Rhythm Pharmaceuticals Announces FDA Approval of IMCIVREE® (Setmelanotide) for Use in Patients with Bardet-Biedl Syndrome

Summary :

• IMCIVREE now available for chronic weight management in adult and pediatric patients 6 years of age and older with monogenic or syndromic obesity due to Bardet-Biedl syndrome .
• First and only FDA-approved therapy that targets impairment in the MC4R pathway – a root cause of early-onset, severe obesity and hyperphagia associated with Bardet-Biedl syndrome.
• Approval based on Phase 3 trial results that demonstrated statistically significant reductions in weight and hunger in patients with Bardet-Biedl syndrome.

Rhythm Pharmaceuticals, Inc. (Nasdaq: RYTM), a commercial-stage biopharmaceutical company committed to transforming the care of people living with rare genetic diseases of obesity, today announced that the U.S. Food and Drug Administration (FDA) has approved the Company’s supplemental New Drug Application (sNDA) for IMCIVREE^® (setmelanotide), a melanocortin-4 receptor (MC4R) agonist, for patients with Bardet-Biedl syndrome (BBS).

With today’s approval, IMCIVREE is indicated for chronic weight management in adult and pediatric patients 6 years old and older with monogenic or syndromic obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) deficiency, or BBS.

About IMCIVREE® (Setmelanotide)

• API -Setmelanotide
• Description – Setmelanotide, sold under the brand name Imcivree, is a medication used for the treatment of genetic obesity caused by a rare single-gene mutation. The most common side effects include injection site reactions, skin hyperpigmentation, headache and gastrointestinal side effects, among others.
• Indication -Setmelanotide is indicated for chronic weight management in patients 6 years and older with obesity due to pro-opiomelanocortin deficiency, proprotein subtilisin/kexin type 1 deficiency, or leptin receptor deficiency. These conditions affect the MC4R signalling pathway.
• Associated Therapies -Chronic Weight Management therapy.
• Mechanism of action – Grehlin and other hunger signals from the gastrointestinal tract stimulate orexigenic neurons, stimulating the release of agouti-related protein. Agouti-related protein inhibits melanocortin 4 receptor (MC4R) activation until satiety signals such as insulin or leptin stimulate anorexigenic neurons. Insulin and leptin stimulate production of the POMC-derived melanocortin peptide α-melanocyte simulating hormone, which is a ligand of MC4R.Setmelanotide is a pro-opiomelanocortin derived peptide that is an agonist of MC4R.¹ It is an approximately 20-fold more potent agonist of MC4R than endogenous α-melanocyte stimulating hormone, with an EC₅₀ of 0.27 nM. By directly agonizing MC4R, upstream genetic deficiencies in the MC4R signalling pathway cannot inhibit satiety, food intake is decreased, and weight loss is achieved.

• Absorption -Setmelanotide has a T_max of 8 hours.
• Protein binding -Setmelanotide is 79.1% protein bound.
• Half-life -The elimination had life of setmelanotide is approximately 11 hours.
• Adverse Reactions  –The most common adverse reactions (incidence ≥20%) included skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, and spontaneous penile erection.

“This FDA approval represents a significant milestone for Rhythm, validating our strategy of developing IMCIVREE for people with hyperphagia and severe obesity caused by rare MC4R-pathway diseases and allowing us to provide our precision therapy to an established community of patients living with BBS and their families who are eagerly awaiting a new treatment option,” said David Meeker, M.D., Chair, President and Chief Executive Officer of Rhythm. “Leveraging the robust infrastructure we put in place following the initial approval of IMCIVREE for obesity due to biallelic POMC, PCSK1 or LEPR deficiency and our new high-touch patient support services to assist patients throughout the journey from diagnosis to ongoing treatment, we are able to make IMCIVREE available for BBS immediately. We look forward to delivering this important medicine to the growing community of patients and families in need of options that can effectively address the obesity and hyperphagia that affect many people living with BBS.”

IMCIVREE was initially approved by the FDA in November 2020 for chronic weight management in adult and pediatric patients 6 years of age and older with obesity due to POMC, PCSK1 or LEPR deficiency. IMCIVREE’s label was updated today to include an FDA-approved test developed under a post-marketing commitment to confirm variants in POMC, PCSK1 or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS).

IMCIVREE is not indicated for the treatment of patients with obesity due to suspected POMC, PCSK1 or LEPR deficiency with POMC, PCSK1 or LEPR variants classified as benign or likely benign, or 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.

In clinical trials, IMCIVREE was generally well-tolerated. Disturbance in sexual arousal, depression and suicidal ideation, increased skin pigmentation and darkening of pre-existing nevi, and benzyl alcohol toxicity in neonates and low birth-weight infants may occur. The most common adverse reactions were skin hyperpigmentation, injection site reactions and nausea.

About Bardet-Biedl syndrome (BBS)

BBS is a rare genetic disease that affects approximately 1,500-2,500 people in the U.S. People living with BBS may experience insatiable hunger, also known as hyperphagia, and severe obesity beginning early in life. BBS may also be associated with cognitive impairment, polydactyly, renal dysfunction, hypogonadism, and visual impairment.

About Rhythm Pharmaceuticals
Rhythm is a commercial-stage biopharmaceutical company committed transforming the lives of patients and their families living with hyperphagia and severe obesity caused by rare melanocortin-4 receptor (MC4R) pathway diseases. Rhythm’s precision medicine, IMCIVREE (setmelanotide), is approved by the U.S. Food and Drug Administration (FDA) for chronic weight management in adult and pediatric patients 6 years of age and older with monogenic or syndromic obesity due to POMC, PCSK1 or LEPR deficiency confirmed by genetic testing, or patients with a clinical diagnosis of Bardet-Biedl syndrome (BBS). The European Commission (EC) and Great Britain’s Medicines & Healthcare Products Regulatory Agency (MHRA) have authorized IMCIVREE for the treatment of obesity and the control of hunger associated with genetically confirmed loss-of-function biallelic POMC, including PCSK1, deficiency or biallelic LEPR deficiency in adults and children 6 years of age and above. IMCIVREE is the first-ever FDA-approved and EC- and MHRA-authorized therapy for patients with these rare genetic diseases of obesity. The Company submitted a Type II variation application to the European Medicines Agency seeking regulatory approval and authorization for setmelanotide to treat obesity and control of hunger in adult and pediatric patients 6 years of age and older with BBS in the European Union. Additionally, Rhythm is advancing a broad clinical development program for setmelanotide in other rare genetic diseases of obesity and is leveraging the Rhythm Engine and the largest known obesity DNA database — now with approximately 45,000 sequencing samples — to improve the understanding, diagnosis and care of people living with severe obesity due to certain genetic deficiencies. Rhythm’s headquarters is in Boston, MA.

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