Summary Basis of Decision for Sohonos

Clinical Pharmacology

Fibrodysplasia ossificans progressiva (FOP) is a genetic condition caused by a gain-of-function mutation in the gene which encodes activin receptor type 1A/activin receptor-like kinase 2 (the ACVR1/ALK2 gene), a bone morphogenetic protein (BMP) type I receptor. The gain-of-function mutation in ALK2 aberrantly activates the BMP-Smad1/5/8 signalling pathway, which diverts normal soft tissue injury repair mechanisms away from tissue regeneration by promoting chondrogenesis and heterotopic bone formation.

Palovarotene, the medicinal ingredient in Sohonos, is an orally bioavailable retinoic acid receptor gamma (RARγ) selective agonist. Retinoic acid receptor gamma is expressed in chondrogenic cells and chondrocytes operating as an unliganded transcriptional repressor. Through binding to RARγ, palovarotene decreases BMP signaling and inhibits Smad1/5/8 signaling, which are deeply involved in the pathogenesis of myositis ossificans, and therefore in the pathogenesis of FOP. Palovarotene prevents chondrogenesis and ultimately heterotopic ossification (HO) by interfering with these pathways, which enables normal muscle tissue repair or regeneration to take place, thereby reducing damage to muscle tissue.

In vitro, palovarotene inhibited BMP-mediated Smad1/5 signalling in a human FOP fibroblast cell line carrying the gain-of-function ALK2 mutation, R206H. In animal models of FOP and injury-induced HO, palovarotene reduced new HO and maintained joint mobility by decreasing mast cell infiltration and fibroproliferative response at the site of injury.

The pharmacokinetics of palovarotene have been well characterized through single and multiple dose studies in healthy subjects as well as in patients with FOP. A study was conducted in which healthy adult subjects received 20 mg palovarotene once daily for 14 days after a standard breakfast. The mean elimination half-life of palovarotene was 8.7 hours, the median time to maximum concentration (T_max) was 4.6 hours, the average maximum concentration (C_max) was 140 ng/mL, and the average exposure as measured by the area under the concentration-time curve (AUC_[0-τ]) was 942 ng*hr/mL. Little or no accumulation was detected following once-daily dosing. The mean steady-state trough plasma concentration was 3.5 ng/mL. Palovarotene was constrained to plasma, with 99.0% mean protein binding observed in vitro. The mean apparent volume of distribution at steady-state (V_ss/F) was 319 L. Palovarotene was eliminated mainly through the feces, with minimal excretion in urine.

The results of an ascending single-dose study demonstrated that the pharmacokinetics of palovarotene was linear and dose-proportional in the range of 0.1 mg to 50 mg in fed, non-smoking subjects. The oral absorption of palovarotene increased when administered with food in healthy subjects. Therefore, palovarotene was administered with food in all studies conducted in patients with FOP, and the Product Monograph states that Sohonos should be taken with food. Plasma AUC and C_max values were comparable when palovarotene was consumed either by swallowing the capsule whole or by sprinkling the contents of the capsule onto applesauce prior to consumption. Both methods of administration were evaluated following a high-fat, high-calorie breakfast.

Palovarotene is metabolized extensively by cytochrome P450 (CYP) 3A4, and to a lesser extent by CYP2C8 and CYP2C19. Five metabolites of palovarotene were observed: M1 (6,7-dihydroxy), M2 (6-hydroxy), M3 (7-hydroxy), M4a (6-oxo), and M4b (7-oxo). These metabolites reached steady-state by Day 4, with high variability in plasma levels. Palovarotene and its four known major metabolites (M2, M3, M4a, and M4b) were found to collectively represent 40% of the total exposure in plasma, based on data collected after the administration of [¹⁴C]-radiolabelled palovarotene. Results of an in vitro RARγ transactivation assay indicated that the M3 and M4b metabolites have 1.7% and 4.2% of the pharmacological activity of the parent drug, palovarotene.

The results of non-clinical drug interaction studies indicated that palovarotene had low potential to induce or inhibit major CYP enzymes and transporters. However, the results of a dedicated drug-drug interaction study showed that the co-administration of palovarotene with a CYP3A4 inhibitor (ketoconazole) significantly increased palovarotene exposure, and co-administration with a CYP3A4 inducer (rifampicin) significantly decreased palovarotene exposure. Based on these outcomes, the Product Monograph states that the co-administration of palovarotene with strong CYP3A4 inhibitors and inducers should be avoided. Palovarotene had no clinically significant effect on midazolam exposure (a CYP3A4 substrate), and was not a perpetrator or victim drug when co-administered with prednisone, a glucocorticoid used in the clinical management of FOP.

A randomized, double-blind, placebo- and positive-controlled, 4-way crossover electrocardiogram assessment study was conducted in which 31 healthy adult subjects received single 20 mg (therapeutic) and 50 mg (supratherapeutic) doses of palovarotene. No pharmacodynamic effects were observed on the corrected QT (QTc) interval, QRS duration, PR interval, or heart rate.

The results of a population pharmacokinetic analysis showed no evidence that age, sex, race, smoking status, or health status affected the pharmacokinetics of palovarotene. Body weight had a significant effect on the pharmacokinetics of palovarotene, as increasing exposure was observed with decreasing weight at the same dose. Based on these findings, weight-adjusted doses were used for skeletally immature children in the clinical studies in order to provide exposure levels similar to those in adolescents and adults receiving 5 mg to 20 mg doses. Therefore, weight-adjusted doses have also been recommended for children under 14 years of age in the Product Monograph.

No dedicated studies were conducted in subjects with renal or hepatic impairment. A population pharmacokinetic analysis showed no clinically significant differences in subjects with mild hepatic impairment, and in subjects with mild or moderate renal impairment. The effects of moderate to severe hepatic impairment and severe renal impairment on the pharmacokinetics of palovarotene have not been evaluated. Therefore, recommendations have been included in the Product Monograph to use caution in patients with moderate hepatic impairment, and to avoid the use of palovarotene in patients with severe hepatic or renal impairment.

For further details, please refer to the Sohonos Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Sohonos was established based on results from the Phase II Studies 201 and 202, and the pivotal Phase III study, MOVE (Study 301). All three studies were conducted in patients with FOP.

Several dosing regimens were evaluated in these studies:

• The 5/2.5 regimen (flare-up treatment): Patients received 5 mg Sohonos once daily for two weeks, followed by 2.5 mg once daily for four weeks.
• The 10/5 regimen (flare-up treatment): Patients received 10 mg Sohonos once daily for two weeks, followed by 5 mg once daily for four weeks.
• The 20/10 regimen (flare-up treatment): Patients received 20 mg Sohonos once daily for four weeks, followed by 10 mg once daily for eight weeks, for a total of 12 weeks, even if symptoms resolved earlier.
• The c/20/10 regimen (chronic/flare-up regimen): Patients received 5 mg Sohonos once daily for up to 24 months. In the event of a flare-up or substantial high-risk traumatic event likely to lead to a flare-up, the dose was escalated to 20 mg once daily for four weeks, followed by 10 mg once daily for eight weeks. If needed, additional flare-up treatment was administered at a dose of 10 mg once daily and extended in four-week increments. Patients returned to a 5 mg dose once daily following resolution of the flare-up.

Data from a non-interventional natural history study (NHS) were also submitted, which included 114 untreated patients with FOP between 4 and 56 years of age.

Phase II program: Studies 201 and 202

Study 201

Study 201 involved 40 patients with FOP, who were randomized in a 3:3:2 ratio to receive treatment according to the 10/5 regimen, the 5/2.5 regimen, or placebo for six weeks. This study evaluated the ability of different doses of Sohonos to prevent HO at the flare-up site in patients with FOP. The six-week treatment period was followed by a six-week observation period. The primary endpoint was the proportion of responders, which was defined as patients who had no or minimal new HO at the flare-up site at Week 6. A 62% decline was observed in the incidence of new HO in patients treated with the 10/5 regimen. No reductions were observed in HO volume, incidence, or joint range of motion in patients treated with the 5/2.5 regimen. Although the results were not statistically significant for either regimen, a trend was observed in patients treated with the 10/5 regimen towards reduced volume, incidence of HO, and joint range of motion.

Study 202

Study 202 was an open-label study that evaluated the long-term safety and efficacy of different dosing regimens of Sohonos treatment in adult and pediatric patients with FOP.

Part A evaluated the efficacy of a six-week 10/5 regimen in pediatric and adult patients with FOP. Forty patients were enrolled, including 20 patients with 28 treated flare-ups, and 20 untreated subjects. Doses were adjusted based on weight. The primary endpoints and key secondary endpoints were the amount of reduction in each of the following: HO volume, frequency of flare-ups, and long-term post-exposure persistence of effect. Patients were monitored through measurements of the volume and incidence of HO and other clinical parameters, and through assessments of physical symptoms, responses to patient questionnaires, and suicidal ideation/mental health. For flare-ups with new HO, a slight improvement in HO volume was observed with the six-week 10/5 regimen, which was negated by an increase from 5,204 mm³ to 7,506 mm³ in the six weeks following withdrawal of Sohonos. These outcomes indicate that a higher dose and a longer flare-up regimen may be more efficacious.

Part B involved 54 patients with 79 treated flare-ups, and included pediatric and adult patients. Adult patients and pediatric patients with at least 90% skeletal maturity were treated according to the chronic/flare-up regimen. Pediatric patients with less than 90% skeletal maturity were treated based on the 20/10 regimen (treated for flare-ups without chronic dosing), and received weight-based dose adjustments.

Part C was ongoing at the time of authorization, and included 48 adult and pediatric patients receiving treatment according to the chronic/flare-up regimen, with weight-based dose adjustments. The data from Part C were integrated with the data from Part B. The primary endpoint was the annualized change in new HO volume. The incidence of flare-ups with new HO was 41.2% in patients treated with the 20/10 regimen, compared to 20.6% in flares treated with the chronic/flare-up (c/20/10) regimen. This demonstrated the effectiveness of chronic dosing. Additionally, the c/20/10 regimen was found to be more effective than the 10/5 regimen in reducing the incidence of HO, with incidences of 20.6% and 35.7% observed in patients treated with each of these regimens, respectively. The volume of HO was higher in patients treated with the 20/10 regimen than in patients treated with the 10/5 regimen, although the outcomes were not statistically significant. However, edema prior to the treatment of flare-ups, known to predict more severe HO episodes, was more prevalent in patients assigned to the 20/10 regimen, which could have skewed the results.

The results obtained from the Phase II studies demonstrated a persistence of HO formation after a six-week treatment regimen was completed. This suggested that the six-week 10/5 regimen was not optimal for all flare-ups. The greater efficacy of higher-dose regimens compared to lower-dose regimens, as well as the efficacy of the chronic/flare-up regimen in the treatment of FOP was demonstrated in Study 202 parts B and C.

Pivotal Study: MOVE (Study 301)

The clinical efficacy of Sohonos was evaluated in the pivotal, single-arm Phase III study, MOVE (Study 301), which enrolled 107 patients with FOP 4 years of age and older. Patients in this study were treated according to the chronic/flare-up regimen, with weight-based dose adjustments. The efficacy of this regimen in preventing new HO was assessed by low-dose, whole body computed tomography (CT) imaging (excluding the head), and compared to data from untreated patients from the NHS. The primary endpoint was the annualized change in new HO volume.

The duration of treatment was 24 months (Part A), followed by a 24-month extension (Part B). All whole body CT images from treated patients in the MOVE study and untreated patients from the NHS were read in a blinded manner. The R206H mutation was identified in 99 of the 107 patients in the MOVE study, and 8 patients had other FOP mutations. Ninety-seven of the 99 patients with the R206H mutation had at least one post-baseline HO volume measurement, and were included in the overall population analysis.

The efficacy analysis was based on data from patients in the overall population (which included all enrolled patients who had a baseline HO volume measurement and at least one post-baseline HO volume measurement) and in the target population (which included female patients 8 years of age and older, and male patients 10 years of age and older). Seventy-seven patients in this target population were treated with Sohonos and had a median age of 14 years (range: 8 to 61 years), and 76 patients were from the NHS (untreated) and had a median age of 18 years (range: 9 to 56 years).

Prespecified analyses of the mean annualized new HO volume were conducted using a Bayesian compound Poisson model with square root transformation. The outcome of these analyses demonstrated that the futility boundary had been crossed. Post hoc analyses were then performed, and the results revealed that using the square root transformation of the data in the Bayesian model moved the statistical conclusion from significant therapeutic benefit of Sohonos to showing futility. Additional analyses were conducted using the Bayesian and weighted linear mixed effect (wLME) models of annualized new HO volume, without square root transformation and including all raw data, which demonstrated the efficacy of Sohonos. Efficacy data from the wLME model, which accounts for the fitted weight of the different lengths of observed patients’ follow-up in the analysis of new HO, showed a 56% reduction (nominal p = 0.0292) in the overall population. The mean annualized new HO was 62% lower in patients treated with Sohonos compared to untreated patients in the overall population (nominal Wilcoxon rank-sum test p = 0.0006).

When the data from the group for patients between 8 (females) or 10 (males) and 14 years of age (defined as the ≥8/10-14 year age group in the Product Monograph) are combined with data from the patients in the >14 year age group (defined as the ≥8/10 year age group), the statistical significance and power are lost. In the ≥8/10 year age group, the mean volume reduction is 11,045 mm³, which represents a 57% reduction in the mean (nominal p = 0.0953). By comparison, there was a 61% reduction in new HO in the >14 year age group, with a reduction of 47% (nominal p<0.05) using a wLME analysis which normalizes for weight. The loss of statistical power is due to extreme variability in HO values in this very small cohort of patients.

The incidence of catastrophic HO was overall lower in patients treated with Sohonos, although one case in this group was severe, with an HO volume exceeding 230,000 mm³. The affected individual was in the ≥8/10-14 year age group and affected the statistical power of the data in the age-based subgroup analysis.

There were no statistically or clinically significant differences identified across treatment groups with regards to functional or patient reported outcomes across groups, including surveys (the FOP Physical Function Questionnaire [FOP-PFQ], the Patient-Reported Outcomes Measurement Information System [PROMIS] Global Health Scale, Cumulative Analogue Joint Involvement Scale [CAJIS] scores, suicide risk scores), range of motion at flare-up location, laboratory values, and clinical examinations.

Collectively, the results demonstrate the clinical efficacy of Sohonos in reducing the formation of HO in adults, in female children 8 years of age and older, and in male children 10 years of age and older with FOP.

Indication

Health Canada approved the following indication:

Sohonos (palovarotene capsules) is indicated to reduce the formation of heterotopic ossification in adults and children aged 8 years and above for females and 10 years and above for males with fibrodysplasia (myositis) ossificans progressiva.

For more information, refer to the Sohonos Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The most common adverse reactions (reported at frequencies higher than 10%) in female patients 8 years of age and older and male patients 10 years of age and older with FOP were dry skin (78%), pruritus (55%), alopecia (41%), rash (39%), erythema (32%), skin exfoliation (31%), skin reaction (24%), drug eruption (17%), skin irritation (12%), dry lip (55%), chapped lips (17%), dry mouth (13%), cheilitis (11%), nausea (11%), paronychia (14%), arthralgia (14%), dry eye (26%), skin abrasion (21%), epistaxis (12%), and headache (17%). The majority of adverse reactions were mild or moderate in severity across all clinical trials.

Treatment-emergent adverse events (TEAEs) were generally similar between chronic and flare-up treatments. The incidence of dose reduction was higher during flare-up treatments (40%) than during chronic treatments (11.1%), which was attributed to higher incidences of mucocutaneous TEAEs.

Night blindness (nyctalopia) has been identified as a potentially dangerous effect associated with systemic retinoids, the class of drugs to which Sohonos belongs. This may be dose-dependent, and can make driving a vehicle at night hazardous during treatment. Night blindness is generally reversible after cessation of treatment, but can also persist in some cases. A single mild case of night blindness was identified during the Sohonos development program, which resolved after 134 days without treatment discontinuation or dose reduction.

A Serious Warnings and Precautions box in the Sohonos Product Monograph highlights the risk of premature physeal (growth plate) closure (PPC) in growing children with FOP, as well as the teratogenic potential of Sohonos.

Premature physeal closure was identified as an important risk associated with Sohonos treatment in growing children. Initially, patients enrolled in the studies were 4 years of age and older. A partial clinical hold was implemented on patients less than 14 years of age following the detection of a high rate of PPC, which was later amended to a permanent hold on female patients less than 8 years of age and male patients below 10 years of age. Premature physeal closure was reported in 24 patients (24%) less than 18 years of age who were treated with Sohonos, which included 10 of 39 patients aged 8 (females) or 10 (males) to less than 14 years (26%), and 14 of 25 patients aged less than 8 (females) or 10 (males) years (56%). Overall, 8 patients had severe PPC, including 5 patients 7 years of age or younger. Therefore, Sohonos is not indicated in female children less than 8 years of age or male children less than 10 years of age. Additionally, close monitoring including X-ray surveillance, is recommended every 3 months.

Sohonos is started at different ages in females (8 years) and males (10 years) due to physiological gender differences in puberty and rapid bone growth. Female children enter puberty at a younger age than male children. Subgroup analysis based on the following age ranges were assessed: male children under 10 years of age and female children under 8 years of age (pre-pubertal), male children between the ages of 10 and 14 and female children between the ages of 8 and 14 (children at the onset of puberty to an age which would estimate a 90% skeletal maturity), children/adolescents between the ages of 14 and 18, and subjects over the age of 18.

Safety signals in the pediatric population prompted a temporary clinical hold on all subjects <14 years of age due to reports of PPC. The Data Safety Monitoring Board analysis revealed an unacceptably high PPC rate in the <8/10 age subgroup (56%) despite the efficacy results (93% based on the wLME analysis normalized volume of HO to subject weight). The benefit-risk profile for this age group was not favourable for Sohonos. The 8/10-14 age subgroup had a lower PPC rate (23%) and a high efficacy rate (62% based on the wLME analysis normalized volume of HO to subject weight), while the >14 and >18 groups both had low PPC rates (<1%) with good efficacy (61% and 19%, respectively).

The retinoid class of drugs, to which Sohonos belongs, is associated with birth defects in humans (teratogenicity). There have been no reports of pregnancy or in utero exposure to Sohonos reported in clinical studies. Sohonos must not be used by patients who are pregnant or intend to become pregnant due to the risk of teratogenicity. To minimize the risk of fetal exposure, Sohonos is to be administered only if all conditions for pregnancy prevention are met.

Health Canada has determined that appropriate risk management measures are in place to address the safety concerns identified for Sohonos, and to support its safe and effective use. Overall, the benefit-harm-uncertainty profile of Sohonos is favourable for the approved indication. For more information, refer to the Sohonos Product Monograph, approved by Health Canada and available through the Drug Product Database.