CADTH Reimbursement Review

Setmelanotide (Imcivree)

Sponsor: Rhythm Pharmaceuticals, Inc.

Therapeutic area: Bardet-Biedl syndrome

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Ethics Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information on the Application Submitted for Review

BBS = Bardet-Biedl syndrome; LEPR = leptin receptor; NOC = Notice of Compliance; PCSK1 = proprotein convertase subtilisin/kexin type 1; POMC = pro-opiomelanocortin; SC = subcutaneously.

Introduction

Bardet-Biedl syndrome (BBS) is a rare genetic disease with highly heterogeneous ciliopathy that affects multiple body systems and causes many variable symptoms, such as retinal degeneration, obesity, renal anomalies, polydactyly, hypogonadism, and intellectual impairments.

Despite a normal weight at birth, a quick weight gain that leads to obesity is considered a major clinical feature of BBS. This rapid weight gain is a common component of BBS that occurs during the first year of life in 72% to 92% of patients. Hyperphagia associated with obesity is also considered a hallmark of BBS. It is thought to be caused by the impairment of the melanocortin-4 receptor (MC4R) pathway, and can affect satiety, appetite regulation, food intake, and energy expenditure. Excessive food-seeking behaviour negatively affects the lives of patients and caregivers. It can create difficulties with productivity and concentration at work and school, affect patients’ emotional and psychosocial status, and impair their relationships and quality of life (QoL). Additionally, uncontrolled hyperphagia can increase the risk of obesity-related morbidities, such as cardiometabolic diseases, liver disease, and diabetes.

The prevalence of BBS is estimated to range from 1 in 100,000 to 1 in 160,000 in the populations of North America and Europe. Approximately 300 to 400 individuals in Canada have BBS; the disorder occurs with greater frequency in certain populations of Newfoundland and Labrador (from 1 in 16,000 to 1 in 18,000).

BBS can be diagnosed based on clinical features (e.g., retinal dystrophy, obesity, postaxial polydactyly) using the Beales diagnostic criteria. The diagnosis may be supported by out-of-country genetic testing. Given that there are no targeted therapies for BBS, management of obesity follows the same approaches as those used for the general population, such as diet and lifestyle modifications. However, adherence to these practices and sustainability of weight loss are especially low in this population.

There are no Health Canada–approved treatments for obesity or control of hunger in patients with BBS. Some pharmacotherapies may be used off-label,¹ such as glucagon-like peptide 1 (GLP1) receptor agonists (e.g., semaglutide injection or liraglutide injection) or gastrointestinal lipase inhibitors (e.g., orlistat). Both types of treatments are reimbursed in some Canadian jurisdictions for adults with type 2 diabetes (semaglutide) or in patients with obesity and 1 weight-related comorbid condition (liraglutide, orlistat).^2,3 The clinical experts consulted by CADTH indicated that only semaglutide was likely to be prescribed off-label for patients with BBS due to its potential to reduce hunger; however, they noted that it does not target the underlying mechanism of BBS-induced hyperphagia and that there are no clinical studies available specifically in populations with BBS. Other pharmacotherapies for obesity management that were not indicated as potentially used off-label in BBS include lixisenatide, naltrexone and bupropion, lisdexamfetamine, and topiramate.¹

Bariatric surgery with gastric banding or sleeve surgery may be used as a last resort in patients with a body mass index (BMI) greater than 40 kg/m² or greater than 35 kg/m² with comorbidities.^4,5 However, there are significant limitations associated with bariatric surgery. For example, it may be dangerous and lack durability for patients with hyperphagia if the patient’s food environment is not tightly controlled. Additionally, cognitive impairment is common in patients with BBS (affecting approximately 62% of patients).⁶

The objective of this review is to review the beneficial and harmful effects of setmelanotide 10 mg/mL injectable solution for weight management in adult and pediatric patients aged 6 years and older with obesity due to BBS.

Stakeholder Perspectives

The information in this section is a summary of the input provided by the patient and clinician groups that responded to CADTH’s call for input and from the clinical expert(s) consulted by CADTH for the purpose of this review.

Patient Input

CADTH received 1 input from the Bardet Biedl Syndrome Foundation, which conducted an online survey and 1-on-1 telephone or video conference interviews with people who have BBS. The majority of survey respondents (61%) were from the US.

According to the input, 71% of patient and caregiver respondents indicated that they or their loved ones currently live with obesity. Patients with BBS think about food constantly and take a long time to feel full after eating. According to the input, BBS-related obesity and hyperphagia affected the emotional and psychological well-being of patients along with their social lives and work or school lives.

The patient input stated that there is no approved treatment for BBS or BBS-related hunger and obesity in Canada. Patients reported that they used environmental tools, such as exercise, supervision from others, calorie-restricted diets, and meal schedules for weight management and found these measures to be somewhat to very effective. However, caregiver respondents noted that these strategies are challenging to implement.

Two patient and 2 caregiver respondents indicated that they or their loved ones had experience with some off-label weight management medications, such as semaglutide and phentermine. They reported that these treatments were somewhat to very effective. One respondent stated that they were using semaglutide at the same time as setmelanotide.

Four patient respondents and 13 caregiver respondents reported having experience with setmelanotide and said the treatment had helped control appetite and hunger, manage weight, and improve QoL.

Patient and caregiver respondents identified not thinking about food constantly, not feeling hungry right after eating, and reducing stigma and/or judgment and stress as key outcomes for the treatment of BBS-related hunger.

Interviews with 1 patient and 4 caregivers who had experience with setmelanotide were provided in the patient input. The results were consistent with the survey input in terms of disease symptoms, improved outcomes, and the recommendation that the drug be available and accessible for all patients living with BBS.

Clinician Input

Input From Clinical Experts Consulted by CADTH

The information in this section is based on input received from a panel of 4 clinical specialists consulted by CADTH for the purpose of this review.

The clinical experts indicated that the primary unmet need is for targeted treatment options for patients with BBS. BBS is a very rare genetic ciliopathy with multisystem manifestations, commonly including early-onset obesity and hyperphagia. The clinical experts indicated that lifestyle interventions for obesity management are particularly inefficient and unsustainable in this population because of biologically driven hyperphagia and other potential manifestations of BBS, such as vision loss, behavioural issues, food-seeking behaviours, cognitive impairment, and others. The experts also highlighted that patients with early-onset obesity due to BBS and hyperphagia may be exposed to their obesity for a substantially longer period of time than people with late-onset common obesity, which places them at greater risk for obesity-related comorbidities.

The clinical expert panel agreed that setmelanotide would be considered a first-line therapy for patients with BBS who have hyperphagia and obesity, and would be used in combination with obesity management recommendations, such as intensive diet and lifestyle changes. It was noted that setmelanotide would be the first available therapy to target the underlying mechanism of BBS-associated hyperphagia, and that setmelanotide would not be expected to have an impact on manifestations in other body systems (e.g., ocular manifestations). The experts reported that, despite a lack of data, combination therapy consisting of setmelanotide and GLP1 receptor agonists was likely to occur in some circumstances, including comorbidity involving BBS with type 2 diabetes. The experts noted that there is some evidence that the response to bariatric surgery may be less durable in populations with hyperphagic obesity, and that there are no data for any other pharmacotherapies in the treatment of patients with BBS.

The experts indicated that genetic testing for the suite of known BBS mutations is currently not available in Canada. It is requested through the provincial ministries of health as an out-of-country test, but does not cause out-of-pocket expenses for patients. The experts stated that clinical diagnosis using the Beales criteria was considered common and sufficient, and that misdiagnosis was unlikely, but that the majority of patients do seek genetic confirmation as well. There was a diversity of opinion among the clinical experts on whether genetic testing should be a requirement for receiving BBS-targeted therapies because there may yet be unknown mutations that cause BBS.

The clinical experts indicated that it is currently unknown which patients are the most or least likely to demonstrate a clinically meaningful response to treatment with setmelanotide. However, it is clinically plausible that differences in the underlying mutation(s) may be relevant for prognosis and treatment effect and that more data are needed in this area. In terms of assessing response, the experts indicated that a 1-year trial period was reasonable and that a meaningful response would consist of a qualitative improvement in hunger and/or health-related quality of life (HRQoL) and a reduction of greater than or equal to 5% of body weight in adults or greater than or equal to 5% BMI in pediatric patients. There were variable opinions on approaches to treatment for patients who do not achieve greater than or equal to 5% weight loss. In 1 approach, setmelanotide would be discontinued, but in another, continuing on setmelanotide would be considered if there were other positive changes; or combination therapy might be considered. Other discontinuation criteria may include severe adverse events (AEs) that cannot be managed by dose reductions or pausing the medication, a lack of impact on hyperphagia after 12 months of treatment, or significant issues with nonadherence. The clinical experts also noted that patient registries for BBS would be of great value because there are still evidence gaps, especially regarding long-term efficacy and safety, given that obesity is a chronic, long-term, relapsing condition.

Clinician Group Input

Input from 1 clinician group, the Canadian endocrinologists treating BBS, was received. Overall, the input aligned with that of the clinical experts consulted by CADTH.

The clinician group reported that BBS is characterized by multisystem manifestations, such as early-onset obesity with hyperphagia and related complications, intellectual and cognitive impairment, delayed development, renal anomalies, polydactyly, retinal dystrophy, hypogonadism, and hypogenitalism. The input stated that 72% to 92% of patients with BBS have obesity and hyperphagia caused by hypothalamic dysfunction leading to reduced MC4R activation. The clinician group commented that obesity should be recognized as a complex, chronic, progressive, and relapsing condition.

The clinician group stated that no targeted therapy exists for the treatment of BBS; the disease is managed symptomatically. The clinicians indicated that hyperphagia is considered the most distressing symptom associated with BBS and is associated with many negative effects on the QoL and physical and mental health of patients with BBS and obesity. They stated that some environmental and lifestyle interventions that are used to manage obesity, such as food supervision, energy intake reduction, and meal schedules, are challenging to implement and not sustainable because these do not address persistent hyperphagia. In addition to that, other symptoms associated with BBS, such as vision impairment, lack of balance or coordination, and intellectual disabilities, could make the implementation of these interventions more complicated.

The clinicians’ input noted that some procedures — such as bariatric surgery and off-label therapies, like liraglutide, semaglutide, and naltrexone hydrochloride plus bupropion hydrochloride — have no evidence of safety or effectiveness in patients living with BBS because these options do not address biologically driven hyperphagia.

The clinician group also indicated that obesity management goals should consider the prevention of morbidities associated with obesity, including but not limited to cardiometabolic disease, diabetes, liver disease, and sleep apnea.

The input suggested that setmelanotide could serve as an additional treatment option in therapy plans along with lifestyle and environmental interventions to address obesity in patients with genetically confirmed BBS aged 6 years or older. The clinician group input indicated that treatment response would be assessed after 12 weeks to 16 weeks of therapy. The input agreed that discontinuation should be considered if a decrease of 5% or greater in weight or baseline BMI has not been achieved, during pregnancy and/or breastfeeding, or if the patient experiences a lack of response, side effects, or renal impairment, or has a contraindication to setmelanotide. The clinician group reported that a holistic multidisciplinary approach is required to care for patients with BBS.

Drug Program Input

The drug programs identified the following jurisdictional implementation issues or questions: relevant comparators, considerations for initiation of therapy, considerations for discontinuation of therapy, and considerations for prescribing of therapy. Refer to Table 3 for details.

Clinical Evidence

Pivotal Studies and Randomized Controlled Trial Evidence

Description of Studies

Study 023 was a phase III, open-label trial with a 14-week, randomized, double-blind, placebo-controlled period followed by a 52-week, open-label period that aimed to evaluate the efficacy and safety of setmelanotide (1 mg to 3 mg daily by subcutaneous [SC] injection) in patients aged greater than or equal to 6 years with BBS or Alström syndrome (AS) and obesity. For the purposes of this review, only the patients with BBS were of interest; results from this subgroup of patients were provided in a posthoc analysis.

Patients were also divided into “pivotal” and “supplemental” cohorts. Pivotal patients were defined as all those enrolled up to the sixth patient with AS; this group included 32 patients with BBS and 6 patients with AS. The supplementary patients (12 patients with BBS and 2 with AS) were included in some secondary and all safety outcomes. Outcomes assessed at 52 weeks of setmelanotide treatment, such as the primary and key secondary outcomes, were measured from the “active treatment baseline” as opposed to the true baseline of the study, which would have been after week 14 for patients who were initially randomized to placebo; this was done so that patients would have approximately 52 weeks of active treatment experience for single-arm outcomes. In contrast, outcomes assessed during the first 14 weeks as placebo-controlled outcomes were measured from “placebo-controlled baseline” (i.e., the true baseline of the study).

The primary outcome of Study 023 was the proportion of pivotal patients aged greater than or equal to 12 years at baseline who were treated with setmelanotide for approximately 52 weeks and achieved a greater than or equal to 10% reduction in body weight, as measured from the active treatment baseline. This single-arm outcome was compared against an external control, sourced from the Clinical Registry Investigating Bardet-Biedl Syndrome (CRIBBS), in which 6.4% of adult patients with BBS were shown to achieve greater than or equal to 10% weight loss over a 1-year period, on average. The CRIBBS data did not include any information regarding significant efforts to lose weight; the data reflect a heterogeneous, real-world approach to BBS management. In Study 023, the prespecified threshold was rounded up to 10% from 6.4% of patients expected to achieve a greater than or equal to 10% reduction in body weight without setmelanotide treatment.

Hunger score was assessed as a key secondary outcome in patients aged greater than or equal to 12 years without cognitive impairment using daily questionnaires developed by the sponsor. Patients rated hunger in terms of average daily hunger, morning hunger, and worst or most hunger over 24 hours, each on a scale of 0 to 10 wherein 10 represented the hungriest possible. Other secondary outcomes included placebo-controlled metrics of weight loss and hunger scores at 14 weeks, measured from a placebo-controlled baseline. Exploratory outcomes included change in waist circumference, change in fasting lipids, and change in HRQoL (| || || || || || || |, Impact of Weight on Quality of Life – Lite [IWQoL-Lite], the Pediatric Quality of Life Inventory [PedsQL], and | || || || || || || || || || || || || || |) as well as safety.

At baseline, patients with BBS included 32 pivotal patients and 12 supplemental patients. Patients were mostly white (68.2% and 86.4% in the setmelanotide and placebo arms, respectively), with mean ages of 18.5 years (standard deviation [SD] = 9.7 years) and 21.5 years (SD = 12.6 years), respectively. There was a high prevalence of cognitive impairment (54.5% and 36.4%, respectively). The mean BMIs were 41.4 kg/m² (SD = 10.0 kg/m²) and 41.6 kg/m² (SD = 10.1 kg/m²) kg/m², respectively. Although genetic confirmation was not required, more than 90% of patients had genetic confirmation of BBS, which was defined as homozygous or compound heterozygous loss-of-function mutation in BBS genes. Of the 22 pivotal and supplemental patients with BBS who were assigned to setmelanotide, 4 were aged less than 12 years and 12 were aged less than 17 years; among the 22 assigned to placebo, 4 were aged less than 12 years and 10 were aged less than 17 years.

Efficacy Results

Key efficacy results of Study 023 are summarized in Table 2.

Body Weight Change After 52 Weeks of Setmelanotide Treatment

Among pivotal patients aged greater than or equal to 12 years with BBS (N = 28), 35.7% (95% confidence interval [CI], 18.6% to 55.9%) had a greater than or equal to 10% reduction in body weight from the active treatment baseline after 52 weeks of treatment with setmelanotide, which was greater than the prespecified assumption of 10% of patients with BBS achieving a greater than or equal to 10% reduction in body weight without setmelanotide treatment. The mean and percent changes in weight among pivotal patients with BBS (N = 28) were −7.24 kg (SD = 8.208 kg) and −6.47 kg (SD = 6.970 kg), respectively. Results were similar when supplemental patients with BBS were also included.

As an ad hoc analysis in response to a request by CADTH to reflect the Health Canada recommendations, the sponsor also provided the estimated proportion of pivotal patients with BBS aged greater than or equal to 12 years who achieved a greater than or equal to 5% reduction in total body weight | || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || |⁷

Change in Hunger Scores After 52 Weeks of Setmelanotide Treatment

Among pivotal patients with BBS aged greater than or equal to 12 years and without cognitive impairment (N = 14), the mean percent change in hunger score after 52 weeks of setmelanotide treatment was −31.80% (95% CI, −48.81% to −14.79%). Of these patients, 71.4% experienced at least a 1-point (≥ 10%) reduction, and 42.9% experienced at least a 2-point (≥ 20%) reduction in the most or worst hunger score. Additionally, 57.1% experienced at least a 25% improvement in the weekly average of the 3 evaluated hunger scores (most or worst score over 24 hours, average score over 24 hours, or morning hunger score). Results were similar when supplemental patients with BBS were also included. There is no known minimally important difference (MID) for these hunger scores.

Body Weight Change After 14 Weeks of Setmelanotide Treatment Compared to Placebo

In the placebo-controlled analysis of pivotal patients aged greater than or equal to 12 years with BBS, patients receiving setmelanotide (N = 14) had a greater mean percentage body weight change (−3.31%; SD = 4.474%) than patients receiving placebo (N = 15) (−0.25%; SD = 2.353%). The difference in mean percent change was −2.96% (95% CI, −5.65% to −0.26%). Similar results were observed when considering both pivotal and supplemental patients with BBS.

Change in Hunger Scores After 14 Weeks of Setmelanotide Treatment Compared to Placebo

Among pivotal patients with BBS aged greater than or equal to 12 years without cognitive impairment, patients treated with setmelanotide (N = 5) had a greater reduction in hunger score than patients treated with placebo (N = 9) in the mean change in average daily hunger score and most or worst hunger score from placebo-controlled baseline to week 14. However, sample sizes were small, and the 95% CI of the difference was very wide and included the null value in the case of the percent change in hunger over 24 hours, mean change in morning hunger, and percent change in morning hunger. Results were similar when considering both pivotal and supplemental patients with BBS.

Subgroup Analyses of Change in Body Weight and Hunger Scores

There were 8 patients with BBS who were aged less than 12 years in Study 023. All had decreases of | || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || |. Including all patients aged greater than or equal to 6 years to less than 12 years with either AS or BBS (n = 11), during the 14-week placebo-controlled period, patients treated with setmelanotide (n = 6) had | || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || | (n = 5) in the same age group.

Subgroup results were directionally consistent among other age-specific subgroups of patients with BBS, including patients aged less than 18 years and greater than or equal to 18 years.

Hunger was also assessed in patients with cognitive impairments by caregiver assessment using the | || || || || || || || || || || || || || || || || || || || || || || || | because there is no validated hunger assessment for this population, and patients with | || || || || || || | share the symptoms of early obesity, intense hunger, and cognitive impairment. The scale ranges from 0 to 30, with higher scores indicating more severe hyperphagia-related behaviours. The mean change from active treatment baseline in the 11 assessed patients was | || || || || || || || || || || || || || |

Health-Related Quality of Life

Exploratory HRQoL outcomes based on the IWQoL-Lite (patients aged ≥ 18 years without cognitive impairment; n = 11) and PedsQL (pivotal patients aged < 18 years without cognitive impairment; n = 9) generally showed improvement from the active treatment baseline to week 52 of setmelanotide treatment; the mean change in IWQoL-Lite was + 11.75 (SD = 10.297), and the mean change in PedsQL was + 11.2 (SD = 14.4). Although no MIDs have been identified in BBS populations specifically for either scale, a general population survey of children identified MIDs for PedsQL as 4.4 (self-report) or 4.5 (parent proxy-report);⁸ MIDs using IWQoL-Lite in patients with general obesity range from 7.7 points to 12 points.^1,2

Some assessed patients had impaired HRQoL at baseline, according to the IWQoL-Lite (n = 8 of 11) and PedsQL (n = 4 of 9); the majority of these patients experienced improved scores after 52 weeks of setmelanotide treatment.

The results of the | || || || || in pivotal patients aged greater than or equal to 16 years without cognitive impairment (n = 13) differed by health state score: | || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || | were identified specific to BBS, obesity, or hyperphagia.

Harms Results

Results for key harms in Study 023 are summarized in Table 2. The harms results discussed here are based on the safety analysis set (SAS; N = 57), which includes patients with BBS or AS to maximize sample size. The results were similar in the BBS subgroup. The sponsor and clinical experts identified a number of AEs of special interest: injection-site reactions, anaphylaxis, bradycardia, hyperpigmentation, melanoma, sexual events, sexually inappropriate behaviours, and select psychiatric events, including anxiety, depression or depressed mood, suicidal ideation, suicide attempts, and aggression.

Common Treatment-Emergent AEs and Serious AEs

The most common treatment-emergent adverse events (TEAEs) experienced by patients were injection-site reactions (erythema, pruritus, bruising, and induration and pain), skin hyperpigmentation, nausea, vomiting, and diarrhea.

Incidences of injection-site reactions, diarrhea, and nausea were similar between treatment arms during the placebo-controlled period, but vomiting was experienced only by setmelanotide-treated patients (n = 7; 25.9%). Incidents of vomiting also occurred in patients initially randomized to placebo when they later received setmelanotide (n = 7; 28.0%) during the open-label period; these tended to occur in the first month of setmelanotide treatment. No events of severe nausea or vomiting occurred.

Over the entire study, 100% of patients with BBS or AS experienced at least 1 AE, and 3 patients (5.8%) experienced at least 1 serious adverse event (SAE). The SAEs experienced over the entire study period included anemia, blindness, suicidal ideation, and anaphylactic reaction (as previously described in a placebo-treated patient), none of which were considered by study investigators to be caused by the study drug.

Discontinuation Due to AEs

During the placebo-controlled period, 2 setmelanotide-treated patients and 3 placebo-treated patients discontinued treatment due to AEs. Of these, 1 placebo-treated patient and 1 setmelanotide-treated patient discontinued due to nausea, and 1 setmelanotide-treated patient but 0 placebo-treated patients discontinued due to vomiting. In the setmelanotide treatment group, other AEs leading to discontinuation included 1 instance each of ocular hyperemia and face edema. In the placebo group, other AEs leading to discontinuation included 1 instance each of anaphylactic reaction, headache, acne, hidradenitis, and hot flush.

Over the entire study, | || || || || || || | discontinued due to any TEAE. The reasons for discontinuation over the entire 66-week study period (N = 57 with BBS or AS) included nausea (n = 3) and vomiting (n = 3), and 1 instance each of discontinuation due to ocular hyperemia, anaphylactic reaction, headache, acne, hidradenitis, hot flush, skin hyperpigmentation, and abdominal pain.

AEs of Special Interest

Hyperpigmentation was experienced frequently and exclusively in setmelanotide-treated patients (63.0% during the placebo-controlled period and 63.5% over the full study period). These events were expected due to the effect of melanocortin receptor agonism during setmelanotide treatment.

Sexual events occurred in some patients: | || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || | during the study period.

The other AEs of special interest were either | || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || |

Deaths

No deaths occurred during the study.

Table 2: Summary of Key Results From Study 023

AS = Alström syndrome; ATB = active treatment baseline; BBS = Bardet-Biedl syndrome; CI = confidence interval; FAS = full analysis set; PCPB = placebo-controlled period baseline; PRO = patient-reported outcome; SD = standard deviation.

^aPatients with BBS (pivotal) aged greater than or equal to 12 years. Hunger and PRO outcomes do not include patients with cognitive impairment. Active treatment baseline refers to when the patient began treatment with setmelanotide (which would have been after week 14 for patients initially randomized to placebo), while placebo-controlled baseline refers to the baseline of the study overall.

^bSix patients (19.35% of the full pivotal population; 21.42% of the pivotal BBS population) had missing measurements at 52 weeks due to study discontinuation and were conservatively considered to have treatment failure. Active treatment baseline refers to when the patient began treatment with setmelanotide (which would have been after week 14 for patients initially randomized to placebo), while placebo-controlled baseline refers to the baseline of the study overall.

^cThe estimated percentage, 95% CI, and P value are based on Rubin’s rule testing the prespecified assumption of 10% of patients with BBS achieving a greater than or equal to 10% reduction in body weight without treatment. Multiplicity adjustment was not conducted. Values are from the posthoc analysis of patients with BBS and should be used for descriptive purposes only.

^dThe P value is 1-sided, based on Rubin’s rule testing the assumption of no change from baseline; the key secondary end point (percent change after 52 weeks) was analyzed first in the prespecified hierarchy at alpha = 0.025. Multiplicity adjustment was not conducted. Values are from the posthoc analysis of patients with BBS and should be used for descriptive purposes only.

^eSafety analysis population (BBS and AS). Difference, 95% CI of difference, and P value are based on Rubin’s rule, and difference is calculated as setmelanotide minus placebo. Multiplicity adjustment was not conducted. Values are from the posthoc analysis of patients with BBS and should be used for descriptive purposes only.

Sources: Study 023 Clinical Study Report⁹ and the report of patients with BBS from Study 023.¹⁰ Details in the table have been taken from the sponsor’s Summary of Clinical Evidence.

Critical Appraisal

Study 023 was a phase III, multicentre study that consisted of a 14-week, randomized, placebo-controlled, double-blind period followed by a 52-week, open-label, single-arm period. To reflect the requested reimbursement criteria, all efficacy outcomes considered in this report were posthoc reanalyses based on the subgroup of patients with BBS; these patients comprised the majority of the overall population. The results of the posthoc analysis were consistent with the results of the prespecified analyses in the full analysis set (FAS). Although the population size was small, BBS is a rare disease with a small patient population, and the sample size exceeded the minimum power calculation conducted by the sponsor. However, the already-small sample size was further restricted for hunger-related outcomes (because cognitively impaired patients were excluded), for exploratory outcomes related to HRQoL (because of the different age requirements associated with the validated scales and the exclusion of cognitively impaired patients), and across many other outcomes (because of missing data). There are inherent risks of bias, confounding, and uncertainty in the estimation of treatment effects from single-arm data due to unidentified, uncontrolled prognostic factors. Moreover, the open-label design of the single-arm period increases the risk of detection bias and performance bias and may lead to overestimation of the treatment effect for subjective outcomes. The duration of treatment for this period was considered appropriate by CADTH clinical experts for evaluating weight loss and hunger; however, longer-term data are also needed, given that obesity in patients with BBS is a long-term, chronic, relapsing condition.

The primary outcome of the proportion of patients achieving a greater than or equal to 10% reduction in body weight at 52 weeks was considered to be conservative, given that a greater than or equal to 5% reduction in body weight is widely accepted by clinical experts as clinically meaningful in patients with BBS and obesity. The trial result was compared to a prespecified threshold of 10% responders based on historical control data. The key secondary hunger-related outcomes were based on a hunger scale that has not been externally validated, confounding the interpretation of a MID; moreover, the results were compared against an assumption of no effect without treatment, which does not control for the possibility of the placebo effect and may be biased in favour of setmelanotide, given that this is a subjective patient-reported outcome (PRO). Primary and key secondary results from the 52-week analyses are supported by the exploratory placebo-controlled outcomes in which, at week 14, a higher percentage of patients in the setmelanotide treatment group had improvement in parameters related to weight loss and hunger compared to patients who received placebo.

The eligibility criteria and population characteristics at baseline were considered to be appropriate and generalizable to the population of interest (i.e., adult and pediatric patients with BBS, obesity, and hyperphagia who may or may not have cognitive impairment or genetic confirmation of diagnosis). Although patients aged greater than or equal to 6 years were included, most outcomes were analyzed in patients aged 12 years and older, and very few patients aged less than 12 years were enrolled in the trial (n = 8). Additionally, although patients with cognitive impairment were enrolled, they were not included in the key secondary and exploratory outcomes related to hunger and HRQoL due to the practical limitations of assessing these outcomes in cognitively impaired populations. Subgroup analyses of younger and cognitively impaired populations generally aligned with the primary and secondary outcomes described, but the interpretation of results was limited due to the small sample sizes. There are also concerns about generalizability of the results to pediatric patients, given that the average maintenance dose in pediatric patients in Study 023 (| || || || || |) exceeded the maximum recommended dose of 2 mg daily. The clinical experts consulted by CADTH indicated that dosing in real-world practice would mostly follow the product monograph, with occasional exceptions for patients aged older than 16 years, who may begin to receive adult dosages based on clinical judgment.

Long-Term Extension Studies

Description of Studies

Study 022 is an ongoing, long-term extension (LTE) study that is nonrandomized, open-label, and single-arm, and includes patients aged greater than or equal to 6 years with BBS and obesity. Enrolled patients are “responders” who have completed 1 of the phase II or phase III studies (i.e., Study 014 or Study 023, respectively), demonstrated tolerability, and achieved a body weight reduction of greater than or equal to 10% (patients aged ≥ 18 years) or a greater than or equal to 0.3 reduction in BMI z score (patients aged < 18 years) after 52 weeks of setmelanotide treatment. Patients received personalized setmelanotide doses titrated to a target of 3 mg once daily. The primary objective was to evaluate safety and tolerability; secondary objectives were to evaluate changes in weight and hunger.

Efficacy Results

At the time of this review, Study 022 was still ongoing, and not all patients had completed the 36-month assessment. However, early findings from 12-month, 18-month, and 24-month assessments indicate that weight-related parameters have tended to stabilize in | || || || || | patients with BBS and obesity. | || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || ||.

Harm Results

During Study 022, 100% of patients experienced at least 1 TEAE. The most common TEAEs were injection-site reactions, skin hyperpigmentation, nausea, and vomiting. Three patients (10%) experienced SAEs. No death related to AEs was reported. It was not reported whether deaths were observed in general.

Critical Appraisal

The open-label design of Study 022 is considered a limitation that could increase the risk of detection bias and performance bias and lead to the overestimation of treatment effect for subjective outcomes. The small sample size, immature data, lack of a control arm, and lack of adjustment for covariates are considered key constraints that limit the interpretation of study outcomes. Additionally, only a brief summary of the trial was available for this review, with limited reporting. Hunger and HRQoL outcomes were not reported.

Indirect Comparisons

The sponsor conducted a feasibility assessment to determine if an indirect treatment comparison of setmelanotide versus 8 general obesity treatments — including semaglutide, lixisenatide, lisdexamfetamine, topiramate, liraglutide, naltrexone-bupropion, orlistat, and bariatric surgery — can be undertaken. Systematic literature reviews were conducted to identify prospective or retrospective clinical studies, published or unpublished, pertaining to the treatment of patients with BBS and obesity. No relevant articles were identified in this patient population; therefore, indirect comparisons were not feasible.

Conclusions

There is an unmet need for targeted treatments that address the underlying biological cause of hyperphagia and obesity caused by BBS, which is a rare, incurable, genetic ciliopathy with multisystem manifestations. Patients and clinicians highlighted that early-onset obesity and hyperphagia are 2 of the most distressing symptoms of BBS, causing significant HRQoL impairment and caregiver burden, and that typical obesity management strategies (such as restricted diet) are less feasible and less sustainable in this population than in general obesity. One completed phase III trial (Study 023) and an ongoing LTE (Study 022) were included in this review. There were notable concerns with the internal validity of the studies. These were driven primarily by the single-arm, open-label design, which introduces significant risk of bias to all subjective clinical outcomes and limits the interpretation of the magnitude of effect attributable to the intervention. However, it is worth noting that BBS is a rare disease with a small patient population for which there are no other targeted pharmacotherapies.

The data submitted to CADTH were considered clinically relevant to the target patient population. Setmelanotide results were consistent with a clinically meaningful reduction in all weight-related parameters — such as change in body weight and BMI across all reported analysis populations and subgroup analyses at 52 weeks — and the results were supported by the exploratory, comparative, 14-week, placebo-controlled outcomes. The results also suggested a consistent reduction in hunger score in both the placebo-controlled and open-label periods. However, the scale used to measure hunger has not been externally validated; therefore, it is inconclusive whether these results are clinically meaningful. Similarly, results for HRQoL outcomes at 52 weeks appeared to support a beneficial effect, but small sample sizes and the single-arm study design made interpreting events attributable to setmelanotide challenging. The long-term efficacy of setmelanotide is unknown because efficacy data from the LTE (Study 022) were immature at the time of this review. There is no evidence of effect regarding other BBS-related manifestations or prognoses aside from obesity. There are concerns about the generalizability of the clinical data to pediatric patients, given that the average maintenance dose in pediatric patients in Study 023 (| || || || || |) exceeded the maximum Health-Canada–recommended dose of 2 mg daily. There are also inherent risks of bias, confounding, and uncertainty in the estimation of treatment effects from single-arm data due to unidentified, uncontrolled prognostic factors. Moreover, the open-label design of the single-arm period increases the risk of detection bias and performance bias, and may lead to an overestimation of the treatment effect for subjective outcomes.

There are potentially notable harms from setmelanotide, including hyperpigmentation and sexual events or inappropriate behaviours. However, these events were generally uncommon, and no treatment-related melanoma has been observed in any setmelanotide trial to date. Behavioural or psychiatric disturbances, such as depression or aggression, were observed in the setmelanotide trials, but are unlikely to be related to study medication. All patients in Study 023 experienced at least 1 AE, but very few were serious; setmelanotide was generally well-tolerated. The most common AEs in patients treated with setmelanotide were injection-site reactions, skin hyperpigmentation, nausea, vomiting, and diarrhea. Vomiting was commonly and exclusively observed in patients treated with setmelanotide, and tended to occur during the first month of treatment; however, no events were severe. No new safety signals have been identified in the ongoing LTE (Study 022).

Overall, the results of Study 023 and Study 022 were consistent with setmelanotide improving important weight-related outcomes for patients with BBS, but the ability to draw firm conclusions on the magnitude of clinical benefit in hunger, HRQoL, and other outcomes was limited. There are uncertainties regarding the long-term efficacy and safety of setmelanotide, given that it is potentially a lifelong treatment.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of setmelanotide 10 mg/mL solution administered as a once-daily SC injection for weight management in adult and pediatric patients aged 6 years and older with obesity due to BBS.

Disease Background

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following information has been summarized and validated by the CADTH review team.

Disease Overview

BBS is a rare and highly heterogeneous ciliopathy caused by genetic variants that lead to dysfunction in the MC4R pathway. It is characterized by various clinical manifestations, including hyperphagia, obesity, postaxial polydactyly, renal anomalies, retinal cone-red dystrophy, learning disabilities, developmental delays, and diabetes.¹² Additionally, cognitive impairment is common in patients with BBS (approximately 62%⁶).

Despite the clinical heterogeneity of BBS, hyperphagia is common, and approximately 72% to 92% of patients with BBS have obesity as a major clinical finding.^6,12 Childhood obesity is considered a dominant feature of BBS that develops early in life.¹³ An analysis of the largest international BBS registry revealed that the proportion of patients with BBS who were overweight or obese exceeded 90% after the age of 6 years, despite most birth weights being in the normal range.¹³ This very early onset of obesity in BBS cases is atypical of general obesity and should raise the possibility of diagnostic screening for BBS and other rare obesity syndromes;¹³ it is thought to be driven by hyperphagia.^14-16 Obesity and hyperphagia in BBS are thought to be associated with genetic defects resulting in impairment of the MC4R pathway, leading to insatiable hunger, decreased metabolism, and severe obesity.¹² Hyperphagia is associated with a severe preoccupation with food, persistent and potentially extreme food-seeking behaviours, and distress or inappropriate behaviours if denied food.^17,18

According to patients and caregivers, hyperphagia and obesity are 2 of the most distressing features of BBS¹³ that significantly decrease their QoL.¹⁸ Weight management is an ongoing struggle for most patients. In particular, patients or caregivers of patients with BBS can experience guilt, stigmatization by family or peers, and judgment regarding their perceived incompetency in managing their or their child’s behaviours and weight.¹⁹ Hyperphagia also has broad negative effects on patients’ emotional state and relationships as well as negative effects on productivity at work and school.²⁰

The prognostic implications of hyperphagia and obesity in BBS are uncertain, although general obesity is acknowledged as a chronic disease that impairs health, increases the risk of long-term medical complications, and reduces lifespan.^21-23 Obesity, especially in children, is a complex disease associated with numerous comorbid conditions, including type 2 diabetes, gallbladder disease, nonalcoholic fatty liver disease, gout, and various cancers.²¹ Moreover, obesity is linked to depression and social isolation^24,25 as well as stigma and discrimination,²⁶ which can be sources of suffering, morbidity, and even mortality.²¹ Obesity accelerates long-term, coexisting health problems in patients with BBS, such as cardiovascular disease, obstructive sleep apnea, liver disease, and diabetes, and impairs QoL.^13,27-31

Prevalence

The overall prevalence of BBS is estimated at approximately 1 case per 100,000 to 1 case per 160,000 population in North America and Europe.^12,32,33 However, it is significantly more prevalent in isolated communities or where consanguinity is common.⁶ For example, the prevalence reaches approximately 1 case per 16,000 to 1 case per 18,000 population in Newfoundland and Labrador.^32,34 It is estimated that approximately 300 to 400 individuals in Canada have BBS, 215 to 370 of whom may have obesity, based on a prevalence estimate of 72% to 92%.^6,12

Diagnosis

Diagnostic Testing Requirements

A diagnosis of BBS is established based on clinical features, which may include rod-cone dystrophy (93% of patients), obesity (72% to 92%), polydactyly (63% to 81%), genital malformations (59% to 98%), learning difficulties (61%), and renal abnormalities (53%).¹² Symptoms may vary significantly across patients; as a result, a clinical diagnosis requires the presence of at least 4 major features or 3 major features plus at least 2 minor features from the diagnostic criteria published by Beales et al.³⁵

Primary features include:

• rod-cone dystrophy

• polydactyly

• obesity

• learning disabilities

• hypogonadism in males

• renal abnormalities.

• Secondary features include:

• speech disorder and/or delay

• strabismus and/or cataracts and/or astigmatism

• brachydactyly and/or syndactyly

• developmental delay

• polyuria and/or polydipsia (nephrogenic diabetes insipidus)

• mild spasticity (especially of the lower limbs)

• diabetes mellitus

• dental crowding and/or hypodontia and/or small roots and/or high, arched palate

• hepatic fibrosis.

However, many of the manifestations of BBS are progressive and may evolve as children grow, complicating physicians’ ability to make a clinical diagnosis based on the diagnostic criteria.⁶ At birth, many individuals with BBS may appear healthy unless they have polydactyly, and some symptoms may emerge gradually during or after the first decade of life.²⁸ Therefore, symptoms may be missed in early childhood, and an ongoing assessment framework is needed to support the diagnosis of suspected BBS.

Availability of Diagnostic Testing

Genetic testing may be conducted to confirm a diagnosis of BBS, but it is not required.³⁶ A genetic testing panel that can identify 12 of the 22 known BBS genes is currently available through some Canadian treatment centres. However, a genetic test that can identify all 22 BBS genes is not currently available in Canada and must be ordered as an out-of-country test. | || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || ||

Standards of Therapy

Contents within this section have been informed by materials submitted by the sponsor and by clinical expert input. The following information has been summarized and validated by the CADTH review team.

Currently, there is no cure for BBS; nor are there any targeted therapies available for the treatment of BBS and its related hyperphagia or obesity. Interdisciplinary symptomatic treatment for patients with BBS aims to aggressively manage diabetes, hypertension, and metabolic syndrome.^12,37 Management of obesity in patients with BBS is similar to management of obesity in the general population, and includes lifestyle modifications, restricted calorie diets, exercise, and psychological interventions, in most cases; it does not address the underlying hyperphagia.¹⁰ The clinical experts consulted by CADTH noted that, although some patients with BBS with obesity and hyperphagia may achieve a greater than or equal to 5% weight loss through lifestyle changes, this is uncommon; the ability to sustain weight loss is especially low in this population.

There are no Health Canada–approved treatments for obesity or control of hunger in patients with BBS. Some pharmacotherapies may be used off-label,¹ such as GLP1 receptor agonists (e.g., semaglutide injection or liraglutide injection) or gastrointestinal lipase inhibitors (e.g., orlistat), which are reimbursed in some Canadian jurisdictions for adults with type 2 diabetes (semaglutide) or in patients with obesity and 1 weight-related comorbid condition (liraglutide, orlistat).^2,3 The clinical experts consulted by CADTH indicated that only semaglutide was likely to be prescribed off-label for patients with BBS (because of its potential to reduce hunger); however, they noted that it does not target the underlying mechanism of BBS-induced hyperphagia and that there are no clinical trials currently available in populations with BBS. Other pharmacotherapies for obesity management that were not indicated as potentially used off-label in BBS include lixisenatide, naltrexone-bupropion, lisdexamfetamine, and topiramate.¹

Bariatric surgery with gastric banding or sleeve surgery may be used as a last resort in a few patients with a BMI of greater than 40 kg/m² or those with a BMI of greater than 35 kg/m² and comorbidities.^4,5 However, there are significant limitations associated with bariatric surgery. For example, it may be dangerous and lack durability for patients with hyperphagia if the patient’s food environment is not tightly controlled.

Drug Under Review

Setmelanotide is an MC4R agonist.³⁸ MC4Rs in the brain are involved in regulating hunger, satiety, and energy expenditure. In genetic forms of obesity related to the leptin-melanocortin pathway associated with insufficient activation of the MC4R, setmelanotide is believed to reestablish the MC4R pathway activity to reduce hunger and promote weight loss through decreased caloric intake and increased energy expenditure.³⁸ Setmelanotide is indicated for weight management in adult and pediatric patients aged 6 years and older with obesity due to BBS.³⁸ It is also indicated for weight management in adult and pediatric patients aged 6 years and older with obesity due to genetically confirmed biallelic pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency due to variants interpreted as pathogenic, likely pathogenic, or of uncertain significance. Setmelanotide is not indicated for the treatment of patients with obesity due to suspected POMC, PCSK1, or LEPR deficiency with POMC, PCSK1, or LEPR variants classified as benign or likely benign, or other types of obesity not related to POMC, PCSK1, or LEPR deficiency or BBS, including obesity associated with other genetic syndromes and general (polygenic) obesity.³⁸

The product monograph notes the following:

• Setmelanotide should be prescribed and supervised by a physician with expertise in obesity with underlying genetic etiology.

• Setmelanotide should be administered once daily, at the beginning of the day, without regard to meals.

• Patients selected for treatment with setmelanotide should have a genetically determined deficiency of POMC, PCSK1, or LEPR or a clinical diagnosis of BBS.

• Response to setmelanotide therapy should be assessed regularly.

• In patients with BBS, weight loss should be evaluated after 22 weeks of treatment. If a patient has not lost at least 5% of baseline body weight (or 5% of baseline BMI for patients with continued growth potential), setmelanotide should be discontinued, because it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.

• In pediatric patients, the impact of weight loss on growth and maturation should be evaluated.³⁸

Setmelanotide is available as a 10 mg/mL solution in a 1 mL multiple-dose vial. The recommended dosage for the treatment of patients with BBS aged 18 years and older is as follows:³⁸

• The starting dose of setmelanotide is 1 mg (0.1 mL) injected SC once daily for 2 weeks.

• Monitor patients for gastrointestinal adverse reactions to adjust dosage.

• The dose may be increased by 0.5 mg daily every 2 weeks, if tolerated, to a maximum dose of 3.0 mg daily.

• If the starting dose is not tolerated, setmelanotide should be discontinued.

• For patients with mild to moderate renal impairment, no dosing adjustments are required.

• For patients with severe renal impairment, the starting dose is 0.5 mg (0.05 mL) and may be increased by 0.5 mg daily every 2 weeks, if tolerated, to a maximum of 1.5 mg daily.

• Setmelanotide is not recommended in patients with any degree of hepatic impairment.

For patients with BBS aged 6 years to 17 years, the recommended dosage is as follows:³⁸

• The starting dose of setmelanotide is 0.5 mg (0.05 mL) injected SC once daily for 2 weeks.

• Monitor patients for gastrointestinal adverse reactions to adjust dosage.

• The dose may be increased by 0.5 mg daily every 2 weeks, if tolerated, to a maximum dose of 2.0 mg daily.

• If the starting dose is not tolerated, setmelanotide should be discontinued.

• It is not recommended to treat pediatric patients who have severe renal impairment with setmelanotide.

• Setmelanotide is not recommended in patients with any degree of hepatic impairment.

It is worth noting that the dosage in the pivotal study (Study 023) differed from the currently recommended dosing:

• During the 14-week, double-blind treatment period, patients aged greater than or equal to16 years were started on setmelanotide once daily through SC injection at 2 mg or matching placebo for 2 weeks, after which they were increased to the target dose of 3 mg SC once daily (or matching placebo) at the beginning of week 3 for the duration of the double-blind period.

• Patients aged less than 16 years were started on setmelanotide 1 mg SC once daily or matching placebo during week 1. This dosage was increased to 2 mg SC once daily or matching placebo at the beginning of week 2, and increased to 3 mg SC once daily or matching placebo at the beginning of week 3 for the duration of the double-blind period.

• After the initial 14-week, double-blind treatment period, all patients immediately transitioned to open-label setmelanotide once daily, administered through SC injection. To preserve the blind, all patients were restarted at their initial age-based dose and re-escalated to the 3 mg target dose. Thus, beginning at week 15, patients aged greater than or equal to 16 years of age received open-label setmelanotide 2 mg SC once daily for 2 weeks, followed by a dose increase to 3 mg SC once daily beginning at week 17 for the duration of the trial; patients aged less than 16 years received open-label setmelanotide 1 mg SC once daily during week 15, 2 mg SC once daily during week 16, and 3 mg SC once daily beginning at week 17 for the duration of the trial.

Setmelanotide was approved by Health Canada through the priority review process. The sponsor has requested reimbursement according to the indication for patients with BBS (i.e., for weight management in adult and pediatric patients aged 6 years and older with obesity due to BBS). This drug has not been previously reviewed by CADTH. No other therapies are currently approved by Health Canada for the treatment of obesity due to BBS.³⁹

Stakeholder Perspectives

Patient Group Input

This section was prepared by the CADTH review team based on the input provided by patient groups. The full original patient input received by CADTH is included in the stakeholder section at the end of this report.

One patient group, the Bardet Biedl Syndrome Foundation, submitted patient input for this review. The foundation connects families and shares information on research, treatment, and therapies for BBS. The input was based on a 30-minute online survey and 1-on-1 telephone or video conference interviews. Of the 41 survey participants, 61% were from the US and 29% were from Canada; 34 respondents were caregivers of patients aged 3 years to 18 years, and 7 were adult patients living with BBS. Additional information was also gathered through interviews with 1 patient and 4 caregivers, all of whom had direct experience with setmelanotide.

Among the patient respondents, 57% indicated that their childhood weight was of concern, and 71% said they are currently living with obesity, with a BMI of greater than or equal to 30.0 kg/m². Among the caregiver respondents, 71% indicated that their loved ones currently live with obesity related to their BBS. Regarding hunger-related symptoms and behaviours, 86% of the patient respondents stated that they take a longer time to feel full after eating and indicated that managing hunger is crucial. In addition, 71% of patient respondents indicated that they think about food constantly. Similarly, most caregiver respondents (85%) stated that their loved ones take a longer time to feel full after eating, and 91% indicated that their loved ones constantly think about food. Nearly half (43%) of patient respondents noted that BBS-related hunger negatively affects their emotional and psychological well-being, their social life, and their ability to travel. Half of caregiver respondents indicated that BBS-related hunger affects their loved one’s social life; similar proportions indicated that it affects their loved one’s emotional and psychological well-being (47%) and work or school life (44%).

The patient input stated that there is no approved treatment for BBS or BBS-related hunger and obesity in Canada. Patient and caregiver respondents discussed their own and their loved ones’ experiences with weight management strategies, such as environmental factors and pharmacologic therapies. Patient respondents found regular exercise plans to be somewhat effective (43%) or very effective (43%), and supervision from others to be somewhat effective (29%) or very effective (29%), in managing their weight. The strategies identified by most caregivers as somewhat to very effective included regular exercise (74%), supervision from others (85%), calorie-restricted diets (56%), and adherence to meal schedules (73%).

However, caregivers noted that despite these strategies, challenges remained in aiding patients with constant hunger, and that the strategies are challenging to implement. When asked to identify the most important outcome of treatment for BBS-related hunger, caregivers identified not thinking about food so much (80%), not feeling hungry right after eating (68%), and reducing stigma and/or judgment (63%). They also identified that effective treatment of BBS-related hunger would reduce stress from the perspective of caregivers and their families.

Two patient respondents had experience with other weight management medications: 1 reported that semaglutide was very effective, and another reported that phentermine was somewhat effective. Two caregiver respondents reported that their loved ones had tried semaglutide. They indicated that it was effective in managing their weight; however, 1 of these respondents stated that semaglutide was being used at the same time as setmelanotide.

Four patient respondents and 13 caregiver respondents from the patient input stated that they or their caregivers had experience with setmelanotide; they indicated that setmelanotide improved appetite and hunger control and management, weight loss, travel, and QoL.

In addition to the survey responses, the patient input summarized the results of interviews with 1 patient and 4 caregivers who had experience with setmelanotide. Their input aligned with the survey answers in terms of symptoms and improved outcomes of weight, hunger control, QoL, and the recommendation that the drug be available and accessible for all patients living with BBS.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., assisting in the critical appraisal of clinical evidence; interpreting the clinical relevance of the results; and providing guidance on the potential place in therapy). In addition, as part of the setmelanotide review, a panel of 4 clinical experts from across Canada was convened to characterize unmet therapeutic needs, assist in identifying and communicating situations where there are gaps in the evidence that could be addressed through the collection of additional data, promote the early identification of potential implementation challenges, gain further insight into the clinical management of patients living with the condition, and explore the potential place in therapy of the drug under review (e.g., potential reimbursement conditions). A summary of this panel discussion is presented in this section.

Unmet Needs

The clinical experts indicated that the primary unmet need is for targeted treatment options for patients with BBS, a genetic ciliopathy that results in multisystem manifestations. The experts highlighted that key features of BBS can include hyperphagia, early-onset obesity, polydactyly, renal disease, genitourinary malformations, ophthalmic manifestations, anosmia or hyposmia, dental abnormalities, developmental delay, cognitive impairment, and gastrointestinal manifestations; moreover, potential consequences of obesity can include hyperglycemia, type 2 diabetes, metabolic syndrome, dyslipidemia, fatty liver disease, hypertension, cardiovascular diseases, obstructive sleep apnea, and hypogonadism, among others, as well as premature death.

The clinical experts indicated that lifestyle interventions for obesity management are particularly inefficient and unsustainable in this population because of biologically driven hyperphagia, the potential for hyperphagia-related behavioural challenges related to food-seeking (particularly in children), and the potential for cognitive impairment as a consequence of BBS. The experts also highlighted that patients with early-onset obesity due to BBS and hyperphagia may be exposed to their obesity for a substantially longer time period than people with late-onset common obesity, placing them at greater risk for downstream obesity-related comorbidities.

Place in Therapy

The clinical expert panel agreed that setmelanotide would be considered first-line therapy for patients with BBS who have hyperphagia and obesity, in combination with obesity management recommendations, such as intensive diet and lifestyle changes. Setmelanotide was noted as the first therapy that would target the mechanism of hyperphagia in BBS, which is a major obstacle in the maintenance of obesity management activities in this population.

The experts noted that, although some patients with BBS with obesity and hyperphagia may achieve weight loss of greater than or equal to 5% through lifestyle changes, the sustainability of weight loss is especially low in this patient population, and it would be clinically and ethically inappropriate to withhold or delay access to pharmacologic treatment for those patients, due to their underlying, biologically driven hyperphagia.

The experts indicated that off-label treatments, such as GLP1 receptor agonists (e.g., semaglutide), have been reported in case studies of adult patients with BBS for the control of hunger obesity, but there is a lack of robust clinical data in this patient population; and, unlike setmelanotide, GLP1 receptor agonists do not address the underlying disease mechanisms of hyperphagia caused by BBS. Moreover, semaglutide is not approved by Health Canada in pediatric patients. For these reasons, the experts agreed that it would be inappropriate to begin treatment with a trial of semaglutide before allowing access to setmelanotide in patients with BBS for the control of obesity and hyperphagia.

Despite a lack of data, the experts believed that combination therapy of setmelanotide and GLP1 receptor agonists was likely to occur in some circumstances, including in patients with BBS who also have type 2 diabetes (i.e., comorbidity). The preferred approach to combination therapy varied among panel members in the case of insufficient response to setmelanotide. One approach would be to initiate combination therapy with setmelanotide and pharmacological therapies, such as GLP1 receptor agonists; another would be to discontinue setmelanotide and not pursue combination therapies. However, it was agreed that a combination of setmelanotide and GLP1 receptor agonists may have a synergistic treatment effect in reducing hunger and helping patients with BBS to improve or maintain weight loss, but there is a lack of clinical data.

The experts noted that there is some evidence that the response to bariatric surgery may be less durable in populations with hyperphagic obesity.

Patient Population

The clinical experts noted that BBS is a very rare disease with elevated prevalence in some locations (e.g., Newfoundland and Labrador), and that approximately 90% of patients with BBS have comorbid obesity by adulthood. The clinical experts agreed that the target population for treatment with setmelanotide would be adult and pediatric patients with BBS, obesity, and hyperphagia, and that reasonable thresholds for obesity were a BMI of greater than or equal to 30 kg/m² for patients aged greater than or equal to 16, or weight greater than the 97th percentile for age and sex in patients aged less than 16 years.

Expert opinion on clinical versus genetic diagnosis of BBS was variable among panel members. In 1 approach, clinical diagnosis of BBS based on the Beales criteria was considered by the experts to be sufficient for treatment with targeted therapies, such as setmelanotide; the experts believed it would be inappropriate to strictly require genetic confirmation because additional BBS-causing mutations are still being discovered. In another approach, the diagnosis of BBS should be based on the clinical diagnosis of BBS using the Beales criteria as well as genetic confirmation. The experts noted that the majority of patients, especially pediatric patients, generally seek genetic confirmation of diagnosis. It is worth noting that the Health Canada–approved product monograph indicates that patients selected for treatment with setmelanotide should have a genetically determined deficiency of POMC, PCSK1, or LEPR, or a clinical diagnosis of BBS; they did not indicate that genetic diagnosis of BBS was needed.³⁸

The experts indicated that genetic testing for the suite of known BBS mutations is currently not available in Canada but can be requested through the provincial ministries of health as an out-of-country test. This does not cause out-of-pocket expense for the patients. The specialists most commonly diagnosing BBS were identified to be pediatricians, pediatric endocrinologists, and pediatric geneticists; however, owing to the multisystem effects and heterogeneous presentation of other symptoms in BBS, some patients may be first identified by specialists working in nephrology or ophthalmology, or by developmental pediatricians. It was also noted by the clinical experts that the average age of diagnosis with BBS is approximately 9 years, and that limited access to pediatric weight management clinics may contribute to delayed obesity management. Although there are no studies of the sensitivity and specificity of the Beales criteria, misdiagnosis was considered by the experts to be unlikely.

The pivotal study (Study 023) of setmelanotide for the treatment of obesity and hunger in patients with BBS excluded patients under 6 years of age; the majority of outcomes were assessed in the population aged greater than or equal to 12 years without cognitive impairment. Although this limits generalizability to patients aged greater than or equal to 6 years to less than 12 years, and those with cognitive impairment, the experts indicated that these are still populations of interest with substantial unmet needs. Moreover, there are practical limitations to the assessment of hunger and PROs in these subpopulations, and to the assessment of weight loss in growing children aged less than 12 years.

Patients who had recently undergone intensive weight control strategies were excluded from the pivotal study of setmelanotide. The clinical experts agreed that this would not reflect clinical practice, given that patients would be expected to combine obesity management strategies with setmelanotide and would not be excluded from treatment for recency of weight-loss activities. However, for the purpose of interpreting the trial results, the clinical experts agreed that this was a conservative trial design element and was not a cause for concern in the implementation of setmelanotide in clinical practice.

The clinical experts indicated that it is currently unknown which patients are the most or least likely to demonstrate a clinically meaningful response to treatment with setmelanotide. However, it is clinically plausible that differences in the underlying mutation may be relevant for prognosis and treatment effect. More data are needed in this area.

Assessing the Response to Treatment

The experts indicated that the most important assessments are changes in hunger, weight, and BMI in adults (or BMI percentile in pediatric patients), and that patients may also be monitored for changes in related biomarkers, such as lipid and glycemic profiles. For the measurement of hunger, formal scales or questionnaires are not currently used in clinical practice, but could feasibly be adopted in the circumstances of a treatment that directly addresses hyperphagia; different approaches would be required for pediatric and cognitively impaired patients. In current clinical practice, hunger is assessed during discussions between physicians and patients or caregivers, with a focus on the frequency and intensity of perceived experiences with hunger, food-seeking behaviours, and behavioural issues that may arise as a result of hunger. Similarly, HRQoL is not formally quantified. Rather, it is elucidated through discussions with patients. When initiating a targeted therapy for BBS, the experts indicated that they would monitor patients approximately once every 3 months in adults and from every month to every 3 months in pediatric patients for the first year of treatment. For stable patients, the frequency of monitoring would be approximately once every 4 months to 6 months.

The approach to assessing response varied slightly between clinical experts. Overall, the experts agreed that a 1-year trial period was reasonable for determining whether a patient was responding to setmelanotide. Generally, a meaningful response during the 1-year trial period would assess as a qualitative improvement in hunger and/or HRQoL and a reduction of greater than or equal to 5% in total body weight in adults or greater than or equal to 5% BMI in pediatric patients. With regards to the threshold of meaningful weight loss, some experts considered this metric of meaningful response to be a potential requirement for treatment renewal after a trial of 1 year. However, it was noted that weight loss takes longer in adults who have long-standing obesity and comorbidities, that BBS is a complex multisystem disease that includes neurologic and behavioural symptoms that add to the complexity of the response criteria, and that many patients with BBS with hyperphagia would continue to gain weight over time when untreated; for these reasons, and because of the potential to prevent or delay downstream comorbidities, some experts expressed that setmelanotide renewal may be more circumstantial and could include patients whose weight has stabilized, but not meaningfully reduced, if they have demonstrated improvement in other key areas, such as hunger, HRQoL, and/or biomarkers of metabolic health, like lipid/glycemic profiles. With regards to qualitative improvements in hunger and/or HRQoL, it was noted that these assessments become more challenging and must be approached differently, such as by relying on assessment by caregivers, if possible, in young pediatric patients and patients with cognitive impairment. It is worth noting that the Health Canada–approved product monograph recommended that in patients with BBS, evaluation of weight loss should occur after 22 weeks of treatment with setmelanotide.³⁸ If a patient has not lost at least 5% of baseline body weight (or 5% of baseline BMI for patients with continued growth potential), then setmelanotide should be discontinued because it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.³⁸ | || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || |⁴⁰

Although there is a lack of long-term data for setmelanotide, the clinical experts agreed that weight loss would be expected to eventually plateau, and that subsequent maintenance of weight would be considered as treatment response in the long-term, after the first year of treatment. Therefore, patients who initially respond and then maintain their weight would be expected to continue with setmelanotide treatment in the absence of any major discontinuation criteria. Patients with an initial response who thereafter regain significant weight would also be expected to continue treatment, with additional assessment to identify and address what factors have changed and caused the weight gain, such as poorly controlled lifestyle modification, nonadherence, or complicating comorbidities. In the opinion of some experts, combining other pharmacotherapies with setmelanotide may also be considered in the circumstances of initial response followed by weight regain, and/or in the circumstances of initial weight maintenance without clinically significant weight loss but with notable improvements in HRQoL, hunger, or lipid and/or glycemic profiles. In general, it was agreed that clinical decision-making would be highly case-by-case for patients with initial response (weight loss) but subsequent weight gain, and that it is not plausible that patients will become resistant to treatment with setmelanotide, based on current data.

Discontinuing Treatment

The clinical experts agreed that treatment would be discontinued in the case of severe AEs that cannot be managed, including but not limited to moderate to severe allergic reactions, significant gastrointestinal symptoms, serious sexual events, suicidal ideation, or depression. In circumstances such as suicidal ideation or depression, a pause in treatment may be considered, rather than permanent discontinuation, to determine whether the AE re-emerges. Treatment may also be discontinued if there is no impact on hyperphagia after 12 months of treatment, or when there are significant issues with nonadherence.

Some clinical experts indicated that discontinuation would be considered in the absence of a clinically meaningful (i.e., ≥ 5%) reduction in total body weight. However, other experts indicated that patients may still be better off with treatment than without, despite a lack of weight loss. Their clinical approach would be to continue treatment on a case-by-case basis, as previously described.

Prescribing Considerations

The experts indicated that BBS is a rare disease with multisystem involvement. Patients may initially be identified through a variety of avenues dictated by their symptoms, and should ideally be followed by a multidisciplinary team, including specialist medical doctors as well as mental health professionals and registered dietitians. The most common prescribing physicians for setmelanotide would likely be endocrinologists or pediatric endocrinologists, but specialists in weight management or genetics may also prescribe. Access to some specialists or supports may be challenging, depending on patients’ geographic locations and other circumstances.

The prescribed dose of setmelanotide would not be expected to exceed 3 mg per day and would include titration of the dose from 1 mg or 2 mg per day according to age and tolerance.

Prescription in combination with other pharmacotherapies was not described to be of interest in the first-line setting, specifically for the treatment of weight loss and hyperphagia in BBS. However, as previously described, the clinical experts considered combination therapy to be a viable approach in some circumstances (with specific approaches differing among experts). Combination therapy with setmelanotide is expected to occur due to necessary treatment for comorbidities, such as the use of semaglutide for treating type 2 diabetes. In some approaches, combination therapy, such as with GLP1 receptor agonists or other appetite-limiting therapies, may be considered, depending on the patient’s experience with and response to setmelanotide (e.g., inadequate response after 1 year or clinically meaningful initial response followed by subsequent weight regain).

Additional Considerations

The clinical experts described that stigma related to obesity may cause patients to be reluctant to access care and is an important consideration when evaluating the impacts of weight loss on HRQoL. The transition from pediatric to adult care may also result in loss of patient follow-up. Also of particular importance is the impact of highly prevalent cognitive impairment in patients with BBS, which can affect the continuity of care, the ability to self-inject (or to measure the injection from a vial), compliance with a treatment regimen, concurrent lifestyle and dietary modifications, and the ability of physicians and caregivers to estimate subjective outcomes, such as HRQoL and hunger. The clinical experts also noted that patient registries for BBS would be of great value because there are still evidence gaps, especially regarding long-term efficacy and safety.

Clinician Group Input

This section was prepared by the CADTH review team based on the input provided by clinician groups. The full original clinician group input(s) received by CADTH have been included in the stakeholder section at the end of this report.

One clinician group provided input for this review: the Canadian endocrinologists treating BBS. Overall, the views of this clinician group were consistent with those of the clinical experts consulted by CADTH.

The clinician group reported that BBS is characterized by early-onset obesity with hyperphagia, intellectual impairment, renal anomalies, polydactyly, retinal degeneration, hypogonadism, and hypogenitalism, and that people with BBS may also have musculoskeletal complications, such as scoliosis, hip dysplasia, and difficulties with balance and coordination. The clinician group indicated that there is an unmet need for treating patients with BBS because there is currently no available targeted therapy. Complications associated with BBS are treated symptomatically, similarly to how they are treated or managed in the general population. Obesity was noted as highly prevalent in patients with BBS (72% to 92% of patients); it is thought to be driven by hyperphagia (insatiable appetite) caused by hypothalamic dysfunction leading to reduced MC4R activation. The clinician group commented that obesity is recognized as a complex, chronic, progressive, and relapsing condition.

The clinician group input stated that most available interventions for weight loss are complicated by hyperphagia, which is considered among the most distressing symptoms of BBS and associated with negative impacts on physical health, mental health, QoL, mobility, finances, activities of daily life, and judgment or discrimination. While environmental control interventions — such as food supervision, energy intake reduction, and meal schedules — are essential to managing and regulating weight for those with BBS, these interventions can be ineffective, unsustainable, and challenging to implement because these do not address persistent hyperphagia. The clinician group also noted that patient engagement in lifestyle interventions can be complicated by other coexisting issues related to BBS, such as low vision, difficulties in balance or coordination, intellectual disabilities, and mental health concerns.

According to the clinician group input, some pharmacologic therapies, such as liraglutide, are now approved for use in those with obesity aged 12 years and older. Semaglutide and naltrexone hydrochloride plus bupropion hydrochloride are approved for those aged 18 years and older. However, there is no evidence of the effectiveness or safety of these drugs in patients living with BBS. Also, these drugs do not address biologically driven hyperphagia. In addition, the safety, efficacy, and durability of the effects of bariatric surgery in this population remain largely unknown.

The clinician group indicated that the most essential obesity management goals include the prevention of weight-related health complications, including cardiometabolic risk, type 2 diabetes, abnormalities in lipid metabolism, nonalcoholic fatty liver disease, obstructive sleep apnea, musculoskeletal pain/discomfort, and difficulties with activities of daily living.

The clinician group input suggested that setmelanotide could serve as a part of the therapy plan, combined with lifestyle interventions for weight management, and could benefit patients with genetically confirmed BBS and obesity who are aged 6 years or older by addressing the underlying cause of hyperphagia. In the opinion of the clinician group, the treatment should be reassessed after 12 weeks to 16 weeks of therapy; if a decrease of 5% or greater in weight or baseline BMI has not been achieved, then the individual is unlikely to experience benefit from setmelanotide. It is unknown which individuals with BBS and obesity are most likely to respond to setmelanotide. The clinician group noted that setmelanotide should be discontinued during pregnancy and/or breastfeeding because the drug’s safety is unknown. Other reasons for discontinuation may include lack of response, presence of side effects, co-existent moderate to severe renal impairment, and contraindication. The clinician group reported that care of patients with BBS requires a multidisciplinary team approach, involving a physician who has expertise in weight management in consultation with other health care providers, such as ophthalmologists, nephrologists, endocrinologists, internal medicine specialists, gastroenterologists, primary care physicians, dietitians, and mental health care providers.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 3.

Table 3: Summary of Drug Plan Input and Clinical Expert Response

BBS = Bardet-Biedl syndrome; BMI = body mass index; HRQoL = health-related quality of life; MOH = Ministry of Health.

Clinical Evidence

The objective of CADTH’s Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of setmelanotide 10 mg/mL solution in 1 mL, multiple-dose vials administered by SC injection for weight management in adult and pediatric patients aged 6 years and older with obesity due to BBS. The focus will be on comparing setmelanotide to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of setmelanotide is presented in 2 sections, and CADTH’s critical appraisal of the evidence is included after each section. The first section, the systematic review, includes pivotal studies and randomized controlled trials (RCTs) that were selected according to the sponsor’s systematic review protocol. The second section includes a sponsor-submitted LTE study. There was no available indirect evidence, and no additional studies were included.

Included Studies

Clinical evidence from the following studies is included in the CADTH review and appraised in this document:

• One pivotal study

• One LTE study

Pivotal Studies and RCT Evidence

Contents within this section have been informed by materials submitted by the sponsor. The following information has been summarized and validated by the CADTH review team.

Description of Studies

Characteristics of the included studies are summarized in Table 4.

Table 4: Details of the Pivotal Study 023 Identified by the Sponsor

AS = Alström syndrome; BBS = Bardet-Biedl syndrome; BMI = body mass index; | || || || || || || | || || | || || |; IWQoL-Lite = Impact of Weight on Quality of Life – Lite; PedsQL = Pediatric Quality of Life Inventory; QoL = quality of life; | || || || || || || || || || || || || || || || || || || || || || || || || || || || .vs. = versus.

Source: Clinical Study Report for Study 023.⁹ Details in the table have been taken from the sponsor’s Summary of Clinical Evidence.

Study 023 included patients who were aged greater than or equal to 6 years, obese, and had a clinical diagnosis of BBS or a diagnosis of AS. These patients were randomized 1:1 through an interactive website response system to receive setmelanotide or matched-administration placebo for 14 weeks (period 1), followed by a 38-week period wherein all patients received open-label setmelanotide treatment (period 2) and then a 14-week period of open-label setmelanotide treatment (period 3) (Figure 1). Stratification was performed according to age group (≥ 12 years versus < 12 years) and disease (BBS versus AS).

Study 023 included 12 sites in Canada (1 site, 6 patients), the US (6 sites), France (2 sites), Puerto Rico (1 site), Spain (1 site), and the UK (1 site).

During the 14-week, double-blind treatment period, patients aged greater than or equal to 16 years were started on setmelanotide once daily through SC injection at 2 mg or matching placebo for 2 weeks. The target dose was increased to 3 mg SC once daily (or matching placebo) at the beginning of week 3 for the duration of the double-blind period.

Patients aged less than 16 years were started on setmelanotide 1 mg SC once daily or matching placebo during week 1. This dose was increased to 2 mg SC once daily or matching placebo at the beginning of week 2, and to 3 mg SC once daily or matching placebo at the beginning of week 3 for the duration of the double-blind period.

After the initial 14-week, double-blind treatment period, all patients immediately transitioned to open-label setmelanotide once daily through SC injection. To preserve the blind, all patients were restarted at their initial age-based dose and re-escalated to the 3 mg target dose. Thus, beginning at week 15, patients aged greater than or equal to 16 years received open-label setmelanotide 2 mg SC once daily for 2 weeks, followed by 3 mg SC once daily beginning at week 17 for the duration of the trial; and patients aged less than 16 years received open-label setmelanotide 1 mg SC once daily during week 15, 2 mg SC once daily during week 16, and 3 mg SC once daily beginning at week 17 for the duration of the trial.

Dose adjustment was not required for patients with mild to moderate renal impairment, although lower starting and target doses were used for patients with severe impairment. The exact values were not reported.

The primary analysis was performed after approximately 52 weeks of setmelanotide treatment; it is important to note that, as a result, patients initially randomized to placebo would require an evaluation at week 66 to reach approximately 52 weeks of setmelanotide treatment, as presented in Figure 1. Dose escalation was repeated for patients in both arms at the start of the 38-week, open-label period to maintain the blinding from during the placebo-controlled period. For the analysis of the primary end point and key secondary end points, baseline was defined as active treatment baseline (i.e., rather than as inclusion in the trial).

Populations

Inclusion and Exclusion Criteria

Study 023 included patients who were aged greater than or equal to 6 years, obese, and had a clinical diagnosis of BBS or a diagnosis of AS. Only the patients with BBS are relevant for the purposes of this review.

Patients with BBS were eligible for Study 023 if they had a clinical diagnosis of BBS based on Beales criteria. Patients were not required to have genetically confirmed diagnoses. Genetically confirmed BBS was defined as homozygous or compound heterozygous loss-of-function mutation in BBS genes. Patients were also required to be obese; obesity was measured using absolute BMI (≥ 30 kg/m² for patients aged ≥ 16 years) or BMI percentile (≥ 97th on growth chart for patients aged 6 years to 15 years). Different measures of obesity and changes in weight were used for different age groups due to the confounding effects of normal weight gains during childhood growth and development.

Patients were considered ineligible if they had recent intensive diet or exercise therapy, recent or current medication related to obesity treatment, or gastric bypass surgery resulting in greater than 10% weight loss with no evidence of weight regain. These exclusion criteria were applied to avoid confounding of weight loss findings and to ensure that weight loss effects could be attributed to setmelanotide treatment. In addition, no specific guidance regarding diet or exercise was given during the trial, although it is possible that patients may have been familiar with, or may have previously attempted, lifestyle modifications to control body weight.

Figure 1: Schema for Study 023

Escal = escalation; SET = setmelanotide.

^aDuring dose escalation, participants aged greater than or equal to 16 years receive setmelanotide 2 mg once daily for 2 weeks, increasing to 3 mg at the beginning of week 3; participants aged less than 16 years receive setmelanotide 1 mg once daily for the first week, 2 mg for the second week, and 3 mg at the beginning of week 3.

Source: Study 023 Clinical Study Report.⁹

Interventions

Patients enrolled in Study 023 received double-blind treatment using setmelanotide (in a mPEG-DSPE formulation) or a matched-administration vehicle placebo during the 14-week, randomized, double-blind, placebo-controlled period (period 1). The placebo formulation had similar excipients to the active formulation. The 2 treatments were indistinguishable: both were clear, colourless to slightly opalescent solutions essentially free of visible particles and were contained in identical vials. A placebo control arm was used because there are no approved treatments to control hunger and obesity in patients with BBS.

Both treatments were administered once daily through SC injection, with the setmelanotide dose started at a lower dose and then escalated toward a target of 3.0 mg/day to improve tolerability. Based on historical data that patients aged greater than or equal to 16 years have minimal (if any) height increase, a daily starting setmelanotide dose of 2.0 mg was selected for patients who were at least 16 years of age at the time of enrolment, with planned dose escalation to 3.0 mg after 2 weeks. As a measure of added caution for patients who were less than 16 years of age, the starting dose was lowered to 1.0 mg, with planned escalation to 2.0 mg at the end of week 1 and then to 3.0 mg at the end of week 2. Similarly, to maintain blinding, setmelanotide dose escalation was performed at the start of the 38-week, open-label period for all patients, regardless of whether they had originally been assigned to receive placebo or setmelanotide. Doses were not to be adjusted after the dose escalation phase unless discussed with and approved by the sponsor.

Patients and/or their caregivers were trained in SC injection (including through practice sessions and education materials) and were responsible for drawing up and administering setmelanotide (or matched placebo) at home in each morning. If patients or their caregivers were unable to successfully administer the drug, assistance was provided by a home health care practitioner. Patients and/or caregivers were given a drug diary to monitor compliance.

Outcomes

A list of efficacy end points assessed in this clinical review report are provided in Table 5. These end points are further summarized in this section. Summarized end points are based on those included in the sponsor’s Summary of Clinical Evidence along with any identified as important to this review, according to stakeholders (such as the clinical expert, clinician groups, or patient groups).

Body Weight

All body weight measurements were done in triplicate at regular time points. Whenever possible, the same scale was used throughout the trial, including at the screening visit, and calibrated on a regular basis. Weight was measured at approximately the same time at each visit and after fasting for at least 8 hours. Patients were to be in light clothing or underwear, with no shoes, and to have emptied their bladder.

Table 5: Outcomes Summarized From Study 023

ATB = active treatment baseline; BMI = body mass index | || || || || || || || || || |; FAS = full analysis set; IWQoL-Lite = Impact of Weight on Quality of Life – Lite; PedsQL = Pediatric Quality of Life Inventory; | || || || || || || || || || || || || || || || || || || || || || || || || || || || .

^aOutcomes were also assessed for patients who were aged 6 years to less than 12 years and for all patients regardless of age.

^bResults for only the patients with BBS were not provided.

Source: Study 023 Clinical Study Report.⁹ Details in the table have been taken from the sponsor’s Summary of Clinical Evidence.

Height for Determination of BMI

Height was measured in centimetres, without shoes, using a wall-mounted stadiometer. All measurements were done in triplicate at regular time points. Height was used along with body weight to determine BMI at different time points in the trial.

Body Mass Index

BMI was calculated for all patients using the following formula: weight (kg) ÷ [height (m)].² BMI accounts for linear growth, assessed by changes in height, observed in the pediatric population.

BMI z Score

The BMI z score was calculated for patients aged less than 18 years. The BMI z score indicates how many standard deviations a given patient’s BMI is from the normal mean of age-matched and sex-matched peers based on normative data from WHO.

BMI 95th Percentile Score

The percentage of the BMI 95th percentile score was calculated for patients aged less than 18 years. The percentage of the BMI 95th percentile score expresses the patient’s BMI as a percentage of the Centers for Disease Control and Prevention 95th percentile in age and sex-matched peers.

Daily Hunger Questionnaire

The daily hunger questionnaire (Figure 2) was administered to patients with no cognitive impairment (per the investigator’s judgment). Due to the unsuitability of using the hunger score tool in younger patients, this was administered only in patients greater than or equal to 12 years of age at baseline. The questionnaire assessed 3 aspects of hunger daily: average hunger in the last 24 hours, most or worst hunger in the last 24 hours, and morning hunger. Responses to the daily hunger questionnaire were recorded in an electronic diary. Each of the 3 items was scored separately (rather than combined) and averaged on a weekly basis.

In addition, hunger was assessed in patients aged 6 years to less than 12 years who were able to assess their own hunger using a pictorial (smiley face) version of the Likert rating scale, with scores from 0 to 4, where 0 = not hungry at all and 4 = hungriest possible. Data for this assessment were not reported because only a small number of patients completed this questionnaire.

In patients who were assessed as cognitively impaired, hunger was evaluated using | || || || || || || || || || || || || || |, a caregiver-completed questionnaire designed to assess behaviours associated with hunger in patients with | || || || || || || || || || | The | || || || was used in patients with BBS because there is no validated hunger assessment specifically for patients who have BBS with cognitive impairment, and patients with | || || | share many of the same obesity-related symptoms as those with BBS, including intense hunger.⁴² The | || || || was administered to caregivers of patients who were assessed as having cognitive impairment. The | || || || is a 10-item, observer-reported outcome measure designed by the sponsor to capture food-related behaviours commonly exhibited by people with | || || ||. As previously noted, the | || || || was used in patients with BBS because there is no validated hunger assessment tool specifically for patients with BBS who have cognitive impairment, and patients with | || | share many of the same obesity-related symptoms as those with BBS, including intense hunger.⁴²

Items 1 to 5 of the | || || || address behaviours that are commonly exhibited more than once in a 24-hour period. These items are answered using a 4-point ordinal response scale ranging from “never” to “more than 4 times.” Items 6 to 10 address behaviours that are less common and potentially indicative of more severe hyperphagia and/or food-seeking behaviour; these items are answered using a dichotomous response scale (i.e., yes or no).

Responses to Items 1 to 5 were assigned scores of 0 (never), 1 (1 to 2 times), 2 (3 to 4 times), or 3 (more than 4 times) over the past 24 hours. Responses to items 6 to 10 were assigned scores of 0 (no) or 3 (yes). A total score was created as the average of the nonmissing items multiplied by 10, yielding a range from 0 to 30, with higher scores suggestive of more severe hyperphagia and/or food-related behaviours. To create weekly scores, the nonmissing daily | || || || total scores were averaged across predesignated 7-day periods. If more than 3 daily total scores were missing, the weekly score was set to missing for that individual. A copy of the | || || || is shown here (Figure 3).

Impact of Weight on IWQoL-Lite

The IWQoL-Lite was administered to patients aged greater than or equal to 18 years without cognitive impairment. The IWQoL-Lite is a validated, 31-item, self-reported, obesity-specific, QoL questionnaire that provides a total score inclusive of 5 domains: physical function, self-esteem, sex life, public distress, and work. The questionnaire is responsive to weight loss and gain and sensitive to both treatment-seeking status and the degree of obesity.⁴³

Pediatric Quality of Life Inventory

The PedsQL was administered to children aged less than 18 years without cognitive impairment and their parent(s). The PedsQL Measurement Model is a validated modular approach to measuring HRQoL in healthy children and adolescents as well as those with acute and chronic health conditions. It is a 23-item reported measure with 4 domains: physical functioning, emotional functioning, social functioning, and school functioning. The total score is the mean score of the transformed items across the 4 domains. The PedsQL Measurement Model integrates both generic core scales and disease-specific modules into 1 measurement system, with instruments developed for children of specific age groups to self-report as well as parent proxies.^8,44 The age-appropriate instrument was administered for children aged less than18 years and their parent(s).

| || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || | || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || | || || || || || || || || || || || || || || || || || || || || || || || || || | | || || || || || || || || || | || || || || || || || || || || || || || || || || || || || || || || || || || || || || | || || || || || || || || || || || || || || || || || || || || || || || ||

Figure 2: Daily Hunger Questionnaire

Source: Summary of Clinical Evidence.³⁹

| || || || || | || || || || || || || || || || || || || || ||

Figure 3: Redacted

Figure was redacted upon at the sponsor’s request.

Source: Summary of Clinical Evidence.³⁹

Waist Circumference

Waist circumference (cm) was measured according to the National Heart, Lung, and Blood Institute criteria⁴⁶ at regular time points. It was measured at approximately the same time at each visit when patients were fasting, wearing light clothing, and had emptied their bladder.

Lipid Profile

Blood samples for lipid profiles were collected at regular time points when patients were in the fasted state. The lipid profile included total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides.

Safety Assessments

Safety in patients with BBS was assessed by evaluating TEAEs, SAEs, and treatment discontinuations. Safety in the combined population of patients with BBS and AS was also assessed through physical, skin, and vital signs examinations, electrocardiograms, and clinical laboratory testing.

Table 6: Summary of Outcome Measures and Their Measurement Properties

BBS = Bardet-Biedl syndrome; BMI = body mass index; HRQoL = health-related quality of life; IWQoL-Lite = Impact of Weight on Quality of Life – Lite; MID = minimal important difference; PedsQL = Pediatric Quality of Life Inventory.

Statistical Analysis

Sample Size and Power Calculation

The sample size for Study 023 was driven by the primary hypothesis and rarity of the patient population. The primary hypothesis was that the proportion of pivotal patients experiencing a weight reduction of greater than or equal to 10% at 52 weeks would be greater than a historical control rate of 10% (refer to the Historical Control Response Rate section).

Early clinical data (from a phase II trial, RM-493 to 014, Study 014) regarding setmelanotide revealed that the anticipated response rate was 66% in patients with BBS or AS.³⁹ Based on that response rate and a 1-sided alpha of 0.025, a sample of 7 patients would provide 91% power to detect a statistically significant difference versus the historical control rate. Nevertheless, to better understand the effect of setmelanotide in this rare patient population, the sponsor planned to enrol approximately 30 patients (including 6 patients with AS) for the pivotal cohort (i.e., all patients enrolled up to the sixth patient with AS), which ultimately included 38 patients (32 patients with BBS and 6 patients with AS).

A cohort of supplemental patients was added to the study protocol midcourse to gain additional treatment experience. The supplemental patients were not included in the primary analysis. Thus, a total of 52 patients were enrolled (44 with BBS and 8 with AS), including 14 supplemental patients. Note that the sample of patients with BBS included all 44 patients with BBS for the 14-week, double-blind, placebo-controlled period, but only 31 patients with BBS from the pivotal cohort had data to 52 weeks; thus, data from the 13 patients with BBS in the supplemental cohort were not included for the 52-week analyses. Pivotal patients were considered to have completed the study if they attended their week 66 visit, while supplemental patients were considered to have completed the study once they completed at least the week 24 visit, after which they were eligible to enrol in a separate LTE study (Study 022).

Historical Control Response Rate

CRIBBS (https://www.bbs-registry.org) is a global registry of patients with BBS that is housed at the Marshfield Research Center in Madison, Wisconsin and led by Dr. Robert Haws, principal investigator of the BBS cohort in Study 023. The registry aims to improve the understanding of BBS clinical features, progression, and management. Patients are assessed approximately once per year (during 1 to 4 annual visits), and data are collected through patient interviews, health provider assessments, and medical records. Approximately 500 patients with BBS from around the world have contributed data to the CRIBBS registry.

Rhythm Pharmaceuticals, Inc. received deidentified, individual patient data from the CRIBBS registry, including longitudinal body weight records, from 371 patients with BBS (aged 0 years to 68 years old, with approximately equal numbers of male and female patients). An analysis of baseline weight (i.e., at entry to the registry) showed that most adult patients with BBS were obese or extremely obese (43.1% and 32.1%, respectively), while only a small proportion were underweight or at normal weight (8.1%) (Table 7).

Table 7: Historical Obesity Data From Adult Patients (≥ 18 Years) With BBS in CRIBBS

BBS = Bardet-Biedl syndrome; BMI = body mass index; CRIBBS = Clinical Registry Investigating Bardet-Biedl Syndrome.

Source: Study 023 Clinical Study Report.⁹ Details in the table have been taken from the sponsor’s Summary of Clinical Evidence.

To estimate the historical control response rate within the pivotal population age group (≥ 12 years), data for 1-year changes in weight were collected for patients with BBS who were greater than or equal to 12 years old (i.e., 153 patients contributing 313 one-year periods for the analysis). After applying a response criterion of greater than or equal to 10% weight lost over a 1-year period, the historical control response rate was calculated to be 6.4% of patients (Table 8). Lower 1-year historical control response rates were observed when the analyses were broadened to patients with BBS who were greater than 6 years of age (i.e., ≥ 5% decrease = 11.5% of patients; ≥ 7.5% decrease = 6.9% of patients; ≥ 10% decrease = 5.2% of patients), which likely reflects the natural growth and weight gain of pediatric patients. Therefore, the historical control response rate was set conservatively (i.e., numerically higher than the CRIBBS estimate) at 10% of patients with BBS who were greater than or equal to 12 years of age achieving a greater than or equal to 10% decrease in body weight.

The CRIBBS data received by the sponsor did not include any information regarding significant efforts to lose weight, although patients with BBS and obesity are encouraged to control and lose weight through diet and exercise; pharmacological and surgical approaches are occasionally used. The protocol for Study 023 also prohibited active diet or weight-loss interventions.

Table 8: Historical Control Response Rates for Categorical Weight Loss Thresholds Over a 1-Year Period

Source: Study 023 Clinical Study Report.⁹ Details in the table have been taken from the sponsor’s Summary of Clinical Evidence.

Statistical Testing

The primary end point was the proportion of pivotal patients (i.e., all patients enrolled up to the sixth patient with AS; 32 patients with BBS and 6 patients with AS) aged greater than or equal to 12 years in the FAS who achieved a greater than or equal to 10% reduction in body weight after approximately 52 weeks of setmelanotide treatment.⁵⁶ The primary and secondary analyses considered all pivotal patients regardless of disease (i.e., including pivotal patients with BBS and pivotal patients with AS);⁵⁶ however, the sponsor conducted analyses of the BBS subpopulation in the same manner described herein, which is the primary focus of the review.⁵⁷

The primary analysis was conducted with an exact binomial test with a 1-sided, 0.025 significance level and a 2-sided, 95% CI calculated using the exact Clopper-Pearson method. No formal test of the difference between BBS and AS was planned, although separate efficacy estimates were planned. Due to the small target sample size, no formal statistical analyses were planned to adjust for possible covariate effects.

The study had several key secondary end points planned for which a prespecified step-down procedure was used to control type I error for the each of the following key secondary analyses:

• body weight percent change from baseline in patients greater than or equal to 12 years of age (mean percent change from baseline in body weight after approximately 52 weeks of treatment for patients in the FAS population)

• daily hunger score percent change from baseline in patients greater than or equal to 12 years of age (mean percent change from baseline in the weekly average of daily hunger scores after approximately 52 weeks of treatment for patients in the FAS population)

• daily hunger score reduction (threshold of 25%) in patients greater than or equal to 12 years of age (the proportion of patients in the FAS population who achieve a greater than or equal to 25% improvement from baseline in the weekly average of the daily hunger score after approximately 52 weeks of treatment).

However, this hierarchical testing procedure was specified for the primary analysis of the original study; thus, it cannot be applied to the posthoc analysis of patients with BBS, who are the focus of this review.

Additional secondary end points (body weight percent change from baseline at 14 weeks and daily hunger score percent change from baseline at 14 weeks) were analyzed in a similar manner. Exploratory end points, including PROs, were summarized using descriptive statistics and analyzed similarly to the primary, key secondary, and secondary end points as appropriate.

Because of the placebo-controlled period, analyses based on approximately 52 weeks of setmelanotide treatment used the active treatment baseline, which was defined as the last available measurement before the first dose of setmelanotide. It is important to note that as a result, pivotal patients randomized to receive placebo during the first 14-week period would not reach 52 weeks of active treatment until approximately week 66; some of these patients had not completed their week 66 visit at the time of the primary analysis. Therefore, the primary analysis included multiple imputation (linear mixed-effect model) to impute the weight measurements to a time point of approximately 52 weeks for patients with less than 52 weeks of active setmelanotide treatment. The final multiple imputed datasets were analyzed using Rubin’s rule.

The same multiple imputation approach was also performed for patients with missing values for reasons not related to study design (e.g., loss to follow-up, early dropout or discontinuation, missed visits). However, these imputed values were then set to the baseline value (i.e., no treatment effect) for the primary analysis, key secondary analyses, and exploratory analyses that were similar to the primary and key secondary analyses. A sensitivity analysis was planned, using the imputed values (i.e., no baseline replacement). For secondary and exploratory end points that were not similar to the primary or key secondary analyses, the imputed values were included in the analyzed dataset and were not replaced with the baseline values.

Subgroup Analyses

Formal subgroup analyses of the pivotal patient group (i.e., patients ≥ 12 years of age in the FAS) were not planned, given the small sample size of the study. However, separate descriptive statistics were provided according to the stratification factors (i.e., ≥ 12 years of age or less, BBS or AS). A separate report was also generated to describe the findings in patients with BBS as a posthoc analysis.

Analysis Populations

Analysis sets are summarized in Table 9.

Table 9: Data Sets Used for the Analyses in Study 023

AS = Alström syndrome; BBS = Bardet-Biedl syndrome; DUS = designated use set; FAS = full analysis set; PCS = placebo-controlled set; SAS = safety analysis set.

Source: Study 023 Clinical Study Report.⁹ Details in the table have been taken from the sponsor’s Summary of Clinical Evidence.

Table 10: Statistical Analysis of Efficacy End Points in Study 023

AG = active growth analysis set; ATB = active treatment baseline; CS = completers’ set; DUS = designated use set; FAS = full analysis set; PCPB = placebo-controlled period baseline; PCS = placebo-controlled analysis set; PPS at EOP1 = per-protocol set at end of period 1; PPS at EOP2 = per-protocol set at end of period 2; SH = stable height; vs. = versus.

Note: Multiplicity adjustment was not required for the primary analysis (a single primary end point) and was not used for secondary end points because of the rarity of the diseases and the small, expected sample size. Nominal P values were used to interpret each end point separately, although a step-down procedure (hierarchical order of testing) was prespecified to control type I error if needed.

^aSubgroup analyses were also performed for patients less than 12 years of age as well as patients with BBS and patients with AS.

Source: Study 023 Clinical Study Report.⁹ Details in the table have been taken from the sponsor’s Summary of Clinical Evidence.

Results

Patient Disposition

A total of 60 patients with BBS or AS were screened, and 8 patients failed screening; among patients with BBS, 51 patients were screened and 44 were randomized to setmelanotide (N = 22) or placebo (N = 22). Reasons for screening failure were not identified in the Clinical Study Report.

Among patients with BBS, trial discontinuation was observed for 2 patients (9.1%) who were randomized to receive setmelanotide and for 6 patients (27.3%) who were randomized to receive placebo. One patient with BBS who was randomized to receive placebo discontinued the trial during the placebo-controlled, double-blind period and before completing active treatment baseline assessments. Therefore, this patient was included in the analyses of the placebo-controlled period, but not in the FAS for the approximately 52-week efficacy analyses.

Pivotal patients were considered to have completed the study if they attended their week 66 visit, while supplemental patients were considered to have completed the study once they had completed at least the week 24 visit, after which they were eligible to enrol in a separate LTE study (Study 022). Among patients with BBS, 90.9% of patients randomized to setmelanotide and 72.7% of those randomized to placebo completed the study.

Table 11: Summary of Patient Disposition for Patients With BBS From Study 023

AE = adverse event; BBS = Bardet-Biedl syndrome.

^aSupplemental patients were considered completed if they enrolled in the extension trial; however, these 2 patients enrolled in the extension trial and were counted as discontinued.

Source: Clinical Study Report of patients with BBS from Study 023.¹⁰ Details in the table have been taken from the sponsor’s Summary of Clinical Evidence.

Baseline Characteristics

The baseline characteristics outlined in the following table are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results. Population sets included are the SAS (which includes both patients with BBS and patients with AS) and the cohort of patients with BBS (pivotal alone as well as pivotal plus supplemental) to reflect the various populations considered in the efficacy and safety results.

Among patients with BBS, a greater proportion were female in the placebo group (15 patients of 22 patients [68.2%]) than the setmelanotide group (9 patients of 44 patients [40.9%]). At the placebo-controlled baseline, the placebo group was slightly older than the setmelanotide group in terms of mean age. Weight, height, race, and BMI were similar at the placebo-controlled baseline between the 2 arms. There were more cognitively impaired patients in the placebo arm (14 patients of 22 patients [63.5%]) compared to the setmelanotide arm (10 patients of 22 patients [45.5%]).

Table 12: Summary of Baseline Characteristics in Study 023

AS = Alström syndrome; ATB = active treatment baseline; BBS = Bardet-Biedl syndrome; BMI = body mass index; PCPB = placebo-controlled period baseline; NA = not applicable; SD = standard deviation.

^aCalculated for 36 patients in the pivotal group with ATB data.

Sources: Study 023 Clinical Study Report;⁹ the report of patients with BBS from Study 023;¹⁰ the sponsor’s response to the CADTH request for additional information.⁵⁷ Details in the table have been taken from the sponsor’s Summary of Clinical Evidence.

Exposure to Study Treatments

Treatment exposure is summarized for the double-blind, placebo-controlled treatment period in Table 13 and for the full study period in Table 14. The median total setmelanotide exposure was 258 mg over the 14-week, double-blind, placebo-controlled period. Similar numbers of doses were administered during that period in the setmelanotide and placebo groups. The median total setmelanotide exposure during the full study was | || || || || || || | for all patients and for patients with BBS. During the study period, 5 patients had dose reductions (setmelanotide = 2 patients; placebo = 3 patients) after discussion with and approval by the sponsor. However, 4 of these patients resumed the full 3.0 mg dosage following a brief reduction. All patients with BBS were titrated to a therapeutic dose of 3 mg daily.

Medications for treating general obesity (e.g., orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion) were not allowed within 3 months of randomization and were prohibited during the study. Use of a GLP1 receptor agonist was permitted up to the dose approved for the treatment of diabetes mellitus as long as 4 conditions were met: it was not prescribed for the treatment of obesity; the dose had been stable for at least 3 months before randomization; the patient had not experienced weight loss during the previous 3 months; and the patient intended to keep the dose stable throughout the course of the study. One patient (1.9% of the SAS population) who was initially randomized to the setmelanotide group in the supplemental cohort had received semaglutide (a GLP1 receptor agonist) as a prior or concomitant medication (not specified in the Clinical Study Report).

Table 13: Redacted

| || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || |

| || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || |

Source: Study 023 Clinical Study Report.⁹ Details in the table have been taken from the sponsor’s Summary of Clinical Evidence.

Table 14: Redacted

| || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || |

| || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || | || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || | || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || |

Source: Study 023 Clinical Study Report.⁹ Details in the table have been taken from the sponsor’s Summary of Clinical Evidence.

Table 15: Prior and Concomitant Medications Used Throughout Study 023 by Patients With BBS or AS (> 10% of Total Patients)

AS = Alström syndrome; BBS = Bardet-Biedl syndrome.

Source: Study 023 Clinical Study Report.⁹ Details in the table have been taken from the sponsor’s Summary of Clinical Evidence.

At least 1 concomitant procedure was performed for 44% of patients (n = 23 patients of 52 patients) in the SAS population (setmelanotide = 37% [n = 10 patients of 27 patients]; placebo = 52% [n = 13 patients of 25 patients]). The only concomitant procedures performed for greater than 10% of patients were limb operations (11.5%; n = 6 patients of 52 patients). No patients underwent any form of bariatric surgery before or during the study.

No subsequent treatment was mandated after patients completed their setmelanotide treatments.

Efficacy

Primary End Point: Proportion of Patients Achieving a Reduction in Body Weight Greater Than or Equal to 10% After 52 Weeks of Setmelanotide

Among pivotal patients with BBS (N = 28), 35.7% (95% CI, 18.6% to 55.9%) had a greater than or equal to 10% reduction in body weight after 52 weeks of setmelanotide treatment, as measured from the active treatment baseline. Results were similar when considering both pivotal and supplemental patients with BBS. The numbers achieving this in both groups exceeded the prespecified assumption that 10% of patients with BBS would achieve a body weight reduction of greater than or equal to 10% without treatment.

Table 16: Proportion of Patients (Aged ≥ 12 Years) With Greater Than or Equal to 10% Reduction in Body Weight After 52 Weeks of Setmelanotide Treatment

BBS = Bardet-Biedl syndrome; CI = confidence interval.

^aThe estimated percentage, 95% CI, and P value are based on Rubin's Rule. The P value is 1-sided, based on testing the prespecified assumption of 10% of patients with BBS achieving a greater than or equal to 10% reduction in body weight without treatment. Multiplicity adjustment was not conducted. Values are from the posthoc analysis of BBS patients and should be used for descriptive purposes only.

^bSix patients (19.35% of the full pivotal population, 21.42% of pivotal BBS population) had missing measurements at 52 weeks due to study discontinuation and were conservatively considered to have treatment failure.

^cN value provided by sponsor in response to CADTH request for additional information.⁵⁸

Sources: Study 023 Clinical Study Report⁹ and the report of patients with BBS from Study 023.¹⁰

Key Secondary End Point: Mean Percent Change in Body Weight After 52 Weeks of Setmelanotide

At 52 weeks, the mean and percent changes in weight among pivotal patients with BBS (N = 28) were −7.24 kg (SD = 8.208 kg; 95% CI, −10.60 kg to −4.24 kg) and −6.47% (SD = 6.970%; 95% CI, −9.17% to −3.77%), respectively. Results considering both pivotal and supplemental patients were similar. Both were greater than the background assumption of no treatment effect in untreated patients with BBS.

Key Secondary End Point: Mean Percent Change in Weekly Average of the Daily Hunger Score After 52 Weeks of Setmelanotide

Among pivotal patients aged greater than or equal to 12 years with BBS and no cognitive impairment (N = 14), the mean percent change in hunger score after 52 weeks of setmelanotide treatment was −31.80% (95% CI, −48.81% to −14.79%). Similar results were observed among the group of pivotal plus supplemental patients with BBS for most or worst hunger over 24 hours and for morning hunger scores (Table 18).

Based on a psychometric analysis of the Study 023 data, which was conducted as recommended in US FDA PRO guidance documents, a 1-point to 2-point reduction (i.e., a 10% to 20% reduction) for the most or worst hunger score was considered a meaningful within-patient reduction by the sponsor. Among pivotal patients with BBS in Study 023 (aged ≥ 12 years old without cognitive impairment), 71.4% of patients experienced a greater than or equal to 1-point reduction, and 42.9% of patients experienced a greater than or equal to 2-point reduction.

Table 17: Body Weight Change and Percent Change From ATB in Patients (Aged ≥ 12 Years) After 52 Weeks of Setmelanotide Treatment

ATB = active treatment baseline; BBS = Bardet-Biedl syndrome; CI = confidence interval; SD = standard deviation.

^aSix patients (19.35%) had missing measurements at 52 weeks due to study discontinuation. Their percent change was considered as 0.

^bThe P value is 1-sided, based on Rubin’s rule testing the assumption of no change from baseline. Multiplicity adjustment was not conducted. Values are from the posthoc analysis of BBS patients and should be used for descriptive purposes only.

Sources: Study 023 Clinical Study Report⁹ and the report of patients with BBS from Study 023.¹⁰

Key Secondary End Point: Proportion of Patients Achieving a Greater Than or Equal to 25% Improvement in the Weekly Average of Daily Hunger Scores After 52 Weeks of Setmelanotide

An estimated 57.1% (95% CI, 28.9 to 82.3) of pivotal patients with BBS (aged ≥ 12 years old without cognitive impairment; N = 14) achieved a greater than or equal to 25% improvement in the weekly average | || || || || || || || || || || || (most or worst score over 24 hours, | || || || || || || || || || || || || || || || || || || || | after 52 weeks of setmelanotide treatment (Table 18).

Secondary End Point: Mean Percent Change From Baseline in Body Weight After 14 Weeks of Setmelanotide Compared With Placebo

In the placebo-controlled analysis of pivotal patients with BBS aged greater than or equal to 12 years, those receiving setmelanotide (N = 14) had an estimated reduction in mean body weight compared to patients receiving placebo (N = 15) (difference = −3.81 kg; 95% CI, −7.03 kg to −0.58 kg). Patients receiving setmelanotide also had a greater mean body weight percent change than those receiving placebo (difference = −2.96%; 95% CI, −5.65% to −0.26%). | || || || || || || || || || || || || || || || || || || || || || || || || || || || |

Notably, patients receiving placebo had very little change in body weight over the 14-week RCT period (mean = −0.21 kg or −0.25% in the pivotal cohort of patients with BBS, | || || || || || || || || || || || || || || || || || || || || |).

Table 18: Change in the Weekly Average of Daily Hunger Score From ATB After 52 Weeks of Setmelanotide Treatment Among Patients (Aged ≥ 12 Years) Without Cognitive Impairment

ATB = active treatment baseline; BBS = Bardet-Biedl syndrome; CI = confidence interval; SD = standard deviation.

^aThe estimated percentage, 95% CI, and P values are based on Rubin’s rule. The P values for change and percent change were testing the assumption of no change from baseline; the key secondary end point (percent change after 52 weeks) was analyzed first in the prespecified hierarchy at alpha = 0.025. The P values for the proportion of patients achieving a greater than or equal to 25% improvement were calculated against a reference value of 10%. Multiplicity adjustment was not conducted. Values are from the posthoc analysis of BBS patients and should be used for descriptive purposes only.

^bIf there were missing measurements after 52 weeks, a multiple imputation model was used to impute the measurements for patients with fewer than 52 weeks of setmelanotide treatment to a time point that approximated 52 weeks of setmelanotide treatment.

^cIf there were missing measurements after 52 weeks due to a reason other than study design, the patient was considered to have failed treatment.

^dThree patients (18.75%) had missing measurements at 52 weeks due to study discontinuation and were considered to have a percent change of 0.

Sources: Study 023 Clinical Study Report⁹ and the report of patients with BBS from Study 023.¹⁰

Table 19: Body Weight Change and Percent Change From Placebo-Controlled Period Baseline After 14 Weeks of Treatment

BBS = Bardet-Biedl syndrome; CI = confidence interval; PCPB = placebo-controlled period baseline; SD = standard deviation.

Note: P values were calculated for each end point without adjustment for multiplicity.

^aDifference, 95% CI of difference, and P value are based on Rubin’s rule, and difference is calculated as setmelanotide minus placebo. Multiplicity adjustment was not conducted. Values are from the posthoc analysis of BBS patients and should be used for descriptive purposes only.

^bIf there were missing measurements after approximately 14 weeks, a multiple imputation model was used to impute the measurements for patients with fewer than approximately 14 weeks of setmelanotide or placebo treatment to a time point that approximated 14 weeks of setmelanotide or placebo treatment.

Sources: Study 023 Clinical Study Report⁹ and the report of patients with BBS from Study 023.¹⁰

Secondary End Point: Mean Percent Change in the Weekly Average of the Daily Hunger Score After 14 Weeks of Setmelanotide Treatment in Comparison to Placebo

Pivotal patients with BBS treated with setmelanotide (N = 5) had an estimated reduction in hunger score compared with patients treated with placebo (N = 9) in | || || || || || || || || || || || || || | and in most or worst hunger over 24 hours (percent change) (Table 20). However, results were inconclusive for some metrics of hunger due to wide 95% CIs that included the null value: | || || || || || || || || || || || || || || || || most or worst hunger over 24 hours (mean change) and | || || || || || || || || || || || || || |

Table 20: Change in the Weekly Average of Daily Hunger Score From Placebo-Controlled Period Baseline After 14 Weeks Among Patients (Aged ≥ 12 Years) With No Cognitive Impairment in Placebo-Controlled Analysis

AS = Alström syndrome; BBS = Bardet-Biedl syndrome; CI = confidence interval; pcgh = percent change; PCPB = placebo-controlled period baseline; SD = standard deviation.

Notes: PCPB is the placebo-controlled period baseline, defined as the last available measurement before the first dose of setmelanotide or placebo.

If there were missing measurements after approximately 14 weeks, a multiple imputation model was used to impute the measurements for patients with fewer than approximately 14 weeks of setmelanotide or placebo treatment to a time point that approximated 14 weeks of setmelanotide or placebo treatment. One patient (5.88%) had missing measurements at 52 weeks due to study discontinuation. Their values were imputed.

^aThe 95% CI of the mean is based on Rubin’s rule. If no imputation is needed for a given treatment, then the 95% CI of the mean reflects an observed CI.

^bThe difference, 95% CI of difference, and P value are based on Rubin’s rule, and the difference is calculated as setmelanotide minus placebo. The null hypothesis (H₀) to be tested is that the mean difference in daily hunger scores (calculated as setmelanotide minus placebo) is greater than or equal to 0. The alternative hypothesis (H₁) is that the percent change is less than 0 (i.e., H₀ pchg ≥ 0 vs. H₁ pchg < 0). The P value is 1-sided. Values are from the posthoc analysis of patients with BBS and should be used for descriptive purposes only.

Sources: Study 023 Clinical Study Report⁹ and the report of patients with BBS from Study 023.¹⁰

Exploratory End Points: QoL

QoL assessments were conducted in patients with BBS without cognitive impairment. Assessment tools varied by age: IWQoL-Lite scores were reported for patients greater than or equal to 18 years old, PedsQL scores for patients less than 18 years old, and | || || for patients greater than or equal to 16 years old.

Adult patients assessed using the IWQoL-Lite (N = 11) had a 12.0-point mean total score improvement from the active treatment baseline to 52 weeks of setmelanotide treatment (Table 21). At the active treatment baseline, the mean total score was 74.9 (SD = 12.6), which falls within the range of moderate impairment (i.e., 71.9 to 79.4) and is much lower than seen in comparative populations without obesity (94.7; SD = 7.6).² Of the assessed patients, 8 of 11 (72.7%) had impaired HRQoL at baseline according to the IWQoL-Lite, and 5 of these patients (62.5%) experienced improvement in their IWQoL-Lite scores over 52 weeks; the remaining 3 had stable IWQoL scores over 52 weeks.

Pediatric patients assessed using the PedsQL (N = 9) had a 11.2-point mean total score improvement from the active treatment baseline to 52 weeks of setmelanotide treatment (Table 21). At the active treatment baseline, the mean total score was 67.2 (SD = 20.1), which is beneath the threshold of 68.2 points that is indicative of impairment.³¹ Of the assessed patients, 4 patients of 9 patients (44.4%) had impaired HRQoL at baseline, according to the PedsQL, and each of the 4 patients experienced improved scores after 52 weeks of setmelanotide.

Patients aged greater than or equal to 16 years assessed using | || || || (N = 13; Table 21) reported some improvements (decreases) in | || || || health state scores from the active treatment baseline to 52 weeks of treatment, with the greatest improvements seen in the scores for mobility and usual activities. No improvement or worsening was seen in self-care scores. Scores for pain and/or discomfort worsened (i.e., increased).

Table 21: Change in QoL Assessment Scores From the Active Treatment Baseline to Week 52 in Pivotal Patients With BBS Without Cognitive Impairment

ATB = active treatment baseline; BBS = Bardet-Biedl syndrome; | || || || || || || || || || || || || || |; IWQoL-Lite = Impact of Weight on Quality of Life – Lite; PedsQL = Pediatric Quality of Life Inventory; QoL = quality of life; SD = standard deviation, VAS = visual analogue scale.

^aHigher scores represent higher QoL (range = 0 to 100, where 100 = best QoL).

^bHigher scores represent higher QoL (range = 0 to 100, where 100 = best QoL).

^c| || || || || || || |, lower scores represent higher QoL (range = 1 to 5, where 5 = extreme problems). However, in VAS, higher scores represent higher QoL (range = 0 to 100, where 100 = best QoL).

Sources: Study 023 Clinical Study Report⁹ and the report of patients with BBS from Study 023.¹⁰

Subgroup and Sensitivity Analyses

Pivotal Patients With BBS, All Ages

Among | || || || || || || || || || || || || || || || || || || || || |, after 52 weeks of setmelanotide treatment, the mean BMI change from the active treatment baseline was | || || || || || || || || || || || || || || || || || || and the mean percent change in BMI was | || || || || || || || || || || || || || | After the 14-week, double-blind, placebo-controlled period, patients treated with setmelanotide had a decrease in BMI relative to patients assigned to placebo | || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || |

Pediatric Patients With BBS Aged Less Than 12 Years

There were 8 patients aged less than 12 years with BBS in Study 023. | || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || |

Including all patients aged from greater than or equal to 6 years to less than 12 years with either AS or BBS, during the 14-week placebo-controlled period, those treated with setmelanotide (N = 6) | || || || || || || || || || || || || || || || || || || || || | compared to placebo-treated patients (N = 5) in the same age group.

Patients With BBS Aged Less Than 18 Years

Among pivotal patients with BBS who were less than 18 years of age (N = 14 to 16), the mean BMI z score dropped by 0.75 points ± 0.46 points (95% CI, −1.02 to −0.49) after 52 weeks of setmelanotide treatment. Of these patients, after 52 weeks of setmelanotide treatment, 85.7% achieved a 0.2-point reduction, and 71.4% achieved a 0.3-point reduction in BMI z score. Mean BMI fell by 3.36 kg/m² ± 2.07 kg/m² (95% CI, −4.55 kg/m² to −2.16 kg/m²), and percent BMI dropped by 9.50 ± 6.44% (95% CI, −13.22 to −5.78). Additionally, there was a reduction in the percentage of patients with BMI 95th percentile scores (−17.30 ± 7.67%; 95% CI, −21.73 to −12.87). This change reflects a shift from class 3 (high-risk) obesity (≥ 140% of the 95th percentile) to class 2 (moderate-risk) obesity (120% to < 140% of the 95th percentile).⁵⁹

During the 14-week, placebo-controlled period, among pivotal patients with BBS aged less than 18 years (N = 22), treatment with setmelanotide was associated with | || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || |

Pivotal Patients With BBS Greater Than or Equal to 18 years of Age

Among pivotal patients with BBS who were greater than or equal to 18 years of age (N = 15), an estimated 60% (95% CI, 32.3% to 83.7%) achieved a greater than or equal to 5% reduction in body weight, and an estimated 46.7% (95% CI, 21.3% to 73.4%) achieved a greater than or equal to 10% reduction in body weight after 52 weeks of setmelanotide treatment. The mean weight change was −9.42 kg ± 9.39 kg (95% CI, −14.63 kg to −4.22 kg) and mean percent weight change was −7.57% ± 7.13% (95% CI, 11.52% to −3.62%). The mean change in BMI was −4.22 kg/m² ± 3.34 kg/m² (95% CI, −6.34 kg/m² to −2.10 kg/m²), and the mean percent BMI change was −9.09% ± 6.76% (95% CI, −13.39% to −4.80%).

During the 14-week placebo-controlled period, patients assigned to setmelanotide had | || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || placebo-treated patients achieved greater than or equal to 5% weight loss.

Hunger Assessments in Cognitively Impaired Patients With BBS

Hunger was also assessed in cognitively impaired patients (aged ≥ 12 years). These assessments were done by caregivers using the | || || || || because there is no validated hunger assessment for this population, and | || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || |.There is no known MID for patients with BBS.

Harms

Refer to Table 22 for the summary of harms in Study 023 among patients with BBS and AS, and Table 23 for data pertaining to the most common harms (≥ 5%) in patients with BBS.

In Study 023, the safety analysis population (SAS) consisted of all patients who received at least 1 dose of the study drug (i.e., placebo or setmelanotide), with results reported for the 14-week, placebo-controlled, double-blind period and full study period. All AEs were coded using the Medical Dictionary for Regulatory Activities system organ class and graded by the investigators using the National Cancer Institute Common Terminology Criteria for Adverse Events.

The definition of a TEAE was any AE with onset after the first administration of study medication through the end of the study (i.e., 28 days after the last dose administered); any event that was present at baseline, but worsened in intensity or was considered drug-related by the investigator by the end of the study; or any event that was deemed related to study drug exposure. In the AE calculations, each patient contributed only once (i.e., the most related occurrence or the most intense occurrence) to each of the incidence rates in the descriptive analysis, regardless of the number of episodes.

No AEs of special interest were prespecified in the protocol. However, the sponsor recognized events that were appropriate for special monitoring, including injection-site reactions, skin hyperpigmentation, and sexual events (male or female). Additional AEs identified by clinical experts as AEs of special interest are also discussed in the Notable Harms section.

Adverse Events

During the 14-week, placebo-controlled period in patients with either BBS (n = 44) or AS (n = 8), 26 of 27 (96.3%) setmelanotide-treated patients and 24 of 25 (96.0%) placebo-treated patients experienced at least 1 TEAE. In the overall study period, 100% of patients experienced at least 1 TEAE (Table 22). Results were similar in the BBS subpopulation (Table 23). The most common TEAEs were injection-site reactions (erythema, pruritus, bruising, induration, pain), skin hyperpigmentation, nausea, vomiting, and diarrhea.

Rates of injection-site reactions were similar between the treatment groups during the 14-week, placebo-controlled period.

There were also similar rates of nausea between the setmelanotide-treated patients (25.9%) and placebo-treated patients (24.0%), although vomiting was observed only in patients treated with setmelanotide (25.9%). Among all patients, nausea and vomiting tended to occur soon after starting setmelanotide treatment, and most events were mild or moderate in severity. These events were infrequent after the first month of setmelanotide treatment. No events of severe nausea or severe vomiting occurred among all patients.

| || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || |

Figure 4: Redacted

Figure redacted upon on sponsor request.

Source: Summary of Clinical Evidence.³⁹

Serious Adverse Events

SAEs were uncommon. During the 14-week, placebo-controlled period in patients with BBS or AS, 1 patient randomized to setmelanotide (3.7%) and 2 patients randomized to placebo (5.8%) experienced at least 1 SAE. In the setmelanotide-treated patient, the SAE was anemia caused by gynecological bleeding, which was judged by the investigator to be related to the initiation of oral contraceptives. In the patients treated with placebo, the SAEs were blindness and anaphylactic reaction.

Over the full study period in patients with BBS or AS, a total of 3 patients (5.8%) experienced at least 1 SAE, which included the previously described events in addition to 2 events of suicidal ideation. Of the 3 patients with SAEs, 1 patient experienced both blindness and 2 events of suicidal ideation that resolved without a change in study medication. These were considered by the investigator to be attributable to concomitant disease.

Withdrawals Due to Adverse Events

During the 14-week, placebo-controlled period in patients with BBS or AS, 2 patients randomized to setmelanotide (7.4%) and 3 patients assigned to placebo (12.0%) withdrew due to any TEAE. The TEAEs leading to withdrawal in setmelanotide-treated patients were nausea, vomiting, ocular hyperemia, and face edema. In placebo-treated patients, the TEAEs were nausea, anaphylactic reaction, headache, acne, hidradenitis, and hot flush. Similar rates of treatment discontinuation due to nausea were observed in the setmelanotide group (3.7%) and placebo group (4.0%) during the placebo-controlled phase, while 1 patient (3.7%) in the setmelanotide group and 0 in the placebo group discontinued treatment due to vomiting.

Over the full study period in patients with BBS or AS, a total of 6 patients withdrew due to any TEAE. These included the previously listed TEAEs with the addition of skin hyperpigmentation and abdominal pain.

Mortality

No deaths were observed.

Notable Harms

Although no AEs of special interest were prespecified in the trial protocol, the sponsor conducted in-depth evaluation of injection-site reactions, hyperpigmentation, and sexual events.

Similar rates of injection-site reactions were observed between the setmelanotide and placebo groups during the double-blind period, which suggests that these reactions were related to the injection and/or excipients (i.e., not to the setmelanotide, but to the mPEG-DSPE vehicle). Results were consistent between the full population (i.e., BBS and AS) and the BBS subpopulation.

Hyperpigmentation events (e.g., changes in skin tone, new mole development, and changes in an existing mole) occurred with setmelanotide treatment during the double-blind period (63.0% versus 0% with placebo) and in the full study period (63.5%) in patients with BBS or AS. Consistent results were observed between the full study population and among the patients with BBS. Just 1 patient (1.9%) discontinued treatment because of hyperpigmentation during the full study period. There were no reports of melanoma related to the observed hyperpigmentation in clinical trials of setmelanotide, including Study 023.

| || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || |. None of the male patients experienced priapism (prolonged or painful erection) that required intervention.

Additional notable harms to consider, as recommended by experts consulted by CADTH, were suicide attempts, depression or depressed mood, anxiety, anaphylaxis, bradycardia, cold abscess at the injection site, aggression, and sexually inappropriate behaviours. There were no suicide attempts recorded during the study. Depression and depressed mood each occurred in 1 patient over the full study period (1 patient who was initially randomized to placebo and another who was initially randomized to setmelanotide). Anxiety was not reported. Anaphylaxis occurred in 1 placebo-treated patient during the double-blind period, as previously described. Bradycardia was not reported. Abscesses occurred in 2 patients over the study period, but these were not specified as cold abscesses, and the location of the occurrences was not specified. Aggression occurred in 3 patients. Finally, sexually inappropriate behaviour occurred in 1 patient over the full study period.

Table 22: Summary of Harms in Study 023 (SAS, BBS and AS)

AE = adverse event; AS = Alström syndrome; BBS = Bardet-Biedl syndrome; NR = not reported; SAE = serious adverse event; SAS = safety analysis set; TEAE = treatment-emergent adverse event.

^aStudy drug permanently withdrawn.

Sources: Study 023 Clinical Study Report⁹ and the report of patients with BBS from Study 023.¹⁰ Details in the table have been taken from the sponsor’s Summary of Clinical Evidence.

Table 23: Summary of Harms Occurring in Greater Than or Equal to 5% of All BBS Patients (Double-Blind, Placebo-Controlled Period and Full Study)

BBS = Bardet-Biedl syndrome; TEAE = treatment-emergent adverse event.

Sources: Study 023 Clinical Study Report⁹ and the report of patients with BBS from Study 023.¹⁰ Details in the table have been taken from the sponsor’s Summary of Clinical Evidence.

Critical Appraisal

Internal Validity

Study 023, the only study included in this review, was a phase III, multicentre study that consisted of a 14-week, randomized, placebo-controlled, double-blind period followed by a 52-week, open-label, single-arm period. The original study protocol and all key primary and secondary outcomes were designed to include patients with either AS or BBS. To reflect the requested reimbursement criteria, all efficacy outcomes considered in this report were posthoc reanalyses based solely on the subgroup of patients with BBS, who comprised the majority of the overall population. The results of the posthoc analysis were consistent with the results of the prespecified analyses in the FAS. Although the population size was small, BBS is a rare disease with a small patient population, and the sample size exceeded the minimum power calculation conducted by the sponsor.

The primary and secondary outcomes pertained to the 52-week, single-arm period, while some exploratory outcomes were evaluated in the context of the 14-week, placebo-controlled period. It is important to note that for 52-week outcomes, the baseline values were selected at the active treatment baseline as opposed to the baseline of enrolment in the trial; as such, for patients initially randomized to placebo, the active treatment baseline would have been at the end of the initial 14-week, placebo-controlled period. Therefore, patients randomized to placebo would also require an evaluation at approximately week 66 of the trial to reach approximately 52 weeks of setmelanotide treatment; multiple imputation was used for patients who had not reached this time point. The approaches taken to handling missing data were considered to be appropriate and potentially conservative. While a step-down procedure (i.e., a hierarchical order of testing) was prespecified to control for type I error in the original study, this procedure would not apply to the posthoc analysis of patients with BBS. As a result, all results from these analyses must be interpreted with consideration for the potential risk of increased type I error. Due to the small target sample size, no formal statistical analyses were planned to adjust for possible covariate effects.

There are inherent risks of bias, confounding, and uncertainty due to the open-label and single-arm design of the study. However, BBS is a rare disease with a small patient population for which there are no other targeted pharmacotherapies. Single-arm data are limited in the estimation of treatment effects due to unidentified, uncontrolled prognostic factors (e.g., age, weight, severity of hyperphagia, and BBS genotype). The open-label design of the single-arm period increases the risk of detection bias and performance bias, and may lead to an overestimation of the treatment effect in subjective outcomes, such as the hunger surveys. The duration of treatment for this period was considered by CADTH clinical experts to be appropriate for evaluating weight loss and hyperphagia. However, longer-term data are also needed, given that obesity is a long-term, chronic, relapsing condition.

The key outcomes assessed during the 52-week, single-arm period included metrics of weight loss and hunger, with additional exploratory outcomes pertaining to HRQoL and metrics of metabolic health. The primary outcome of Study 023 was the percentage of patients aged at least 12 years who achieved a greater than or equal to 10% reduction in body weight after 52 weeks of active treatment, which was compared against an assumption of 10% response without treatment. The threshold of greater than or equal to 10% reduction in body weight exceeds the MID identified by the clinical experts (5% to 7%) in obesity management. The threshold of 10% for the response rate was also agreed to be conservative. It was based on historical control data illustrating that fewer than approximately 7% of patients with BBS lost greater than or equal to 10% of their body weight over a 3-year period in a heterogenous, real-world population. These real-world patients may also have been engaged in intensive weight loss activities or receiving interventions that would have been disallowed in Study 023, which further supports the view that the threshold was conservative.

The measurement of hunger was based on daily hunger questionnaires designed by the sponsor, and the estimation of MIDs was conducted using data from the same trial. As such, the questionnaire and its MIDs are not externally validated for validity, reliability, and responsiveness, which limits the interpretability of these results. Statistical analyses were performed against an assumption of no response without treatment; while it is clinically plausible that hunger does not spontaneously resolve in patients with BBS, the measurement of subjective outcomes in single-arm trials is nonetheless confounded by the placebo effect, which may introduce bias leading to overestimation of the treatment effect; as such, the lack of control arm limits interpretability. The clinical experts consulted by CADTH considered the relatively high proportion of patients achieving a 25% improvement in hunger on setmelanotide treatment at 52 weeks to be an encouraging result, but they did not have specific experience with this or other hunger-related questionnaires in clinical practice.

During the 14-week, placebo-controlled period, randomization and concealment were carried out appropriately, and maintenance of blinding was preserved during the transition to the open-label phase by re-escalating patients to setmelanotide after week 14 regardless of their initial randomization. Treatment with placebo or setmelanotide during the RCT was administered in the same manner, with indistinguishable, clear, colourless to opalescent solutions in identical vials; the placebo formulation had similar excipients to the active formulation. However, hyperpigmentation occurred in more than half of setmelanotide-treated patients and in no placebo-treated patients, which may have allowed patients or clinicians to guess treatment assignments. Similarly, vomiting occurred in more than a quarter of setmelanotide-treated patients, but in no placebo-treated patients during the placebo-controlled period, and again in more than a third of patients who had been initially randomized to placebo when they transitioned to setmelanotide during the single-arm period; this also may have unblinded patients or clinicians to their initial randomization.

The baseline and disease characteristics between treatment groups were considered by clinical experts consulted by CADTH to be reasonably similar to 1 another; the observed differences in the proportion of females between the active and placebo groups were not considered to confound the treatment effect. While differences in the proportion of patients with cognitive impairment were also not expected to confound the treatment effect, these did further reduce the available sample size for outcomes — such as the key secondary hunger-related metrics that excluded patients with cognitive impairment — due to the practical limitations of assessing PROs in cognitively impaired populations. The duration of the 14-week, placebo-controlled period has inherent limitations for the assessment of weight loss; however, it was considered appropriate for the assessment of reductions in hyperphagia, according to clinical experts consulted by CADTH.

In both patients with BBS and patients with AS, drop-outs occurred during the placebo-controlled phase in 2 patients assigned to placebo, but in 0 patients assigned to setmelanotide. Over the full study period, among patients with BBS, a total of 8 patients discontinued prematurely; however, 2 of these patients were counted as discontinued due to transferring to the extension trial when they were meant to be counted as completed. As such, there were no concerns about imbalanced or excessive dropout. However, there was substantial missingness in all exploratory outcomes. Low sample sizes in the exploratory QoL and hunger outcomes were due to many patients being ineligible for inclusion in the analyses due to cognitive impairment or age.

External Validity

In discussions with clinical experts consulted by CADTH, the inclusion and exclusion criteria of Study 023 were appropriate and generalizable to the population of interest (i.e., adult and pediatric patients with BBS, obesity, and hyperphagia who may or may not have cognitive impairment and may or may not have genetic confirmation of diagnosis). Although patients aged greater than or equal to 6 years were included, most outcomes analyzed only patients aged greater than or equal to 12 years; very few patients aged less than 12 years were enrolled in the trial (n = 8). Additionally, although patients with cognitive impairment were enrolled, they were not considered in the key secondary and exploratory outcomes related to hunger and QoL due to the practical limitations of assessing these outcomes in cognitively impaired populations. The subgroup analyses of younger and cognitively impaired populations had small sample sizes and used different metrics for measurement by necessity. Although reasonable from the perspective of trial design, the generalizability of the trial results for these subpopulations is nonetheless more uncertain. Overall, the primary, secondary, and exploratory outcomes were considered to be appropriately selected.

The clinical experts noted that the eligibility criterion disallowing recent intensive weight-loss activities would not reflect clinical practice, but that this was not a cause for concern in the implementation of setmelanotide in real-world clinical practice. In clinical practice, patients would be expected to be engaged in other obesity management strategies, such as calorie-reduced diets, and would not be excluded from pharmacotherapy for recency of weight-loss activities. This limitation in the generalizability of results is beneficial from an internal validity standpoint because it removes the potentially confounding factor of lifestyle intervention.

The baseline characteristics of the trial population were also considered by the experts to be appropriately generalizable to the Canadian context of patients with BBS and obesity. Although there were some differences identified between the setmelanotide and placebo arms of the placebo-controlled period, these differences were not considered to be concerning by the consulted experts. Moreover, the differences do not complicate the interpretation of the 52-week outcomes, which include patients regardless of initial randomization.

The dosing in Study 023 differed from that recommended in the product monograph. According to the product monograph, patients 18 years of age and older should be started on 1 mg daily, increasing by 0.5 mg daily every 2 weeks to a maximum of 3.0 mg daily, if tolerated; during the trial, patients 16 years of age or older started on 2 mg daily for 2 weeks, then increased to 3 mg daily, if tolerated. For pediatric patients, the recommended starting dose is 0.5 mg, increased by 0.5 mg daily every 2 weeks to a maximum of 2.0 mg daily. In Study 023, patients age less than 16 started at 1 mg daily for 1 week, increased to 2 mg daily for 1 week, and increased to a maximum of 3 mg daily, if tolerated. In summary, the trial had higher starting doses and shorter periods of intermediate dosing during the titration phase for all ages, and higher target doses for patients aged 16 years or older. The clinical experts consulted by CADTH indicated that dosing in real-world practice would mostly follow the product monograph, with occasional exceptions for patients older than 16, who may begin to receive adult dosing, based on clinical judgment.

Given that there are no other Health Canada–approved treatments that target the underlying mechanism of BBS-related hyperphagia and obesity, there were no appropriate comparators aside from placebo. There is a lack of data on the efficacy and safety of the potential off-label use of semaglutide and other pharmacotherapies; by extension, there is an evidence gap regarding the comparative efficacy between setmelanotide and these therapies.

Of the locations participating in the clinical trial, 1 was in Canada and included 6 enrolled patients. Given the rarity of the disease and the locations of other participating sites (i.e., in the US and western Europe), this was considered acceptable for generalization to the Canadian context.

One potential difference from clinical practice in Study 023 may be the level of background care provided in the study, such as training and, if needed, at-home assistance with self-injection. In real-world practice, adherence is often lower than in clinical trials. Given the high prevalence of cognitive impairment in patients with BBS and the lifelong, incurable nature of the disease, equitable access to training and support should be considered.

LTE Studies

Contents within this section have been informed by materials submitted by the sponsor. The following information has been summarized and validated by the CADTH review team.

Description of Studies

One LTE study was submitted for review. Study 022⁶⁰ is an ongoing, open-label extension study of the index trial Study 023⁹ to examine the long-term safety and tolerability of setmelanotide in patients greater than or equal to 6 years old with BBS and obesity for up to 36 months of treatment. The primary objective is to evaluate safety and tolerability. The secondary objectives are to evaluate changes in weight and hunger.

Populations

Patients were eligible to enrol in Study 022 if they had completed 1 of the index trials (i.e., Study 014⁶¹ or Study 023⁹) and had been were considered “responders” and demonstrated acceptable tolerability in the index trial. A responder was defined as a patient who achieved a greater than or equal to 10% body weight reduction (for patients aged ≥ 18 years) or a greater than or equal to 0.3 reduction in BMI z score (for patients aged < 18 years) after 52 weeks of setmelanotide treatment in the index trial. Responder patients began the LTE trial after index trial completion without a gap between visits. Visits occurred every 3 months throughout the study. The study started on March 18, 2021, and is still ongoing.

Interventions

Patients enrolled in Study 022 continued their personalized setmelanotide dose (titrated for each patient with a target of 3 mg once daily) without any specific guidance regarding diet or exercise.

Outcomes

Efficacy variables included measurements of change in BMI up to 36 months from the Study 023 baseline, including absolute and percentage change in BMI and body weight for adult patients (i.e., ≥ 18 years of age) and BMI z score in the 95th percentile for patients aged less than 18 years.

Hunger was assessed once every 3 months. However, hunger scores were not reported. The justification provided was that hunger scores are relative and are most informative when comparing pretreatment with posttreatment scores.

The frequency and severity of TEAEs, SAEs, AEs leading to discontinuation, and AEs leading to death were assessed and summarized as of June 2022.

Statistical Analysis

No statistical analysis for hypothesis testing was planned.

Results

Patient Disposition

Patient disposition is summarized in Table 24. Out of the 44 patients with BBS who were randomized in Study 023, 23 participants enrolled in the LTE study. Patients could also enrol after completing Study RM-493 to 014, a phase II basket trial in patients with rare genetic diseases of the MC4R pathway, including BBS (ClinicalTrails.gov identification number: NCT03013543); in total, 7 patients from RM-493 to 014 enrolled in Study 022.

Three patients discontinued the LTE trial: 1 due to an AE (auditory hallucination) that was considered unlikely to be related to treatment; 1 based on their own decision; and 1 because they transitioned to another setmelanotide clinical trial. The remainder (90%) are ongoing.

Table 24: Patient Disposition

LTE = long-term extension.

^aAuditory hallucination that was determined to be unlikely to be related to treatment.

Source: Study 022 Clinical Study Report.⁶⁰ Details in the table have been taken from the sponsor’s Summary of Clinical Evidence.

Baseline Characteristics

Patient characteristics at baseline are summarized in Table 25.

Table 25: Summary of Baseline Characteristics of the LTE Submitted by the Sponsor

BMI body mass index; LTE = long-term extension; SD = standard deviation.

Source: Study 022 Clinical Study Report.⁶⁰ Details in the table have been taken from the sponsor’s Summary of Clinical Evidence.

Exposure to Study Treatments

Not reported.

Efficacy

At the time of this review, Study 022 was still ongoing, and not all patients had completed the 36-month assessment. Early findings from the 12-month, 18-month, and 24-month assessments were available.

Change in BMI up to 36 Months Among All Patients With BBS

Changes from baseline in BMI for all patients (11 adult patients and 19 pediatric patients) were −13.78% ± 4.58% (n = 30) at month 12; −11.97% ± 9.33% (n = 29) at month 18; −10.74% ± 12.24% (n = 24) at month 24; and | || || || || || || || || || || || || || || |. The proportions of all patients who achieved a greater than or equal to 10% reduction in BMI from the index trial baseline were 76.7% (23 of 30 patients) at month 12; 62.1% (18 of 29 patients) at month 18; 54.2% (13 of 24 patients) at month 24; and | || || || || || || || || || || || || || || | adult patients experienced BMI increases above baseline at months 18, 24, and/or 36.

Table 26: Changes in BMI After up to 36 Months of Setmelanotide Treatment

BBS = Bardet-Biedl syndrome; BMI = body mass index; CI = confidence interval; SD = standard deviation.

Source: Study 022 Clinical Study Report.⁶⁰ Details in the table have been taken from the sponsor’s Summary of Clinical Evidence.

Change in Body Weight up to 36 Months Among Adult Patients With BBS

Changes from baseline in BMI for all patients (i.e., 11 adult patients, 19 pediatric patients) were −14.34% ± 3.14% (n = 11); −12.42% ± 9.83% (n = 11); −11.73% ± 11.11% (n = 10), and | || || || || || || || || || | for months 12, 18, 24, and 36, respectively. The proportions of adult patients who achieved a greater than or equal to 10% weight reduction from baseline were 63.6% at month 18 (7 patients of 11 patients); 60.0% at month 24 (6 patients of 10 patients), and | || || || || || || || || || |

Table 27: Changes in Body Weight in Adults After up to 36 Months of Setmelanotide Treatment

BBS = Bardet-Biedl syndrome; CI = confidence interval; SD = standard deviation.

Source: Study 022 Clinical Study Report.⁶⁰ Details in the table have been taken from the sponsor’s Summary of Clinical Evidence.

Change in BMI z Score up to 36 Months Among Pediatric Patients With BBS

Changes from baseline in BMI z score were −0.82 ± 0.35 (n = 19), −0.92 ± 0.41 (n = 17), −0.85 ± 0.45 (n = 19), and | || || || || || || | at months 12, 18, 24, and 36, respectively. The proportions of pediatric patients who achieved a greater than or equal to 0.3 change in BMI z score from baseline were 100.0% at month 18 (17 of 17 patients), 92.3% at month 24 (12 of 13 patients), and | || || || | | || || | at month 36 (| || || | patients).

Change in Weight-Related Parameters Beyond 36 Months

The results of | || || patients who received setmelanotide treatment for greater than 36 months were available. The longest time on treatment was 5 years (| || || || || || || || || || || || || || || || || || || || |). Findings are consistent with previous months’ measures, with BMI reduction tending to decrease or stabilize. However, | || pediatric patients experienced an increase in their BMI at months 24 and 36.

Table 28: Changes in BMI z Score Among Pediatric Patients After up to 36 Months of Setmelanotide Treatment

BMI = body mass index; CI = confidence interval; SD = standard deviation.

Source: Study 022 Clinical Study Report.⁶⁰ Details in the table have been taken from the sponsor’s Summary of Clinical Evidence.

Harms

All AEs presented in the following table were treatment-emergent and analyzed in the SAS.

In Study 022, AEs were reported for all enrolled patients at the time of the data cut-off; however, setmelanotide was well-tolerated, and no patients experienced SAEs related to the treatment except for 1 patient who discontinued due to auditory hallucination, which was believed to be unrelated to the study medication. The most frequently reported TEAEs included injection-site pruritis (73.3%) and erythema (70.0%), skin hyperpigmentation (66.7%), injection-site bruising (53.3%), and induration and pain (46.7%). Injection-site edema, nausea, and vomiting occurred in greater than or equal to 33.3% of patients. SAEs were reported by 3 participants (10.0%). No death related to AEs was reported.

The sponsor concluded that the systemic safety profile of Study 022 was generally consistent with the safety findings from Study 023 and suggested that this medication is effective and safe for the long-term treatment of obesity and control of hunger in adult and pediatric patients greater than or equal to 6 years of age with BBS and obesity.

Table 29: Summary of Harms in Study 022

SAE = serious adverse event; TEAE = treatment-emergent adverse event.

Note: The data cut-off date was June 2022. The study is still ongoing.

Source: Study 022 Clinical Study Report.⁶⁰ Details in the table have been taken from the sponsor’s Summary of Clinical Evidence.

Critical Appraisal

Internal Validity

Study 022 was designed as an open-label extension study to assess the long-term efficacy and safety of setmelanotide dosing regimens in the treatment of adult and pediatric patients with BBS. The open-label and single-arm design could bias the magnitude of the efficacy of outcomes and subjective safety parameters due to unblinded exposure to the study medication during the treatment period.

The lack of hunger and HRQoL measures, the lack of adjustment for covariates, and the absence of statistical testing are considered limitations.

External Validity

The external validity of the LTE is similar to that reported for the parent trial. It is reasonable to expect that the same strengths and limitations related to generalizability apply to the extension study, with the addition that this is an inherently enriched population, given that patients needed to complete the parent study before enrolling; this introduces some selection bias for responders.

Indirect Evidence

Contents within this section have been informed by materials submitted by the sponsor. The following information has been summarized and validated by the CADTH review team.

A feasibility assessment was conducted for indirect treatment comparisons of setmelanotide versus 8 general obesity treatments, including semaglutide, lixisenatide, lisdexamfetamine, topiramate, liraglutide, naltrexone-bupropion, orlistat, and bariatric surgery. Systematic literature reviews were conducted to identify prospective or retrospective clinical studies, published or unpublished, pertaining to the treatment of patients with BBS and obesity. No relevant articles were identified in this patient population; therefore, indirect comparisons were not feasible.

Discussion

Summary of Available Evidence

One phase III, 52-week, open-label trial with a 14-week, randomized, double-blind, placebo-controlled period was included in this review (Study 023), as well as an associated LTE (Study 022). Study 023 enrolled 52 patients, 44 of whom had BBS and 8 of whom had AS; only the patients with BBS are of interest for this review. The patients with BBS had a clinical diagnosis per the Beales criteria, were greater than or equal to 6 years of age, were obese (BMI ≥ 30 kg/m² for patients ≥ 16 years of age, or weight > 97th percentile for age and sex on growth chart assessment for patients 6 years to 15 years of age), and had not participated in recent or current intensive diet and/or exercise regimens or recently received pharmacotherapies that could affect the efficacy results related to obesity. Patients were randomized to either setmelanotide at an age-specific starting dose of 1 mg or 2 mg (escalating toward a target dose of 3 mg once daily through SC injection) or a matching-administration placebo for the first 14 weeks of the study. Thereafter, all patients received setmelanotide with the same starting and target dose, with dosing re-escalated to preserve the initial blinding, for 52 weeks. The primary outcome of Study 023 was the proportion of pivotal patients age greater than or equal to 12 years at baseline treated with setmelanotide for approximately 52 weeks who achieved a greater than or equal to 10% reduction in body weight from the active treatment baseline. Secondary outcomes included change in body weight and hunger scores after 52 weeks on setmelanotide and at 14 weeks compared to placebo. Additional exploratory outcomes included safety and tolerability, PROs related to hunger and HRQoL (e.g., based on hunger questionnaires, the IWQoL-Lite, the PedsQL, and | || || ||) and pharmacokinetics. For this review, the focus was on the BBS subgroup, including both pivotal and supplemental patients for all outcomes where possible.

At baseline, the patients with BBS included in Study 023 had a mean age of 18.5 years in the group randomized to setmelanotide and 21.5 years in the group randomized to placebo; in each group, 12 patients and 10 patients were under 17 years of age, and there were 9 female patients (40.9%) and 15 female patients (68.2%), respectively. Cognitive impairment was present in 12 patients (54.5%) and 8 patients (36.4%). The mean weights at placebo-controlled baseline were 110.45 kg and 106.5 kg, respectively, and the mean BMIs were 41.4 and 41.6, respectively.

The associated LTE, Study 022, is an ongoing, 36-month, open-label extension study that recruited a total of 30 responders with BBS and obesity, aged greater than or equal to 6 years, who completed either Study 023 (n = 23) or the phase II trial, Study 014 (n = 7). Of the 30 recruited patients, 27 are still ongoing in the trial. Early findings from months 12, 18, and 24 are available.

It was not feasible to conduct indirect treatment comparisons of setmelanotide to other active therapies due to a lack of data in patients with BBS.

Efficacy

There are limitations to the interpretability of the efficacy results from Study 023 due to the single-arm, open-label design. These design elements increase the risk of bias for subjective clinical outcome assessments and may lead to the overestimation of treatment effects for both benefits and harms. However, BBS is a rare disease with a small patient population for which there are no other targeted pharmacotherapies, and the 14-week, exploratory, placebo-controlled outcomes provide some supportive comparative effectiveness evidence. Additionally, the trial incorporated conservative design elements that could partially mitigate the increased risk of bias introduced from the study design. However, ultimately, the final direction and magnitude of bias are unknown.

Additionally, dosing in Study 023 differed from the recommended dosing described in the product monograph. The product monograph indicates that patients aged 18 years and older should start on 1 mg daily, increasing by 0.5 mg daily every 2 weeks to a maximum of 3.0 mg daily, if tolerated; however, during the trial, patients aged 16 years or older started on 2 mg daily for 2 weeks and then increased to 3 mg daily, if tolerated. For pediatric patients, the recommended starting dose in the product monograph is 0.5 mg, increasing by 0.5 mg daily every 2 weeks to a maximum of 2.0 mg daily; however, in Study 023, patients aged less than 16 years started at 1 mg daily for 1 week, increasing to 2 mg daily for 1 week, and then to a maximum of 3 mg daily, if tolerated. In summary, the trial had higher starting doses and shorter periods of intermediate dosing during the titration phase for all ages, and higher target doses for patients aged 16 years or older. Given that the average maintenance dose for pediatric patients with BBS was | || || || per day after titration,¹¹ which exceeds the maximum recommended dose, this presents some uncertainty in generalizability. The average dose in adults after titration was | || || | per day, which aligns with the recommended dosing.¹¹ The clinical experts consulted by CADTH indicated that dosing in real-world practice would mostly follow the product monograph, with occasional exceptions for patients who are older than 16 years and may begin to receive adult dosing, based on clinical judgment.

For the primary outcome of the proportion of patients who achieved a weight-loss response, both the target of weight loss (≥ 10% reduction in total body weight, compared to the well-accepted MID of ≥ 5%) and the prespecified target for the proportion of responders (≥ 10% responders, rounded up from the observed 6.4% in historical control data) were considered to be quite conservative. These conservative design elements could partially mitigate the increased risk of bias introduced from the study design. However, ultimately, the final direction and magnitude of bias are unknown. The estimated response rate of 33.7% (95% CI, 16.9% to 50.6%) exceeded the target of 10% responders after 52 weeks of setmelanotide treatment in pivotal patients aged greater than or equal to 12 years.

In the exploratory, placebo-controlled analyses assessed at 14 weeks, setmelanotide was associated with a greater difference in mean percentage change in body weight (i.e., −3.43%; 95% CI, −5.67% to −1.19), and placebo-treated patients had a mean change of 0 kg or −0.23% body weight (SD = 2.137%). These results are supportive of the treatment effect of setmelanotide.

Input from clinician and patient groups indicated that hyperphagia is among the most distressing symptoms of BBS and represents an important unmet need. In Study 023, although there appears to be an improvement in hunger at 52 weeks (and in comparison to placebo at 14 weeks), the hunger questionnaires developed by the sponsor and the associated MIDs have not been externally validated. Therefore, it is not possible to conclude on whether the observed benefits in hunger scores are clinically meaningful or can be interpreted as attributable to setmelanotide.

Exploratory HRQoL outcomes based on the IWQoL-Lite and PedsQL in patients without cognitive impairment generally showed a trend toward improvement greater than the reported MIDs (in general populations or general obesity) after 52 weeks of setmelanotide treatment. No MIDs were provided for the | || || ||, and results were inconsistent between the health state scales. No outcomes comparing setmelanotide to placebo were available for HRQoL-related outcomes. However, very small sample sizes, the lack of MIDs specific to BBS, and the single-arm, open-label nature of these assessments reduce the certainty associated with these results. As a result, the effect of setmelanotide on HRQoL is inconclusive.

The exploratory outcomes of waist circumference and lipid profile changes also suggest some improvement after 52 weeks of setmelanotide treatment. The clinical experts consulted by CADTH indicated that there are no firm MIDs established, but that improvement in these parameters is encouraging in clinical practice. Ultimately, it is not possible to conclude on whether these changes are clinically meaningful.

Subgroup analyses were conducted with different analysis sets based on age among pivotal patients with BBS for weight-related outcomes, and the results were consistent with the primary and secondary outcomes previously described. Age groups considered include all ages (≥ 6 years), less than 12 years, less than 18 years, and greater than or equal to 18 years. The results for patients aged less than 12 years and greater than or equal to 18 years will be highlighted here. Among pivotal patients with BBS who were less than 12 years of age (n = 8), | || || || || || || || || || || || || || || || || || || || || |; this magnitude of change in BMI z score is greater than reported clinically meaningful reductions in pediatric BMI z scores (−0.15 to −0.20).⁵⁹ Among pivotal patients with BBS who were greater than or equal to 18 years of age, | || || || || | of patients achieved a clinically meaningful (≥ 5%) reduction in body weight and | || || || achieved a greater than or equal to 10% reduction in body weight after 52 weeks of setmelanotide treatment. As previously described, the interpretability of the magnitude of effect at 52 weeks is limited due to the open-label, single-arm nature of the trial. However, the exploratory 14-week outcomes for weight-related parameters in the age-specific subgroups support the possibility of a treatment effect associated with setmelanotide versus placebo in terms of weight loss measured according to body weight change, BMI, or BMI z score.

The clinical experts consulted by CADTH indicated that weight loss is expected to plateau over time, and that maintenance of weight loss would be considered a continued treatment response after the first year of setmelanotide. At the time of this review, the LTE (Study 022) was still ongoing, and not all patients had completed the 36-month assessment. Early findings from 12-month, 18-month, and 24-month assessments indicate that weight-related parameters tended to stabilize in 26 patients of the 30 patients with BBS and obesity, while the remaining 4 patients experienced BMI increases above baseline. However, due to the immaturity of the data and the potentially lifelong treatment period for patients with BBS, the long-term efficacy of setmelanotide is highly uncertain. There is also a data gap regarding the efficacy of off-label treatments for general obesity in BBS populations, and by extension, the comparative efficacy of setmelanotide versus off-label therapies in BBS. The efficacy and safety of combination therapies are also unknown but may be used in clinical practice for this population, such as for patients with BBS who are also receiving semaglutide for comorbid diabetes. The clinical experts consulted by CADTH suggested that it is clinically plausible that combination therapies have a synergistic effect on control of hunger and weight loss.

Notably, Health Canada recommends discontinuation of setmelanotide for patients who have not lost at least 5% of baseline total body weight (or 5% of baseline BMI for patients with continued growth potential) after 22 weeks of treatment, inclusive of the approximately 8 weeks required for initial dose titration and the minimum of 14 weeks on a therapeutic dose (for patients requiring the maximum dose).³⁸ It was concluded that patients who are not responders at 22 weeks are unlikely to achieve and sustain clinically meaningful weight loss with continued treatment. The 5% threshold for weight loss is consistent with both widely accepted MIDs and the clinical expert opinion provided to CADTH. However, the timing of the 22-week assessment differs from Study 023 in which, based on the study design, key outcomes were assessed at 52 weeks of active therapy, and exploratory, placebo-controlled outcomes were assessed at 14 weeks from baseline; additionally, it differs from the recommendations given by the clinical experts consulted by CADTH, who proposed a 1-year trial period of setmelanotide. As an ad hoc analysis in response to a request by CADTH to reflect the Health Canada recommendations, the sponsor also provided the estimated proportion of pivotal patients with BBS aged greater than or equal to 12 years who achieved a greater than or equal to 5% reduction in total body weight after | | || || || || || || || || || || || || || || | || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || |.⁷

Harms

To maximize the available sample size, the analysis of harms is based on the SAS of Study 023, which included all 52 enrolled patients with either AS or BBS. Results were consistent between this cohort and the subgroup of patients with BBS. Overall, nonserious AEs were very common during the 14-week, placebo-controlled period and were similar between setmelanotide-treated patients and placebo-treated patients (96.3% and 96.0% of whom experienced at least 1 AE, respectively). Over the 52-week, open-label period, 100% of patients experienced at least 1 AE. The most common TEAEs were injection-site reactions (erythema, pruritus, bruising, and induration and pain), skin hyperpigmentation, nausea, vomiting, and diarrhea. Injection-site reactions were similar between treatment arms during the placebo-controlled period. It is important to note that the placebo formulation contained excipients that were similar to those used in the active formulation. Given this fact, it would not be unexpected to observe a similar rate of injection-site reactions in the placebo-treated group, and it is unlikely that these reactions were due to setmelanotide. Local injection-site tolerance has been assessed in all setmelanotide toxicity studies, and the most common findings were that inflammatory injection-site reactions related mainly to the primary excipient, mPEG-DSPE, with the possible involvement of setmelanotide at high doses. Although rates of nausea and diarrhea were very similar between treatment arms, vomiting occurred in setmelanotide-treated patients only (25.9%); 1 setmelanotide-treated patient withdrew due to vomiting. | || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || ||. No events of severe vomiting or nausea occurred. SAEs were uncommon and occurred in only 3 patients over the study period; none were considered related to the study drug by study investigators. TEAEs that led to study drug withdrawal were otherwise similar between treatment arms during the placebo-controlled period. No deaths occurred.

AEs of special interest identified by the sponsor and/or by clinical experts included injection-site reactions (as previously described), anaphylaxis, bradycardia, hyperpigmentation, melanoma, sexual events, and select psychiatric events, including anxiety, depression, suicidal ideation, suicide attempts, and aggression. Anxiety was not reported in the study. No patients experienced melanoma or suicide attempts. Anaphylaxis was experienced by only 1 placebo-treated patient, who withdrew during the placebo-controlled period as a result. Hyperpigmentation was experienced frequently and exclusively in setmelanotide-treated patients (in 63.0% during the RCT period and 63.5% over the full study period); these events were expected due to the effect of melanocortin receptor agonism during setmelanotide treatment. One patient discontinued due to hyperpigmentation. Sexual events occurred in some patients: | || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || || during the study period. Depression and depressed mood each occurred in 1 patient over the full study period. One patient experienced 2 events of suicidal ideation that resolved without study drug discontinuation and were concurrent with an SAE (blindness); none of these were considered related to the study drug. Aggression occurred in 3 patients.

Preliminary results of the LTE study, Study 022, supported the safety-related conclusions of Study 023. No new safety signals were identified. However, the study is ongoing, and more data are needed to support the long-term safety of setmelanotide. Overall, the clinical experts consulted by CADTH considered the safety profile of setmelanotide to be acceptable.

Conclusion

There is an unmet need for targeted treatments that address the underlying biological causes of hyperphagia and obesity in BBS, a very rare, incurable, genetic ciliopathy with multisystem manifestations. Patients and clinicians highlighted that early-onset obesity and hyperphagia are 2 of the most distressing symptoms, causing significant caregiver burden and impairment to HRQoL, and that typical obesity management strategies — such as restricted diet — are less feasible and less sustainable in this population than in general obesity. One completed phase III trial (Study 023) and an ongoing LTE (Study 022) were included in this review. There were notable concerns about the internal validity of these studies. These concerns were driven primarily by the single-arm, open-label trial designs, which introduce significant risk of bias to all subjective clinical outcomes and limit the interpretation of the magnitude of effect attributable to the intervention. However, BBS is a rare disease with a small patient population for which there are no other targeted pharmacotherapies.

The data submitted to CADTH were considered clinically relevant to the target patient population. Setmelanotide results were consistent with a clinically meaningful reduction in all weight-related parameters, such as change in body weight and BMI, across all reported analysis populations and subgroup analyses at 52 weeks, and the results were supported by the exploratory, comparative, 14-week, placebo-controlled outcomes. The results also suggested a consistent reduction in hunger scores in both the placebo-controlled and open-label periods; however, the scale used to measure hunger has not been externally validated. Therefore, whether these results are clinically meaningful is inconclusive. Similarly, results of the HRQoL outcomes at 52 weeks appeared to support a beneficial effect of setmelanotide, but small sample sizes and the single-arm study design made interpreting these events challenging. The long-term efficacy of setmelanotide is unknown because efficacy data from the LTE (Study 022) were immature at the time of this review. There is no evidence of effect regarding other BBS-related manifestations or prognosis aside from obesity. There are concerns about the generalizability of the clinical data to pediatric patients, given that the average maintenance dose in pediatric patients in Study 023 (| || || || || || || || || ||¹¹) exceeded the maximum recommended dose of 2 mg daily. There are also inherent risks of bias, confounding, and uncertainty in the estimation of treatment effects from single-arm data due to unidentified, uncontrolled prognostic factors. Moreover, the open-label design of the single-arm period increases the risk of detection bias and performance bias, and may lead to an overestimation of the treatment effect for subjective outcomes.

There are potentially notable harms of setmelanotide — including hyperpigmentation, sexual events, or inappropriate behaviours — but these events were generally uncommon, and no treatment-related melanoma has been observed in any setmelanotide trial to date. Behavioural or psychiatric disturbances, such as depression or aggression, were observed in the setmelanotide trials, but were unlikely to be related to study medication. All patients in Study 023 experienced at least 1 AE, but very few were serious; setmelanotide was generally well-tolerated. The most common AEs in setmelanotide-treated patients were injection-site reactions, skin hyperpigmentation, nausea, vomiting, and diarrhea. Vomiting was commonly and exclusively observed in patients treated with setmelanotide, and tended to occur during the first month of treatment; however, no events were severe. No new safety signals have been identified in the ongoing LTE (Study 022).

Overall, the results of Study 023 and Study 022 were consistent with setmelanotide improving important weight-related outcomes for patients with BBS. However, the ability to draw firm conclusions about the magnitude of clinical benefit in hunger, HRQoL, and other outcomes was limited. There are uncertainties regarding the long-term efficacy and safety of setmelanotide, given that it is potentially a lifelong treatment.

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