dm+d

Unassigned

New Medicines

ImcivreeObesity due to leptin receptor (LepR), pro-opiomelanocortin (POMC) or proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiencies in adults and children

Information

Imcivree
New molecular entity
Rhythm
Rhythm

Development and Regulatory status

Phase III Clinical Trials
Approved (Licensed)
Launched
Yes
Yes
Jul 21Approved in EU [24].
May 21Recommended for EU approval by CHMP – the full indication is ‘Imcivree is indicated for the treatment of obesity and the control of hunger associated with genetically confirmed loss-of-function biallelic pro-opiomelanocortin (POMC), including PCSK1, deficiency or biallelic leptin receptor (LEPR) deficiency in adults and children 6 years of age and above’. Imcivree will be available as 10 mg/ml solution for injection [23].
Mar 21Setmelanotide has rare pediatric disease status in US [22].
Mar 21Launched in US [22].
Nov 20U.S. FDA has approved setmelanotide for obesity due to POMC, PCSK1 or leptin receptor deficiency confirmed by genetic testing [21].
Aug 20EMA accept NDA for priority review [19].
Jul 20Filed in EU for treatment of POMC deficiency obesity and LEPR deficiency obesity [18].
Jun 20Has orphan drug status in EU for treatment of POMC and LepR deficiency [17].
May 20FDA accepts the NDA for setmelanotide for treatment of POMC deficiency obesity and LEPR deficiency obesity, grants Priority Review and assigns a Prescription Drug User Fee Act (PDUFA) goal date of November 27, 2020 [16].
Mar 20Granted orphan drug status in US for treatment of alström syndrome [15].
Mar 20Rhythm intends to submit a MAA to the EMA for setmelanotide in patients with POMC deficient and LepR deficiency obesity in Q2 2020 [15].
Mar 20Rhyhm Pharmaceuticals announces it has completed the rolling submission of a NDA to the FDA for setmelanotide for th treatment of POMC deficiency obesity and LEPR deficiency obesity. The company also reported that it has request priority review for the application [15].
Aug 19Rhythm is on track to complete submission of a rolling New Drug Application (NDA) to the FDA that will cover both POMC and LEPR deficiency obesities late in Q4 19 or Q1 20. Rhythm intends to request priority review of the application, which, if granted, could result in a six-month review process. Additionally, Rhythm also expects to submit a Marketing Authorization Application (MAA) with the EMA, which will cover both POMC and LEPR deficiency obesities [14].
Aug 19Rhythm plans to file setmelanotide for approval by the FDA in 2020 [11].
Jul 18EMA grants PRIority MEdicines (PRIME) designation to setmelanotide for treatment of obesity and the control of hunger associated with deficiency disorders of the melanocortin-4 receptor pathway [14].
Jan 18Rhythm confirms plans to file in the US based on one-year data from a cohort of 10 patients. The company currently has eight patients enrolled in its pivotal PIII trial, and expects to complete enrollment of the 10 required patients in H1 18. In addition, the company plans to continue enrolling supplemental patients who may not complete one year of treatment at the time of NDA filing, including patients between six and 11 years of age under the implementation of a pediatric amendment, to provide additional important data regarding the use of setmelanotide in people living with POMC deficiency obesity. The company continues to expect to report initial data from this trial in H1 19 [8].
May 17FDA has expanded a previously granted Breakthrough Therapy Designation (BTD). The expanded BTD is for the treatment of obesity associated with genetic defects upstream of the MC4 receptor in the leptin-melanocortin pathway (the MC4 pathway), which includes both pro-opiomelanocortin (POMC) and leptin receptor (LepR) deficiency obesity [5].
Jan 16Granted orphan drug status in the US for Prader-Willi syndrome [4].
Jan 16Rhythm Pharmaceuticals has an exclusive license from Ipsen to develop setmelanotide in the USA [2].
Jan 16Granted breakthrough therapy status in the US for pro-opiomelanocortin (POMC) deficiency obesity [1].

Category

First-in-class small-peptide, melanocortin-4 receptor (MC4R) agonist.
Patients with POMC deficiency obesity have extreme and unrelenting appetite and obesity because of impaired function in the MC4 pathway [1]. POMC deficiency is a form of monogenic obesity resulting in severe early-onset obesity, adrenal insufficiency, red hair and pale skin. It is has been described in less than 10 patients. Patients with POMC deficiency usually present in the neonatal period with hypoglycaemic seizures, hyperbilirubinaemia and cholestasis [3].
Obesity due to leptin receptor (LepR), pro-opiomelanocortin (POMC) or proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiencies in adults and children
Subcutaneous infusion

Further information

Yes

Trial or other data

Nov 20Analysis of two PIII studies (NCT02896192 and NCT03287960; n=21) found that patients treated with setmelanotide achieved 10% weight loss at approximately 1 year (8/10 pts in POMC trial and 5/11 pts in LEPR trial) suggesting a potential role in the treatment of obesity and hyperphagia caused by POMC or LEPR deficiency [20].
Aug 19Topline data from two PIII studies of setmelanotide show statistically and clinically significant improvement with setmelanotide in treatment of pro-opiomelanocortin (POMC) and leptin receptor (LEPR) deficiency obesity. Eight of ten patients with POMC deficiency obesity met the primary endpoint of >10% weight loss over one year (p10% weight loss over one year (p=0.0001). The drug also met a number of secondary outcomes in both indications [12, 13].
Nov 18PII/III study (NCT03013543) is still recruiting; now due to complete collection of primary outcome datain May 21 [10].
May 18Additional PII data for setmelanotide from 3 pts with leptin receptor deficiency (LepR) obesity show that its effects can extend for >1 year. Setmelanotide achieved significant reductions in hunger feelings and weight for 2 young men, one of whom lost more than 21% body weight over the first 26 weeks of treatment, which was sustained for another 35 weeks. He also saw a reduction from 9 to 1 or 2 on a 10-point hunger scale. The second man also experienced significant weight loss and also saw his hunger score slashed from 9.5 to 2 [9].
Mar 18PII/III study (NCT03013543) is due to complete collection of primary outcome data (effect on weight loss at 1 year) in Sep 18 [7].
Oct 17Rhythm releases efficacy and adverse event data from a PII trial in patients with Bardet-Biedl syndrome (BBS), which includes five patients who presented with morbid obesity and hyperphagia at initiation. Within 6-19 weeks of initiation, four patients experienced cumulative weight loss of 12.1% (17.8 kg), 7.9% (7.9 kg), 9.7% (11.8 kg), and 9.7% (9.5 kg) respectively. One patient showed no weight loss; however, achieved apparent weight stabilization. Hunger scores improved in all patients. Treatment has been well tolerated with adverse effects including mild injection site reactions and increased skin pigmentation [6].
Jul 17PII/III study (NCT02896192) is due to complete collection of primary outcome data (effect on weight loss at 1 year) in Apr 2018 [7].
Feb 17PII/III study to assess the effects of setmelanotide in 10 patients with early onset POMC deficiency obesity due to bi-allelic loss-of function POMC or PCSK1 genetic mutations starts (RM-493-012; NCT02896192). Recruitment will take place in Germany, the UK and France [6].
Jan 17PIIa/III study to determine the effect of setmelanotide on weight, hunger assessments and other factors in 25 patients in the US with rare genetic disorders of obesity, including POMC deficiency, LepR deficiency, Bardet-Biedl syndrome and Alstrom syndrome starts (RM-493-014; NCT03013543) [6].
Dec 16PII trial in US (NCT02311673) complete [4].
Jun 15PII trial to investigate the efficacy of setmelanotide in the treatment of obese patients deficient for the pro-opiomelanocortin POMC gene begins (EudraCT2014-002392-28). The open-labelled, phase II trial is intended to enrol six patients in Germany [2].
Mar 14PI/II study (NCT01867437) completes [2].
May 13Rhythm Pharmaceuticals & the National Institute of Diabetes and Digestive and Kidney Diseases in the US initiate a crossover PIb/II trial to investigate the effect of setmelanotide on energy expenditure in obese patients with a BMI of 30-40kg/m2 (NCT01867437). Setmelanotide will be dosed at 1mg/day for 3 days, and the primary endpoint is resting energy expenditure measured in a room calorimeter, on day 3 of each treatment period. The trial will enrol 12 patients [2].

Evidence based evaluations

ImcivreeObesity and hyperphagia in Bardet-Biedl syndrome or Alström syndrome

Information

Imcivree
Licence extension / variation
Rhythm
Rhythm

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Pre-registration (Filed)
Yes
Yes
Sep 21Rhythm say they remain on track to submit a type II amendment to the EMA in Q4 2021 2021 for both BBS and Alström syndrome.[4]
Sep 21Rhythm Pharmaceuticals files sNDA to the US FDA for Obesity (severe obesity and hyperphagia due to Bardet-Biedl syndrome and Alström Syndrome in adolescents, adults and children). [4-6]
Mar 20Granted orphan drug status for treatment of obesity associated with Alström syndrome in the US. Previous granted orphan status for BBS in the US, and both conditions in the EU. Also has breakthrough status in the US for AS and BBS [3].

Category

First-in-class small-peptide, melanocortin-4 receptor (MC4R) agonist
Prevalence for BBS in Europe is 0.7 per 100,000. It affects around 1 in 100,000 babies born and it is estimated that there are around 560 affected individuals in the UK. Alström Syndrome UK know of about 80families in the UK who are affected but they estimate this figure is an underestimate. AS affects males and females in equal numbers. Exact incidence is unknown; estimates range from 1 in 10,000 to less than 1 in 1 million individuals in the general population [1].
Obesity and hyperphagia in Bardet-Biedl syndrome or Alström syndrome
Subcutaneous infusion

Further information

Yes

Trial or other data

Sep 21Company presents new subgroup analysis of PIII data showing that setmelanotide achieved statistically significant weight loss and hunger reduction vs. placebo at 14 weeks in pts with Bardet-Biedl syndrome. Patients ≥ 12 years treated with setmelanotide (n=14) demonstrated average weight loss of 3.8 kg or 3% of body weight (p<0.05) vs. (n=15) reduction in ‘most hunger score’ of 20.4% from baseline (p<0.05) at 14 weeks. In those < 12 years, those on setmelanotide (n=16) achieved an average BMI reduction of 1.5 kg/m2 (or 3.8%) greater than pts treated with placebo (n=16), p<0.05). [4]
Sep 21Company presents topline analyses from the PII Basket Trial (NCT03013543). Setmelanotide showed clinically meaningful weight loss or BMI-Z reduction and hunger reduction at 3 months in pts with SRC1 or SH2B1 deficiency (weight loss was seen in 9 of 30 pts (30%) with obesity due to variants of the SRC1 gene; and in 15 of 35 (43%) with obesity due to variants of the SH2B1 gene, including 16p11.2 chromosomal deletions. Mean overall weight loss from baseline to 3 months in adults (n=20) was - 4% and mean overall BMI-Z score reduction in children (n=10) was -0.21 - data showed a clear separation between pts who responded to setmelanotide at 3 months and those who did not; mean body weight for adults who responded (n=6) was 7.9% (90% CI, −9.7 to −6.0) vs. 2.3% non-responders (n=14) and in children, BMI-Z reduction in responders (n=3) was 0.48 (90% CI, −0.95 to −0.01) vs. 0.09 (90% CI, −0.11 to −0.07) in non-responders (n=7). Reduction in weight was significant in those with obesity due to SH2B1 variants and 16p11.2 Deletion Syndrome. [4,5]
Mar 21PIII study (NCT03746522) completes [2].
Dec 20Rhythm Pharmaceuticals announces that the PIII trial (NCT03746522) met its primary and all key secondary endpoints, demonstrating statistically significant and clinically meaningful reductions in weight and hunger scores [3].
Dec 18PIII study to confirm the efficacy and safety of setmelanotide, a potent melanocortin receptor type 4 (MC4R) agonist, for the treatment of obesity and hyperphagia in patients with Bardet Biedl syndrome (BBS) or Alström syndrome (AS) starts (NCT03746522). Primary efficacy endpoint will evaluate the proportion of patients (≥12 years of age at baseline) who lose ≥10% of their baseline body weight following approximately (~) 52 weeks of treatment with setmelanotide compared to a historical control rate. The study will consist of 3 treatment periods. Eligible patients will enter a 14 week, randomized, double-blind, placebo-controlled treatment period (Period 1) that will be followed by a 38 week open label treatment period (Period 2) in which all patients will receive setmelanotide. The primary analysis will be performed after Period 2. Following Period 2, patients will continue open-label treatment for 14 weeks (Period 3) after which they may be enrolled into a separate treatment extension study. 52 patients aged 6 years and older will be recruited in the US, UK, Canada, France, Spain and Puerto Rico [2].

Evidence based evaluations