Topline data position GLP-1 newcomer survodutide as ‘potential leading treatment’ for MASH
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Key takeaways:
- Survodutide improved metabolic dysfunction-associated steatohepatitis in 83% of patients.
- Phase 2 data show improvement after 48 weeks without worsening of fibrosis stages F1, F2 and F3.
Topline findings from a phase 2 trial showed that survodutide achieved “statistically significant improvement” for metabolic dysfunction-associated steatohepatitis and liver fibrosis in 83% of patients, Boehringer Ingelheim announced.
The topline data also demonstrated that survodutide (Boehringer Ingelheim, Zealand Pharma), a glucagon-like peptide-1 receptor agonist, successfully attained biopsy-proven improvement in MASH after 48 weeks without worsening of fibrosis stages F1, F2 and F3. This phase 2 data could place survodutide as a strong contender among competing GLP-1 agonist developers to develop the first pharmacotherapy approved for patients with MASH.
“I am thrilled to see these statistically significant results from the phase 2 trial of survodutide in MASH and fibrosis,” principal investigator Arun Sanyal, MD, professor of medicine, physiology and molecular pathology at Virginia Commonwealth University School of Medicine, said in a press release. “These data position survodutide as a potential leading treatment for a population with great unmet medical needs and will bring hope to people living with MASH and with fibrosis.”
In the double-blind, placebo-controlled phase 2 trial, 295 patients with MASH and fibrosis (stage 1-3) received weekly subcutaneous survodutide with a dose escalation to either 2.4 mg, 4.8 mg or 6 mg. After 48 weeks, the trial met its primary endpoint of biopsy-proven improvement of MASH without worsening of fibrosis. More than 80% of patients who received survodutide achieved statistically significant improvement in MASH compared with just 18% of patients who received placebo a response difference of 64.8% (CI 51.1% - 78.6%; P <.0001).
Additionally, survodutide met all secondary trial endpoints, including a statistically significant improvement in liver fibrosis.
“The MASH results show survodutide has potential to become a best-in-class treatment and we believe its true differentiator is the action of the glucagon receptor agonism which works directly on the liver,” Carianne Brouillon, PharmD, head of human pharma at Boehringer Ingelheim, said in the release. “In order to bring this potential treatment to the more than one billion people affected by interconnected cardiovascular, renal, metabolic diseases, we will move forward as quickly as possible in MASH.”
Brouillon added: “We are also progressing with survodutide in other related conditions, having already initiated our phase 3 clinical trial program for obesity.”
The company noted full data from the phase 2 trial is set to be presented “in the coming months.”
Perspective
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Sobia Nasir Laique, MD
MASLD is rapidly becoming the leading global cause of chronic liver disease complications, including cirrhosis and hepatocellular carcinoma. Fueled by the rising prevalence of obesity and type 2 diabetes, MASLD is projected to become the leading indication for liver transplantation in the United States.
The development of therapeutic agents for treating MASLD with fibrosis is ongoing. While the recent FDA approval of Rezdiffra (resmetirom, Madrigal Pharmaceuticals) signifies a significant advance, most patients will likely require combination therapy to manage their co-existing cardiometabolic comorbidities. GLP-1RAs have demonstrated remarkable success in this regard, having also shown promise in MASH clinical trials.
Survodutide, a glucagon/GLP-1 receptor dual agonist, exhibits encouraging efficacy in this phase 2 clinical trial. Notably, with survodutide, there was a statistically significant improvement in liver fibrosis, which has not been previously observed with GLP-1RAs.
The potential for enhanced therapeutic efficacy of GCGR /GLP-1R dual agonists is attributed to their direct hepatic effects. GCGR agonism promotes increased energy expenditure via hepatic farnesoid X receptor signaling and FGF21 induction. This translates to stimulation of hepatic glucose production (glycogenolysis and gluconeogenesis), enhanced lipolysis and suppression of hepatic steatosis.
The encouraging findings from this trial warrant further evaluation in larger, confirmatory phase 3 studies. MASLD represents a complex, multisystem disorder driven by underlying metabolic dysfunction. Therefore, a comprehensive management strategy is crucial.
This approach, ideally incorporating precision-medicine techniques that address individual patient profiles, should target both hepatic complications and mortality while simultaneously addressing underlying metabolic derangements contributing to MASLD pathogenesis. This multifaceted approach will be essential for achieving optimal patient outcomes.
References
Iruzubieta P, et al. Clin Liver Dis. 2023; doi:10.1016/j.cld.2023.01.016.
Newsome PN, et al. N Engl J Med. 2021; doi:10.1056/NEJMoa2028395.
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