Grogan, Donna R.

ABSTRACT Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive heterotopic ossification (HO), often heralded by flare-ups, leading to reduced movement and life expectancy. This placebo-controlled, double-blind trial (NCT02190747) evaluated palovarotene, an orally bioavailable selective retinoic acid receptor gamma agonist, for prevention of HO in patients with FOP. Patients experiencing a flare-up were enrolled in two cohorts: (1) patients ≥15 years were randomized 3:1 to palovarotene 10/5 mg (weeks 1–2/3–6) or placebo; (2) patients ≥6 years were randomized 3:3:2 to palovarotene 10/5 mg, palovarotene 5/2.5 mg (weeks 1–2/3–6), or placebo. Cohort data were pooled. The primary endpoint was the proportion of responders (no/minimal new HO at flare-up body region by plain radiograph) at week 6. Change from baseline in HO volume and new HO incidence were assessed by computed tomography (CT) at week 12. Tissue edema was assessed by magnetic resonance imaging (MRI) or ultrasound. Forty patients (aged 7–53 years) were enrolled (placebo: n = 10; palovarotene 5/2.5 mg: n = 9; palovarotene 10/5 mg: n = 21). Disease history was similar between groups. In the per-protocol population, the proportion of responders at week 6 by plain radiograph was 100% with palovarotene 10/5 mg; 88.9% with palovarotene 5/2.5 mg; 88.9% with placebo (Cochran-Armitage trend test: p = 0.17). At week 12, the proportions were 95.0% with palovarotene 10/5 mg; 88.9% with palovarotene 5/2.5 mg; 77.8% with placebo (Cochran-Armitage trend test: p = 0.15). Week 12 least-squares mean (LSmean) new HO volume, assessed by CT, was 3.8 × 103 mm3 with palovarotene 10/5 mg; 1.3 × 103 mm3 with palovarotene 5/2.5 mg; 18.0 × 103 mm3 with placebo (pairwise tests versus placebo: p ≤ 0.12). Palovarotene was well-tolerated. No patients discontinued treatment or required dose reduction; one patient had dose interruption due to elevated lipase. Although these findings were not statistically significant, they support further evaluation of palovarotene for prevention of HO in FOP in larger studies. © 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).

Background: ATTR-CM is believed to have a relatively indolent course, with a median survival of ~5 years from heart failure symptoms; however, no data exist as to the rate of progression after disease diagnosis. ATTR-CM is associated with genetic variants, including V122I (present in ~ 3.5% of African Americans), or wild-type TTR (senile systemic amyloidosis - SSA). While there is no effective treatment other than heart transplantation, therapies designed to slow or halt amyloid deposition are in development. The purpose of this study was to characterize the natural history of ATTR-CM to support future therapeutic trials. Methods: Patients with ATTR-CM due to V122I (n = 11) and SSA (n = 18), were enrolled 10.4 ± 11.9 months after diagnosis (range: 0 – 60 months) and assessed every 6 months for up to two years by echocardiography and cardiac magnetic resonance imaging (CMR), with functional capacity assessed by 6-minute walk, and biochemical profile including cardiac troponins and NT-pro-B-type natriuretic peptide (BNP). Baseline data from the full cohort (n = 29), and available data from those completing the 12 month assessment (n = 15) are presented for this on-going study. Results : At baseline, both groups were similar in terms of gender, duration of disease from diagnosis, NYHA, troponin/NT-BNP, and echo or CMR-measured LV wall thickness. SSA patients were older (mean age 76 vs. 71y, P = 0.03), Caucasian (100% vs 0%, P < 0.001), with a history of atrial fibrillation (83% vs. 27%, p = 0.003). During a mean follow-up of 442 days (30–768), there have been 7 deaths (4 V122I; 3 SSA) and 1 cardiac transplantation (SSA), and 10 of 29 (34.5%) were hospitalized at least once (90% for cardiac reasons). For those subjects with a 12 month assessment, LV ejection fraction declined by echo (2.8 %) and CMR (12 %), with minimal changes in wall thickness. Increases were seen in NT-Pro-BNP (87%) and troponin (I: 186%; T: 70%). Worsening of NYHA class occurred in 43% of patients; 6-minute walk distance decreased by 19.2%. Conclusions : Despite reports of a relatively indolent course of ATTR-CM, preliminary data from this ongoing study are the first to demonstrate that quantifiable noninvasive parameters worsen over a 1 year follow up period and are associated with adverse clinical outcomes.

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