Study methodology and insights from the palovarotene clinical development program in fibrodysplasia ossificans progressiva
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SUBMITTER: Pignolo R
PROVIDER: S-EPMC10642058 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:Abstract Objectives Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized byheterotopic ossification (HO) and progressive restriction of mobility. To date, no approved disease-modifying treatments for FOP exist, but interim phaseIII MOVE trial (NCT03312634) results suggest marked efficacy for palovarotene (PVO). 1 The PIVOINE rollover trial (NCT05027802) has been designed to allow treatment continuity and further evaluation of PVO safety and efficacy; the methodology is given here. Methods Patients will receive 5 mg PVO daily, or the parent study completion dose, for a maximum of 3 years; during flare-ups, patients will receive 20 mg daily for 4 weeks, then 10 mg daily for 8 weeks. Enrollment criteria: completion of a parent study (end of study/treatment visit of NCT03312634 or NCT02279095/NCT02979769), ≥14 years of age, full skeletal maturity if aged <18 or deemed to be final adult height. PIVOINE aims to enroll 61 patients; recruitment has not begun. The primary outcome will be the incidence and description of all treatment-emergent adverse events, collected continuously over the study period. Secondary outcomes (collected every 6 months; reported as raw values and change from the inclusion visit for outcomes specified by *) include: range of motion* (using Cumulative Analogue Joint Involvement Scale total score), the use of aids, assistive devices and adaptations*, physical function* (using adult form of the FOP-Physical Function Questionnaire; total score and upper extremities and mobility sub-scores), the frequency of healthcare utilization, and physical and mental health* (using Patient Reported Outcomes Measurement Information System Global Health Scale). Lung function will be assessed via observed and percentage predicted (PP) forced vital capacity (FVC)*, forced expiratory volume in 1 second (FEV 1)*, diffusion capacity of the lung for carbon monoxide*, and the absolute and PP FEV 1 /FVC ratio*. The number of investigator-reported flare-ups*, including duration and outcomes, will be reported along with the percentage of patients with new bone growth. Summary Results from PIVOINE, estimated to end in November 2024, will allow further evaluation of PVO in FOP. References 1. Pignolo R et al. ASBMR 2020;35(Suppl 1): 16–17 Funding: Sponsored by Ipsen. Presentation: No date and time listed
| S-EPMC9624757 | biostudies-literature
Project description:Fibrodysplasia ossificans progressiva (FOP) is a severely disabling heritable disorder of connective tissue characterized by congenital malformations of the great toes and progressive heterotopic ossification that forms qualitatively normal bone in characteristic extraskeletal sites. The worldwide prevalence is approximately 1/2,000,000. There is no ethnic, racial, gender, or geographic predilection to FOP. Children who have FOP appear normal at birth except for congenital malformations of the great toes. During the first decade of life, sporadic episodes of painful soft tissue swellings (flare-ups) occur which are often precipitated by soft tissue injury, intramuscular injections, viral infection, muscular stretching, falls or fatigue. These flare-ups transform skeletal muscles, tendons, ligaments, fascia, and aponeuroses into heterotopic bone, rendering movement impossible. Patients with atypical forms of FOP have been described. They either present with the classic features of FOP plus one or more atypical features [FOP plus], or present with major variations in one or both of the two classic defining features of FOP [FOP variants]. Classic FOP is caused by a recurrent activating mutation (617G>A; R206H) in the gene ACVR1/ALK2 encoding Activin A receptor type I/Activin-like kinase 2, a bone morphogenetic protein (BMP) type I receptor. Atypical FOP patients also have heterozygous ACVR1 missense mutations in conserved amino acids. The diagnosis of FOP is made by clinical evaluation. Confirmatory genetic testing is available. Differential diagnosis includes progressive osseous heteroplasia, osteosarcoma, lymphedema, soft tissue sarcoma, desmoid tumors, aggressive juvenile fibromatosis, and non-hereditary (acquired) heterotopic ossification. Although most cases of FOP are sporadic (noninherited mutations), a small number of inherited FOP cases show germline transmission in an autosomal dominant pattern. At present, there is no definitive treatment, but a brief 4-day course of high-dose corticosteroids, started within the first 24 hours of a flare-up, may help reduce the intense inflammation and tissue edema seen in the early stages of the disease. Preventative management is based on prophylactic measures against falls, respiratory decline, and viral infections. The median lifespan is approximately 40 years of age. Most patients are wheelchair-bound by the end of the second decade of life and commonly die of complications of thoracic insufficiency syndrome.
| S-EPMC3253727 | biostudies-literature
Project description: Not available
| S-EPMC4592076 | biostudies-literature
Project description:Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disease caused by heterozygous missense mutations in Activin A receptor type I which is also known as Activin-like kinase 2 (ALK2), a type I receptor of Bone Morphogenetic Proteins(BMP). Patients with FOP usually undergo episodic flare-ups and the heterotopic ossification in soft and connective tissues. Molecular mechanism study indicates that Activin A, the ligand which normally transduces Transforming Growth Factor Beta signaling, abnormally activates BMP signaling through ALK2 mutants in FOP, leading to heterotopic bone formation. To date, effective therapies to FOP are unavailable. However, significant advances have recently been made in the development of FOP drugs. In this article, we review the recent advances in understanding the FOP mechanism and drug development, with a focus on the small-molecular and antibody drugs currently in the clinical trials for FOP treatment.
| S-EPMC9499916 | biostudies-literature
Project description: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).
| S-EPMC9804935 | biostudies-literature
Project description:BackgroundInflammation is a major driver of heterotopic ossification (HO), a condition of abnormal bone growth in a site that is not normally mineralized.Purpose of reviewThis review will examine recent findings on the roles of inflammation and the immune system in fibrodysplasia ossificans progressiva (FOP). FOP is a genetic condition of aggressive and progressive HO formation. We also examine how inflammation may be a valuable target for the treatment of HO. Rationale/Recent findings: Multiple lines of evidence indicate a key role for the immune system in driving FOP pathogenesis. Critical cell types include macrophages, mast cells, and adaptive immune cells, working through hypoxia signaling pathways, stem cell differentiation signaling pathways, vascular regulatory pathways, and inflammatory cytokines. In addition, recent clinical reports suggest a potential role for immune modulators in the management of FOP.Future perspectivesThe central role of inflammatory mediators in HO suggests that the immune system may be a common target for blocking HO in both FOP and non-genetic forms of HO. Future research focusing on the identification of novel inflammatory targets will help support the testing of potential therapies for FOP and other related conditions.
| S-EPMC10967946 | biostudies-literature
Project description:Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder of progressive heterotopic ossification (HO) caused by a recurrent activating mutation of ACVR1/ALK2, a bone morphogenetic protein (BMP) type I receptor. FOP is characterized by progressive HO, which is associated with inflammation in the setting of dysregulated BMP signaling, however, a variety of atypical neurologic symptoms are also reported by FOP patients. The main objective of this study is to investigate the potential underlying mechanism that is responsible for the observed atypical neurologic symptoms. We evaluated two mouse models of dysregulated BMP signaling for potential CNS pathology through non-invasive magnetic resonance imaging (MRI) studies and histological and immunohistochemical approaches. In one model, BMP4 is over-expressed under the control of the neuron-specific enolase promoter; the second model is a knock-in of a recurrent FOP mutation of ACVR1/ALK2. We also retrospectively examined MRI scans of four FOP patients. We consistently observed demyelinated lesions and focal inflammatory changes of the CNS in both mouse models but not in wild-type controls, and also found CNS white matter lesions in each of the four FOP patients examined. These findings suggest that dysregulated BMP signaling disturbs normal homeostasis of target tissues, including CNS where focal demyelination may manifest as the neurologic symptoms frequently observed in FOP.
| S-EPMC3894630 | biostudies-literature
Project description:Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease that is characterized by the formation of heterotopic bone tissues in soft tissues, such as skeletal muscle, ligament, and tendon. It is difficult to remove such heterotopic bones via internal medicine or invasive procedures. The identification of activin A receptor, type I (ACVR1)/ALK2 gene mutations associated with FOP has allowed the genetic diagnosis of FOP. The ACVR1/ALK2 gene encodes the ALK2 protein, which is a transmembrane kinase receptor in the transforming growth factor-? family. The relevant mutations activate intracellular signaling in vitro and induce heterotopic bone formation in vivo. Activin A is a potential ligand that activates mutant ALK2 but not wild-type ALK2. Various types of small chemical and biological inhibitors of ALK2 signaling have been developed to establish treatments for FOP. Some of these are in clinical trials in patients with FOP.
| S-EPMC6145951 | biostudies-literature
Project description:Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic condition characterized by extraskeletal bone formation. Most of the musculoskeletal characteristics of FOP are related to dysregulated chondrogenesis, with heterotopic ossification being the most typical feature. Activating mutations of activin receptor A type I (ACVR1), a bone morphogenetic protein (BMP) type I receptor, are responsible for the skeletal and nonskeletal features. The clinical phenotype is always consistent, with congenital bilateral hallux valgus malformation and early-onset heterotopic ossification occurring spontaneously or, more frequently, precipitated by trauma. Painful, recurrent soft-tissue swellings (flare-ups) precede localized heterotopic ossification that can occur at any location, typically affecting regions near the axial skeleton and later progressing to the appendicular bones. A diagnosis of FOP is suspected in a proband presenting with hallux valgus malformation, heterotopic ossification, and confirmed by the identification of a heterozygous pathogenic variant in the ACVR1/ALK2 gene. Avoiding unnecessary surgical procedures, prescribing prophylactic corticosteroids, preventing falls, and using protective headgear represent essential interventions for care management. Different classes of medications to contain acute inflammation flare-ups have been proposed, with high dose corticosteroids and nonsteroidal anti-inflammatory drugs usually utilized. Here, we report on two FOP patients, with typical clinical features summarizing the principal aspects of FOP, and we aim to provide comprehensive information outlining some unusual findings, possibly contributing to FOP's definition and management.
| S-EPMC8391109 | biostudies-literature
Project description:Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disease caused by increased BMP pathway signaling due to mutation of ACVR1, a bone morphogenetic protein (BMP) type 1 receptor. The primary clinical manifestation of FOP is extra-skeletal bone formation (heterotopic ossification) within soft connective tissues. However, the underlying ACVR1 mutation additionally alters skeletal bone development and nearly all people born with FOP have bilateral malformation of the great toes as well as other skeletal malformations at diverse anatomic sites. The specific mechanisms through which ACVR1 mutations and altered BMP pathway signaling in FOP influence skeletal bone formation during development remain to be elucidated; however, recent investigations are providing a clearer understanding of the molecular and developmental processes associated with ACVR1-regulated skeletal formation.
| S-EPMC9068236 | biostudies-literature