An official website of the United States government
NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Indication: 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
CADTH recommends that Sohonos be reimbursed by public drug plans to reduce the formation of heterotopic ossification (HO) in adults and children aged 8 years and above for females and 10 years and above for males with fibrodysplasia ossificans progressiva (FOP), if certain conditions are met.
Sohonos should only be covered to treat patients who have a clinical diagnosis of FOP and the R206H ACVR1 mutation as confirmed by genetic testing, and who do not have completely fused joints over the whole body.
Sohonos should only be reimbursed if prescribed by an expert in the diagnosis and management of FOP and if the cost of Sohonos is reduced. While receiving Sohonos, patients (and their caregivers, for pediatric patients) and their physicians should have ongoing and regular discussions to assess the benefits and risks of treatment with Sohonos.
FOP is a very rare disease in which muscles and tendons are gradually replaced by bone, creating a second skeleton of extra bone. Patients with FOP have painful episodes of muscle swelling, lose function as joints fuse, and have a shortened lifespan. Patients gradually lose the ability to move and perform daily self-care activities, with the main cause of death being complications from a restricted chest wall. There are approximately 20 known patients with FOP in Canada.
There is a need for treatments to help patients maintain or improve mobility, improve episodes of muscle swelling, stop or slow new bone formation, and reduce pain.
Treatment with Sohonos is expected to cost approximately $1,022,894 per year for patients aged 14 years and older and $622,373 per year for patients younger than 14 years.
The CADTH Canadian Drug Expert Committee (CDEC) recommends that palovarotene be reimbursed to reduce the formation of heterotopic ossification (HO) in adults and children aged 8 years and above for females and 10 years and above for males with Fibrodysplasia (myositis) Ossificans Progressiva (FOP), only if the conditions listed in Table 1 are met.
CDEC recognized the significant unmet need in a small patient population with a condition with high morbidity for which no other effective treatments are currently available. FOP is a disease of progressive immobilization and shortened lifespan, for which there are no other disease-modifying treatments. It is an ultra-rare disease, and there were approximately 20 known patients with FOP in Canada at the time of the review.
There was evidence from 1 single-arm, open-label, phase III study (MOVE) that treatment with palovarotene may result in added clinical benefit for patients with FOP aged 8 years and older for females and 10 years and older for males (referred to as the target population). Patients in the MOVE study, who were treated with palovarotene, were compared to untreated patients in an external cohort from the sponsor’s natural history study, and the analysis in the target population included 77 patients from the MOVE study and 79 patients from the natural history study. Palovarotene treatment was associated with a reduction in annualized new HO volume, with an estimated percent reduction of 48.6% (mean reduction of 10,443 mm3; 95% confidence interval [CI], –23,538 mm3 to 26,534 mm3) using a weighted linear mixed-effects (wLME) model and 25% (ratio of mean change = 0.75; 95% credible interval [CrI], 0.51 to 1.11) using a Bayesian analysis. There are no minimal important difference (MID) estimates available for HO volume, but the treatment effect was considered to be clinically meaningful according to clinical expert opinion. Patients identified a need for treatments that reduce or stop new HO, help them maintain or improve mobility, reduce frequency and severity of flare-ups, and reduce pain. No improvements were observed with palovarotene in the number of reported flare-ups, range of motion, physical function, or health-related quality of life (HRQoL). CDEC recognized the significant unmet need of patients with FOP and concluded that palovarotene may meet 1 of the needs identified by patients, the reduction of new HO.
Using the sponsor-submitted price for palovarotene and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio (ICER) for palovarotene plus standard of care (SoC) was $13,055,900 per quality-adjusted life-year (QALY) gained, compared with SoC alone. At this ICER, palovarotene plus SoC is not cost-effective at a $50,000 per QALY willingness-to-pay (WTP) threshold for adults and children aged 8 years and older for females and 10 years and older for males with FOP. A price reduction is required for palovarotene to be considered cost-effective at a $50,000 per QALY threshold.
Reimbursement Conditions and Reasons.
FOP is an ultra-rare congenital disease of uncontrolled, progressive, and abnormal growth of bone in nonskeletal tissues (e.g., muscles, tendons, and ligament) through the process of HO. FOP is caused by a recurrent heterozygous activating mutation of ACVR1, which is a member of the protein family bone morphogenetic protein type I receptors. The mutation occurs as a random event during the formation of reproductive cells (eggs or sperm) in the patient’s biological parent or in early embryonic development. Although FOP is a congenital condition, ossification does not occur before birth. HO occurs in infancy and progresses throughout life. It may occur without warning or following a flare-up induced by trauma (e.g., intramuscular childhood immunizations, falls, surgery, biopsy) or various viral illnesses. In the affected areas, ossification eventually leads to stiffness and limited movement of joints. As the disease progresses, patients with FOP experience increasingly limited mobility — affecting balance, walking, and sitting — and/or joint range of motion. The development of bone at multiple soft tissue sites eventually leads to ankylosis (fusion) of the affected joints, including the spine and thoracic cage. Patients whose jaws are affected have difficulty eating and/or speaking. Eventually, FOP may result in complete immobilization. The permanent and cumulative effects of HO result in severe functional limitations in joint mobility and progressive disability, such that most patients with FOP require a wheelchair by their third decade of life. As mobility begins to deteriorate due to HO, patients with FOP are at increased risk for a multitude of health morbidities, including fractures, severe restrictive lung disease, right-sided congestive heart failure, scoliosis, pressure ulcers, severe weight loss due to jaw ankylosis, gastrointestinal issues, and acute and chronic pain. Hearing impairment occurs in approximately half of all patients with FOP. As disability progresses, HRQoL decreases. In addition to being extremely debilitating, FOP is associated with shortened lifespan, with an estimated median lifespan of 56 years. Death among patients with FOP is mainly due to complications of restrictive chest wall disease. The worldwide prevalence of FOP is estimated to be 1 in 2 million, although due to global high rates of misdiagnosis, the number of those with FOP may be closer to 1 in 1 million. The prevalence of FOP does not differ across sex, race, ethnicity, or geography. There are approximately 900 confirmed cases of FOP worldwide. Based on registry data, the estimated prevalence of FOP in Canada is 0.559 per million persons. Based on clinical expert input, there are approximately 20 known patients with FOP in Canada.
Palovarotene has been approved by Health Canada to reduce the formation of HO in adults and children aged 8 years and older for females and 10 years and older for males with FOP. Palovarotene is a selective agonist of retinoic acid receptor gamma. It is available as an oral tablet and the dosage recommended in the product monograph is 5 mg once daily for chronic treatment. At the onset of the first symptom indicative of an FOP flare-up — or substantial high-risk traumatic event likely to lead to a flare-up — Health Canada recommends, under the guidance of a health care professional, a flare-up regimen of 20 mg once daily for 4 weeks followed by 10 mg once daily for 8 weeks, for a total of 12 weeks (20 mg to 10 mg flare-up regimen) even if symptoms resolve earlier. Chronic treatment with palovarotene should reinitiated after completion of the flare-up treatment. A weight-based dosage is required in children who are younger than 14 years of age.
To make its recommendation, the committee considered the following information:
The information in this section is a summary of input provided by the patient groups who responded to CADTH’s call for patient input and from clinical experts consulted by CADTH for the purpose of this review.
Patient input was provided from the CFOPN and the CORD in 1 joint submission. Together, these patient groups provided input from 3 patients with FOP currently receiving palovarotene, and 1 caregiver of a patient living in Canada with FOP. Patient input was collected via telephone interviews between October 31, 2022, and November 9, 2022. In addition, a summary of patient and caregiver public testimonies given before the FDA Endocrinologic and Metabolic Drugs Advisory Committee (October 31, 2022) was included.
Patients and caregivers reported experiencing stress from “unrelenting vigilance” to avoid activities that may result in injury and trigger flare-ups (with onset that is often unpredictable or without a precipitating event) resulting in permanent bone growth, which contributes to progressive loss of physical movement and independence The disease deprives patients of normal activities and life experiences, contributing to stigmatization, isolation, and despair. The extreme mental and physical toll of FOP is underscored by the following quote from a caregiver: “…my child is well aware of [her] body slowly failing […] outward deformations, the inability to take full breaths […] limited abilities to participate in social events and no […] physical events […] Each day brings with it additional agonizing truths […] not knowing what tomorrow will bring or the real potential for a much-shortened life span.” Due to absence of approved effective therapies for FOP, patents are left to restricting their lifestyle to protect against potentially injurious flare-ups and control disease progression. However, giving up all potentially injurious activities deprives patients of experiences of pleasure and meaning, with no assurance of preventing flare-ups or disease progression. Patients with FOP expressed a desire for access to treatments that reduce symptoms and prevent disease progression. Patients listed the following treatment outcomes as important: maintenance of or increased mobility, reduced frequency and severity of flare-ups, reduced pain, and reduced or halted new bone growth. For some patients, simply halting disease progression such that they could adapt to their existing disease state and continue to enjoy activities that provide meaningful experiences would bring them satisfaction. Of those patients who have had experience with palovarotene, all expressed a desire to continue its use for as long as possible. Treatment with palovarotene has allowed these patients to maintain or even increase their mobility and has provided them with hope for improved quality of life and independence with continued use.
According to the clinical experts consulted by CADTH for the purpose of this review, an ideal treatment for patients with FOP would be one that could be administered as early as possible — even in utero — and that could prevent and/or reduce HO, while prolonging life lived with good quality of life. The clinical experts agreed that palovarotene should be used as first-line therapy, with supportive pharmacological and non-pharmacological measures in place. However, the clinical experts cautioned that the optimal time to start treatment with palovarotene for pediatric patients is uncertain. The clinical experts agreed that palovarotene would be the main treatment for both adults and children. The clinical experts agreed that for patients aged 16 years and older, palovarotene may be combined with corticosteroids during flare-ups. Bisphosphonates may also be used concurrently with palovarotene, regardless of age. The clinical experts highlighted the practice of minimizing polypharmacy in the pediatric population younger than 16 years of age. Accordingly, consideration should be given to initiating palovarotene as the sole treatment in patients younger than 16 years; corticosteroids or other drugs may be added when it is deemed clinically that adjuvant therapy is needed.
Regarding gene mutations associated with FOP, the clinical experts noted that since palovarotene works downstream of the ACVR1 receptor, patients harbouring any gene mutations of the receptor resulting in HO formation through the Smad 1/5/8 pathway may benefit from palovarotene treatment. Accordingly, any mutation that works on the Smad pathway and upregulates it should be amenable to treatment with palovarotene. The clinical experts noted that assessment of patients or caregiver compliance to the treatment regimen is important to determine suitability before prescribing palovarotene. The clinical experts agreed that patients who do not have ankylosis of the whole body would benefit from treatment with palovarotene to prevent progressive disability. The clinical experts highlighted that patients with more advanced disease may benefit less from palovarotene, since the extent to which HO can be reversed is unclear; however, they may still derive benefits from palovarotene through the prevention of new bone formation or HO reversal to preserve jaw function and lung capacity. Of note, the clinical experts stressed that the use of palovarotene in young patients whose growth plates have not fused should only be undertaken after careful consideration and consultation with patients and their families. The clinical experts opined that when considering treatment with palovarotene in patients with open epiphyses, there is still uncertainty with regard to whether the potential benefits of treatment with palovarotene outweigh the potential harms.
The clinical experts noted that the preservation of function is the most important marker of treatment response. The clinical experts advocated the use of clinical parameters (e.g., Cumulative Analogue Joint Involvement Scale [CAJIS]) to assess response to treatment. In addition, the clinical experts noted that response to treatment with palovarotene should also include assessing prevention of comorbidities such as the inability to walk, need for a wheelchair, inability to work, inability to continue performing activities of daily living, decreased respiratory function, hearing loss, and — for patients with advanced disease — loss of jaw function and lung function. The clinical experts anticipate that treatment with palovarotene would continue indefinitely. Accordingly, the clinical experts advocated for continual assessment of the risks and benefits of its use. The clinical experts suggested that the efficacy and safety of palovarotene be assessed annually in adults, and in children, every 6 months for efficacy and every 3 months for safety. Given the progressive nature of FOP, the clinical experts suggested that treatment response should be monitored for at least 2 years before a decision to discontinue treatment is made, unless the decision to stop treatment is by patient choice, there is nonadherence to treatment, or the patient is experiencing intolerable adverse events (AEs). The clinical experts noted increasing HO load as detected by whole-body CT scan (excluding the head) and deteriorating CAJIS score may suggest lack of treatment response.
The clinical experts agreed that all patients with FOP should be diagnosed and managed by a specialist physician who is either experienced in the management of FOP or has academic expertise in FOP, due to the rarity of the condition. In addition, palovarotene should be prescribed by such a specialist. The clinical experts suggested that all patients should be seen in person by their specialist for baseline assessment with the CAJIS before prescribing palovarotene, and for periodic reassessments. The clinical experts agreed that a family doctor could collaborate with the expert physician in the continued monitoring and treatment of palovarotene. In children, the palovarotene prescription would typically be in the hands of their bone disease specialist. Using a team approach, led by a specialist, the clinical experts agreed that patients experiencing mucocutaneous AEs may see their family doctor for follow-up care. The clinical experts agreed that oral treatment with palovarotene can be taken at home or in any outpatient setting. In the event of a flare-up, the clinical experts encouraged the practice of instructing patients to take pictures of the flare-up site and inform their physician of the event. The clinical experts added that all patients should be provided with up to a 3-day supply of flare-up dosing in the event that a flare-up occurs during pharmacy closure or unavailability of a physician over a weekend. Given the issues associated with treatment assessment in this patient population (i.e., lack of validated instruments, heterogeneity among patients, heterogeneity over time within each patient, and flare-ups), the clinical experts suggested the creation of a pan-Canadian expert panel accessible to each jurisdiction to adjudicate both initiation and renewal of palovarotene treatment and thereby facilitate a national, consensus-based approach to access.
Clinical group input was provided by 5 clinicians with experience treating patients with FOP who attended the Canadian Endocrine Update. Some of the clinicians providing input have participated in clinical trials for the drug under review, with 1 clinician reporting on a patient with experience using palovarotene. The main unmet need of patients with FOP identified by the clinician group was the nonavailability of treatment(s) that alter the natural course of the disease. The clinician group anticipates that palovarotene would be used as a single drug (with or without corticosteroids) administered daily, with the potential for short-term dose increases during flare-ups. Further, the clinical group noted that palovarotene has the potential to be used in combination with other investigational drugs with different mechanisms of action in the future. The clinical group suggests that all patients who meet the approved Health Canada indication for palovarotene should be considered for treatment. Accordingly, consideration for treatment initiation as listed by the clinical group suggested lifetime patient monitoring by a multidisciplinary care team that includes specialists in pediatric and adult orthopedics, surgeons, and rheumatologists. The clinician group suggests that treatment with palovarotene should be discontinued in the event of notable adverse effects (e.g., premature epiphyseal fusion in children) or in the event of, or intention for, pregnancy in individuals of childbearing potential. According to input by the clinical group, there are no current tools for measuring outcomes in patients with FOP. The clinician group indicated that the following outcomes should be used to determine response to treatment: annualized change in HO volume, maintenance of mobility, reduction in rate of flare-ups, disease stability, and maintenance of HRQoL. The clinical group stressed that the decision to initiate and discontinue treatment with palovarotene should be made with careful patient counselling and shared decision-making.
Responses to Questions From the Drug Programs.
One sponsor-conducted study that met the CADTH review protocol criteria was included in this systematic review. The MOVE study is an ongoing, multicentre, nonrandomized, open-label phase III study evaluating the efficacy of palovarotene in decreasing new HO volume in adults and pediatric patients aged 4 years and older with FOP compared to untreated patients who participated in the sponsor-conducted FOP natural history study (Study PVO-1A-001). The MOVE study was conducted in 2 parts. In Part A, eligible patients received chronic dosing with palovarotene for up to 24 months and underwent flare-up–based treatment if they experienced a flare-up, as defined a priori, or a traumatic event likely to lead to a flare-up, as confirmed by the investigator. In Part B, all patients were provided palovarotene for an additional 24 months until palovarotene was commercially available to obtain longer-term safety data. No new patients were enrolled into Part B of the MOVE study. The primary efficacy end point for the MOVE study was annualized change in new HO volume, with the key secondary outcome being the proportion of patients with new HO. Secondary outcomes included number of body regions with new HO, proportion of patients reporting flare-ups, and flare-up rate per patient-month exposure. Exploratory outcomes included change in range of motion (ROM) as measured by the CAJIS for FOP; change in physical function as measured by the FOP–Physical Function Questionnaire (FOP-PFQ); change in physical and mental function for patients aged 15 years or older, and mental function for patients younger than 15 years of age using the Patient Reported Outcome Measurement Information System (PROMIS); and incidence and volume of catastrophic HO.
After the discovery of a high rate of premature epiphyseal fusion in growing children enrolled in the MOVE study, and interruption of the study due to futility at the time of interim analysis 2, the target population was amended to only include adults and children aged 8 years and older for females and 10 years and older for males. All analyses related to the target population were based on post hoc analyses.
Overall, patients in the target population were predominately male (MOVE study, 54.4%; natural history study, 51.1%) and white (MOVE study, 74.7%; natural history study, 75.0%). Patients enrolled in the MOVE study were, on average, younger than those enrolled in the natural history study (14.4 years versus 20.4 years). A greater proportion of patients were between the ages of 8 and 14 years for females and 10 to 14 years for males in the MOVE study than in the natural history study (43.0% versus 23.9%). Moreover, patients in the MOVE study were, on average, younger than those in the natural history study at the time of FOP diagnosis (6.5 years versus 7.5 years). Other notable imbalances in baseline characteristics between patients in the MOVE study and the natural history study included: reported hearing loss (MOVE study, 45.6%; natural history study, 35.2%); symptoms of pain (MOVE study, 73.4%; natural history study, 85.2%); lethargy (MOVE study, 7.6%; natural history study, 26.1%) and change in mood and behaviour (MOVE study, 11.4%; natural history study, 39.8%) during last flare-up; unknown (MOVE study, 73.4%; natural history study, 44.3%) or other (MOVE study, 8.9%; natural history study, 23.9%) reported cause of last flare-up; bone formation as a result of last flare-up (MOVE study, 51.9%; natural history study, 0%); and slightly worse loss of movement as a result of last flare-up (MOVE study, 2.5%; natural history study, 20.5%).
The analysis, using a Bayesian compound Poisson model with no square-root transformation and negatives set to 0 by body region, estimated a 25% reduction (ratio of mean change, 0.75; 95% CrI, 0.51 to 1.11) in the volume of annualized new HO among patients treated with palovarotene in the MOVE study compared to untreated patients in the natural history study.
Post hoc analysis of annualized new HO, with no square-root transformation and negative values included, estimated an annualized new HO volume in patients treated with palovarotene in the MOVE study and untreated patients in the natural history study of 11,419 mm3 (standard error [SE] = 3,782) and 25,796 mm3 (SE = 6,066 mm3), respectively. Compared to patients in the natural history study, a 55.7% reduction in mean annualized new HO volume was observed among patients treated with palovarotene in the MOVE study. Based on the wLME model, patients treated with palovarotene in the MOVE study had an estimated reduction in new HO volume of 10,443 mm3 per year (95% CI, −23,538 mm3 to 26,534 mm3 per year; P = 0.1124) compared to untreated patients in the natural history study when controlling for baseline HO divided by age. Accordingly, the wLME model estimated a 49% reduction in mean annualized new HO volume in patients treated with palovarotene in the MOVE study compared to untreated patients in the natural history study. The Wilcoxon rank sum test reported P value was 0.0107.
The proportions of patients with any new HO among patients treated with palovarotene in the MOVE study and untreated patients in the natural history study at month 12 were 62.2% and 57.4%, respectively.
The proportion of patients with 0 body regions with new HO at month 12 was 37.8% in the MOVE study and 42.6% in the natural history study. The proportion of patients with 1 body region with new HO at month 12 was 31.1% in the MOVE study and 22.1% in the natural history study. No clear, consistent trends were observed differentiating patients in the MOVE study from those in the natural history study.
The proportion of patients with catastrophic new HO volumes exceeding 100,000 mm3, 50,000 mm3, or 30,000 mm3 at month 12 in the MOVE study was 1.3%, 9.1%, and 11.7%, respectively. Among patients in the natural history study, the proportion of patients with catastrophic new HO volumes exceeding 100,000 mm3, 50,000 mm3, or 30,000 mm3 at month 12 was 3.8%, 11.4%, and 13.9%, respectively.
The proportion of patients with catastrophic annualized new HO volumes exceeding 100,000 mm3, 50,000 mm3, or 30,000 mm3 at the last time point in the MOVE study was 1.3%, 6.5%, and 16.9%, respectively. At the last time point in the natural history study, the proportion of patients with catastrophic new HO volumes exceeding 100,000 mm3, 50,000 mm3, or 30,000 mm3 at month 12 was 6.3%, 15.2%, and 24.1%, respectively.
Among patients in the target population, 67.1% of those in the MOVE study and 63.9% of those in the natural history study reported flare-ups. Based on post hoc analysis of the principal safety set, the rate of flare-up per patient-month was 0.11 (95% CI, 0.08 to 0.16) in the MOVE study and 0.06 (95% CI, 0.05 to 0.08) in the natural history study.
Overall, the mean volume of new HO at flare-up sites was 19,610 mm3 (95% CI, 11,135 mm3 to 28,084 mm3) among patients in the MOVE study and 40,157 mm3 (95% CI, 9,189 mm3 to 71,124 mm3) among patients in the natural history study. Mean volume of new HO away from flare-up site (following a flare-up) was 7,626 mm3 (95% CI, 3,845 mm3 to 11,407 mm3) among patients in the MOVE study and 26,399 mm3 (95% CI, 8,539 mm3 to 44,259 mm3) in the natural history study.
Range of motion (ROM) was assessed on 12 joints (i.e., both shoulders, elbows, wrists, hips, knees, and ankles) and 3 body regions (i.e., jaw, cervical spine [neck], and thoracic and lumbar spine) using the CAJIS. The CAJIS is a clinician-administered analogue scale of gross mobility restriction. Total CAJIS scores range from 0 to 30, with higher scores indicative of greater impairment. At baseline, mean CAJIS scores were similar between patients treated with palovarotene in the MOVE study (10.8; standard deviation [SD] = 6.4) and untreated patients in the natural history study (12.6; SD = 7.0). At month 12, both patients treated with palovarotene in the MOVE study and untreated patients in the natural history study experienced an increase (deterioration) in mean CAJIS score from baseline of 0.6 (SD = 2.1) and 0.6 (SD = 2.4), respectively.
Physical function was assessed using age-appropriate forms of the FOP-PFQ. The FOP-PFQ is a disease-specific, patient-reported outcome measure that assesses physical function. Lower FOP-PFQ scores are indicative of more difficulty and therefore greater functional impairment. At baseline, mean percentages of worse scores on the FOP-PFQ were similar between patients treated with palovarotene in the MOVE study (mean = 46.1; SD = 27.6) and untreated patients in the natural history study (mean = 47.6; SD = 28.0). At month 12, both patients treated with palovarotene in the MOVE study and untreated patients in the natural history study experienced an increase (deterioration) from baseline in mean percentage of worse score on the FOP-PFQ of 2.94 (SD = 8.09) and 4.70 (SD = 9.02), respectively.
HRQoL was assessed using age-appropriate forms of the PROMIS Global Health Scale short form. The PROMIS Global Health Scale is a set of person-centred measures that evaluate and monitor physical, mental, and social health in adults and children in the general population or living with chronic conditions. PROMIS scores were converted to T-scores for analysis. A T-score of 50 is normal, with an increment of 10 representing 1 SD away from the norm. A T-score less than 50 was indicative of worse health, while a T-score greater than 50 was indicative of better health. In patients aged 15 years and older, mean baseline scores were similar between the MOVE study and the natural history study on the PROMIS Global Physical Health (MOVE study, 43.15 [SD = 7.93]; natural history study, 43.35 [SD = 8.66]) and Global Mental Health T-scores (MOVE study, 52.17 [SD = 7.95]; natural history study, 52.70 [SD = 9.40]). Mean change from baseline on the Global Physical Health scale in patients in the MOVE study at months 6, 12, and 18 were −0.15 (SD = 3.92), −0.20 (SD = 5.16) and −1.91 (SD = 6.28), respectively. Among patients in the natural history study, the mean change from baseline on the Global Physical Health Scale at months 6, 12, and 18 were −0.37 (SD = 6.79), −1.19 (SD = 6.62) and −0.66 (SD = 5.57), respectively.
In patients under the age of 15 years, baseline PROMIS Global Health scores were similar among patients in the MOVE study and the natural history study at 43.2 (SD = 7.9) and 43.4 (SD = 8.7), respectively. Mean T-score change from baseline among patients treated with palovarotene in the MOVE study at months 6, 12, and 18 were −0.15 (SD = 3.92), 0.20 (SD = 5.16), and −1.91 (SD = 6.28), respectively. Among untreated patients in the natural history study, mean T-score change from baseline at months 6, 12, and 18 were −0.37 (SD = 6.79), −1.19 (SD = 6.62), and −0.66 (SD = 5.57), respectively.
In the MOVE study, at least 1 AE was reported by 96% and 94.3% of patients during the chronic dosing and flare-up dosing regimens, respectively. The most commonly reported AEs were related to mucocutaneous issues (83.3%), including dry skin (52.5%) and rashes (19.2%); gastrointestinal issues (63.6%), including dry lips (34.3%); infections and infestations (58.6%), including upper respiratory infection (20.2%); and musculoskeletal and connective tissue disorders, including arthralgia (24.2%) and pain in extremities (18.2%). Overall, the reporting of AEs was similar during the chronic dosing and flare-up dosing regimens, with the exception of AEs related to gastrointestinal issues, which tended to be reported more often with chronic dosing than with flare-up dosing (63.6% versus 47.1%).
At least 1 serious adverse event (SAE) was reported by 19.2% and 17.1% of patients during chronic dosing and flare-up dosing regimens, respectively. The most common SAE was epiphyses premature fusion, which was observed in 11.1% of patients during chronic dosing and in 10% of patients during the flare-up dosing regimen.
More patients required dose modification of palovarotene due to AEs during flare-up treatment (40%) than during chronic treatment (11.1%). The most common reasons for dose modification were due to drug eruption (chronic dose, 3.0%; flare-up dose, 12.9%), generalized pruritis (flare-up dose, 8.6%), erythema (flare-up dose, 4.3%), and pruritis (flare-up dose, 4.3%).
Treatment interruptions due to AEs occurred among 16.2% and 15.7% of patients during the chronic dosing and flare-up dosing regimens, respectively. The most common AE leading to treatment interruption was epiphyses premature fusion, which occurred in 6.1% of patients while on the chronic dosing regimen.
Withdrawal from the MOVE study due to AEs occurred in 6.1% and 5.7% of patients during the chronic dosing and flare-up dosing regimens, respectively. Withdrawal due to epiphyses premature fusion occurred in 1 patient during each of the dosing regimen phases.
There were no deaths to due AEs during the study period.
Of the notable harms of interest, during chronic treatment, dry skin occurred in 52.5% of patients and dry lips occurred in 34.3% of patients. During flare-up treatment, dry skin occurred in 45.7% of patients and dry lips occurred in 20.0% of patients. Epiphyses premature fusion was observed in 11.1% of patients during chronic dosing and in 10% of patients during flare-up dosing. Hearing loss, pneumonia, suicidal ideation, and fractures occurred in less than 5% of patients who received treatment in the MOVE study. There were no reported cases of osteoporosis, low bone density, decreased bone density, or onycholysis.
Mean change in linear height z score in patients aged 8 years (for females) or 10 years (for males) to younger than 14 years was –0.36 (SD = 0.43) in those treated with palovarotene in the MOVE study and –0.20 (SD = 0.34) in untreated patients in the natural history study. Among patients aged 14 years to younger than 18 years, mean change in linear height among those who received treatment with palovarotene in the MOVE study (−0.02; SD = 1.54) was less than the mean change in linear height among those who were untreated in the natural history study (−0.55; SD = 1.61). Compared to untreated patients in the natural history study, a greater proportion of patients in the MOVE study aged 8 years (for females) or 10 years (for males) to younger than 14 years (61.3% versus 41.2%) and aged 14 years to younger than 18 years (92.3% versus 88.9%) were documented with a pathological growth velocity rate of less than 4 cm per year. A similar trend was observed for other growth measures among patients aged 8 years (for females) or 10 years (for males) to younger than 14 years, in which a greater proportion of patients treated with palovarotene in the MOVE study were documented with a pathological growth velocity rate of less than 2 cm per year for knee height (61.3% versus 52.9%), and a pathological growth velocity rate of less than 1.5 cm per year for tibial length (60.7% versus 50.0%). Among patients aged younger than 18 years, the proportion of patients with any epiphyseal growth plate abnormalities documented at month 12 was similar at 45.8% in both the MOVE study and the natural history study.
Patient group, clinician group, clinical expert, and drug program input gathered in the course of this CADTH review, as well as relevant literature, was reviewed to identify ethical considerations relevant to the use of palovarotene to reduce the formation of HO in adults and children aged 8 years and older for females with FOP and 10 years and older for males with FOP.
Ethical considerations arising in the context of FOP highlighted the significant, disabling, and life-shortening impact of the disease on patients, as well as the burden on caregivers and families; challenges to, and harms associated with, delays in timely diagnosis; and the absence of disease-modifying therapies.
Ethical considerations arising in the evidence used to evaluate palovarotene indicated that there is uncertainty about the safety and efficacy of palovarotene, and especially the magnitude of its treatment effect, which limits clinical assessments of risks and benefits associated with pursuing or forgoing treatment, as well as pharmacoeconomic assessments of cost-effectiveness.
The use of palovarotene presents potential risks for patients, including a risk of premature epiphyseal closure in growing children, retinoid-associated AEs, and osteoporosis. Patients and clinical experts expressed a willingness to undertake some risks for the potential benefit of a therapy that could slow or halt disease progression, given the severity of untreated FOP and absence of alternative disease-modifying therapies. Robust informed consent processes are required to discuss the evidentiary uncertainty and balance of risks and benefits, including for pediatric patients. As an orally administered pill, palovarotene is relatively accessible for patients, but equitable access requires attending to potential geographic and diagnostic barriers to access.
Ethical considerations for health systems related to the implementation of palovarotene highlight the challenges of funding decisions and fair allocation of scarce resources, and issues related to high-cost drugs for rare diseases, including pan-Canadian approaches to providing equitable reimbursement and access, and challenges associated with assessing opportunity costs.
Cost and Cost-Effectiveness.
CADTH identified key limitations with the sponsor’s analysis:
CADTH reanalysis included changes to the market shares of palovarotene to reflect the number of patients in Canada anticipated to receive palovarotene. In the CADTH base case, the budget impact of reimbursing palovarotene to reduce the formation of HO in patients with FOP (females aged 8 years and older; males aged 10 years and older) is expected to be $4,288,612 in Year 1, $4,775,024 in Year 2, and $5,272,705 in Year 3, for a 3-year total of $14,336,341.The estimated budget impact is highly sensitive to the number of patients eligible for palovarotene and assumptions about its uptake.
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Alun Edwards, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Allan Grill, Mr. Morris Joseph, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Ms. Heather Neville, Dr. Danyaal Raza, Dr. Emily Reynen, and Dr. Peter Zed.
Meeting date: March 24, 2023
Regrets: One expert committee member did not attend.
Conflicts of interest: None
Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services.
While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH.
CADTH is not responsible for any errors, omissions, injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the contents of this document or any of the source materials.
This document may contain links to third-party websites. CADTH does not have control over the content of such sites. Use of third-party sites is governed by the third-party website owners’ own terms and conditions set out for such sites. CADTH does not make any guarantee with respect to any information contained on such third-party sites and CADTH is not responsible for any injury, loss, or damage suffered as a result of using such third-party sites. CADTH has no responsibility for the collection, use, and disclosure of personal information by third-party sites.
Subject to the aforementioned limitations, the views expressed herein are those of CADTH and do not necessarily represent the views of Canada’s federal, provincial, or territorial governments or any third party supplier of information.
This document is prepared and intended for use in the context of the Canadian health care system. The use of this document outside of Canada is done so at the user’s own risk.
This disclaimer and any questions or matters of any nature arising from or relating to the content or use (or misuse) of this document will be governed by and interpreted in accordance with the laws of the Province of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusive jurisdiction of the courts of the Province of Ontario, Canada.
The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document for non-commercial purposes only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors.
Redactions: Confidential information in this document may be redacted at the request of the sponsor in accordance with the CADTH Drug Reimbursement Review Confidentiality Guidelines.
About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system.
Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.
Indication: 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
Sponsor: Ipsen Biopharmaceuticals Canada, Inc.
Final recommendation: Reimburse with conditions
Copyright © 2023 - Canadian Agency for Drugs and Technologies in Health. Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial- NoDerivatives 4.0 International licence (CC BY-NC-ND).
Your browsing activity is empty.
Activity recording is turned off.
See more...
