Sohonos (palovarotene) / Ipsen - LARVOL DELTA

Characteristics of RWE used in Regulatory Decision-Making for Marketing Authorization Applications (MAAs) (ISPOR 2025) - "Descriptive analyses were performed to identify trends in the characteristics of drugs and of the RWE. 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

Pharmacokinetics and pharmacodynamics after intratracheal all-trans retinoic acid (ATRA) dosing in premature rabbits exposed to hyperoxia (PAS 2024) - "Design/ RAR/RXR selectivity, cell viability and permeability, and lung tissue binding of all-trans retinoic acid (ATRA), AGN195183 (AGN), LGD100268 (LGD) and palovarotene (PALO) were tested in vitro... ATRA was identified as pan-RAR/RXR agonist. AGN was classified as RARα agonist, whilst PALO and LGD as RARβ-γ and pan-RXR agonists, respectively (Figure 1). ATRA and AGN showed the lowest epithelial permeability through Caco-2 cells."

PK/PD data • Preclinical • Bronchopulmonary Dysplasia • Pulmonary Disease • Respiratory Diseases • RARA • RARRES1

Palovarotene Action Against Heterotopic Ossification Includes a Reduction of Local Participating Activin A-Expressing Cell Populations. (PubMed, JBMR Plus) - "© 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research"

Journal

Palovarotene. (PubMed, Am J Health Syst Pharm) - No abstract available

Journal

Study methodology and insights from the palovarotene clinical development program in fibrodysplasia ossificans progressiva. (PubMed, BMC Med Res Methodol) - P=N/A, P2, P3 | "A flexible clinical development program is necessary for underexplored rare diseases to overcome the many challenges faced. Here, the NHS provided a longitudinal evaluation of FOP progression and interventional trials were based on emerging data. The studies described informed the design and endpoints implemented in the phase III MOVE trial (NCT03312634) and provide a foundation for future clinical trial development."

Clinical • Journal • Genetic Disorders • Rare Diseases • RARG

The Pharmacokinetic Profile of Palovarotene: An Open-Label Phase I Trial Investigating the Effect of Food and Potential for Drug-Drug Interaction in Healthy Participants. (PubMed, Eur J Drug Metab Pharmacokinet) - P1 | "These data support palovarotene administration after a meal, as a whole capsule or sprinkled on food. Palovarotene at 20 mg/day is a not a clinical inducer of CYP3A4. These results provide insights into palovarotene pharmacokinetics, aiding optimization of administration for patients with FOP."

Journal • P1 data • PK/PD data • CYP3A4

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

New trial

FDA has approved palovarotene (Sohonos) as 1st Rx for fibrodysplasia ossifcans progressiva (FOP), a severely disabling condition that causes abnormal bone formation in place of soft and connective tissues. https://bit.ly/3LJJiTo https://bit.ly/3RLBQuR

Regulatory

Heterotopic Ossification in Palovarotene-Treated and Untreated Individuals with Fibrodysplasia Ossificans Progressiva: Matched and Weighted Analyses (ISPOR 2023) - P=N/A, P3 | "Propensity score matched and weighted analyses revealed significantly lower annualized increases in HO volume in patients who received palovarotene treatment, supporting its potential as a therapeutic option in FOP."

Clinical • Genetic Disorders

Reduction of New Heterotopic Ossification (HO) in the Open-Label, Phase 3 MOVE Trial of Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP). (PubMed, J Bone Miner Res) - P=N/A, P3 | "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."

Journal • P3 data • Genetic Disorders • Musculoskeletal Diseases • Orthopedics • RARG