- New Drug Application granted Priority Review status, with a decision anticipated on 30 November 2021
- European Medicines Agency (EMA) and Swissmedic have also validated the Marketing Authorization Application (MAA) for palovarotene with Swissmedic granting palovarotene a priority review
PARIS–(BUSINESS WIRE)– Regulatory News:
Ipsen (Euronext: IPN; ADR: IPSEY) today announced that its New Drug Application (NDA) for palovarotene, an oral, investigational, selective RARγ agonist for the prevention of heterotopic ossification (new bone formation) as a potential treatment option for people living with the progressive disabling and ultra-rare genetic disorder fibrodysplasia ossificans progressiva (FOP), has been accepted by the U.S. Food and Drug Administration (FDA). The target regulatory action date assigned by the FDA under a Priority Review status is 30 November 2021.
FOP is an ultra-rare genetic disorder with an estimated prevalence of 1.36 per million individuals; however, the number of confirmed cases varies by country.1,2 It is characterized by new bone formation outside of the normal skeletal system, like in soft connective tissues, a process known as heterotopic ossification (HO),3 which can be preceded by painful soft-tissue swelling or “flare-ups”.2 Flare-up episodes are common and are a substantial contributor to the formation of new HO, however HO can form in the absence of a flare-up. HO, once formed, is irreversible and leads to loss of mobility and shortened life expectancy.3
Dr. Howard Mayer, Executive Vice President and Head of Research and Development, Ipsen, said “With no approved treatments for this progressive and debilitating disease, there remains a great unmet medical need for the FOP community. This year marks 15 years since the discovery of the mutation in the gene ALK2/ACVR1 which causes FOP, and the palovarotene submission is the first worldwide for a potential treatment in this disease. Our teams at Ipsen are now focused on working closely with regulatory authorities to bring this potential treatment option to people living with FOP around the world. We want to thank all the people living with FOP, their families, caregivers and healthcare teams who have participated in the palovarotene clinical program.”
The NDA for palovarotene is primarily based on data from the ongoing MOVE trial, the first global multi-center Phase III trial in FOP. MOVE is an open-label, single-arm trial, evaluating the efficacy and safety of a chronic/flare-up dosing regimen of palovarotene in decreasing new annualized HO volume in patients with FOP. Post hoc analyses* of the primary endpoint from the trial demonstrated a 62% reduction in mean annualized new HO volume in participants treated with palovarotene (8,821 mm3) (n=97) versus untreated participants from a natural-history study (23,318 mm3) (n=98) (nominal weighted linear mixed effects [wLME] model est. –11,611mm3, p-value = 0.0292). Overall, 29.3% of participants reported at least one serious adverse event (AE), including premature physeal closure (PPC) or epiphyseal disorder in 27.1% of the participants who were skeletally immature at baseline.4 As of the data cut-off, the most common treatment related AEs included skin and subcutaneous tissue disorders (97%), gastrointestinal disorders (77.8%), and infections and infestations (74.7%).4
“This FDA filing acceptance marks a significant milestone for Ipsen and those living with this relentless condition of FOP, which we hope will have a significant impact,” said Robert J. Pignolo, M.D., Ph.D., Chair, Geriatric Medicine & Gerontology, Mayo Clinic College of Medicine. “News of this potential new treatment will be welcomed by the FOP community, and we await further updates from the FDA. With ultra-rare conditions by their nature affecting very few people around the world it is so important we continue to make progress and advance the management of diseases like FOP.”
In addition to the European Medicines Agency (EMA) and Swissmedic MAA validations, Ipsen anticipates additional applications to other regulatory agencies in due course.
About the palovarotene FOP clinical program
The Phase III MOVE (NCT03312634) trial is an ongoing open-label, single-arm trial evaluating the efficacy and safety of a chronic/flare-up dosing regimen of palovarotene, which comprises a 5mg daily dose that is increased at the start of a flare-up to 20mg for four weeks, followed by 10mg for eight weeks. At the end of the flare-up dosing period, the dose returns to the chronic 5mg daily dose. All dosing is weight-adjusted in skeletally immature participants (those under the age of 18 years with less than 90% skeletal maturity on hand/wrist x-rays performed at screening). The trial is being conducted in Argentina, Australia, Brazil, Canada, France, Italy, Japan, Spain, Sweden, the United Kingdom, and the United States.5 There are two ongoing Phase II (PVO-1A-202 [NCT02279095] and PVO-1A-204 [NCT02979769]) extension trials: 1) Study 202, an open-label extension of Study 201, the initial Phase II randomized, double-blind, multi-center trial; and 2) Study 204, an open-label trial to evaluate the safety and efficacy of different palovarotene dosing regimens in patients with FOP in France.
In December 2019, a partial clinical hold was applied to participants under the age of 14 years participating in the Phase II (PVO-1A-202/204 and PVO-2A-201) and Phase III (PVO-1A-301) studies at all clinical sites globally. This was due to reports of premature physeal closure (PPC). A decision to pause dosing of palovarotene in all remaining participants in the global Phase III MOVE trial (PVO-1A-301), as well as the ongoing Phase II (PVO-1A-202/204) extension studies in FOP was made by Ipsen on January 24, 2020, based on results of a futility analysis as part of the pre-specified interim analysis (Bayesian compound Poisson analysis with square root transformation of the new HO volume data).
*Encouraging therapeutic activity was observed in post hoc analyses of interim data for the Phase III MOVE trial and shared with, and acknowledged by, the Independent Data Monitoring Committee (IDMC). Post hoc analyses included Bayesian compound Poisson analysis without square-root transformation, and weighted linear mixed-effects models (with/without square-root transformation of the new HO volume data). As such, the Company amended the protocol for the Phase III MOVE trial to include updates to the statistical-analysis section, including additional analyses requested by the IDMC, to be performed in addition to the primary pre-specified analysis. The protocol amendments are based on the IDMC’s observation that the protocol pre-specified statistical model may have negatively affected the efficacy analysis and appears to have shifted the statistical conclusion from significant therapeutic benefit to showing futility of the treatment. Dosing for eligible study patients ≥14 years of age has resumed as of March 26, 2020 across the Phase II and Phase III programs for palovarotene in FOP.
Palovarotene is an oral investigational, selective retinoic-acid receptor gamma (RARγ) agonist being developed as a potential treatment for people living with the debilitating ultra-rare genetic disorder fibrodysplasia ossificans progressiva (FOP). Palovarotene, which received rare pediatric disease and breakthrough therapy designations from the FDA for the potential treatment of FOP, was acquired by Ipsen through the acquisition of Clementia Pharmaceuticals in April 2019.
About fibrodysplasia ossificans progressiva (FOP)
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by bone that forms outside the normal skeleton, in muscles, tendons, or soft tissue.3 FOP has an estimated prevalence of 1.36 per million individuals; however, the number of confirmed cases varies by country.1,2
Ipsen is a global specialty-driven biopharmaceutical group focused on innovation and Specialty Care. The Group develops and commercializes innovative medicines in three key therapeutic areas – Oncology, Neuroscience, and Rare Diseases. Ipsen also has a well-established Consumer Healthcare business. With total sales over €2.5 billion in 2020, Ipsen sells more than 20 drugs in over 115 countries, with a direct commercial presence in more than 30 countries. Ipsen’s R&D is focused on its innovative and differentiated technological platforms located in the heart of the leading biotechnological and life sciences hubs (Paris-Saclay, France; Oxford, UK; Cambridge, US). The Group has about 5,800 employees worldwide. Ipsen is listed in Paris (Euronext: IPN) and in the United States through a Sponsored Level I American Depositary Receipt program (ADR: IPSEY). For more information on Ipsen, visit www.ipsen.com
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1 Lilijesthrom, M & Bogard, B 2016, ‘The global known FOP population’, FOP Drug Development Forum, Boston, MA, 24-25 October.
2 Baujat et al. Prevalence of fibrodysplasia ossificans progressiva (FOP) in France: an estimate based on a record linkage of two national databases. Orphanet Journal of Rare Diseases. 2017; 12:123.
3 Kaplan FS, et al. The medical management of fibrodysplasia ossificans progressiva: current treatment considerations. Proc Intl Clin Council FOP 1:1-111, 2019.
4 Pignolo R, Al Mukaddam, M, Baujat, G, Berglund, S, Cheung, A, De Cunto, C, Delai, P, Di Rocco, M, Haga, N, Hsiao, E, Kannu, P, Keen, R, Mancilla, E, Grogan, D, Marino, R, Strahs, A & Kaplan, F 2020, ‘Palovarotene (PVO) for fibrodysplasia ossificans progressiva (FOP): data from the phase III MOVE trial’, ASBMR Virtual Meeting, 11-15 September.
5 ClinicalTrials.gov. An efficacy and safety study of palovarotene for the treatment of fibrodysplasia ossificans progressiva. (MOVE), clinicaltrials.gov, viewed March 2021, <https://clinicaltrials.gov/ct2/show/NCT03312634>.
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