progressiva (FOP; MIM#135100), is characterized by progressive heterotopic ossification (HO) that leads to severe disability. Individuals with FOP are extremely sensitive to even minor traumatic events. There has been substantial recent interest in clinical trials for novel and urgently‐needed treatments for FOP. The International Clinical Council on FOP (ICC) was established in 2016 to provide consolidated and coordinated advice on the best practices for clinical care and clinical research for individuals who suffer from FOP. The Clinical Trials Committee of the ICC developed a focused list of key considerations that encompass the specific and unique needs of the FOP community – considerations that are endorsed by the entire ICC. These considerations complement established protocols for developing and executing robust clinical trials by providing a foundation for helping to ensure the safety of subjects with FOP in clinical research trials.