Imcivree Drug Information

Acquired HO (Adults and Pediatric Patients Aged 4 Years and Older) Clinical

Trial Overview The efficacy of IMCIVREE for weight reduction in adults and pediatric patients aged 4 years and older with acquired HO was assessed in a randomized, double-blinded, placebo-controlled 56- to 60-week clinical trial. The trial enrolled patients 4 years and older with acquired HO due to hypothalamic injury or dysfunction. Adult patients had a BMI of ≥30 kg/m 2 andpediatric patients had a BMI ≥95 th percentile for age and sex.

In Trial 1, eligible patients were randomized to either setmelanotide or placebo and entered an up to 8-week dose titration period followed by a 52-week treatment period. Efficacy analyses were conducted for 142 patients. A total of 142 patients with acquired HO were randomized and analyzed; 47% were adults, 31% were aged 12 to less than 18 years, and 23% were 4 to less than 12 years; 40% were male; 75% were White, 11% were Asian, 5% were Black or African American, and 9% had an unknown or not reported race; 11% were Hispanic or Latino ethnicity and less than 1% had an unknown or not reported ethnicity; and the mean BMI was 36 kg/m 2 (range: 21-70 kg/m 2 ). Effect of IMCIVREE on BMI in Patients with Obesity and a Clinical Diagnosis of Acquired HO The proportion of patients who discontinued trial drug in Trial 1 were 10.6% of the IMCIVREE-treated group and 12.5% of the placebo-treated group.

The primary efficacy parameter was mean percent change in BMI from baseline after 52 weeks on a therapeutic regimen of setmelanotide compared to placebo. After 52 weeks of treatment at the therapeutic dose, the mean percent change in BMI compared to placebo was -18.40% (Table 9), and greater proportions of patients treated with IMCIVREE achieved at least 5%, 10%, and 15% BMI reduction compared to placebo (Table 9 and Figure 1). The cumulative frequency distributions of change in BMI are shown in Figure 1 for Trial 1. One way to interpret this figure is to select a change in BMI of interest on the horizontal axis and note the corresponding proportions of patients (vertical axis) in each treatment group who achieved at least that degree of BMI reduction. For example, a vertical line arising from ‑10% change in BMI in Trial 1 intersects the IMCIVREE and placebo curves at approximately 61%, and 5%, respectively, which correspond to the values shown in Table 1. Note: Based on observed percent change of BMI from baseline after 52 weeks treatment, and patient-level average of 100 multiply imputed datasets (washout MI method) for patients with missing values A reduction of BMI Z-score and BMI 95 th percentile for pediatric patients less than 18 years of age was observed.

In Trial 1, patients 12 years and older who were able to self-report their hunger (n=110), 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”). After 52 weeks of treatment at the therapeutic dose, IMCIVREE resulted in a statistically significant reduction in hunger compared to placebo (Table 10). IMCIVREE resulted in a reduction in waist circumference and general numeric improvements in blood pressure, lipids, and glycemic parameters compared with placebo. image description image description image description

Bardet-Biedl Syndrome (Adults and Pediatric Patients Aged 6 Years and Older) Clinical

Trial Overview The efficacy of IMCIVREE for weight reduction in adults and pediatric patients aged 6 years and older with obesity and a clinical diagnosis of Bardet-Biedl syndrome (BBS) were assessed in a 66-week clinical trial, which included a 14 week randomized, double-blind, placebo-controlled period and a 52-week open-label period (Trial 2 ). The trial enrolled patients aged 6 years and above with obesity and a clinical diagnosis of BBS. Adult patients had a BMI of ≥30 kg/m2 and pediatric patients had weight ≥97th percentile using growth chart assessments. In Trial 2, eligible patients entered a 14-week, randomized, double-blind, placebo-controlled treatment period (Period 1) in which patients received IMCIVREE or placebo, followed by a 52 week open-label treatment period (Period 2) in which all patients received IMCIVREE. To maintain the blind during Period 1, dose titration to a fixed dose of 3 mg given subcutaneously once daily was performed during the first 2 weeks of both Period 1 and Period 2. Efficacy analyses were conducted in 44 patients at the end of Period 1 (Week 14, placebo-controlled data) and in 31 patients during the active-treatment period, defined as the period from randomization to Week 52 in patients initially randomized to IMCIVREE, and from Week 14 to Week 66 in patients initially randomized to placebo. Analyses of the active-treatment period include patients who had either completed 52 weeks from the start of IMCIVREE treatment or discontinued the trial early at the time of the prespecified data cutoff.

A total of 44 patients with obesity and a clinical diagnosis of BBS were enrolled; 50% were adults, 32% were aged 12 to <18 years, and 18% were aged 6 to <12 years; 46% were male; 77% were White, 5% were Black or African American, 2% were Asian, and 16% had an unknown or not reported race; 2% were Hispanic or Latino ethnicity and 14% had an unknown or not reported ethnicity; and the mean BMI was 41.5 kg/m2 (range: 24.4-66.1 kg/m2) at baseline. Effect of IMCIVREE on BMI in Patients with Obesity and a Clinical Diagnosis of BBS In patients aged ≥6 years with obesity and a clinical diagnosis of BBS in Trial 2, the mean percent change in BMI after 52 weeks of IMCIVREE treatment was -7.9% (Table 11), 61.3% of patients achieved a ≥5% BMI decrease from baseline, and 38.7% had a ≥10% decrease in BMI (Table 12). Table 11: Percent Change from Baseline in BMI after 52 Weeks from the Start of IMCIVREE Treatment in Patients Aged ≥6 Years with Obesity and a Clinical Diagnosis of BBS (Trial 2)* Abbreviations: CI = confidence interval; SD = standard deviation *BBS patients (N=31) who completed 52 weeks from the start of IMCIVREE treatment or discontinued the trial early. Five patients who discontinued trial early were defined as 0 percent change.

Statistic Result Baseline BMI (kg/m 2 ) Mean (SD)

Median 41.5 Min, Max 24.4, 61.3

BMI after 52 Weeks (kg/m 2 ) Mean (SD)

Median 39.1 Min, Max 20.4, 60.9 95% CI 35.2, 41.9 Percent Change

from Baseline to 52 Weeks (%) Mean (SD) -

Median -8.8 Min, Max -25.4, 5.3 95% CI -10.4, -5.5 Table 12

Proportion of IMCIVREE-Treated Patients Aged ≥6 Years with Obesity and a Clinical Diagnosis of BBS Who Achieved at Least 5% and 10% BMI Decrease from Baseline After 52 Weeks from the Start of IMCIVREE Treatment (Trial 2) Abbreviations: CI = confidence interval; SD = standard deviation *BBS patients (N=31) who completed 52 weeks from the start of IMCIVREE treatment or discontinued the trial early. Five patients who discontinued trial early were defined as not achieving 5% or 10% reduction. Parameter Statistic Result Patients* Achieving at Least 5% BMI Loss at 52 Weeks % 61.3 95% CI 42.2,

Patients* Achieving at Least 10%

BMI Loss at 52 Weeks % 38.7 95% CI 21.8,

During the 14-week double-blind, placebo-controlled portion of Trial 2 (Period 1), there

was a statistically significant difference in BMI reduction between the IMCIVREE-treated group and the placebo-treated group ( Table 13). Table 13. Percent Change from Baseline in BMI after 14 Weeks of Treatment in Patients Aged ≥6 Years with Obesity and a Clinical Diagnosis of BBS (Trial 2)* Abbreviations: CI = confidence interval; SD = standard deviation *BBS subjects who completed the 14-week double-blind, placebo-controlled period (N=44). Parameter IMCIVREE (N = 22) Placebo (N = 22) Baseline BMI (SD) 41.4

BMI at 14 Weeks (SD) 39.5 41.6 Percent Change from Baseline to

14 Weeks (SD) -4.6 -

Placebo-Adjusted Difference -4.5 95% CI -6.5, -2.5 Effect of

IMCIVREE on Hunger in Patients with Obesity and a Clinical Diagnosis of BBS In Trial 2, patients 12 years and older who were able to self-report their hunger (n=14), 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”). Weekly means of daily maximal hunger scores after 52 weeks from the start of IMCIVREE treatment are summarized in Table 14. Hunger scores decreased in IMCIVREE-treated patients during the 14-week placebo-controlled period and during the open-label treatment period. Table 14: Daily Hunger Scores – Change from Baseline in IMCIVREE-Treated Patients Aged ≥12 Years with Obesity and a Clinical Diagnosis of BBS After 52 Weeks From the Start of IMCIVREE Treatment (Trial 2) Abbreviations: BBS = Bardet-Biedl syndrome; CI=confidence interval; Max=maximum; Min=minimum; NC=Not calculated; SD=Standard Deviation. Note: Baseline is the last assessment prior to initiation of setmelanotide in both trials.

Note: The Daily Hunger Questionnaire is not administered to patients <12 years or to patients with cognitive impairment as assessed by the Investigator. Timepoint Statistic Result Baseline N 14 Mean (SD) 6.99 Median 7.29 Min, Max 4.0,

Change at Week 52 N 14 Mean (SD) -2.12 Median -1.69 Min

Max -6.7,

Supportive of

IMCIVREE’s effect on weight loss, there were general numeric improvements in blood pressure, lipids, and waist circumference. However, because of the limited number of patients studied and the lack of a control group, the treatment effects on these parameters could not be accurately quantified.

POMC

PCSK1, and LEPR Deficiency (Adults and Pediatric Patients Aged 6 Years and Older) Overview of Clinical Trials The efficacy of IMCIVREE for weight reduction in adults and pediatric patients 6 years of age and older with obesity due to POMC, PCSK1, or LEPR deficiency were assessed in 2 identically designed, 1-year, open-label trials, each with an 8‑week, double-blind withdrawal period. Trial 3 ( NCT02896192 ) enrolled patients aged 6 years and above with obesity and genetically confirmed or suspected POMC or PCSK1 deficiency. Trial 4 ( NCT03287960 ) enrolled patients aged 6 years and above with obesity and genetically confirmed or suspected LEPR deficiency.

The trials enrolled patients with homozygous or presumed compound heterozygous pathogenic, likely pathogenic variants, or VUS for either the POMC or PCSK1 genes (Trial 3) or the LEPR gene (Trial 4). In both trials, the local genetic testing results were centrally confirmed using Sanger sequencing. Patients with double heterozygous variants in 2 different genes were not eligible for treatment with IMCIVREE. In both trials, adult patients had a body mass index (BMI) of ≥30 kg/m 2. Weight in pediatric patients was ≥95 th percentile using growth chart assessments. IMCIVREE dose titration occurred over a 2- to 12-week period, followed by a 10-week, open-label treatment period with IMCIVREE. Patients who achieved at least a 5-kilogram 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 withdrawal period lasting 8 weeks, including 4 weeks of IMCIVREE followed by 4 weeks of placebo (investigators and patients were blinded to this sequence). Following the withdrawal sequence, patients re-initiated treatment with IMCIVREE at their therapeutic dose for up to 32 weeks.

Efficacy analyses were conducted in 21 patients (10 in Trial 3 and 11 in Trial 4) who had completed at least 1 year of treatment at the time of a prespecified data cutoff. Six additional patients enrolled in the trials (4 in Trial 3 and 2 in Trial 4) who had not yet completed 1 year of treatment at the time of the cutoff were not included in the efficacy analyses. Of the 21 patients included in the efficacy analysis in Trials 3 and 4, 62% were adults and 38% were pediatric patients aged 16 years or younger.

In Trial 3, 50% of patients were female, 70% were White, and the median BMI was 40 kg/m 2 (range: 26.6‑53.3) at baseline. In Trial 4, 73% of patients were female, 91% were White, and the median BMI was 46.6 kg/m 2 (range: 35.8‑64.6) at baseline. Effect of IMCIVREE on Body Weight in Patients with Obesity due to POMC, PCSK1, or LEPR Deficiency In Trial 3, 80% of patients with obesity due to POMC or PCSK1 deficiency met the primary endpoint, achieving a ≥10% weight loss after 1 year of treatment with IMCIVREE. In Trial 4, 46% of patients with obesity due to LEPR deficiency achieved a ≥10% weight loss after 1 year of treatment with IMCIVREE (Table 15). Table 15: Body Weight (kg) – Proportion of IMCIVREE-Treated Patients with Obesity due to POMC, PCSK1, or LEPR Deficiency Who Achieved at Least 10% Weight Loss from Baseline at 1 Year in Trials 3 and 4 Abbreviations: CI = confidence interval Note: The analysis set includes patients who received at least 1 dose of trial drug and had at least 1 baseline assessment. 1 From the Clopper-Pearson (exact) method 2 Testing the null hypothesis: Proportion =5% Parameter Statistic Trial 3 (POMC or PCSK1) (N=10) Trial 4 (LEPR) (N=11) Patients Achieving at Least 10% Weight Loss at Year 1 n (%) 8 (80%) 5 (46%) 95% CI 1 (44.4%, 97.5%) (16.8%, 76.6%) P-value 2 <0.0001 0.0002 When treatment with IMCIVREE was withdrawn in the 16 patients who had lost at least 5 kg (or 5% of body weight if baseline body weight was <100 kg) during the 10 week open-label period in Trials 3 and 4, these patients gained an average of 5.5 kg in Trial 3 and 5.0 kg in Trial 4 over 4 weeks.

Re initiation of treatment with IMCIVREE resulted in subsequent weight loss (see Figure 2). Table 16: Percent Change from Baseline in Weight in IMCIVREE-Treated Patients Aged ≥6 Years with Obesity due to POMC, PCSK1, or LEPR Deficiency at 1 Year in Trials 3 and 4 (Full Analysis Set) Abbreviations: CI = confidence interval; SD = standard deviation Note: This analysis includes patients who received at least 1 dose of trial drug, had at least 1 baseline assessment. 1 ANCOVA model containing baseline body weight as a covariate 2 Testing the null hypothesis: mean percent change=0 Parameter Statistic Trial 3 (POMC or PCSK1) (N=10) Trial 4 (LEPR) (N=11) Baseline Body Weight (kg) Mean (SD) 118.7

Median 115.0 132.3 Min, Max 55.9, 186.7 89.4, 170.4 1-Year Body Weight

(kg) Mean (SD) 89.8

Median 84.1 120.3 Min, Max 54.5, 150.5 81.7, 149.9 Percent Change from

Baseline to 1 Year (%) Mean (SD) -23.1 -

Median -26.7 -9.8 Min, Max -35.6, -1.2 -23.3, 0.1 LS Mean 1

-23.12 -9.65 95% CI 1 (-31.9, -14.4) (-16.0, -3.3) P-value 2 0.0003 0.0074 Figure 2: Mean Percent Change in Body Weight from Baseline in Patients Aged ≥6 Years with Obesity due to POMC, PCSK1, or LEPR Deficiency by Visit (Trial 3 and Trial 4 ) BL=Baseline (day of first dose) V2 to V3 = variable dose titration period (2 to 12 weeks) V3 to V6 = 10-week open-label treatment period V6 to V8 = 8-week placebo withdrawal period (4 weeks active, 4 weeks placebo) V8 to V12 = 32-week open-label treatment period FV = Final visit; time point for primary efficacy analysis Note: This figure includes patients who had lost at least 5 kg (or 5% of body weight if baseline body weight was <100 kg) during the 10-week open-label period. Effect of IMCIVREE on Hunger in Patients with Obesity due to POMC, PCSK1, or LEPR Deficiency In Trials 3 and 4, patients 12 years and older self-reported their daily maximal hunger in a diary, assessed by the Daily Hunger Questionnaire Item 2. Hunger was scored on an 11-point numeric rating scale from 0 (“not hungry at all”) to 10 (“hungriest possible”). Weekly means of daily hunger scores at Baseline and Week 52 are summarized in Table 17. Table 17: Daily Hunger Scores – Change from Baseline at 1 Year in IMCIVREE-Treated Patients Aged ≥12 Years with Obesity due to POMC, PCSK1, or LEPR Deficiency in Trials 3 and 4 with Available Hunger Data Note: This analysis includes patients aged 12 years and older who received at least 1 dose of study drug and had available data. Three patients in Study 2 had missing hunger data at Week 52. Hunger score was captured in a daily diary and was averaged to calculate a weekly score for analysis.

Hunger ranged from 0 to 10 on an 11-point scale where 0 = “not hungry at all” and 10 = “hungriest possible.” Parameter Statistic Hunger in 24 Hours Trial 3 (POMC or PCSK1(N=8) Trial 4 (LEPR) (N=8) Baseline Hunger Score Median 7.9

Median 7.0, 9.1 5.0, 8.4 1-Year Hunger Score Min, Max 5.5 4.4

Min, Max 2.5, 8.0 2.1,

Change from Baseline to 1 Year Median -2.0 -3.4 Min, Max -6.5

-0.1 -4.7,

Hunger scores generally worsened during the double-blind, placebo withdrawal period among those

patients who had experienced an improvement from baseline, and scores improved when IMCIVREE was reinitiated. Supportive of IMCIVREE’s effect on weight loss, there were general numeric improvements in blood pressure, lipids, glycemic parameters, and waist circumference. However, because of the limited number of patients studied and the lack of a control group, the treatment effects on these parameters could not be accurately quantified.

Figure 1

POMC

PCSK1, and LEPR Deficiency and BBS (Pediatric Patients Aged 2 to Less Than 6 Years) Clinical Trial Overview The efficacy of IMCIVREE for weight reduction in pediatric patients aged 2 to less than 6 years with obesity due to POMC, PCSK1, or LEPR deficiency or BBS were assessed in a 52-week clinical trial. Patients with PCSK1 deficiency were eligible but noneenrolled. POMC and LEPR deficiency were confirmed by genetic testing demonstrating biallelic variants interpreted as pathogenic, likely pathogenic, or of undetermined significance; BBS was diagnosed clinically with genetic confirmation.

Obesity was defined as baseline BMI ≥97thpercentile for age and sex and body weight ≥20 kg. In Trial 5, IMCIVREE dose titration occurred over an 8-week period, followed by a 44-week open-label treatment period with IMCIVREE. Twelve patients were enrolled (3 patients with POMC deficiency, 4 patients with LEPR deficiency, and 5 patients with BBS); 58% were male; 58% were White, 8% were Asian, and 33% had an unknown or not reported race; 8% were Hispanic or Latino ethnicity and 17% had an unknown or not reported ethnicity; and the mean BMI was 29.9 kg/m2 (range: 19-43 kg/m2) at baseline. Efficacy analyses were conducted in all 12 patients at the end of treatment.

Effect of IMCIVREE on BMI in Patients Aged 2 to Less Than 6 Years with POMC or LEPR Deficiency or BBS In Trial 5, 8% of patients discontinued trial drug. The mean percent change in BMI after 52 weeks of IMCIVREE treatment was -33.8%, -13.1%, and -9.7% in patients with POMC deficiency, LEPR deficiency, and BBS, respectively (Table 18). Table 18: Percent Change from Baseline in BMI after 52 Weeks of IMCIVREE Treatment in Patients Aged 2 to Less Than 6 Years with Obesity due to POMC Deficiency, LEPR Deficiency, or BBS (Trial 5) Statistic POMC (N=3) LEPR (N=4) BBS (N=5) Baseline BMI (kg/m 2 ) N 3 4 5 Mean (SD) 27.8 39.3

Median 28.4 41.2 23.0 Min, Max 26.0, 28.9 32.2, 42.5 19.3, 29.0

BMI at Week 52 (kg/m 2 ) N 3 4 5 Mean (SD) 18.3 34.0 2

Median 18.0 32.7 22.2 Min, Max 17.3, 19.7 29.5, 41.1 17.9, 25.2

Percent Change from Baseline to 52 Weeks (%) Mean (SE) -33.8 -13.1 3 -

Median -37.6 -15.1 -9.0 Min, Max -39.3, -24.3 -22.1, 0 -21.6, 2.5

95% CI 1 -54.1, -13.4 -30.4, 4.2 -20.7,

Abbreviations: CI = confidence interval; SD = standard deviation 1 Two-sided 95%

CI is calculated with Student’s t-distribution. 2 Using last observation carried forward (LOCF), the mean BMI (SD), median, min, and max at Week 52 are 34.9, 32.7 29.5, and 44.9, respectively. Using observed data only, the mean BMI (SD), median, min, and max at Week 52 are 31.6, 32.2, 29.5, and 33.1, respectively. 3 Week 52 results are based off baseline observation carried forward (BOCF) for 1 patient lost to follow up after Week 8. Results using last observation carried forward are -10.8 (-34.4, 12.8) and using observed data excluding 1 patient lost to follow up are –17.4 (-37.2, 2.4). Supportive of IMCIVREE’s effect on weight loss, general numeric improvements in waist circumference were observed.