The FDA has granted Breakthrough Therapy designation to Zealand Pharma’s survodutide (BI 456906), a dual glucagon/GLP-1 receptor agonist for the treatment of adults living with non-cirrhotic MASH and moderate or advanced fibrosis (stages 2 or 3). The Breakthrough Therapy designation expedites the development and review of medicines for serious or life-threatening diseases that have shown preliminary clinical evidence indicating substantial improvement over available treatments.
Survodutide is a glucagon/GLP-1 receptor dual agonist that activates both the glucagon and GLP-1 receptors, which play a role in controlling metabolic functions. Survodutide is being evaluated in a robust Phase III clinical development program, including the LIVERAGE studies for people living with MASH and fibrosis and the SYNCHRONIZE studies for people living with overweight or obesity.
In addition, Zealand’s partner, Boehringer Ingelheim announced the initiation of two Phase III clinical trials for survodutide for the treatment of adults living with metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis (scarring).
LIVERAGE will examine whether survodutide can improve MASH and/or fibrosis after 52 weeks of treatment and reduce the risk of end-stage liver disease outcomes after approximately seven years of treatment in approximately 1,800 adults living with MASH and moderate or advanced liver fibrosis (stages 2 or 3). LIVERAGE-Cirrhosis will examine whether survodutide can reduce the risk of end-stage liver disease outcomes after approximately four and a half years of treatment in approximately 1,590 adults living with MASH and compensated cirrhosis (fibrosis stage 4), a condition where the liver presents severe scarring.
“Representing one of the most serious and fastest-growing obesity-related co-morbidities with limited treatment options available today, we are both pleased and excited to see Boehringer Ingelheim advance survodutide into two Phase III trials in MASH in both F2/F3 patients (moderate to advanced fibrosis) as well as F4 patients (cirrhosis),” said Dr David Kendall, Chief Medical Officer of Zealand Pharma. “The US FDA Breakthrough Therapy Designation follows the impressive and groundbreaking Phase II data with survodutide in MASH and fibrosis presented earlier this year which provided evidence of clear differentiation that position survodutide as a potentially leading incretin-based therapy for obesity and MASH in the future.”
LIVERAGE and LIVERAGE-Cirrhosis are global Phase III clinical trials investigating the efficacy and safety of survodutide in adults with MASH and fibrosis stages 2 or 3 and in those with compensated MASH cirrhosis (stage 4), respectively. LIVERAGE will enrol approximately 1,800 adults, and LIVERAGE-Cirrhosis will enrol approximately 1,590 adults. In each trial, participants will be randomized to receive weekly injections of either survodutide, reaching a maximum dose of 6 mg, or placebo.
LIVERAGE consists of two parts. The two primary endpoints of part one are proportion of patients achieving MASH resolution without worsening of fibrosis, and at least a 1-point improvement in fibrosis without worsening of MASH, after 52 weeks of treatment. The primary endpoint of part two, which will continue for approximately seven years, is time to first occurrence of liver-related events or all-cause mortality.
The primary endpoint of LIVERAGE-Cirrhosis, which will continue for approximately four and a half years, is the time to first occurrence of all-cause mortality or liver-related events.
Dasiglucagon
Separately, the FDA has issued a Complete Response Letter (CRL) for Part 1 of the New Drug Application (NDA) for Zealand Pharma’s dasiglucagon for the prevention and treatment of hypoglycemia in paediatric patients 7 days of age and older with congenital hyperinsulinism (CHI) for up to 3 weeks of dosing.
Dasiglucagon is a glucagon receptor agonist that works by causing the liver to release stored sugar to the blood and is being evaluated for the prevention and treatment of hypoglycemia in infants and children with congenital hyperinsulinism. Dasiglucagon is designed to be administered by continuous subcutaneous infusion using a wearable pump system.
The CRL is related to the timing of a reinspection at a third-party contract manufacturing facility that was completed in August/September 2024. The third-party manufacturer has not yet received its inspection classification following the reinspection. A prior inspection of the facility had identified deficiencies that did not involve dasiglucagon. These prior deficiencies had been resolved as of this reinspection. The CRL did not state any concerns about the clinical data package or safety of dasiglucagon.
“We at Zealand Pharma are acutely aware of the significant unmet medical need for newborns and children with congenital hyperinsulinism who have either no or very limited treatment options today,” said Kendall. “We are committed to working with the FDA and our third-party manufacturing partner to bring dasiglucagon to patients living with this devastating disease in the months ahead.”
The regulatory review of dasiglucagon is being conducted in two parts under the same NDA. Part 1 relates to dosing of up to 3 weeks and Part 2 relates to the use beyond 3 weeks. Supporting the use of dasiglucagon in CHI beyond 3 weeks, the FDA requested additional analyses from existing continuous glucose monitoring (CGM) datasets from the Phase 3 clinical program. Zealand expects to submit these data by the end of 2024.
CHI is a severe, ultra-rare genetic disease, primarily affecting infants and children, in which the pancreatic beta cells dysfunction and secrete too much insulin, leading to frequent, recurrent, and often severe episodes of hypoglycemia. Persistent episodes of hypoglycemia can result in seizure, brain damage and death. It is estimated that CHI develops in one out of 50,000 (or more) children, corresponding to 180-300 newborns being diagnosed with the disease in the US and Europe every year.
CHI has a significant impact on patient quality of life. Complex care requirements, including continuous intravenous infusion of glucose, can result in lengthy and frequent hospitalizations and make daily social activities difficult for both patients and their families. The only currently approved medical treatment for hyperinsulinism is diazoxide, which can be associated with increased risk of fluid retention, pulmonary hypertension, and congestive heart failure. Glucagon and the somatostatin analog octreotide may be used but are not approved therapies. It is estimated that more than 50% of CHI patients do not respond adequately to the medical treatment options currently available, so there remains a significant unmet medical need for more and better treatment options.
Comments