New data from Phase 2 ZUPREME-1 trial at the American Diabetes Association 2026 Scientific Sessions further support potential of petrelintide to redefine the weight management experience for people living with overweight and obesity

Zealand Pharma's Petrelintide Shows Double-Digit Weight Loss in Phase 2 ZUPREME-1 Trial

Zealand Pharma announced additional data from its Phase 2 ZUPREME-1 trial of investigational petrelintide, an amylin analog, presented at the American Diabetes Association 2026 Scientific Sessions. The trial demonstrated clinically meaningful, double-digit body weight reductions of up to 10.7% at Week 42 compared to 1.7% for placebo. Petrelintide was well-tolerated, with GI-related adverse events generally similar to placebo and only 1.5% discontinuation due to GI AEs. The treatment also showed improvements in cardiometabolic risk factors like waist circumference, hsCRP, and triglycerides. These results reinforce petrelintide's potential for chronic weight management, with Phase 3 trials planned for initiation in the second half of 2026.

• The ZUPREME-1 trial demonstrated significant efficacy, with participants receiving petrelintide achieving mean reductions in body weight from baseline to Week 42 of up to 10.7%, compared to a 1.7% reduction for placebo (p<0.001). This clinically meaningful double-digit weight loss was observed across all five treatment arms, highlighting petrelintide's potential as an effective long-term therapy for chronic weight management.
• Petrelintide exhibited a favorable tolerability and safety profile, with gastrointestinal (GI)-related adverse events (AEs) generally similar to placebo. Most GI AEs were mild, and notably, only 1.5% of participants discontinued petrelintide due to GI AEs. Nausea was the most common GI AE (19.6% vs 6.2% for placebo), while vomiting was rare, supporting high treatment persistence.
• Beyond weight reduction, petrelintide treatment was associated with meaningful improvements in key cardiometabolic disease risk factors. These benefits included reductions in waist circumference (7.9-10.8cm vs 4.3cm for placebo), high-sensitivity C-reactive protein (17-41% vs 6% for placebo), and triglycerides (12-21% vs 9% for placebo), indicating broader positive health outcomes for patients.

ZUPREME-1: Petrelintide's Double-Digit Weight Loss and Tolerability Profile

Recent clinical investigations in overweight and obesity demonstrate significant advances in both pharmacological and non-pharmacological interventions. These studies span from novel GLP-1 receptor agonists to comparative analyses of established treatments, providing critical insights for clinical decision-making. The evidence encompasses both safety profiles and efficacy outcomes across diverse patient populations.

• LIGHT 1 Study (2024) evaluated efsubaglutide alfa, a novel long-acting GLP-1 receptor agonist, in a multicenter, randomized, double-blind, placebo-controlled phase 2a trial with 50 participants across five dose cohorts (5-20 mg). The study demonstrated mean weight reduction of 7.16% versus 0.86% with placebo, with 82.5% of treated participants achieving ≥5% weight loss compared to 0% on placebo. Safety profile showed predominantly mild-to-moderate gastrointestinal adverse events during dose escalation, with no treatment-related serious adverse events.

• Size Plus Study (India) compared synthetic semaglutide to innovator semaglutide in a phase III multicenter randomized non-inferiority trial with 249 adults with obesity. Both formulations achieved substantial weight loss (-14.39% vs -14.61%), meeting non-inferiority criteria with 86.67% and 83.95% of participants achieving >10% weight loss respectively. Treatment-emergent adverse events occurred in 55.42% of synthetic semaglutide participants versus 54.22% with innovator product, demonstrating comparable safety profiles.

• Mazdutide Meta-Analysis of five randomized controlled trials examined this dual GLP-1 and glucagon receptor agonist in adults with obesity. The analysis revealed significant reductions in percentage body weight (-12.42%), absolute weight (-9.76 kg), and waist circumference (-7.98 cm), along with improvements in systolic blood pressure and lipid parameters. Adverse events showed slight increase (RR = 1.12) but were characterized as mild to moderate in severity.

• Acupuncture Systematic Review (2024) analyzed 20 RCTs with 2,261 participants examining various acupuncture modalities for obesity treatment. Compared to lifestyle interventions, acupuncture provided additional weight loss of 1.72 kg, while demonstrating superior weight reduction of 1.56 kg versus placebo treatments and 3.0 kg versus medications. Safety data was limited, with only one trial systematically reporting adverse events, showing mild effects in 16.7% of acupuncture participants.

• Digital Interventions Systematic Review (2025) evaluated digital health technologies in 15 studies involving 911 pediatric and adolescent participants. Digital interventions combined with conventional care resulted in clinically meaningful fat mass reduction (-2.63%) compared to conventional care alone. However, safety outcomes were not systematically reported across studies, representing a significant knowledge gap in this therapeutic area.

Petrelintide's Amylin Analog MoA and Competitive Landscape

Several long-acting amylin analogues are being developed alongside petrelintide, all targeting amylin receptor (AMYR) agonism for obesity and type 2 diabetes treatment. These represent a second generation of non-aggregating compounds designed based on recent understanding of amylin-calcitonin receptor complex structure and amylin structure-function properties.

Addressing Durability and Tolerability Challenges in Obesity Treatment

Current obesity treatment faces significant systemic and structural challenges that limit its effectiveness across multiple domains. Four major systemic barriers have been identified: uncertainty about which healthcare providers should prescribe and manage obesity pharmacotherapy, the requirement for lifelong treatment to sustain pharmacological benefits, inconsistent third-party reimbursement that restricts patient access, and drug shortages exacerbated by high demand and direct-to-consumer marketing. These challenges are compounded by persistent reimbursement barriers across Medicaid, Medicare, and commercial insurance plans, while drug shortages and the proliferation of compounded formulations raise serious safety and ethical concerns. Additionally, most healthcare professionals lack specific training in obesity management, and existing clinical guidelines rarely address comprehensive rehabilitation interventions.

Treatment effectiveness is fundamentally limited by both pharmacological constraints and patient-related factors. While GLP-1-based agents demonstrate substantial weight reduction, they require ongoing therapy to maintain outcomes, with nearly half of patients discontinuing GLP-1 receptor agonist treatment within one year due to unwanted side effects. The mechanism of these agents can lead to gastrointestinal complications including constipation and diarrhea during treatment, and patients may experience greater difficulty maintaining weight loss and stable glucose control after discontinuation since the appetite-suppressing and glycemic-regulating effects are no longer present. Furthermore, obesity intervention demands high self-discipline and compliance from individuals, which often makes weight loss less predictable and prone to rebound, while emotional eating serves as a learned coping strategy that represents one of the biggest intrapersonal obstacles to effective weight control.

Knowledge gaps and awareness deficiencies represent another critical limitation in current treatment approaches. The vast majority of individuals remain unaware that evidence-based nutrition counseling, weight loss medications, and bariatric surgery are legitimate therapeutic options for overweight and obesity. Large proportions of the population lack awareness about key risk factors including family history, age, inadequate vegetable and fruit intake, low socioeconomic status, smoking, medications, stress, and insufficient sleep. This knowledge deficit extends to both prevention and treatment approaches, contributing to the insufficient success of current interventions despite the increasing prevalence of overweight and obesity in developed societies. The treatment landscape is further constrained by the reality that obesity management remains in a preliminary developmental stage, with a relative lack of effective options for early diagnosis, treatment, and long-term management.

Amylin Analog Petrelintide: A Potent New Player in Weight Management

Zealand Pharma's recent Phase 2 ZUPREME-1 trial data for petrelintide, a dual amylin and calcitonin receptor agonist (DACRA), marks a significant moment in the evolving landscape of chronic weight management. The reported double-digit body weight reductions, reaching up to 10.7% at Week 42, are clinically meaningful and position petrelintide as a strong contender. Beyond weight loss, the observed improvements in cardiometabolic risk factors such as waist circumference, hsCRP, and triglycerides suggest a broader therapeutic benefit for patients grappling with obesity and its associated comorbidities.

A key differentiator highlighted by these results is petrelintide's favorable tolerability profile. While gastrointestinal side effects, particularly nausea, are common during the initiation of amylin analogues and GLP-1R agonists, the low 1.5% discontinuation rate due to GI adverse events in this trial is particularly encouraging. This could provide a crucial advantage in patient adherence and overall treatment success, offering a potentially more tolerable option in a market where GI issues can limit uptake.

However, the strategic path forward for petrelintide is not without its complexities. The obesity treatment paradigm is rapidly advancing, with the emergence of multi-agonists that combine amylin receptor activation with other mechanisms, such as GLP-1R agonism. CagriSema, a co-formulation of cagrilintide (an AMYR/CTR agonist) and semaglutide (a GLP-1R agonist), and the unimolecular AMYR/CTR/GLP-1R multi-agonist amycretin, represent formidable competition. These agents have demonstrated robust efficacy, and petrelintide will need to prove its competitive edge in larger Phase 3 trials.

Furthermore, while petrelintide shows strong clinical promise, research indicates that its agonistic activity might be 'insufficient' compared to natural agonists, with more efficient DACRAs like BGM1812 already in preclinical development. This suggests a potential for future generations of even more potent amylin-based therapies, which could impact petrelintide's long-term market share. Successfully navigating these competitive and scientific dynamics will be crucial as Zealand Pharma prepares to initiate Phase 3 trials in the second half of 2026, aiming to solidify petrelintide's place as a valuable new therapeutic option.