Imcivree

Pharmacotherapeutic group: anti-obesity preparations, excl. diet products, centrally acting anti-obesity products, ATC code: A08AA12 Mechanism of action Setmelanotide is a selective MC4 receptor agonist. MC4 receptors in the brain are involved in regulation of hunger, satiety, and energy expenditure. In genetic forms of obesity associated with insufficient activation of the MC4 receptor, setmelanotide is believed to re-establish MC4 receptor pathway activity to reduce hunger and promote weight loss through decreased caloric intake and increased energy expenditure. Pharmacodynamic effects Skin pigmentation Setmelanotide is a selective MC4 receptor agonist with less activity at the melanocortin 1 (MC1) receptor. The MC1 receptor is expressed on melanocytes, and activation of this receptor leads to accumulation of melanin and increased skin pigmentation independently of ultraviolet light (see sections 4.4 and 4.8). Clinical efficacy and safety POMC, including PCSK1, deficiency and LEPR deficiency The safety and efficacy of setmelanotide for the treatment of POMC and LEPR deficiency obesity were established in 2 identically designed, 1‑year open-label pivotal studies, each with a double-blind, placebo-controlled withdrawal period: • Study 1 (RM-493-012) enrolled patients aged 6 years and above with genetically confirmed POMC (including PCSK1) deficiency obesity. • Study 2 (RM-493-015) enrolled patients aged 6 years and above with genetically confirmed LEPR deficiency obesity. In both studies, adult patients had a body mass index (BMI) of ≥30 kg/m 2 . Weight in children was ≥95th percentile using growth chart assessment. Dose titration occurred over a 2- to 12‑week period, followed by a 10‑week open-label treatment period. Patients who achieved at least a 5 kg weight loss (or at least 5% weight loss if baseline body weight was <100 kg) at the end of the open-label treatment period continued into a double-blind, placebo-controlled, withdrawal period lasting 8 weeks (4‑week placebo treatment and 4‑week setmelanotide treatment). Following the withdrawal sequence, patients re-initiated active treatment with setmelanotide at the therapeutic dose for up to 32 weeks. Twenty-one patients (10 in Study 1 and 11 in Study 2) have been treated for at least 1 year and are included in the efficacy analyses. Additional supportive data were gathered in an investigator-led study and an ongoing extension study. Study 1 (RM-493-012) In Study 1, 80% of patients with POMC deficiency obesity met the primary endpoint, achieving a ≥10% weight loss after 1 year of treatment with setmelanotide and 50% of patients with POMC deficiency obesity achieved a predefined clinically meaningful ≥25% improvement in hunger score from baseline at 1 year (Table 15). Statistically significant and clinically meaningful mean percent decreases from baseline for body weight of 25.6% were reported for Study 1. Changes in hunger were assessed using a patient and caregiver questionnaire completed daily for 'most hunger over the last 24 hours' at 1 year for patients ≥12 years of age. Statistically significant and clinically meaningful mean percent decreases from baseline for hunger as a weekly average in the last 24 hours of 27.1% were reported for Study 1 (Table 16). When treatment with setmelanotide was withdrawn in patients who had lost weight during the 10‑week open-label period, these patients gained weight (Figure 1) and the mean hunger scores increased over the 4 weeks of placebo treatment. Table 15 Proportion of patients achieving at least 10% weight loss and the proportion of patients achieving at least 25% improvement in daily hunger from baseline at 1 year in Study 1 Parameter Statistic Patients achieving at least 10% weight loss at 1 year (N=10) n (%) 90% CI 1 P-value 2 8 (80.0%) (49.31%, 96.32%) <0.0001 Patients achieving at least 25% hunger improvement from baseline at 1 year (N=8) n (%) 90% CI 1 P-value 1 4 (50.0) (19.29, 80.71) 0.0004 Note: The analysis set includes patients who received at least 1 dose of study drug and had at least 1 baseline assessment. 1 From the Clopper-Pearson (exact) method 2 Testing the null hypothesis: proportion =5% Table 16 Percent change from baseline in weight and hunger at 1 year in Study 1 Parameter Statistic Body weight (kg) (N=9) Hunger score 1 (N=7) Baseline Mean (SD) Median Min, Max 115.0 (37.77) 114.7 55.9, 186.7 8.1 (0.78) 8.0 7, 9 1 year Mean (SD) Median Min, Max 83.1 (21.43) 82.7 54.5, 121.8 5.8 (2.02) 6.0 3, 8 Percent change from baseline to 1 year (%) Mean (SD) Median Min, Max LS Mean 90% CI P-value -25.6 (9.88) -27.3 -35.6, -2.4 -25.39 (-28.80, -21.98) <0.0001 -27.06 (28.11) -14.29 -72.2, -1.4 -27.77 (-40.58, -14.96) 0.0005 Note: This analysis includes patients who received at least one dose of study drug, had at least one baseline assessment, and demonstrated ≥5 kg weight loss (or 5% of body weight if weight was <100 kg at baseline) over the 12-week open-label treatment period and proceeded into the double-blind, placebo-controlled withdrawal period. 1 Hunger ranges from 0 to 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. Hunger score was captured in a daily diary and was averaged to calculate a weekly score for analysis. Figure 1 Percent body weight change from baseline by visit (Study 1 [N=9]) Study 2 (RM-493-015) In Study 2, 46% of patients with LEPR deficiency obesity met the primary endpoint, achieving a ≥10% weight loss after 1 year of treatment with setmelanotide and 73% of patients with LEPR deficiency obesity achieved a predefined clinically meaningful ≥25% improvement in hunger score from baseline at 1 year (Table 17). Statistically significant and clinically meaningful mean percent decreases from baseline for body weight of 12.5% were reported for Study 2. Changes in hunger were assessed using a patient and caregiver questionnaire completed daily for 'most hunger over the last 24 hours' at 1 year for patients ≥12 years of age. Statistically significant and clinically meaningful mean percent decreases from baseline for hunger as a weekly average in the last 24 hours of 43.7% were reported for Study 2 (Table 18). When treatment with setmelanotide was withdrawn in patients who had lost weight during the 10‑week open-label period, these patients gained weight (Figure 2) and the mean hunger scores increased over the 4 weeks of placebo treatment. Table 17 Proportion of patients achieving at least 10% weight loss and the proportion of patients achieving at least 25% improvement in daily hunger from baseline at 1 year in Study 2 Parameter Statistic Patients achieving at least 10% weight loss at 1 year (N=11) n (%) 90% CI 1 P-value 2 5 (45.5%) (19.96%, 72.88%) 0.0002 Patients achieving at least 25% hunger improvement from baseline at 1 year (N=11) n (%) 90% CI 1 P-value 1 8 (72.7) (43.56, 92.12) <0.0001 Note: The analysis set includes patients who received at least 1 dose of study drug and had at least 1 baseline assessment. 1 From the Clopper-Pearson (exact) method 2 Testing the null hypothesis: proportion =5% Table 18 Percent change from baseline in weight and hunger at 1 year in Study 2 Parameter Statistic Body weight (kg) (N=7) Hunger score 1 (N=7) Baseline Mean (SD) Median Min, Max 131.7 (32.6) 120.5 89.4, 170.4 7.0 (0.77) 7.0 6, 8 1 year Mean (SD) Median Min, Max 115.0 (29.6) 104.1 81.7, 149.9 4.1 (2.09) 3.0 2, 8 Percent change from baseline to 1 year (%) Mean (SD) Median Min, Max LS Mean 90% CI P-value -12.5 (8.9) -15.3 -23.3, 0.1 -12.47 (-16.10, -8.83) <0.0001 -43.7 (23.69) -52.7 -67, 0 -41.93 (-54.76, -29.09) <0.0001 Note: This analysis includes patients who received at least one dose of study drug, had at least one baseline assessment, and demonstrated ≥5 kg weight loss (or 5% of body weight if weight was <100 kg at baseline) over the 12-week open-label treatment period and proceeded into the double-blind, placebo-controlled withdrawal period. 1 Hunger ranges from 0 to 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. Hunger score was captured in a daily diary and was averaged to calculate a weekly score for analysis. Figure 2 Percent body weight change from baseline by visit (Study 2 [N=7]) Bardet‑Biedl Syndrome Study 3 (RM‑493‑023) The safety and efficacy of IMCIVREE for the treatment of patients aged 6 years and older with obesity due to BBS were assessed in a 1‑year clinical study with a 14‑week placebo‑controlled period (Study 3 [RM‑493‑023]). The study enrolled patients aged 6 years and above with obesity and BBS. Adult patients had a BMI of ≥30 kg/m 2 . Paediatric patients had a BMI ≥97 th percentile for age and sex using growth chart assessments. Eligible patients entered a 14‑week, randomized, double‑blind, placebo‑controlled treatment period (Period 1) followed by a 38‑week open‑label treatment period (Period 2) in which all patients received setmelanotide. To maintain the blind through Period 2, dose titration to a fixed dose of 3 mg was done during the first 2 weeks of both Period 1 and Period 2. Thirty-two patients have been treated for at least 1 year and are included in the efficacy analyses. In Study 3, 35.7% of patients with BBS aged ≥12 years and 46.7% of patients with BBS aged ≥18 years met the primary endpoint, achieving a ≥10% weight loss after 1 year of treatment with setmelanotide (Table 19). The effect of IMCIVREE on body weight in patients assessed by the investigator as cognitively impaired was similar to patients who were not cognitively impaired. In Study 3, ~52 weeks of treatment with setmelanotide resulted in clinically meaningful reductions in BMI Z‑scores occurring in 100% of the BBS patients aged <12 years, with consistent results observed in patients ≥12 and <18 years of age. In patients aged <18 years, the mean reduction from baseline in BMI Z‑score was 0.75 and the mean reduction from baseline in percent of the 95 th percentile for BMI for age and sex was 17.3%. Patients 12 years and older who were able to self‑report their hunger, recorded their daily maximal hunger in a diary, which was then assessed by the Daily Hunger Questionnaire Item 2. Hunger was scored on an 11‑point scale from 0 (“not hungry at all”) to 10 (“hungriest possible”). Statistically significant and clinically meaningful mean percent decreases from baseline at 1 year for most/worst hunger of 30.5% were reported for Study 3 (Table 20). Table 19 Body weight (kg) – proportion of all patients, patients with BBS aged ≥12 years and patients with BBS aged ≥18 years achieving at least 10% weight loss from baseline at 1 year (Study 3 [Full Analysis Set]) Parameter Statistic 1 Patients ≥12 years Patients ≥18 years Patients achieving at least 10% weight loss at year 1 N % 95% CI 1 P‑value 28 35.7 (18.6, 55.9) 0.0002 15 46.7 (21.3, 73.4) 0.0003 1 Estimated %, 95% confidence interval and p‑value are based on Rubin's Rule. P‑value is one‑sided and compared with alpha=0.025. Table 20 Daily hunger scores – change from baseline at 1 year in all patients and patients with BBS aged ≥12 years (Study 3 [Full Analysis Set]) Timepoint Statistic Patients ≥12 years Baseline N Mean (SD) Median Min, Max 14 6.99 (1.893) 7.29 4.0, 10.0 Week 52 N Mean (SD) Median Min, Max 14 4.87 (2.499) 4.43 2.0, 10.0 Change at week 52 N Mean (SD) Median Min, Max 95% CI 1 p-value 1 14 -2.12 (2.051) -1.69 -6.7, 0.0 -3.31, -0.94 0.0010 % Change at week 52 N Mean (SD) Median Min, Max 95% CI 1 p-value 1 14 -30.45 (26.485) -25.00 -77.0, 0.0 -45.74, -15.16 0.0004 Abbreviations: CI=confidence interval; Max=maximum; Min=minimum; SD=Standard Deviation. 1 95% CI and p‑value are based on Rubin's Rule; p‑value is one‑sided. Note: Baseline is the last assessment prior to initiation of setmelanotide in both studies. Note: The Daily Hunger Questionnaire is not administered to patients <12 years or to patients with cognitive impairment as assessed by the Investigator. Supportive of IMCIVREE's effect on weight loss, there were general numeric improvements in cardiometabolic parameters, such as blood pressure, lipids, glycaemic parameters, and waist circumference. Paediatric population Study 4 (RM‑493‑033) The safety and efficacy of setmelanotide for the treatment of patients aged 2 to <6 years with obesity due to POMC or LEPR deficiency or BBS were assessed in a 1‑year open-label, non-controlled study (Study 4 [RM‑493‑033]). The study enrolled patients aged 2 to <6 years with a BMI ≥97 th percentile for age and sex using growth chart assessments and a body weight of at least 15 kg at baseline. Eligible patients entered the study and received setmelanotide. Twelve patients were enrolled in the study and are included in the efficacy analyses. Given the study design and small sample size, efficacy findings require careful consideration. In Study 4, 85.7% of patients with POMC or LEPR deficiency obesity and 80.0% of the patients with BBS met the primary endpoint, achieving a ≥0.2 BMI Z-score reduction after 1 year of treatment with setmelanotide (Table 21). The mean percent change from baseline to Week 52 in BMI was ‑25.597% for patients with POMC or LEPR deficiency obesity and ‑9.719% for patients with BBS (Table 22). Table 21 BMI Z‑score – proportion of all patients, patients with POMC or LEPR deficiency obesity, patients with BBS aged 2 to < 6 years achieving at least 0.2 reduction in BMI Z‑score from baseline at 1 year (Study 4 [safety population]) Parameter Statistic 1 Patients with POMC or LEPR (n=7) Patients with BBS (n=5) Total (N=12) Patients achieving at least 0.2 reduction in BMI Z‑score at year 1 N % 95% CI 1 6 85.7 (54.1, 100) 4 80.0 (28.4, 99.5) 10 83.3 (58.7, 99.8) 1 Two-sided 95% CI was calculated using the Clopper-Pearson Method. Table 22 Percent change in BMI from baseline at 1 year (Study 4 [safety population]) Patients with POMC or LEPR (n=7) Patients with BBS (n=5) Total (N=12) Parameter Statistic % % % Baseline N Mean (SD) Median Min, Max 7 34.347 (7.0673) 32.196 25.99, 42.54 5 23.716 (3.5184) 22.986 19.31, 29.04 12 29.918 (7.8559) 28.670 19.31, 42.54 Actual change from baseline to 1 year N Mean (SD) Median Min, Max 6 -8.250 (3.2392) -9.237 -11.16, -2.65 5 -2.363 (2.1579) -2.191 -4.94, 0.58 11 -5.574 (4.0697) -4.940 -11.16, 0.58 Percent change from baseline to 1 year (%) N Mean (SD) 95% CI 1 Median Min, Max 6 -25.597 (11.4911) (-37.66, -13.54) -23.237 -39.28, -8.24 5 -9.719 (8.8383) (-20.69, 1.26) -8.978 -21.62, 2.54 11 -18.380 (12.8851) (-27.04, -9.72) -21.624 -39.28, 2.54 1 Two-sided 95% CI is calculated with Student's t-distribution. In Study 4, ~52 weeks of treatment with setmelanotide resulted in a clinically meaningful reduction in BMI Z‑score of ‑5.185 for patients with POMC or LEPR deficiency obesity and ‑1.331 for patients with BBS. The mean reduction from baseline in percent of the 95 th percentile for BMI for age and sex was ‑47.595% for patients with POMC or LEPR deficiency obesity and ‑14.462% for patients with BBS. In clinical studies, 54 of the patients treated with setmelanotide were aged 2 to 17 years at baseline (21 patients with POMC, PCSK1 or LEPR deficiency and 33 patients with BBS). Overall, efficacy and safety in these younger patients showed similar trends as seen in older patients studied, with seemingly meaningful decreases in BMI demonstrated. In patients who had not yet completed their growth, a trend towards appropriate progression in pubertal development and increases in height were observed during the study period. In clinical studies, 42 of the patients treated with setmelanotide were aged 6 to 17 years at baseline (14 patients with POMC, PCSK1 or LEPR deficiency and 28 patients with BBS). Overall, efficacy and safety in these younger patients were similar to older patients studied. Significant decreases in BMI were demonstrated. In patients who had not yet completed their growth, appropriate progression in pubertal development and increases in height were observed during the study period. The European Medicines Agency has deferred the obligation to submit the results of studies with setmelanotide in one or more subsets of the paediatric population in treatment of appetite and general nutrition disorders (see section 4.2 for information on paediatric use).