Sohonos (palovarotene) / Ipsen - LARVOL DELTA

Palovarotene for patients with multiple hereditary exostosis: results of MO-Ped, a terminated, randomized, placebo-controlled, double-blind phase 2 trial. (PubMed, Sci Rep) - P2 | "Interpretation of results was limited by the reduced treatment duration and smaller than expected cohort. The trial yielded important data on the natural history of MHE.Trial registration: NCT03442985 (first posted 22 February 2018)."

Clinical • Journal • P2 data • Pediatrics

FOPal: A Study to Document and to Further Describe Long-term Safety and Effectiveness of Palovarotene in Participants With Fibrodysplasia Ossificans Progressiva (FOP) (clinicaltrials.gov) - P=N/A | N=100 | Recruiting | Sponsor: Ipsen | N=70 ➔ 100 | Trial completion date: Jan 2034 ➔ Dec 2035 | Trial primary completion date: Dec 2033 ➔ Dec 2035

Enrollment change • Trial completion date • Trial primary completion date

Fibrodysplasia Ossificans Progressiva: childhood onset from missense mutation (c.974G>C, p.G325A) in ACVR1 (AAP-NCE 2025) - "Palovarotene, a retinoid that may reduce ossification, is not yet approved for young children due to the risk of premature epiphyseal closure... This case highlights the critical need for early recognition of FOP in children with unexplained soft tissue masses and congenital skeletal anomalies. Early diagnosis facilitates genetic counseling and symptom management to slow disease progression. Continued research is necessary to clarify the role of ACVR1 variants in disease severity and management."

Clinical • Genetic Disorders • Immunology • Mood Disorders • Myositis • Orthopedics • Osteosarcoma • Sarcoma • Solid Tumor • ACVR1 • IL6 • TGFB1

A Narrative Review of Phase II and III Clinical Trials for the Pharmacological Treatment of Fibrodysplasia Ossificans Progressiva (FOP): Efficacy, Safety, and Challenges in Treatment Strategies. (PubMed, Drug Des Devel Ther) - "Promising pharmacological approaches include retinoic acid receptor γ (RARγ) agonists, such as palovarotene, and monoclonal antibodies targeting activin A, like garetosmab. Nevertheless, safety concerns and the complexities of clinical trial implementation highlight the need for innovative approaches to ensure effective and equitable treatments. Future research should prioritise long-term safety, efficacy, and patient-centred outcomes to improve FOP management."

Journal • P2 data • P3 data • Review • Genetic Disorders • Rare Diseases

Monoallelic variants in ACVR1 in a cohort of Egyptian individuals with fibrodysplasia ossificans progressiva. (PubMed, Clin Dysmorphol) - "Our study highlights the progressive nature of the disease and the importance of early diagnosis to avoid lethal complications such as locked jaw and airway obstructions that affect swallowing and breathing. An early accurate diagnosis gives an opportunity for the affected individuals in the future to be candidates for the agonist Palovarotene drug that prevents the complications arising from ectopic ossification."

Journal • ACVR1

Morpholino-Mediated Exon Skipping Targeting Human ACVR1/ALK2 for Fibrodysplasia Ossificans Progressiva. (PubMed, Methods Mol Biol) - "Here, we describe a method to reduce ACVR1 expression in FOP patient cells by exon skipping in ACVR1 mRNAs using phosphorodiamidate morpholino oligomers (PMOs). This strategy can be applied to the screen to select antisense oligomers to knockdown not only ACVR1 but also genes which cause other autosomal-dominant genetic diseases."

Journal • Genetic Disorders • Musculoskeletal Diseases • ACVR1

The first approved drug for abnormal bone formation: palovarotene challenges and way forward. (PubMed, J Pak Med Assoc) - "Given its novelty, research on palovarotene is still in its infancy. Consequently, challenges surrounding the introduction of palovarotene needs to be studied along with its potential indications and advantages in the disorders characterised by abnormal bone formation."

Journal • Immunology • Inflammation • Myositis • Orthopedics • Pain

All Restricted Spines are not Spondyloarthritis: Fibrodysplasia Ossificans Progressiva (FOP) in Monozygotic Twins presenting to Rheumatology Clinic. (PubMed, Mediterr J Rheumatol) - "The first FDA-approved drug, palovarotene, was approved in 2023...This highlights the need for awareness of this condition among both adult and paediatric rheumatologists so that harmful biopsies and surgeries can be avoided, and patients can start on newer therapies early in the disease. It can be considered a rare mimic of ankylosing spondylitis; however, the characteristic features can very well identify the disorder clinically."

Journal • Ankylosing Spondylitis • Immunology • Inflammatory Arthritis • Pain • Pediatrics • Rheumatology • Seronegative Spondyloarthropathies • Spondylarthritis

Progressive Soft Tissue Swelling in a Pediatric Patient Leading to the Diagnosis of Fibrodysplasia Ossificans Progressiva: A Case Report. (PubMed, Pediatr Dermatol) - "The diagnostic process, which included imaging, skin biopsy, and a thorough infectious and autoimmune workup, emphasized the challenges in identifying FOP due to its rarity; however, bilateral congenital hallux valgus, often present in FOP, can be a clue for early diagnosis. While corticosteroids provide temporary relief, long-term management now includes palovarotene, a novel therapy to suppress HO."

Journal • Genetic Disorders • Immunology • Musculoskeletal Pain • Pain • Pediatrics • ACVR1

Characteristics of RWE used in Regulatory Decision-Making for Marketing Authorization Applications (MAAs) (ISPOR 2025) - " Seven medicines were analyzed: idecabtagene vicleucel (ide-cel), omburtamab, sotorasib, alpelisib, palovarotene, tacrolimus, and omaveloxolone. MAAs containing RWE submitted to the FDA were predominantly for rare diseases medicines and for first-in-class indications. Acceptability of RWE varied based on entire body of evidence. Further investigation into factors influencing RWE acceptability and its integration into MAAs across other regulators such as EMA is warranted."

Hematological Disorders • Rare Diseases

Advancements in mechanisms and drug treatments for fibrodysplasia ossificans progressiva. (PubMed, J Zhejiang Univ Sci B) - "Currently, researchers are intensively studying the pathogenesis of FOP at various stages and developing promising drug candidates, including saracatinib, palovarotene, and rapamycin. This review provides an overview of progress in understanding the mechanism of FOP and the development of therapeutic drugs, with the goal of providing insights for further research and the development of new treatment methods."

Journal • Review • Genetic Disorders • ACVR1

A Study of the Blood Levels of Palovarotene in Participants With Abnormal Liver Function Compared to Healthy Adult Participants After Intake of a Single Dose (clinicaltrials.gov) - P1 | N=32 | Recruiting | Sponsor: Ipsen

New P1 trial • Hepatology

Palovarotene in fibrodysplasia ossificans progressiva: review and perspective. (PubMed, Expert Opin Pharmacother) - "While post hoc analyses indicate that palovarotene may have modest benefits for the inhibition of new HO formation in FOP, a number of limitations and concerns remain about its generalized use. Although the long-term risks and benefits of treatment with palovarotene remain unknown, the regional approval of palovarotene marks a milestone for the FOP community at the very beginning of a new era of clinical trials."

Journal • Review • RARG

PIVOINE: A Rollover Study to Further Evaluate the Safety and Efficacy of Palovarotene Capsules in Male and Female Participants Aged ≥14 Years With Fibrodysplasia Ossificans Progressiva (FOP) Who Have Completed the Relevant Parent Studies. (clinicaltrials.gov) - P3 | N=63 | Completed | Sponsor: Ipsen | Active, not recruiting ➔ Completed

Trial completion

FOPal: A Study to Document and to Further Describe Long-term Safety and Effectiveness of Palovarotene in Participants With Fibrodysplasia Ossificans Progressiva (FOP) (clinicaltrials.gov) - P=N/A | N=70 | Recruiting | Sponsor: Ipsen | Not yet recruiting ➔ Recruiting | Trial completion date: Dec 2035 ➔ Jan 2034 | Trial primary completion date: Dec 2035 ➔ Dec 2033

Enrollment open • Trial completion date • Trial primary completion date

Palovarotene (Sohonos), a synthetic retinoid for reducing new heterotopic ossification in fibrodysplasia ossificans progressiva: history, present, and future. (PubMed, JBMR Plus) - "Post hoc analyses of phase II and phase III clinical trials showed that palovarotene has significant disease-modifying effects for FOP, but with significant risks such as premature growth plate closure in some younger subjects. This review provides an overview of retinoid and RAR roles in skeletal development and discusses the identification of palovarotene as a potential FOP therapy, the clinical data supporting its regulatory approval in some countries, and the potential applications of this drug for other relevant disorders besides FOP."

Journal • Review • Developmental Disorders • Genetic Disorders • Inflammation • Rare Diseases • ACVR1 • RARA

Review of Real-World Evidence (RWE) in Marketing Authorization Applications (MAAs) Highlight Differences in Evidentiary Standards Among Regulatory and Health Technology Assessment (HTA) Bodies (ISPOR-EU 2024) - " Six medicines were identified: idecabtagene vicleucel (ide-cel), omburtamab, sotorasib, alpelisib, palovarotene, and tacrolimus. RWE supporting effectiveness in MAAs was accepted more frequently by FDA than EMA, while HTA review highlighted differing standards of RWE acceptability. Consideration should be given to these differences when generating RWE for regulatory decision-making and appraisals."

Clinical • HEOR • Real-world • Real-world evidence • Review

FOPal: A Study to Document and to Further Describe Long-term Safety and Effectiveness of Palovarotene in Participants With Fibrodysplasia Ossificans Progressiva (FOP) (clinicaltrials.gov) - P=N/A | N=70 | Not yet recruiting | Sponsor: Ipsen | Trial completion date: Jan 2034 ➔ Dec 2035 | Trial primary completion date: Dec 2033 ➔ Dec 2035

Trial completion date • Trial primary completion date

Current and emerging treatment modalities for fibrodysplasia ossificans progressiva. (PubMed, Expert Opin Pharmacother) - "Approval of palovarotene, as the first retinoid indicated for reduction in the volume of new HO, may revolutionize the therapeutic landscape. However, long-term safety and efficacy data for palovarotene are currently lacking."

Journal • Review • Mood Disorders

The Impact of Palovarotene Treatment on Heterotopic Ossification in Patients with Fibrodysplasia Ossificans Progressiva With and Without Flare-Ups: Data from the Phase III MOVE Trial and Natural History Study (ASBMR 2024) - No abstract available

Clinical • P3 data • Growth Hormone Deficiency (Pediatric) • Orthopedics • Pediatrics

Analysis of the Actions of RARγ Agonists on Growing Osteochondromas in a Mouse Model. (PubMed, Int J Mol Sci) - "The activation of Stat3 by palovarotene was confirmed using immunoblotting and immunohistochemistry. These findings suggest that palovarotene treatment is effective against pre-existing osteochondromas and that the Stat3 pathway is involved in the antitumor actions of palovarotene."

Journal • Preclinical • Immunology • Oncology • Osteoarthritis • Pain • Rheumatology

Alphaherpesvirus manipulates retinoic acid metabolism for optimal replication. (PubMed, iScience) - "RA enhanced antiviral defenses by promoting ABCA1- and ABCG1-mediated lipid efflux. Treatment with the retinoic acid receptor (RAR) agonist palovarotene protected mice from HSV-1 infection, thus providing a potential therapeutic strategy against viral infections."

Journal • Herpes Simplex • Infectious Disease • ABCA1 • ABCG1

FOPal: A Study to Document and to Further Describe Long-term Safety and Effectiveness of Palovarotene in Participants With Fibrodysplasia Ossificans Progressiva (FOP) (clinicaltrials.gov) - P=N/A | N=70 | Not yet recruiting | Sponsor: Ipsen | Initiation date: Apr 2024 ➔ Jul 2024

Trial initiation date

The role of GDF5 in regulating enthesopathy development in the Hyp mouse model of XLH. (PubMed, J Bone Miner Res) - "Treatment of Hyp mice with the BMP signaling blocker palovarotene attenuated BMP/IHH signaling in Hyp entheses, thus indicating that BMP signaling plays a pathogenic role in enthesopathy development and that IHH signaling is activated by BMP signaling in entheses...Taken together, these results demonstrate that while GDF5 is not essential for modulating BMP/IHH signaling in WT entheses, inappropriate GDF5 activity in Scx + cells contributes to XLH enthesopathy development. As such, inhibition of GDF5 signaling may be beneficial for the treatment of XLH enthesopathy."

Journal • Preclinical • Pain • Renal Disease

The Role of GDF5 in Regulating Enthesopathy Development in the Hyp mouse Model of XLH (ENDO 2024) - "Therefore, Hyp mice were treated daily with palovarotene, a retinoid acid gamma receptor agonist that blocks BMP signaling, from postnatal day (P) 7 (prior to enthesopathy development) to P30...Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO."

Preclinical • Pain • Renal Disease • FGF23