Summary Basis of Decision for Imcivree

As described above, the clinical review of the New Drug Submission for Imcivree was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada .

Clinical Pharmacology

Setmelanotide (the medicinal ingredient in Imcivree) is a synthetic peptide that functions as a melanocortin-4 (MC4) receptor agonist. In the brain, MC4 receptors (MC4Rs) are involved in the regulation of hunger, satiety, and energy expenditure. In genetic forms of obesity related to the leptin-melanocortin pathway that are associated with insufficient activation of the MC4 receptor, setmelanotide is believed to re-establish MC4 receptor pathway activity, thereby reducing hunger and promoting weight loss through decreased caloric intake and increased energy expenditure. Setmelanotide appears to restore some of the effect of diminished pro-opiomelanocortin (POMC) neuronal function in patients with POMC, proprotein convertase subtilisin/kexin type 1 (PCSK1) and leptin receptor (LEPR) deficiencies, and Bardet-Biedl syndrome (BBS), in the upstream leptin-melanocortin pathway, which impact the functioning of the MC4 receptor pathway.

Pharmacodynamic and pharmacokinetic data were obtained from fifteen studies, two of which were ongoing. In these studies, setmelanotide was administered subcutaneously in the abdomen via either an injection or a 24-hour continuous infusion. The study populations consisted mainly of obese but otherwise healthy subjects, or patients with the rare genetic diseases of obesity related to the MC4 receptor pathway (i.e., BBS or deficiencies in POMC, PCSK1, or LEPR). The studies enrolled mostly adults (18 years of age or older) with a limited number of patients 6 to 17 years of age. No bioavailability or bioequivalence studies were performed.

Pharmacodynamics

Skin Hyperpigmentation

Skin hyperpigmentation, attributed to the activation of the melanocortin 1 (MC1) receptor, was observed in the non-clinical and clinical studies. Setmelanotide has off-target activity at the MC1 and melanocortin 3 (MC3) receptors at clinically relevant concentrations. The MC1 receptor is expressed on melanocytes. Activation of this receptor leads to accumulation of melanin and increased skin pigmentation independently from exposure to ultraviolet light.

Cardiovascular Effects

In non-clinical studies with setmelanotide, interspecies discordance for cardiovascular effects was observed. In clinical studies with setmelanotide, limited data was available due to the small number of patients, however, two serious cardiovascular adverse event cases were reported: increase in heart rate (HR) and blood pressure (BP) due to an overdose of 5 mg and bradycardia. Based on these results, possible adverse effects pertaining to significant changes in corrected QT interval (QTc), HR, and BP at clinical concentration levels of setmelanotide could not be ruled out. An increase in HR and BP could not be excluded in case of an overdose or at the maximum recommended human dose (MRHD) of 3 mg per day. Of note, a QTc study investigating the effect of supratherapeutic setmelanotide doses on cardiac repolarization was ongoing at the time of this submission. A statement regarding the recommended management of overdosage, including monitoring of HR and BP has been added to the Imcivree Product Monograph.

Immunogenicity

Due to limited information, the impact of antibody development on the pharmacokinetics, pharmacodynamics, safety, and/or efficacy of Imcivree could not be concluded. A statement reflecting the number of patients with BBS or with deficiencies in POMC, PCSK1 and LEPR who developed antibodies with positive titers against setmelanotide or endogenous alpha-melanocyte-stimulating hormone (α-MSH) was included in the Imcivree Product Monograph.

Pharmacokinetics

After a once-daily subcutaneous injection of 3 mg of setmelanotide in otherwise healthy subjects with obesity (total number [n] = 6), the mean steady-state setmelanotide maximum concentration (C_max,ss) was 37.9 ng/mL, the mean area under the concentration-time curve to the end of the dosing period (AUC_tau) was 495 h*ng/mL, and the mean trough concentration (C_trough) was 6.77 ng/mL. Steady-state plasma concentrations of setmelanotide were achieved within 2 days with daily dosing of 1-3 mg setmelanotide. The accumulation of setmelanotide in the systemic circulation during once-daily dosing over 12 weeks was approximately 30%. Setmelanotide AUC and C_max increased dose-proportionally following multiple-dose subcutaneous administration in the proposed dose range (1-3 mg).

In otherwise healthy obese subjects, steady-state plasma concentrations increased slowly after a once-daily subcutaneous injection of setmelanotide, reaching maximum C_max at a median time to C_max (T_max) of 8.0 h. Steady-state plasma concentrations of setmelanotide were achieved within 2 days of once-daily administration of 2.0 mg.

In vitro experiments indicated that setmelanotide is not a substrate of organic anion transporting polypeptides (OATPs) OATP1B1, OATP1B3, OAT1, OAT3, or organic cation transporter (OCT)2. In vitro data indicate that setmelanotide is unlikely to be a p-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) substrate.

Setmelanotide did not appear to be metabolised by rat, monkey, or human hepatic microsomes or hepatocytes, or kidney microsomes. Setmelanotide is stable in human, rat, and monkey hepatocytes. Setmelanotide is expected to be metabolized into small peptides by catabolic pathways.

The effective elimination half-life (t_½) of setmelanotide was approximately 11 hours. The total apparent steady-state clearance following subcutaneous injection of 3 mg of setmelanotide once daily was estimated from the population pharmacokinetic model to be 4.86 L/h.

At steady state, approximately 39% of the administered setmelanotide dose was excreted unchanged in urine during the 24-hour dosing interval following subcutaneous injection of 3 mg setmelanotide once daily in otherwise healthy obese subjects.

Special Populations

No clinically significant differences in the pharmacokinetics of setmelanotide were observed based on sex or disease. The pharmacokinetic parameters of C_max, AUC, C_trough and T_max, were comparable among patients with different genetic defects (BBS, deficiencies in POMC, PCSK1 and LEPR) and otherwise healthy subjects with obesity. These findings supported the recommendation to combine the setmelanotide dosage and dose adjustment for patients with different rare genetic diseases of obesity related to MC4R pathway.

The effect of age (65 years or older), pregnancy, or hepatic impairment on the pharmacokinetics of setmelanotide is unknown.

A dose adjustment is required for patients with severe renal impairment, but not for patients with mild and moderate renal impairment. At a dose of 2 mg, the exposure parameters, AUC from 0 to the last quantifiable time point (AUC_0-t) and AUC from 0 to infinity (AUC_0-inf), were approximately 13%-15%, 34%-35%, and 86%-96% higher for adult subjects with mild, moderate, and severe renal impairment, respectively, as compared to subjects with normal renal function. Setmelanotide clearance was about 12%, 26%, and 49% lower in mild, moderate, and severe renal impairment, respectively, as compared to patients with normal renal function. Half-life was progressively longer with worsening renal function, with mean values of about 13 hours in subjects with normal renal function and 24 hours in subjects with severe renal impairment. Due to nausea/vomiting requiring treatment in subjects receiving a dose 1 mg or higher in the severe impairment cohort, the starting dose was reduced to 0.5 mg for these subjects while the healthy control subjects received a 2 mg dose. Therefore, a starting dose of 0.5 mg is recommended in patients 12 years of age and older with severe renal impairment, with a limited maximum dose of 1.5 mg (exposure expected to be equivalent to that of the MRHD of 3 mg in adults with normal renal function).

Renal impairment did not appear to affect plasma protein binding. The average fraction unbound (f_u) was approximately 0.21 and was independent of renal function status.

From the simulations using the zero-absorption model, there is a difference in setmelanotide pharmacokinetic parameters based on age category (pediatrics versus adults). Simulations from the population pharmacokinetic analyses suggest that AUC and C_max are 100% and 92% higher in pediatric patients 6 to less than 12 years of age as compared to patients greater than or equal to 17 years of age. For patients aged 12 to less than 17 years, the setmelanotide AUC and C_max were 44% and 37% higher, respectively as compared to patients greater than or equal to 17 years.

Based on the exposure data of patients less than 18 years old taken from all combined patient studies (including the population-pharmacokinetic analysis), an accumulation of setmelanotide in plasma is suspected at subcutaneously injected doses higher than 2 mg. In 20 pivotal patients with BBS (study duration of 52 weeks, pivotal patients were those who had completed 1 year or more of treatment at data cut-off), an increase of about 58% in the levels of the pro-inflammatory biomarker interleukin 6 (IL-6) in urine was reported. It is suspected that high exposure to setmelanotide could exert stress on the kidneys. The effects of chronic exposure to setmelanotide (>52 weeks) on human renal function is unknown. Therefore, the maximum dose should be reflective of the potential accumulation of setmelanotide in patients 6 to 17 years of age. Based on these findings, a maximum dose of 2 mg was recommended for this age group.

Drug-Drug Interactions

Setmelanotide has low potential for pharmacokinetic drug-drug interactions related to cytochrome P450 (CYP) enzymes and transporters. Interactions with other drugs have not been established.

The clinical pharmacology data support the use of Imcivree for the recommended indication.

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

Clinical Efficacy

The clinical efficacy of Imcivree was assessed in two identically designed, 52-week open-label studies (RM-493-012 and RM-493-015) in patients 6 years of age and older with obesity due to genetically confirmed POMC, PCSK1 or LEPR deficiency, with variants considered pathogenic, likely pathogenic, or of uncertain significance was assessed. Each study enrolled 15 patients with homozygous or presumed compound heterozygous pathogenic, likely pathogenic variants, or variants of unknown significance for either the POMC or PCSK1 genes (Study RM-493-012) or the LEPR gene (Study RM-493-015). Patients with double heterozygous variants in two different genes were not eligible for treatment with Imcivree. Inclusion criteria included a body mass index (BMI) of 30 kg/m² or higher for adult patients and weight in the 95^th percentile or higher for pediatric patients.

The primary efficacy analysis included only the pivotal patients who had completed 1 year or more of treatment at the data cut-off. Twenty-one of the 30 patients enrolled in both studies were considered pivotal, of whom, 12 were adults (18 years of age or older), 7 were 12 to less than 18 years of age, and 2 were 7 to 11 years of age. Data from the other 9 patients were considered in supplemental analyses as these patients enrolled later in the studies and had not completed 1 year of treatment. There were 10 pivotal and 5 supplemental patients in Study RM-493-012 and 11 pivotal and 4 supplemental patients in Study RM-493-015. Of the pivotal patients included in the primary efficacy analysis from Study RM-493-012, 50.0% were female, 70% were Caucasian, and the mean BMI was 40.41 kg/m² (range: 26.6-53.3 kg/m²) at baseline, while for Study RM-493-015, 72.7% were female, 90.9% were Caucasian, and the mean BMI was 48.17 kg/m² (range: 35.8-64.6 kg/m²) at baseline.

In both studies, a dose titration period was followed by 10 weeks of treatment with Imcivree 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 less than 100 kg) continued into a double-blind withdrawal period consisting of 4 weeks of Imcivree administration followed by 4 weeks of placebo, followed by 32 weeks of continued treatment with Imcivree.

A third study (RM-493-023) assessed the efficacy and safety of Imcivree in patients 6 years of age or older with obesity and BBS. This study which consisted of a 14-week, randomized, double-blind, placebo-controlled treatment period, followed by 52 weeks of open-label treatment. The inclusion criteria were a BMI greater than or equal to 30 kg/m² for patients 16 years of age and older and weight in the 97^th percentile or higher for age and sex in patients 6 to 15 years of age. The study enrolled 52 patients with two different conditions, including 44 patients with BBS. Forty-three of these BBS patients were treated, of whom 21 were adults (18 years of age or older), 14 were 12 to less than 18 years of age, and 8 were 6 to 11 years of age. The mean baseline BMI was 41.5 kg/m². Of the 28 pivotal patients included in the efficacy analysis, 15 were adults, and 13 were 12 to 17 years of age. Overall, 50% of patients were female, 86% were Caucasian, and the mean BMI was 42.4 kg/m² (range: 24.4-61.3 kg/m²) at baseline.

The primary efficacy endpoint in all studies was the number of pivotal patients who lost 10% or more of their baseline weight after 52 weeks of treatment with Imcivree administered once daily subcutaneously. Supportive data was derived from supplemental patients, who had enrolled later. Secondary efficacy endpoints included the mean weekly measurement of the hunger over the previous 24 hours at 52 weeks in patients 12 years of age and older.

In patients with POMC, PCSK1, or LEPR deficiency, the primary efficacy endpoint was met with statistical significance for 8 of the 10 pivotal patients (80%) in Study RM-493-012, and 5 of the 11 pivotal patients (45.5%) in Study RM-493-015. In supportive analyses conducted on pivotal and supplemental patients combined, 85.7% patients in Study RM-493-012 and 53.3% of patients in Study RM-493-015 patients met the primary endpoint. When treatment with Imcivree was withdrawn in patients who had lost weight during the 10-week open-label period, these patients generally gained weight and their mean hunger scores increased over the 4 weeks of placebo treatment.

For Study RM-493-023, the primary efficacy analysis included two different populations of patients 12 years of age and older. The efficacy analyses were not powered for disease subgroups, therefore the efficacy claimed for BBS patients 12 years of age and older was conducted as an ad-hoc analysis. Based on the results of this analysis, the primary endpoint was met by 10 of 28 (35.7%) pivotal BBS patients aged 12 years or older. This analysis mirrored the results of pivotal patients 12 years of age and older in the full analysis set. Supportive analysis including supplemental patients 12 years of age older with BBS (total number [n] = 35) reached a similar result, with 33.7% of patients reaching the primary endpoint. Treatment with Imcivree for 52 weeks also resulted in BMI Z-score reductions in patients less than 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, the weekly mean of hunger over the previous 24 hours was assessed by a questionnaire as a secondary endpoint in patients 12 years of age and older. Although some of the patients’ weekly mean worst hunger scores decreased, the degree of change was highly variable among patients. Changes in hunger and weight were not highly correlated and hunger is not without measurement error. Further, this measurement could not be assessed in the patients less than 12 years of age. In addition, many patients did not lose weight, and even gained weight in the long-term extension studies. Although not every patient in the long-term extension study continued to lose weight, most patients continued to lose weight or maintained the weight loss from the index study. Maintenance of weight loss is meaningful as these patients typically continue to gain weight.

Indication

The New Drug Submission for Imcivree was filed by the sponsor with the following indication:

Setmelanotide is a MC4R agonist indicated in adult and pediatric patients 6 years of age and older with impairments in the MC4R pathway due to genetic diseases, for the 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

To support safe and effective use of the product, Health Canada approved the following indication:

Imcivree is indicated for weight management in adult and pediatric patients 6 years of age and older with obesity due to:

• Bardet-Biedl syndrome (BBS)

• 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

Limitations of Use:

Setmelanotide is not indicated for the treatment of patients with the following conditions as setmelanotide would not be expected to be effective:

• Obesity due to suspected POMC, PCSK1, or LEPR deficiency with POMC, PCSK1, or LEPR variants classified as benign or likely benign

• 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

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

Clinical Safety

The clinical safety of Imcivree was evaluated in the studies described in the Clinical Efficacy section. These studies included two 52-week, open-label clinical studies of 30 patients with obesity due to POMC, PCSK1, or LEPR deficiency, and one 52-week open-label study, including a 14-week placebo-controlled period, in 43 patients with BBS.

In the 30 treated patients with POMC, PCSK1, or LEPR deficiency, the most common adverse reactions included injection site reactions (90%), hyperpigmentation (57%), nausea (53%), headache (50%), diarrhea (40%), spontaneous penile erection (40% of males), abdominal pain (33%), vomiting (33%), melanocytic naevus (30%), back pain (30%), fatigue (27%), depression (23%), asthenia (23%), dizziness (17%), and dry mouth (13%).

In the 43 treated patients with BBS, during the 14-week placebo-controlled period, the most common reported adverse reactions in Imcivree-treated patients compared to placebo-treated patients were hyperpigmentation disorders (67% versus [vs.] 0%, respectively) and vomiting (11% vs. 0%, respectively). During the 52-week active-treatment period, the most common adverse reactions were hyperpigmentation (63%), injection site reactions (51%), nausea (26%), spontaneous penile erection (25% of males), vomiting (19%), melanocytic naevus (14%); diarrhea (14%), headache (7%), and fatigue (5%).

Serious adverse events included suicidal ideation and depression. The most common adverse events leading to discontinuation were nausea, vomiting, and abdominal pain. The most common tolerability concerns, such as injection site reactions, diarrhea, nausea, vomiting, and abdominal pain were not serious and usually resolved quickly. Overall, the observed safety profile is consistent in children and adults, although safety data were very limited, especially in children 6 to 11 years of age. As such, the detection of rare adverse events is unlikely and there is a need for long‑term data to detect adverse reactions associated with prolonged exposure.

Risk management includes warnings added to the Imcivree Product Monograph advising patients to conduct a complete skin examination before and during treatment, and to monitor for increases in skin pigmentation and changes to pre-existing nevi. Furthermore, as the long-term effect of Imcivree 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 the risk of prolonged penile erections (lasting more than 4 hours), which has not been 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. As Imcivree 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 has been included in the Imcivree Product Monograph warning against use in this age group, even though this is outside of the approved indications.

Overall, the therapeutic benefits of Imcivree seen in the pivotal studies are considered to outweigh the potential risks. The efficacy and safety data are limited, especially in younger patients, mostly due to the rarity of these conditions. The safety risks are generally manageable, with risk mitigation through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Imcivree Product Monograph to address the identified safety concerns.

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

As described above, the review of the non-clinical component of the New Drug Submission for Imcivree was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The non-clinical package was considered complete and included studies of pharmacology (primary/secondary and safety), toxicology (with toxicokinetic data), and pharmacokinetics (in vitro and single injections in animals).

Setmelanotide is a melanocortin 4 receptor agonist with increased functional potency on this receptor compared to its endogenous ligand alpha-melanocyte stimulating hormone (α-MSH) based on in vitro data. Setmelanotide has off-target activity on both the melanocortin 1 (MC1) and melanocortin 3 (MC3) receptors. Skin hyperpigmentation was observed in non-clinical and clinical studies that was attributed to the activation of the MC1 receptor.

Setmelanotide resulted in statistically significant decreases in body weight gain in both rodents and non-human primates. Reduction in body weight gain was observed in both lean and obese models which included both diet-induced obese animals (non-human primates and rodents) and genetic models of obesity (rodents). Notably, significant decreases in body weight gain were not always accompanied by a reduction in food intake.

The risk of human ether-à-go-go-related gene (hERG) block for setmelanotide was considered low. However, interspecies discordance was observed for cardiovascular effects; increases in heart rate and blood pressure were observed in rats and minipigs but not in non-human primates.

Minimal accumulation of setmelanotide in plasma (in mPEG-2000-DSPE; excipient used as a vehicle in formulation) is expected at clinically relevant doses based on non-human primate and rodent studies. Both setmelanotide and the excipient mPEG-DSPE were primarily excreted in urine.

In repeat-dose studies, minimal vacuolation of epithelial cells and aggregation of vacuolated macrophage in the choroid plexus were reported in rats and non-human primates, respectively. Hyperpigmentation was observed in all setmelanotide-treated groups with no microscopic changes that were indicative of atypical melanocyte proliferation. Inflammatory injection‑site reactions observed in both species were attributed primarily to mPEG-DSPE with possible involvement of setmelanotide at high doses. By the end of the recovery phase, vacuolated cells and skin hyperpigmentation were partially resolved and body weight gain was higher in setmelanotide-treated groups as compared to control groups, in both species.

Setmelanotide was not genotoxic nor carcinogenic in transgenic mice. Based on the integrated analysis of weight of evidence factors, a two-year rat carcinogenicity study was not required due to the lack of pro-carcinogenic concern.

No effects on female or male rat fertility were observed and no clear evidence of teratogenicity was observed in either rabbit or rats. In rabbits, an increase in resorption number and higher post-implantation loss were observed at clinically relevant doses, which were attributed to the severe reduction in food consumption and decrease in body weight. Setmelanotide was detected in rat dam’s milk but not in the nursing pups’ plasma.

In the juvenile toxicity study, inflammatory injection‑site reactions were similar to those observed in adult rats. No systemic toxicity was observed, including no effects on sexual maturation, growth parameters, behavioral performance, learning and memory, reproductive performance, ophthalmology, or systemic organ histopathology. During the recovery phase, all setmelanotide-treated groups had statistically significantly higher body weight gains than controls.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Imcivree Product Monograph. In view of the intended use of Imcivree, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

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

The chemistry and manufacturing information submitted for Imcivree has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored under refrigerated conditions (2 ºC to 8 ºC) in the original carton. After removal from the refrigerator, vials may be kept at temperatures ranging from refrigerated to room temperature (2 °C to 30 °C) for up to 30 days. After the vial is punctured (opened), Imcivree must be discarded after 30 days.

Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. In addition, none of the excipients used in the formulation of Imcivree is of human or animal origin.