Yet Another Injectable Combo Achieves Near 15% Weight Loss in Trial

SAN DIEGO -- Another investigational treatment containing a GLP-1 receptor agonist induced major weight loss in people with obesity in a phase II study, though a fourth of participants on the study drug discontinued for toxicity.

Once-weekly injectable survodutide -- a glucagon/GLP-1 receptor dual agonist -- helped people in the highest dose group lose an average of 14.9% of their body weight over 46 weeks in the primary analysis based on planned maintenance dose treatment, found Carel Le Roux, MBChB, PhD, of University College Dublin in Ireland, and colleagues.

As shown in the study presented at the American Diabetes Association (ADA) Scientific Sessions, all of the four survodutide doses tested performed significantly better for weight loss compared with placebo:

• Survodutide 4.8 mg: -14.9% average drop in body weight

• Survodutide 3.6 mg: -13.2%

• Survodutide 2.4 mg: -12.5%

• Survodutide 0.6 mg: -6.2%

• Placebo: -2.8%

"We have not achieved the weight nadir," Le Roux said during an ADA press conference. "It's very likely that we will see the weight nadir only being somewhere around 18 months after we start treatment."

These numbers were slightly higher in a sensitivity analysis based on the actual treatment patients ultimately received, as patients who couldn't tolerate gastrointestinal (GI) adverse events during dose escalation could remain on a lower dose than the one they were randomized to. Here, the highest dose yielded an 18.7% body weight loss, followed by 16.7%, 13.6%, and 6.8% weight loss in the 3.6-mg, 2.4-mg, and 0.6-mg groups, respectively, compared with a loss of 2% in the placebo group.

More than 95% of participants on the three higher survodutide doses had weight loss of at least 5% -- the threshold for being clinically relevant -- and about 80% on these doses achieved weight loss of at least 10% in the actual treatment analysis.

With the highest dose of survodutide, two-thirds of participants achieved at least 15% in weight loss. And weight loss dropped by 20% or more in more than a third of participants who stayed on this dose (37.8%).

A total of 387 patients were included in the study, with a mean age of 49, body mass index of 37.1, and body weight of 105.7 kg (233 lb). Survodutide (formerly BI 456906) was first initiated during a 20-week rapid, biweekly dose escalation followed by a 26-week maintenance phase.

As expected, the most common adverse events were GI-related, including nausea (56% for all survodutide doses vs 20% for placebo), vomiting (27% vs 5%), diarrhea (22% vs 10%), and constipation (21% vs 5%). Nausea and vomiting were more common at the higher doses (62-65% and 30-35%, respectively).

Overall, 25% of those on survodutide discontinued treatment for adverse events (including 29% of those on the highest dose) versus 4% of those on placebo. A large share of discontinuations were due to GI-related events (17%) and these occurred most often during the rapid dose escalation phase (prior to week 20), said Le Roux.

"What we are learning is it has to do with our dose escalation," he said, "because if you dose escalate somebody and they feel nauseous and you force titrate them to the next level, they're going to vomit. What we do in clinical practice is simply if you dose escalate somebody and they feel nauseous, you keep them on that dose until the nausea subsides before you dose escalate. But of course in phase II studies, you have to get to the dose."

Rates of GI-related adverse events with survodutide were higher than what's been noted for other anti-obesity agents. For example, 44% of on-treatment participants in the STEP 1 trial of semaglutide 2.4 mg (Wegovy) experienced nausea versus 17% in the placebo group, and only 4.5% on semaglutide discontinued due to GI-related adverse events in that trial.

Survodutide was one of several investigational agents that succeeded in major weight loss trials presented at the ADA meeting -- others of which include the triple agonist retatrutide, a high-dose semaglutide pill in the OASIS 1 trial, and the novel GLP-1 pill orforglipron.

"We don't yet know who will respond to what therapies," commented panel member Ania M. Jastreboff, MD, PhD, of Yale University School of Medicine in New Haven, Connecticut, who headed the retatrutide trial. "Just like for other diseases and diabetes, we don't have one medicine to treat everyone. We really have to think about all the tools that we can have. Different individuals will respond to different therapies."

"We also have to think about individualizing care down the road as these emerge," she added. "Looking at weight-related comorbidities that patients may have and tailor that treatment depending on which therapeutic may actually help those other weight-related diseases."

OASIS 1 lead investigator Filip Knop, MD, PhD, of the University of Copenhagen in Denmark, added that with a more crowded market, we will start to see some of the other obesity drugs dropping in price. Agreeing with this, Lee Kaplan, MD, PhD, of the Obesity, Metabolism, and Nutrition Institute in Boston, who led the retatrutide data on nonalcoholic fatty liver disease, said that the availability of less expensive medications will help to decrease the overall cost burden of care on patients.

"Our next challenge is how do we keep people on these treatments for the rest of their lives," added Le Roux. "Because we know if people are not treating the disease of obesity and discontinue [the treatment], they're probably going to end up heavier than they were when they started."

Co-developers Boehringer Ingelheim and Zealand Pharma said survodutide is also being evaluated in a phase II study in adults with nonalcoholic steatohepatitis (NASH) and liver fibrosis, with results expected in late 2023. In June, the FDA granted fast track designation to survodutide for the treatment of NASH.

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