For the second time in a week, Zealand Pharma’s weight loss pipeline has delivered mixed results, this time in a Phase 2 trial for the Roche-partnered asset petrelintide.
Zealand Pharma’s Roche-partnered obesity asset cut weight to a degree William Blair analysts dubbed “intriguing,” but the asset “underwhelmed” on blood sugar reduction for diabetes. The mid-stage readout was the second from Zealand’s pipeline of next-gen weight loss assets to disappoint investors in a week.
In the Phase 2 ZUPREME-2 trial, petrelintide, a long-acting human amylin analog, achieved up to 9.2% mean weight loss at week 28 depending on the dose, compared to just 2% for placebo comparators, according to Zealand’s Thursday press release. The study, which featured 220 patients with obesity or overweight who also had type 2 diabetes (T2D), therefore hit its primary endpoint of statistically significant and clinically meaningful reductions in body weight at that time point, compared to placebo.
The results—which were based on efficacy estimand, or the estimated treatment effect assuming patients remained on treatment for the duration of the study—are in line with Eli Lilly’s rival amylin receptor agonist eloralintide and the approved GLP-1 Zepbound, William Blair analysts said in a Wednesday afternoon note. Both of those drugs achieved about 7% placebo-adjusted weight loss at the same time point, according to the firm. Meanwhile, Zealand’s asset outperformed Novo’s Wegovy, which notched 4–5% weight loss in that time frame.
Nevertheless, William Blair analysts said they were “disappointed” the asset did not yield greater weight loss.
Moreover, petrelintide only reduced A1C, a measure of average blood sugar levels that is used as key marker of disease control in T2D, at a rate of up to 0.65% compared to an increase of 0.23% for placebo participants, according to Zealand’s release. The aforementioned rival therapies achieved A1C reductions within a range of 1.3%–2.1%, William Blair said. The firm was also concerned by the increase seen in the placebo arm, which is “unusual in the context of obesity and/or T2D studies.”
On a more positive note, safety results were as expected, leaving William Blair with continued conviction in the asset’s differentiated tolerability profile. Gastrointestinal-related adverse events did crop up, but most were mild and occurred during the escalation period, and resulted in a discontinuation rate due of just 1.9% of participants in the treatment arm, versus 1.7% of those taking placebo. The therapy seems to provide “an improved treatment experience” over approved weight loss drugs like Wegovy and Zepbound, the analysts said.
“Overall, based on the collective Phase II ZUPREME-1 and ZUPREME-2 trial results, we believe petrelintide demonstrated highly encouraging tolerability, though the magnitude of weight loss (along with HbA1c reduction in ZUPREME-2) disappointed,” William Blair wrote. “Our current view is that petrelintide will likely be used primarily in the maintenance setting, which demands a therapeutic intervention that exhibits placebo-like tolerability for chronic use.” Petrelintide could also find a foothold in the overweight segment of the market, helping these patients lose weight without safety concerns and improve cardiovascular risk, the firm added.
The ZUPREME-2 reveal comes a week after Zealand and partner Boehringer Ingelheim reported disappointing Phase 3 weight loss results for the glucagon/GLP-1 receptor dual agonist survodutide.
Similar to the new petrelintide readout, survodutide underperformed expectations. The company reported weight loss of up to 13.1% at 76 weeks, but an adjacent publication in The New England Journal of Medicine put the value at 9.8% for patients who received the highest dose.
Shares of Zealand dropped more than 8% to $248.50 on the Danish market following last week’s results, and trended further down today, resting at around $240 as of publication.
The mixed results won’t hold back petrelintide, however. Zealand and Roche recently kicked off a Phase 3a program for the asset. ZUPREME-3, ZUPREME-4 and ZUPREME-5 will include 7,000 patients with obesity or overweight without T2D, with T2D and with cardiovascular disease, respectively.
But after a busy few weeks of readouts, investors will have to wait a while for the next big catalyst for Zealand, William Blair pointed out. The company does have a strong cash position, share buyback program and a deep pipeline.
“While we believe these factors should support long‑term value creation and eventual share price appreciation, the lack of meaningful catalysts within the next year that could alter investor sentiment on petrelintide limits near-term upside and supports a more balanced risk/reward profile,” the firm wrote.
Roche licensed petrelintide in March 2025 to pair with its own dual GLP-1/GIP receptor agonist CT-388. The deal offered Zealand $1.65 billion upfront, while the total deal value, including milestones and other payments, could reach $5.3 billion.
