Regulatory Decision Summary for Imcivree

This New Drug Submission (NDS) was filed to obtain market authorization for Imcivree (setmelanotide) for the treatment of adult and pediatric patients 6 years of age and older with impairments in the melanocortin 4 receptor (MC4R) pathway due to genetic diseases, for the proposed indication of treatment of obesity and control of hunger in Bardet-Biedl syndrome (BBS), biallelic pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency. The review was filed under the Priority Review Policy.

Setmelanotide is a melanocortin 4 (MC4) receptor agonist. MC4 receptors in the brain are involved in the regulation of hunger, satiety, and energy expenditure. Genetic forms of obesity are related to the leptin-melanocortin pathway that are associated with insufficient activation of the MC4 receptor. These rare genetic conditions include pro-opiomelanocortin POMC, proprotein subtilisin/kexin type 1 (PCSK1) and leptin receptor (LEPR) deficiency, and Bardet-Biedl syndrome (BBS), all associated with severe obesity and hyperphagia with onset at a young age. Setmelanotide is believed to re-establish this pathway activity and promote weight loss through decreased caloric intake and increased energy expenditure.

Simulations from the population pharmacokinetic (Pop-PK) analyses suggest that AUC_ss and C_max are 100% and 92% higher in patients 6 to 11 years of age, and 44% and 37% higher for patients aged 12 to 16 years of age, as compared to patients ≥17 years of age.

Based on the exposure data of patients <18 years of age from all combined patient studies (including Pop-PK analysis), an accumulation of setmelanotide in plasma at subcutaneous-injected doses higher than 2 mg is suspected in this age group. The effects of chronic exposure to setmelanotide (> 52 weeks) on human renal function is unknown.

A dose adjustment is required for patients with severe renal impairment, but not for patients with mild and moderate renal impairment.

The efficacy and safety in patients ≥6 years of age with obesity due to genetically confirmed POMC, PCSK1 or LEPR deficiency, with variants considered pathogenic, likely pathogenic, or of uncertain significance, were assessed in two identically designed 52-week open-label studies (RM-493-012 and RM-493-015). In both studies, a dose titration period was followed by 10 weeks at the therapeutic dose. Patients who achieved at least a 5 kg weight loss at the end of the open-label treatment period (or at least 5% weight loss if baseline body weight was <100 kg) continued into a double-blind withdrawal period consisting of 4 weeks of setmelanotide administration followed by 4 weeks of placebo, then followed by 32 weeks of continued treatment with setmelanotide. Inclusion criteria included a body mass index (BMI) of ≥30 kg/m² for adults, and ≥95th percentile for pediatric patients.

Each study enrolled 15 patients. Mean baseline BMI was 40 kg/m² in study RM-493-012 and 48 kg/m² in study RM-493-015. A total of 21 of the 30 patients enrolled in both studies were considered pivotal and included in the efficacy analysis; of these, 12 patients were adults, 7 patients were ≥12 to <18 years of age, and 2 patients were 7 to 11 years of age. The other 9 patients were considered supplemental as they enrolled later in the studies.

The efficacy and safety in patients ≥6 years of age with obesity and Bardet-Biedl syndrome (BBS) were assessed in a single pivotal study (RM-493-023) consisting of a 14-week, randomized, double-blind, placebo-controlled treatment period, followed by 52 weeks of open-label treatment. Inclusion criteria included a BMI ≥30 kg/m² for patients ≥16 years of age and ≥97^th percentile for age and sex in patients 6 to 15 years of age. This study enrolled 52 patients with two different conditions, including 44 patients with BBS. Of these, a total of 43 patients were treated, of which 21 patients were adults, 14 patients were 12 to <18 years of age, and 8 patients were 6 to 11 years of age. Mean baseline BMI was 41.5 kg/m². Of the 28 pivotal patients included in the efficacy analysis, 15 patients were adults, and 13 patients were 12 to 17 years of age.

The primary efficacy endpoint in all studies was the number of pivotal patients who lost ≥10% of baseline weight after 52 weeks of treatment with setmelanotide injected subcutaneously once daily, with supportive data from supplemental patients, who enrolled later.

Due to the trial design of the pivotal studies and the small number of patients over a wide age range, the optimal dosing is challenging to assess. In study RM-493-012, a therapeutic daily dose of 1.5 mg was used for most pivotal patients (6/10) and 2/5 supplemental patients, 2.0 mg for 1 pivotal and 2 supplemental patients, 2.5 mg for 3 pivotal patients, and 3.0 mg for only 1 supplemental patient. In study RM-493-015, a therapeutic dose of 1.5 mg daily was used for 1 pivotal and 1 supplemental patients, 2.0 mg for 2 pivotal and 1 supplemental patients, 2.5 mg for 6 pivotal patients, and 3.0 mg for 2 pivotal and 1 supplemental patients. In total, 76% of pivotal patients therefore received doses outside of the recommended dosage initially proposed by the Sponsor. In study RM-493-023, all patients were titrated to 3 mg daily, preventing assessment of efficacy at lower doses. The Sponsor agreed that the therapeutic dose ranged from 1.5 mg to 2.5 mg in most patients.

The dosage was therefore revised to reflect the therapeutic doses used in the clinical trials and exposure results from the pharmacokinetic data.

The primary efficacy endpoint was met with statistical significance by 8 of 10 pivotal patients (80%) in study RM-493-012, and 5 of 11 patients (45.5%) in study RM-493-015.

When treatment with setmelanotide was withdrawn in patients who lost weight during the 10-week open-label period, patients generally gained weight and the mean hunger scores increased over the 4 weeks of placebo treatment.

The primary efficacy analysis in study RM-493-023 included 2 different populations of patients ≥12 years of age. An ad-hoc subgroup analysis was conducted in the 28 pivotal patients with BBS. The primary endpoint was met by 10 of 28 (35.7%) BBS patients. This analysis was not adequately powered but mirrored the results of pivotal patients ≥12 years of age in the full analysis set. Treatment with setmelanotide for 52 weeks also resulted in BMI Z-score reductions in patients <12 years of age who were not included in the primary analysis, consistent with the results of patients 12 to 17 years of age.

In all studies, hunger over the previous 24 hours was assessed as a secondary endpoint in patients ≥12 years of age. Although some of the patients’ weekly mean maximal hunger scores decreased, the degree of change was highly variable among patients. The Sponsor acknowledged that changes in hunger and weight were not highly correlated, and that hunger is not without measurement error. Further, this measurement could not be assessed in the patients <12 years of age.

The safety of setmelanotide was assessed in 30 patients with POMC, PCSK1, or LEPR deficiency. The most common adverse drug reactions (ADRs) were injection site reactions (90%), hyperpigmentation (57%), nausea (53%), headache (50%), spontaneous penile erection (40% of males), diarrhea (40%), abdominal pain (33%), vomiting (33%), melanocytic naevus (30%), back pain (30%), fatigue (27%), depression (23%), asthenia (23%), dizziness (17%), and dry mouth (13%).

The safety was assessed in 43 patients with BBS. During the 14-week placebo-controlled period, the most common reported ADRs in setmelanotide-treated patients compared to placebo-treated patients were hyperpigmentation disorders (67% vs 0%, respectively) and vomiting (11% vs 0%, respectively). During the 52-week active-treatment period, the most common ADRs were hyperpigmentation (63%), injection site reactions (51%), nausea (26%), spontaneous penile erection (25% of males), vomiting (19%), melanocytic naevus (14%), diarrhea (14%), and headache (7%).

Overall, the most common tolerability concerns, such as injection site reactions, diarrhea, nausea, vomiting, and abdominal pain, were not serious and usually resolved quickly. Serious adverse events included suicidal ideation and depression. Overall, the observed safety profile is consistent in the pediatric and adult population, although the safety data was very limited, especially in patients 6 to 11 years of age.

Risk management includes Warnings in the Product Monograph to conduct a complete skin examination on all patients before and during treatment, to monitor increases in skin pigmentation and changes to pre-existing nevi. Further, as the effect of long-term effect of setmelanotide use is unknown, patients with a personal or family history of melanoma or pre-melanoma lesions should not be treated with Imcivree. Other warnings include that the risk of prolonged penile erections (>4 hours) is not fully characterized, and that patients should be monitored for depression and suicidal thoughts or behaviour, which can be serious and are important potential risks associated with Imcivree. Since setmelanotide contains the preservative benzyl alcohol, which is associated with serious and fatal adverse reactions including “gasping syndrome” in neonates and low birth weight infants, a statement warns against use in this age group, even though this is outside of the approved indications.

A Risk Management Plan (RMP) for Imcivree was submitted by Rhythm Pharmaceuticals, Inc., to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will put in place to minimise risks associated with the product.

The efficacy and safety data are limited, especially in younger patients, mostly due to the rarity of these conditions, making it unlikely to detect rare adverse reactions. There is a need for longer-term data to detect adverse reactions associated with prolonged exposure. However, the weight loss represents a significant benefit and safety risks are generally manageable, with risk mitigation through labelling and post-market monitoring. Overall, the benefit-risk profile is considered favorable for patients with obesity due to POMC, PCSK1, or LEPR deficiency and BBS.