GLP-1 alternative well-tolerated, could lead to similar rate of weight loss
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Key takeaways:
- An amylin alternative to GLP-1s was well-tolerated in otherwise healthy people with overweight or obesity.
- Petrelintide was associated with an up to 8.6% weight loss from baseline to 16 weeks.
SAN ANTONIO — Petrelintide, a novel once-weekly amylin analog, was well-tolerated in a cohort of healthy people with overweight or obesity, while conferring up to 8.6% weight loss at 16 weeks, a speaker reported.
At ObesityWeek, Tim Heise, MD, lead scientist and co-founder of Profil, a company specializing in early phase clinical research in obesity and diabetes, presented data from a phase 1 tolerability trial of once-weekly petrelintide (ZP8396, Zealand Pharmaceuticals) for overweight and obesity.
“You are all aware of the data with the two once-weekly GLP-1 receptor agonist-based therapies that are currently approved for weight management, offering an impressive mean weight loss of 15% to 21%. But you are also aware there are a number of gastrointestinal adverse events, often leading to treatment discontinuation. In fact, there are data showing that discontinuations rated are as high as 70% within 1 year of initiation. So we might need alternative medications, at least for those who don’t tolerate these compounds very well,” Heise said during the presentation. “One candidate might be amylin, which is a pancreatic hormone involved in satiety regulation and has been shown to have high efficacy in metabolic diseases.”
Petrelintide is a novel 36-amino-acid long-acting acylated amylin analog designed for once-weekly subcutaneous delivery. It is chemically and physically stable with a neutral pH and has potent agnostic effect on amylin and calcitonin receptors, according to the presentation.
Heise said in a prior phase 1 single-ascending-dose trial, presented at a poster session at the 2023 American Diabetes Association Scientific Session, petrelintide was well-tolerated and showed potential to reduce body weight.
Therefore, the objective of the present phase 1b multiple ascending dose trial was to observe the safety and tolerability of multiple subcutaneous injections of petrelintide in adults with overweight or obesity, but who were otherwise healthy.
The primary endpoint was treatment-emergent adverse events. Secondary and exploratory endpoints included assessment of petrelintide’s pharmacokinetics and effect on body weight.
A total of 48 people were enrolled into one of four cohorts: maximum dose escalation to 2.4 mg for 12 weeks; maximum dose escalation to 4.8 mg for 8 weeks; maximum dose escalation to 9 mg for 6 weeks; and placebo.
All patients were on treatment for a total of 16 weeks plus 9 weeks of follow-up.
Participants had a mean age of 47 years, 79% were men and mean baseline body weight was 92 kg.
Petrelintide demonstrated dose-proportional pharmacokinetics from 0.6 mg to 9 mg and a terminal half-life of approximately 10 days, and its pharmacokinetic profile was shown to be suitable for once-weekly dosing and demonstrated 85% bioavailability after subcutaneous dosing, Heise said during the presentation.
Overall, three people discontinued treatment, but just one was adjudicated as due to a treatment-related adverse event.
At 16 weeks, Heise and colleagues observed the following weight reductions:
- 4.8% reduction at the 2.4 mg maximum dose (mean baseline weight, 98.1 kg);
- 8.6% reduction at the 4.8 mg maximum dose (mean baseline weight, 89.5 kg);
- 8.3% reduction at the 9 mg maximum dose (mean baseline weight, 87.7 kg); and
- 1.7% reduction in the placebo group (mean baseline weight, 92.7 kg).
Heise said that the observed 16-week reductions in body weight from baseline were similar compared with reductions observed over the same period among people treated with semaglutide, but noted that the STEP 1 semaglutide phase 3 trial had more female participants, who tend to have larger overall weight reductions than men from GLP-1s.
Although 92% to 100% of participants experienced at least one treatment-emergent adverse event in both the petrelintide and placebo groups, the majority of patients continued treatment to 16 weeks, with the most common adverse events being metabolism and nutrition disorders; respiratory, thoracic and mediastinal disorders; and gastrointestinal disorders. Nausea and constipation were the most common gastrointestinal disorders, according to the presentation.
“With all of these caveats, I think it’s fair to say that the data indicate that the 8.6% we saw with petrelintide in body weight loss is in the right ballpark with what we saw with GLP-1 receptor agonists,” Heise said during the presentation. “We conclude that this phase 1 trial demonstrated excellent tolerability of petrelintide and achievement of clinically relevant weight loss after 16 weeks, and therefore, petrelintide will be investigated in a phase 2 obesity trial, which is just about to start.”
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Heise T, et al. Oral-085. Presented at: ObesityWeek; Nov. 3-6, 2024; San Antonio.
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