ADA: Safety data offset efficacy for survodutide
Boehringer Ingelheim revealed more data behind previously reported top-line results for its dual-acting obesity drug survodutide, including strong activity against visceral and liver fat.
The efficacy results were, however, undermined by safety concerns, dragging down the share price of Zealand Pharma – which licenses survodutide to privately held Boehringer – and the company was trading more than 25% down this morning.
The sell-off seems to have been prompted by concerns about a high dropout rate due to gastrointestinal side effects with the injectable GLP-1/glucagon agonist, which came in at 19%, versus 2.9% with placebo.
The results come from the SYNCHRONIZE-1 trial in people overweight and living with obesity without diabetes and the SYNCHRONIZE-MASLD study in overweight/obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Both were presented at the American Diabetes Association (ADA) over the weekend.
Boehringer and Zealand revealed in April that in SYNVHRONIZE-1, survodutide achieved weight loss of up to 16.6% at 76 weeks, compared to a 3.2% drop with placebo. At ADA, a subanalysis was also revealed that showed a relative reduction of up to 34.0% visceral fat around organs, which is known to lead to metabolic dysfunction and is closely connected to impaired liver function.
That sub-study also showed that patients treated with survodutide had liver fat reduction of up to 63.1%, which also points to metabolic benefits beyond the overall weight loss result. Overall, the weight loss seen with the drug is roughly in line with that achieved with Novo Nordisk's widely used injectable GLP-1 agonist Wegovy (semaglutide).
Other results suggested that most of the weight loss came from fat, with 10.8% coming from loss in muscle mass, adding to the picture of a positive impact on metabolic health. The SYNCHRONIZE-1 data has now been published in the New England Journal of Medicine.
There was a similar picture in SYNCHRONIZE-MASLD, revealed for the first time at ADA and simultaneously published in Nature Medicine, with 84.2% of survodutide-treated patients achieving a 30% or greater reduction in liver fat versus 24.3% of the placebo group.
Almost two-thirds (61%) of the survodutide group saw their liver fat reduce to normal levels, compared to 5.7% with placebo, and weight loss came in at 12.2% and 1%, respectively.
The big challenge for Boehringer and Zealand Pharma will be to make the case for survodutide's metabolic benefits as a counterpoint to what looks like a less favourable side-effect profile compared to current drugs, like Wegovy and Eli Lilly's dual GIP/GLP-1 agonist Zepbound (tirzepatide).
"There is a critical need for treatments that also drive meaningful improvements in overall metabolic health, and these findings are encouraging for potential new solutions," said Carel le Roux of Imperial College London, the lead author of SYNCHRONIZE-1.
"For patients, improving metabolic health is about more than weight loss alone, it can help reduce the risk of serious complications linked to obesity, including cardiovascular disease, type 2 diabetes, and liver-related conditions, while supporting better long-term health outcomes and quality of life," he added.
One reason for the high toxicity and discontinuation rates could be the use of a rigid dose-escalation regimen in SYNCHRONIZE-1, which investigators said left no leeway to rein back dosing – even temporarily – if side effects appeared. Greater flexibility was introduced later on, but too late to have an impact on the overall result.
Another complication – and one that could affect all obesity studies – was that there was a fairly high weight loss in the placebo group that has been attributed to subjects turning to other medicines when disappointed by progress with their weight loss. Around 15% of the placebo group were obtaining GLP-1 drugs independently of the trial.
Boehringer and Zealand did not reveal any filing plans for survodutide. They are also running two phase 3 trials in metabolic dysfunction-associated steatohepatitis (MASH) – LIVERAGE and LIVERAGE-Cirrhosis – but these are not due to read out until 2029 onwards.
"Obesity is a complex disease linked to how the body manages metabolism. Excess visceral fat, which is found primarily around the abdomen, is a known contributor to metabolic dysfunction and is closely connected to impaired liver function," said Shashank Deshpande, head of human pharma at Boehringer.
"By tackling obesity alongside visceral fat and liver fat, survodutide has the potential to redefine what a targeted weight management therapy can achieve, as we aim to address key drivers of metabolic dysfunction often associated with obesity."
