FDA Approves Sohonos (palovarotene) for the Treatment of Fibrodysplasia Ossificans Progressiva
PARIS, FRANCE, 16 August 2023 -- Ipsen (Euronext: IPN; ADR: IPSEY) announced today approval by the U.S. Food and Drug Administration (FDA) of Sohonos™ (palovarotene) capsules as a retinoid indicated for the reduction in volume of new heterotopic ossification in adults and pediatric patients aged 8 years and older for females and 10 years and older for males with fibrodysplasia ossificans progressiva (FOP).
“The FDA approval of Sohonos is a breakthrough for the U.S. FOP community. For the first time doctors have an approved medicine available to them, shown to reduce the formation of new, abnormal bone growth, known as heterotopic ossification (HO), which causes debilitating mobility challenges and has a devastating impact on the lives of people with FOP,” said Howard Mayer, Head of Research and Development, Ipsen. “Development of medicines for rare diseases takes commitment and belief from everyone involved. We at Ipsen are sincerely grateful to the FOP community of patients and medical experts, as the first-ever treatment in the U.S. for managing FOP would not be possible without their participation in the clinical trials and ongoing support.”
FOP impacts the lives of an estimated 400 people in the U.S. and 900 people globally.1,2 As the disease continuously progresses with flare-up episodes causing rapid bone growth, HO severely restricts mobility and function.3,4 Most people living with FOP inevitably lose the ability to eat and drink on their own, cannot provide selfcare or use the restroom themselves, and are unable to maintain employment.5 By the age of 30 years old, the majority of people with FOP require a wheelchair and full-time caregiver assistance.3,6 The management of FOP has previously been limited to palliative care and ultimately, FOP shortens the median life expectancy to 56 years, untimely death is often caused by bone formation around the ribcage leading to breathing problems and cardiorespiratory failure, or falls resulting in fractures or head injuries because joint ankylosis prevents bracing from a fall.7
“FOP is life-altering to the individuals diagnosed and their families. There’s not a day that goes by where those impacted don’t worry about the debilitating physical pain of muscle that is replaced by bone, another joint locking or the relentless emotional toll of losing the ability to do an activity they love, or hold a loved one close,” explained Michelle Davis, Executive Director of International FOP Association. “The first treatment for FOP has been proven to reduce the volume of new abnormal bone growth, which may result in better health outcomes for people living with FOP.”
The FDA approval is based on the pivotal efficacy and safety data from the Phase III MOVE trial, the first and largest multicenter, open-label trial in adult and pediatric patients. The 18-month data published in the Journal of Bone and Mineral Research,8 included 107 patients (12 percent of the estimated number of individuals worldwide living with FOP) who received oral palovarotene compared with untreated individuals from Ipsen’s global FOP Natural History Study.9 The study results demonstrated palovarotene effectively reduced annualized heterotopic ossification volume compared with no treatment beyond standard of care, (54% reduction with weighted linear mixed effect model).8 The study also demonstrated that palovarotene has a well-characterized safety profile, with adverse events consistent with the systemic retinoid class. The most common treatment emergent adverse reactions reported in the study were mucocutaneous events such as dry skin, lip dryness, alopecia, drug eruption, rash, and pruritus and musculoskeletal events such as arthralgia and premature growth plate closure in growing children. 8
“As a clinician caring for patients with FOP, I personally see the daily challenges and stresses that our patients and their families must contend with,” said Dr Edward Hsiao, Professor of Medicine, Division of Endocrinology and Metabolism, University of California, San Francisco. “The published Phase III MOVE study showed that Sohonos can decrease new heterotopic ossification, and that palovarotene can be tolerated by many patients with FOP. Sohonos is not for everyone. As with all medicines there are risks in this case especially for young children who may develop early growth plate closure. In addition, Sohonos has the same side effects as other retinoids, including dryness of the skin and mucus membranes. However, since the accumulation of HO in FOP is progressive, irreversible, and life altering, this medication is an important treatment option for our FOP community.”
Sohonos, the first and only treatment for FOP
Sohonos is an oral medicine with particular selectivity for the gamma subtype of retinoic-acid receptors, which are an important regulator of skeletal development and ectopic bone in the retinoid signaling pathway. The medicine is designed to mediate the interactions between the receptors, growth factors and proteins within the retinoid signaling pathway to reduce new abnormal bone formation in FOP. The recommended dosing for Sohonos includes a chronic daily dosage of 5 mg (or weight-based equivalent for pediatric patients under 14 years of age), which can be modified/increased for flare-up symptoms. Sohonos may be prescribed immediately in the U.S. for eligible patients.
To ensure access to Sohonos for eligible individuals in the U.S., Ipsen Cares patient support program is available as a resource to people living with FOP and their caregivers to provide educational support and address coverage, access and reimbursement questions (1-866-435-5677).
Sohonos received Orphan Drug and Breakthrough Therapy Designations from the U.S. Food and Drug Administration (FDA) for the treatment of FOP and was granted Priority Review of the New Drug Application (NDA). Sohonos, under the generic name palovarotene, is also under review with a number of other regulatory authorities. In July 2023, the European Commission did not grant marketing authorization for palovarotene. SohonosTM (palovarotene capsules) is currently authorized for use in eligible patients in U.S., Canada,10 and with a conditional approval in the United Arab Emirates.
With this approval the FDA also issued a Rare Pediatric Disease Priority Review Voucher (PRV). The voucher can be used for subsequent drug applications that would not qualify for a priority review.
Important Sohonos Safety Information
WARNING: EMBRYO-FETAL TOXICITY and PREMATURE PHYSEAL CLOSURE IN GROWING PEDIATRIC PATIENTS
Premature Epiphyseal Closure
SOHONOS is contraindicated in patients during pregnancy, or with a history of allergy or hypersensitivity to retinoids, or to any component of SOHONOS.
Warnings and Precautions
- Embryo-Fetal Toxicity: SOHONOS can cause fetal harm and is contraindicated during pregnancy. Advise females of reproductive potential to use an effective method of contraception during treatment with SOHONOS and for 1 month after the last dose. If a pregnancy occurs during Sohonos treatment, discontinue treatment immediately and refer the patient to an obstetrician/gynecologist experienced in reproductive toxicity.
- Premature Epiphyseal Closure in Growing Pediatric Patients: SOHONOS can cause irreversible premature epiphyseal closure and potential adverse effects on growth. Prior to starting treatment with SOHONOS, all growing pediatric patients should undergo baseline assessment of skeletal maturity and continued monitoring until patients reach skeletal maturity or final adult height. If appropriate, temporary or permanent discontinuation may be warranted.
- Mucocutaneous Adverse Reactions: Dry skin, lip dry, pruritis, rash, alopecia, erythema, skin exfoliation [skin peeling] and, dry eye occurred with SOHONOS. Prophylactic measures to minimize risk and/or treat the mucocutaneous adverse reactions are recommended (e.g., skin emollients, sunscreen, lip moisturizers, or artificial tears). Some may require dose reduction or discontinuation. Photosensitivity reactions have been associated with the use of retinoids and may occur with SOHONOS. Precautionary measures for phototoxicity are recommended (e.g., use of sunscreens, protective clothing, and use of sunglasses).
- Metabolic Bone Disorders: Increased risk of radiologically observed vertebral fractures and decreased vertebral bone mineral content and bone density. Periodic radiological assessment of the spine is recommended. Retinoids have been associated with hyperostotic changes (bone spurs) and calcification of tendons or ligaments may occur with SOHONOS.
- Psychiatric Disorders: New or worsening psychiatric events were reported with SOHONOS including depression, anxiety, mood alterations, and suicidal thoughts and behaviors. Monitor for development of new or worsening psychiatric symptoms during treatment with SOHONOS. Patients and/or caregivers should contact their healthcare provider if new or worsening psychiatric symptoms develop during treatment with SOHONOS.
- Night Blindness: This may be dose-dependent, making driving a vehicle at night potentially hazardous during treatment. Advise patients to be cautious when driving or operating any vehicle at night and seek medical attention in the event of vision impairment.
The most common adverse reactions (≥ 10%) in clinical trials include dry skin, lip dry, arthralgia, pruritus, pain in extremity, rash, alopecia, erythema, headache, back pain, skin exfoliation [skin peeling] , nausea, musculoskeletal pain, myalgia, dry eye, hypersensitivity, peripheral edema, and fatigue.
- CYP3A4 inhibitors may increase SOHONOS exposure. Avoid concomitant use of strong or moderate CYP3A4 inhibitors, as well as grapefruit, pomelo or juices containing these fruits.
- CYP3A4 inducers may decrease SOHONOS exposure. Avoid concomitant use of strong or moderate CYP3A3 inducers.
- The use of both vitamin A and SOHONOS at the same time may lead to additive effects. Concomitant administration of vitamin A in doses higher than the recommended daily allowance and/or other oral retinoids must be avoided due to risk of hypervitaminosis A.
- Systemic retinoid use has been associated with cases of benign intracranial hypertension (pseudotumor cerebri), some of which involved the concomitant use of tetracyclines. Avoid coadministration of SOHONOS with tetracycline derivatives.
Use in Specific Populations
- Pregnancy: SOHONOS is contraindicated during pregnancy. Obtain a negative serum pregnancy test within 1 week prior to SOHONOS therapy and periodically, as needed, over the course of treatment with SOHONOS and 1 month after treatment discontinuation unless patient is not at risk of pregnancy. If pregnancy occurs during treatment with SOHONOS, stop treatment immediately and refer the patient to an obstetrician/gynecologist or other specialist experienced in reproductive toxicity for evaluation and advice.
- Lactation: Advise females that breastfeeding is not recommended during treatment with SOHONOS, and for at least 1 month after the last dose.
- Females and Males of Reproductive Potential: Advise females of reproductive potential to use effective contraception at least 1 month prior to and during treatment, and for 1 month after the last dose unless continuous abstinence is chosen.
- Pediatric Use: All growing pediatric patients should undergo baseline assessment of growth and skeletal maturity before starting treatment and continued clinical and radiographic monitoring every 6-12 months until patients reach skeletal maturity or final adult height
- Renal or Hepatic Impairment: Use of SOHONOS in patients with severe renal impairment, or with moderate or severe hepatic impairment is not recommended.
Please see full Prescribing Information, including BOXED WARNING on Ipsen.com/us
Ipsen is a global, mid-sized biopharmaceutical company focused on transformative medicines in Oncology, Rare Disease and Neuroscience. With total sales of €3.0bn in FY 2022, Ipsen sells medicines in over 100 countries. Alongside its external-innovation strategy, the Company’s research and development efforts are focused on its innovative and differentiated technological platforms located in the heart of leading biotechnological and life-science hubs: Paris-Saclay, France; Oxford, U.K.; Cambridge, U.S.; Shanghai, China. Ipsen has around 5,300 colleagues worldwide and is listed in Paris (Euronext: IPN) and in the U.S. through a Sponsored Level I American Depositary Receipt program (ADR: IPSEY). For more information, visit ipsen.com
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1 Pignolo RJ, et al Prevalence of fibrodysplasia ossificans progressiva (FOP) in the United States: estimate from three treatment centers and a patient organisation. Orphanet J Rare Dis (2021) 16 : 350
2 Baujat G, et al. Prevalence of fibrodysplassia ossificans progressiva (FOP) in France: an estimate based on a record linkage of two national databases. Orphanet J Rare Dis (2017) 12: 123
3 Pignolo RJ, et al. Self-reported baseline phenotypes from the International Fibrodysplasia Ossificans Progressiva (FOP) Association Global Registry. Bone 2020;134:115274.
4 Pignolo et al. The Natural History of Fibrodysplasia Ossificans Progressiva: A Prospective, Global, 36-Month Study. Genetics in Medicine. 2022. https://doi.org/10.1016/j.gim.2022.08.013
5. Al Mukaddam M, et al. Val Health 2022;25:S273 (POSA427)
6 Pignolo RJ, et al. Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons. Pediatr Endocrinol Rev 2013;10 Suppl 2:437– 48.
7 Kaplan et al, Early Mortality and Cardiorespiratory Failure in Patients with Fibrodysplasia Ossificans Progressiva. The Journal of Bone & Joint Surgery. 2010. doi: 10.2106/JBJS.I.00705
8 Pignolo RJ, et al. Reduction of New HO in the Open-Label, Phase 3 MOVE Trial of Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP). J Bone Miner Res. 2022.
9. Pignolo RJ, et al. The natural history of fibrodysplasia ossificans progressiva: A prospective 36-month study. Gen Med. 2022,ISSN 1098-3600,https://doi.org/10.1016/j.gim.2022.08.013.
10. Government of Canada, Notice: Multiple Additions to the Prescription Drug List (PDL). Viewed 30 November 2022, https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/prescription-drug-list/notices-changes/multiple-additions-2022-01-24.html.
Posted: August 2023