CHMP Recommends Approval of Therapies to Treat the Rare Disorders PFIC and POMC

Rare Daily Staff

The European Medicines Agency’s Committee for Medicinal Products for Human Use) issued positive opinions recommending approval of Albireo’s Bylvay for the treatment of PFIC and Rhythm Pharmaceuticals’ setmelanoitde for the treatment of obesity and the control of hunger associated with confirmed loss-of-function biallelic proopiomelanocortin (POMC), including PCSK1, deficiency or biallelic leptin receptor (LEPR) deficiency in adults and children 6 years of age and above.

A positive CHMP opinion is a scientific recommendation for marketing authorization and one of the final steps before the European Commission (EC) makes a decision on a company’s marketing authorization application (MAA). An EC marketing authorization through the centralized procedure is valid in all 27 European Union member countries as well as the European Economic Area countries Iceland, Liechtenstein and Norway.

Progressive familial intrahepatic cholestasis (PFIC) is a rare devastating disorder affecting young children that causes progressive, life-threatening liver disease. In many cases, PFIC leads to cirrhosis and liver failure within the first 10 years of life. The most prominent and problematic ongoing manifestation of PFIC is pruritus, or intense itching, which often results in a severely diminished quality of life.

Currently, the standard of care is a liver transplant. Bylvay, a potent, once-daily, non-systemic ileal bile acid transport inhibitor (IBATi), could be the first non-surgical treatment for PFIC.

“Today’s positive CHMP opinion for Bylvay brings us one step closer to having the first-ever, non-surgical treatment that could reduce the burden of PFIC on families and children,” said Ron Cooper, president, and CEO of Albireo. “Our hope is to provide children both short-term relief from symptoms such as pruritus and long-term improvements in important parameters such as growth with Bylvay.”

The positive opinion for Bylvay was supported by data from PEDFIC 1 and PEDFIC 2, the largest, global, phase 3 trials ever conducted in PFIC. In PEDFIC 1, a randomized, double-blind study, placebo-controlled study, Bylvay met both its pruritus (p=0.004) and serum bile acid (p=0.003) primary endpoints and was well tolerated with low incidence of diarrhea/frequent bowel movements (9.5% of treated patients vs. 5.0% of placebo patients). PEDFIC 2, a long-term, open-label phase 3 extension study, reaffirmed Bylvay delivered sustained reductions in sBAs as well as improvements in pruritus assessments, growth, and other markers of liver function in patients treated up to 48 weeks. Across both studies, Bylvay was well tolerated with diarrhea/frequent stools being the most common treatment-related gastrointestinal adverse events. No serious treatment related adverse events were observed.

In anticipation of an accelerated approval path for European Commission decision on its marketing authorization application, Albireo expects to be able to launch the drug in the second half of 2021. In addition, Albireo also anticipates an upcoming regulatory decision by the U.S. Food and Drug Administration for the treatment of pruritus in patients with PFIC. The FDA has granted a Priority Review for the NDA and has set an action date of July 20, 2021. Albireo is also studying the use of Bylvay in other rare pediatric cholestatic diseases with the BOLD phase 3 clinical trial in patients with biliary atresia and the ASSERT phase 3 clinical trial in Alagille syndrome. Topline data from the ASSERT trial is expected in 2022, and data from the BOLD trial is expected in 2024.

Rhythm Pharmaceuticals’ setmelanotide, which also received a recommendation for approval from CHMP, is under review for the treatment of obesity and control of hunger associated with confirmed loss-of-function biallelic proopiomelanocortin (POMC), including PCSK1 deficiency or biallelic leptin receptor (LEPR) deficiency in adults and children 6 years of age and above.

POMC, PCSK1 or LEPR deficiency obesities are ultra-rare diseases caused by variants in POMC, PCSK1 or LEPR genes that impair the MC4 receptor pathway, which is a pathway in the hypothalamus that regulates hunger, energy expenditure and, consequently, body weight. People living with obesity due to POMC, PCSK1 or LEPR deficiency struggle with extreme, insatiable hunger beginning at a young age, resulting in early-onset, severe obesity. As an MC4 receptor agonist, setmelanotide is designed to restore impaired MC4 receptor pathway activity arising due to genetic deficits upstream of the MC4 receptor.

“People living with these rare genetic diseases experience early-onset, rapid weight gain and severe, insatiable hunger, and, despite significant effort to control their weight and appetite with supportive care and lifestyle interventions, patients often regain weight after any short-term period of weight loss,” said Karine Clément, professor of nutrition at Pitié-Salpêtrière Hospital, Sorbonne Université and head of the INSERM Nutriomics Laboratory in Paris. “With this positive opinion based on data from the largest clinical trials to date in these patient populations, people living with POMC, PCSK1 or LEPR deficiency obesities in Europe may soon have a therapeutic option with the potential to reduce their hunger and body weight.”

The CHMP opinion on setmelanotide, which has the PRIority MEdicines (PRIME) designation, will now be reviewed by the European Commission. A final decision on the marketing authorization application for setmelanotide is anticipated in July 2021. If approved by the European Commission, setmelanotide would be the first treatment in the EU indicated for these rare genetic diseases of obesity and would be commercialized under the brand name IMCIVREE.

 “We look forward to the European Commission’s decision in the coming months, as we continue to build our global infrastructure to support commercial availability and broaden our ongoing clinical development program to explore setmelanotide’s potential in other rare genetic diseases of obesity,” said David Meeker, chair, president, and CEO of Rhythm.

The CHMP based its positive opinion on the results from two pivotal trials in which setmelanotide achieved statistically significant and clinically meaningful weight loss and reduction in hunger in patients with POMC, including PCSK1, and LEPR deficiency obesity. Across both studies, statistically significant and clinically meaningful reductions in body mass index (BMI) for adults and BMI-Z scores, which represent the number of standard deviations from median BMI by child age and sex, were achieved. These two studies, which are the largest studies conducted in these disease states to date, were identically designed one-year, open-label studies, each with a double-blind, placebo-controlled withdrawal period. Additional supportive data were gathered in an investigator-led study and an ongoing extension study.

IMCIVREE is approved in the United States for chronic weight management in adult and pediatric patients 6 years of age and older with obesity due to POMC, PCSK1 or LEPR deficiency confirmed by genetic testing, and is the first-ever FDA approved therapy for these rare genetic diseases of obesity.