In the race to make the most tolerable obesity drug, there seems to be no clear winner—at least not according to analysts parsing the data presented at the American Diabetes Association annual meeting this week.
As the weight loss treatment space reaches a new saturation point, Novo Nordisk, Eli Lilly and their closest—but still distant—competitors continue to vie for a greater share of the ever-expanding market. At the American Diabetes Association’s 85th Scientific Sessions in Chicago this week, they showcased safety data that could set their respective therapies apart.
While Lilly might be sitting pretty on the efficacy side of things—the company’s Zepbound (tirzepatide) generated higher weight loss than Novo’s Wegovy in a head-to-head study published in the New England Journal of Medicine in May—its next-gen candidates ran into safety scrutiny at ADA. But so too did Novo. And analysts were particularly critical of Amgen’s MariTide, which has shown mediocre efficacy in addition to tolerability issues that have similarly challenged weight loss candidates across the board. Viking Therapeutics, on the other hand, got by relatively unscathed, with efficacy and safety data prompting analysts to give the underdog a real shot at breaking into the space.
The Frontrunners Stumble
On Monday, Lilly reported that its investigational antibody bimagrumab, when used alongside Novo’s Wegovy (semaglutide), helps patients lose additional weight while also preserving muscle mass—a key point of consternation for GLP-1 therapies. However, analysts at BMO Capital Markets shared concerns about the candidate’s safety profile, writing in a note to investors, “Transient increases in ALT [alanine aminotransferase, a liver enzyme] and more permanent elevations in lipases give us some pause.”
And while liver enzymes didn’t trip up Lilly’s oral candidate orforglipron—as some analysts had anticipated—in the Phase III ACHIEVE-1 trial in type 2 diabetes, William Blair noted adverse effects in another organ: the stomach. When dosed at the highest level, GI issues like nausea, vomiting and constipation did not appear to taper off as they typically do with GLP-1s like Zepbound and Wegovy, the firm noted. “[We are] concerned by the persistence of both severe and frequent gastrointestinal adverse events beyond the titration period.” Lilly executives on Saturday in an investor call objected to this characterization of at least one side effect observed in the trial, diarrhea, instead attributing it to geographic variabilities.
Meanwhile, Novo sought to offset missed expectations for its highly anticipated CagriSema—long-acting amylin analog cagrilintide combined with semaglutide—by touting a side effect profile “comparable with the GLP1-RA class,” with low dropout rates, in the Phase III REDEFINE-1 and REDEFINE-2 studies. “What people haven’t seen in detail yet is the side effect profile, as in, there will be a lot of comfort in that substantial weight loss potential,” said Martin Holst Lange, executive vice president for development, according to The Financial Times.
However, William Blair analysts pointed to injection site reaction as a potential flaw that could keep CagriSema from succeeding against Zepbound—as the drugs have comparable efficacy. In REDEFINE-1, 12% of patients on CagriSema experienced injection-site reaction adverse events. Separately, the semaglutide and cagrilintide arms clocked 2.6% and 17%, respectively, leading the analysts to conclude that this adverse event is “primarily due to the cagrilintide component.”
Challengers Step Into the Ring
While Lilly and Novo look to secure a foothold for their next-gen weight loss candidates, Amgen is trying to get in the game for the first time. Its opening gambit, MariTide, failed to impress investors when Phase II results released in November 2024 came in lower than 25% weight loss expectations. While Amgen touted 19.9% weight loss, that result only applied to patients who stayed on MariTide for the entire 52 weeks, according to STAT News. When accounting for all participants, including those who discontinued the treatment, that number fell to 16.2%.
In the Phase II trial, nausea and vomiting were the most frequently reported AEs, with those in the obesity arm treated with 420 mg of MariTide every eight weeks seeing the highest rates (92%) and those in the four-week dose-escalation obesity cohort experiencing the lowest rates (43%), according to data published in the New England Journal of Medicine on Saturday.
At ADA, Amgen presented full data from part 1 of the study and hosted a call with management where the company outlined a “3-step dose escalation” strategy. BMO said in an investor note that this “may lead to improved tolerability in Phase III,” but cautioned that efficacy questions remain. “While we are encouraged by the selection of a dosing strategy with more favorable tolerability, we believe the efficacy impact in Phase III is difficult to predict given the lack of a dose response seen in Phase II. We are not throwing the towel in on MariTide but note Amgen’s work is cut out for them with improvements needed in the Phase III.”
Amgen’s two 72-week Phase III trials of MariTide—one studying the drug in patients without type 2 diabetes with obesity or overweight and one in people with type 2 diabetes with obesity or overweight—will randomize patients to one of three target doses. Both studies—aptly named Maritime-1 and Maritime-2—are underway and expected to read out in 2027.
Another obesity player waiting in the wings, Viking Therapeutics, is also expecting topline data from a Phase III trial of VK2735 in mid to late 2027, according to Truist Securities. After reviewing the data from ADA, Truist analysts wrote in a note on Thursday that they are “hard-pressed to find a drug that could de-throne” tirzepatide. However, with VK2735, “as a potential second to market GLP1/GIP dual agonist, with what appears to be better profile than tirzep, [Viking] has a real shot at making material inroads in obesity, even as a later entrant amongst giants LLY and NOVO,” they said.
Truist based this partly on efficacy—the candidate elicited 13.1% placebo-adjusted weight loss at 13 weeks in Phase II—but equally important, they said, is VK2735’s tolerability profile, “which, based on comparison of study discontinuation rates, look competitive.”
GLP-1 therapies are expected to make up nearly 10% of a total $1.75 trillion prescription drug market by 2030, according to a new report by Evaluate, so it’s no wonder Lilly, Novo, Amgen and Viking—among multiple others—are looking for any possible advantage to edge out the competition.
