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Garetosmab in fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial.

ABSTRACT: Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody (n = 20) or placebo (n = 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n = 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at least one treatment-emergent adverse event during period 1, notably epistaxis, madarosis and skin abscesses. Five deaths (5 of 44; 11.4%) occurred in the open-label period and, while considered unlikely to be related, causality cannot be ruled out. The primary efficacy end point in period 1 (total lesion activity by PET-CT) was not met (P = 0.0741). As the development of new HO lesions was suppressed in period 1, the primary efficacy end point in period 2 was prospectively changed to the number of new HO lesions versus period 1. No placebo patients crossing over to garetosmab developed new HO lesions (0% in period 2 versus 40.9% in period 1; P = 0.0027). Further investigation of garetosmab in FOP is ongoing. ClinicalTrials.gov identifier NCT03188666 .

SUBMITTER: Di Rocco M

PROVIDER: S-EPMC10579054 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Garetosmab in fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial.

Di Rocco Maja M Forleo-Neto Eduardo E Pignolo Robert J RJ Keen Richard R Orcel Philippe P Funck-Brentano Thomas T Roux Christian C Kolta Sami S Madeo Annalisa A Bubbear Judith S JS Tabarkiewicz Jacek J Szczepanek Małgorzata M Bachiller-Corral Javier J Cheung Angela M AM Dahir Kathryn M KM Botman Esmée E Raijmakers Pieter G PG Al Mukaddam Mona M Tile Lianne L Portal-Celhay Cynthia C Sarkar Neena N Hou Peijie P Musser Bret J BJ Boyapati Anita A Mohammadi Kusha K Mellis Scott J SJ Rankin Andrew J AJ Economides Aris N AN Trotter Dinko Gonzalez DG Herman Gary A GA O'Meara Sarah J SJ DelGizzi Richard R Weinreich David M DM Yancopoulos George D GD Eekhoff E Marelise W EMW Kaplan Frederick S FS

Nature medicine 20230928 10

Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody (n = 20) or placebo (n = 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n = 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at lea ...[more]

PMID: 37770652

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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).

Project description:Abstract Objectives Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder caused by activin receptor-like kinase-2/activin A receptor type 1(ALK2/ACVR1) mutation and characterized by heterotopic ossification (HO) inducing progressive restriction of mobility. IPN60130 is a selective ALK2/ACVR1 inhibitor, currently being investigated for the treatment of FOP. 1 Here, we describe methodology of the FALKON trial (NCT05039515) designed to compare efficacy and safety of IPN60130 with placebo in patients with FOP. Methods Patients will be randomized to oral placebo, or low or high dose IPN60130 for 12 months; patients receiving placebo will then transition to IPN60130 for 12 months. Patients will be randomized to receive placebo, or low or high dose IPN60130 orally for 24months. Enrollment criteria include: age of ≥5years, clinical FOP diagnosis with a disease-causing mutation, and either a flare-up, new HO, new joint ankylosis, or increase in Cumulative Analogue Joint Involvement Scale (CAJIS) score in the prior year. Recruitment is ongoing to enroll 90 patients. The primary efficacy outcome will be the annualized change from Baseline (CfB) in HO volume to Month 12, assessed using low-dose whole-body computed tomography (CT). Secondary efficacy outcomes to be compared with placebo at Month 12 include: CfB in volume of new HO lesions, CfB in number of HO lesions, flare-up rate and number of flare-up days, number of body regions with new HO, CfB in pain intensity, and the proportion of patients with any new HO. Additional secondary endpoints include CfB in HO volume in treated patients versus placebo and participants receiving standard of care in a FOP natural history study (NCT02322255) at Month 24. Safety will be assessed via the incidence of adverse events (AEs) and serious AEs over 25 months. Patients aged ≥15 years will be eligible for a sub-study assessing HO using [ 18 F]NaF positron emission tomography-CT. Summary Results from the FALKON trial, expected to complete in August 2025, will enable evaluation of the efficacy and safety of IPN60130 in patients with FOP. References 1. Davis A et al. J Bone Miner Res 2019;34(Suppl 1): 290Funding: Sponsored by Ipsen Presentation: No date and time listed

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.

Dataset Information

Garetosmab in fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial.

Publications

Garetosmab in fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial.

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