• Positive opinion from Committee for Medicinal Products for Human Use recommending approval of Bylvay® (odevixibat) based on Phase III ASSERT clinical-trial data in Alagille syndrome (ALGS) already received in July 2023;
• Committee for Orphan Medicinal Products confirms a negative opinion of its review recommending not to maintain the orphan designation for Bylvay in ALGS;
• Ipsen plans to submit a new Marketing Authorisation Application for the treatment of ALGS by the end of 2023 under a new brand name.
This is despite a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in July 2023. Orphan designation has a strong influence on the reimbursement mechanisms and access for patients to medicines in some countries in the E.U. In order to maintain Bylvay’s orphan designation in the approved treatment of progressive familial intrahepatic cholestasis (PFIC), Ipsen is planning to resubmit to the EMA under a new brand name for the treatment of ALGS by the end of 2023.
“We stand by our commitment to bring as soon as possible a much-needed treatment option to patients with Alagille syndrome and their families in the E.U., as we believe in the potential benefit this medicine could provide to the Alagille community,” said Christelle Huguet, Executive Vice President and Head of Research and Development for Ipsen. “We are disappointed with the opinion of the COMP as the Orphan Medicinal Product Regulation aims to stimulate research and development for rare diseases. The current approach to assessing “significant benefit” threatens to undermine the aims of this Regulation.”
The CHMP and COMP reviewed data from the Bylvay clinical-trial program, including ASSERT, a double-blind, randomized, placebo-controlled Phase III, multi-center efficacy and safety trial conducted in ALGS. Positive data from ASSERT, presented at the 2023 European Society for Pediatric Gastroenterology Hepatology and Nutrition congress, demonstrated that Bylvay provided highly statistically significant and clinically meaningful improvements in pruritus, starting as early as one week after initiation of treatment and were sustained over the 24 weeks of the trial. More than 90% of patients were pruritus responders (≥ one point change at any time during 24 weeks). The overall incidence of treatment-emergent adverse events was similar to placebo. No patients discontinued the trial, and 96% of patients rolled over into the open-label extension trial.
Bylvay received regulatory approval in 2021 in the U.S. as the first medicine-treatment option for patients aged three months or older living with cholestatic pruritus due to PFIC, and for the treatment of PFIC in patients aged six months or older in the E.U. In June 2023, Bylvay also received regulatory approval in the U.S. for the treatment of cholestatic pruritus in patients aged 12 months or older with ALGS.
Bylvay received orphan exclusivity for the treatment of PFIC in the U.S. and the E.U. Bylvay also received orphan designation for the treatment of ALGS in the U.S. and the E.U. In a potential future third indication under development, the rare pediatric cholestatic liver disease biliary atresia, Bylvay received orphan designation in the U.S. and the E.U. and is in late-stage development with the Phase III BOLD trial.
ASSERT Phase III clinical trial data
ASSERT was a double-blind, randomized, placebo-controlled trial designed to evaluate the safety and efficacy of 120 µg /kg/day Bylvay for 24 weeks in relieving pruritus in patients with ALGS with 32 sites across North America, Europe, the Middle East, and Asia Pacific. The trial enrolled patients aged 0 to 17 years with a genetically confirmed diagnosis of ALGS. In the primary analysis, the trial met the primary endpoint showing highly statistically significant improvement in pruritus as measured by the PRUCISION Observer-Reported Outcome scratching score (0-4 point scale), from baseline at month 6 (weeks 21 to 24), compared to the placebo arm (p=0.002). More than 90% of patients were pruritus responders (≥ 1 point change at any time during the 24 weeks). The trial also met the key secondary endpoint, showing a highly statistically significant reduction in serum bile acid concentration from baseline to the average of weeks 20 and 24 (compared to the placebo arm p=0.001). Statistically significant improvements in multiple sleep parameters were observed as early as week 1-4 compared to patients on placebo with continued improvement through week 24. In the trial, there were no patient discontinuations and 96% of patients rolled over into the open-label extension trial. Bylvay had an overall adverse event incidence similar to placebo and a low incidence of drug-related diarrhea (11.4% vs. 5.9% placebo).
About Bylvay® (odevixibat)
Bylvay (bylvay.com) is a potent, once-daily, non-systemic ileal bile acid transport inhibitor that acts locally in the small intestine and has minimal systemic exposure. It is approved in the U.S. for the treatment of pruritus in patients three months of age or older with PFIC, where it has orphan exclusivity. Bylvay was first launched as a treatment option for patients with PFIC in the U.S. in 2021, where it is supported by a program designed to assist with access to treatment and patient support. Bylvay also received regulatory approval in the E.U. for the treatment of PFIC in patients aged six months or older. It has launched in over nine countries and has secured public reimbursement across several major markets including Germany, Italy, the U.K., France and Belgium. In June 2023, Bylvay was also approved in the U.S. for the treatment of cholestatic pruritus in patients from 12 months of age with Alagille syndrome.
Important Safety Information
• PFIC: The most common adverse reactions are diarrhea, liver test abnormalities, vomiting, abdominal pain, and fat-soluble vitamin deficiency.
• ALGS: The most common adverse reactions are diarrhea, abdominal pain, hematoma, and weight decrease.
• Liver Test Abnormalities: Patients should obtain baseline liver tests and monitor during treatment. Dose reduction or treatment interruption may be required if abnormalities occur. For persistent or recurrent liver test abnormalities, consider treatment discontinuation.
• Diarrhea: Treat dehydration. Treatment interruption or discontinuation may be required for persistent diarrhea.
• Fat-Soluble Vitamin (FSV) Deficiency: Patient should obtain baseline vitamin levels and monitor during treatment. Supplement if deficiency is observed. If FSV deficiency persists or worsens despite FSV supplementation, discontinue treatment.
About Alagille syndrome (ALGS)
ALGS is an inherited rare, genetic disorder that can affect multiple organ systems in the body including the liver, heart, skeleton, eyes and kidneys. Liver damage may result from having fewer than normal, narrowed or malformed bile ducts, which leads to toxic bile acid build-up, which in turn can cause scarring and progressive liver disease. Approximately 95% of patients with the condition present with chronic cholestasis, usually within the first few months of life and as many as 88% also present with severe, intractable pruritus. The estimated global incidence of ALGS is 3 in 100,000 live births. Currently in the U.S., it is estimated that there are 1,300 patients who may be eligible for IBATi treatment.
Ipsen (ipsen.com ) is a global, mid-sized biopharmaceutical company focused on transformative medicines in Oncology, Rare Disease and Neuroscience. With total sales of €3.0bn in FY 2022, Ipsen sells medicines in over 100 countries. Alongside its external-innovation strategy, the Company’s research and development efforts are focused on its innovative and differentiated technological platforms located in the heart of leading biotechnological and life-science hubs: Paris-Saclay, France; Oxford, U.K.; Cambridge, U.S.; Shanghai, China.
In March 2023, Ipsen completed the acquisition of Albireo Pharma Inc, a leading innovator in bile-acid modulators to treat rare liver conditions, and the marketing authorization holder of Bylvay.
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