The US Food and Drug Administration has approved French drugmaker Ipsen’s drug for a rare bone disorder, making it the first treatment available to patients with the condition that causes abnormal bone growth.
The drug, Sohonos, has been approved for adults and children with fibrodysplasia ossificans progressiva (FOP), an uncommon genetic connective tissue disorder that causes progressive loss of mobility and reduced life expectancy, for girls over eight and boys over 10.
FOP occurs in about one in 1 600 000 newborns, and only about 800 people worldwide are known to have the disease.
Sohonos (palovarotene) capsules will be sold at an estimated annual list price of $624 000 based for 5mg (dose) per day, the company told Reuters, but that dose may vary depending on the patient’s weight and disease state.
The drug approval, based on data from a late-stage study showing a 54% reduction in the volume of new abnormal bone formation in patients compared with standard of care, puts Ipsen ahead of other drugmakers like Regeneron Pharmaceuticals, which is also developing an experimental drug (garetosmab), for the disorder and will seek approval in 2024.
Currently, FOP patients rely on high doses on steroids at the start of a flare-up, which entail unpredictable episodes of soft tissue swelling, pain, reduced movement and stiffness.
Sohonos will carry a warning for embryo-foetal toxicity and premature epiphyseal closure, which can lead to stunted growth and deformities in bone.
Study details
Reduction of New Heterotopic Ossification (HO) in the Open-Label, Phase 3 MOVE Trial of Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP)
Robert Pignolo, Edward Hsiao, Mona Al Mukaddam, et al.
Published in Journal of Bone & Mineral Research on 30 December 2022
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 annualised change in new HO volume versus NHS participants (by low-dose whole-body computed tomography [WBCT]), analysed 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 utilised BcPM with square-root transformation and HO data collapsed to equalise 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 annualised 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.
Reuters article – US FDA approves French drugmaker Ipsen’s rare bone disorder drug (Open access)
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