Product information and disease description Place of product in therapy Approaches to treatment Current treatment options and standard of care

Retinoic acid receptor gamma agonists

10 evidence topics · 7 sources

Status of palovarotene in the international clinical guideline

“Palovarotene, an RAR -γ agonist, has been approved in the United States, Canada, UAE, Australia, and Russia but not approved in Europe.” (opens the source at this quote in a new tab)
“Regulatory-approved medications have been approved by at least 1 regulatory authority (eg, US Federal Drug Administration, or FDA). Currently, only chronic and episodic use of palovarotene (Sohonos) has received limited regulatory approval.” (opens the source at this quote in a new tab)

Chronic and flare-up dosing regimen

“Initiate flare-up treatment at the onset of the first symptom indicative of a FOP flare-up or substantial high-risk traumatic event likely to lead to a flare-up (e.g., surgery, intramuscular immunization, mandibular blocks for dental procedures, muscle fatigue, blunt muscle trauma from bumps, bruises, falls, or influenza-like viral illnesses).” (opens the source at this quote in a new tab)
“The recommended SOHONOS daily dosage for patients under 14 years of age is weight-based ranging from 2.5 mg to 5 mg daily (see Table 1).” (opens the source at this quote in a new tab)

Premature epiphyseal closure and growth monitoring

“Premature epiphyseal closure was identified by scheduled imaging in 27% of subjects who were less than 18 years of age at enrollment and was more common in younger compared with older subjects (31% in subjects between 8/10 years to 14 years and no subjects 14 years or older).” (opens the source at this quote in a new tab)
“Continued monitoring is recommended every 6 to 12 months until patients reach skeletal maturity or final adult height.” (opens the source at this quote in a new tab)
“SOHONOS is not recommended for use in patients younger than 8 years of age for females and 10 years of age for males because of the potential for premature epiphyseal closure.” (opens the source at this quote in a new tab)

Mucocutaneous and bone adverse reactions

“Mucocutaneous adverse reactions including dry skin, lip dry, pruritus, rash, alopecia, erythema, skin exfoliation [skin peeling], and dry eye occurred in most (98%) patients treated with SOHONOS.” (opens the source at this quote in a new tab)
“In FOP clinical trials, SOHONOS resulted in decreased vertebral bone mineral content and bone density, and an increased risk of radiologically observed vertebral (T4 to L4) fractures in treated adult and pediatric patients compared to untreated patients.” (opens the source at this quote in a new tab)

Prespecified and post hoc analyses of the phase 3 MOVE trial

“During the prespecified analysis at month 18 of the phase III MOVE trial (interim analysis 3; IA3), which represents the most complete dataset from this trial, no statistically significant difference was found in the mean volume of annualized new HO in patients treated with palovarotene in MOVE compared with untreated patients from the NHS, leading to a temporary suspension of the study.” (opens the source at this quote in a new tab)
“Subsequent post hoc analyses showed that the mean annualized new HO volume was 54% lower in MOVE compared with the NHS (weighted linear mixed effects [wLME] analysis, p = .039), supporting the approval of palovarotene in patients with FOP in several countries.” (opens the source at this quote in a new tab)

Month-48 efficacy and safety of palovarotene

“Across 48 mo, mean annualized new HO volume was numerically lower (46.4%) in palovarotene-treated patients compared with untreated patients; however, this difference was not significant (nominal p = .0585).” (opens the source at this quote in a new tab)
“The proportions of patients with new HO and number of affected body regions were similar in palovarotene-treated patients and untreated patients (significance not assessed); flare-up rates were consistent with published literature.” (opens the source at this quote in a new tab)
“In 80 patients aged <18 yr in MOVE, palovarotene treatment occurred for a mean (SD) of 166.0 (75.2) wk; 24 (30.0%), all aged <14 yr, had premature physeal closure events.” (opens the source at this quote in a new tab)

Refusal of marketing authorisation in the European Union

“At the time of the initial evaluation, the Agency considered that no firm conclusions could be drawn on the benefits of the medicine, as the applicant’s conclusion was based on a post-hoc analysis which was neither scientifically nor clinically justified and pre-specified study objectives were not met.” (opens the source at this quote in a new tab)
“Regarding safety, the risk of premature physeal closure (a disruption to the areas of new bone growth in the end of long bones, which keeps them from growing normally), which is a known risk with retinoid treatment in growing patients, could not adequately be mitigated with the risk minimisation measures proposed by the company.” (opens the source at this quote in a new tab)

Regulatory review history in Canada and the United States

“Palovarotene was first reviewed and approved by the Health Canada in January 2022.” (opens the source at this quote in a new tab)
“The FDA advisory committee voted 10 in favor and 4 against the evidence showing palovarotene to be effective for blocking new HO formation in FOP, and voted 11 for and 3 against the evidence showing that the benefits of palovarotene outweighed the risks for treating patients with FOP.” (opens the source at this quote in a new tab)

Prespecified square-root transformed analysis did not reach significance at interim analysis 3

“Prespecified futility criteria were met using this analysis method at IA2; however, following post hoc results obtained at IA2, Bayesian analysis of nontransformed data was reconsidered at IA3 when all patients had completed 18 months of follow-up.” (opens the source at this quote in a new tab)
“At IA3, the prespecified Bayesian analysis fitted a 5% reduction in square-root transformed annualized volume of new HO in palovarotene-treated patients in MOVE versus NHS participants untreated beyond standard of care.” (opens the source at this quote in a new tab)
“The post hoc Bayesian analysis fitted a 36% reduction in non-transformed mean annualized volume of new HO in palovarotene-treated patients compared with NHS participants (probability of any reduction in new HO: 99.4%) (Supplemental Fig. S6).” (opens the source at this quote in a new tab)

Comparability of MOVE and its external natural history control

“Baseline demographics and characteristics for the MOVE Principal Enrolled Population (N = 99) and NHS comparator population (N = 111) showed more individuals aged <18 years in MOVE (75/99 [75.8%]) than in the NHS (66/111 [59.5%]); the two populations were otherwise similar (Table 1).” (opens the source at this quote in a new tab)
“Among these 39 patients who contributed data to both studies, mean annualized new HO volume was 54% lower with palovarotene compared with their prior phase receiving no treatment beyond standard of care in the NHS (Supplemental Fig. S7).” (opens the source at this quote in a new tab)