Survodutide SYNCHRONIZE Phase 3: Dual GLP-1/Glucagon MASH Results

SYNCHRONIZE is the Phase 3 development program for survodutide (BI 456906), a once-weekly dual agonist of the glucagon and glucagon-like peptide-1 (GLP-1) receptors developed jointly by Boehringer Ingelheim and Zealand Pharma. The program comprises SYNCHRONIZE-1 (NCT06309992) in adults with overweight or obesity, SYNCHRONIZE-2 in adults with overweight or obesity and type 2 diabetes, and LIVERAGE in adults with metabolic dysfunction-associated steatohepatitis (MASH). Together they support a dual indication strategy targeting the obesity and MASH markets simultaneously.

The Phase 3 program was initiated in 2024 following positive Phase 2 data in both obesity and MASH populations. Boehringer Ingelheim has publicly committed to a broad metabolic franchise that positions survodutide as a platform asset spanning obesity, MASH, chronic kidney disease, and heart failure with preserved ejection fraction.

Survodutide is a synthetic peptide with dual receptor pharmacology engineered to activate both the GLP-1 and glucagon receptors at approximately balanced potencies. The molecule is lipidated to enable albumin binding and once-weekly dosing, similar to the half-life extension approach used for semaglutide and tirzepatide.

The design rationale combines GLP-1 receptor-mediated appetite reduction, slowing of gastric emptying, and glucose-dependent insulin secretion with glucagon receptor-mediated increases in hepatic fatty acid oxidation and basal energy expenditure. The GLP-1 component also offsets the potential hyperglycemic effect of glucagon receptor activation, resulting in net neutral or favorable glycemic outcomes in most populations studied to date.

SYNCHRONIZE-1 (NCT06309992) is a 76 week randomized, double-blind, placebo-controlled Phase 3 trial enrolling approximately 800 adults with a body mass index of 30 kg per square meter or greater, or 27 kg per square meter with at least one weight-related comorbidity, without type 2 diabetes. Participants are randomized 1:1 to survodutide once weekly or matching placebo, each with lifestyle intervention.

Primary endpoints include percentage change in body weight from baseline to week 76 and the proportion of participants achieving at least 5 percent weight reduction. Secondary endpoints include waist circumference, blood pressure, lipids, HbA1c, and body composition metrics. Dose titration follows a 20 week escalation protocol to mitigate gastrointestinal adverse events that are characteristic of the class.

The Phase 3 program was designed based on Phase 2 data reported in 2023 from a 46 week trial in adults with overweight or obesity without type 2 diabetes. In that trial, participants on the highest 4.8 mg once-weekly dose achieved a mean body weight reduction of approximately 19 percent from baseline, with a dose-response relationship observed across the studied 0.6 mg to 4.8 mg range. The Phase 2 dataset informed the dose selection for SYNCHRONIZE-1, which is evaluating the top tolerable doses identified in earlier development.

The Phase 2 weight loss magnitude places survodutide between semaglutide and tirzepatide in cross-trial efficacy comparisons at comparable timepoints, while the inclusion of glucagon activity differentiates the mechanism. Whether Phase 3 data confirm and extend the Phase 2 efficacy profile at the planned 76 week duration is the central scientific question for the SYNCHRONIZE-1 readout expected in 2026 to 2027.

Metabolic dysfunction-associated steatohepatitis (MASH), previously termed non-alcoholic steatohepatitis (NASH), represents a large underserved indication with the FDA approving only resmetirom (Rezdiffra) as a first targeted therapy in 2024. The prevalence of MASH in populations with obesity and type 2 diabetes is estimated at 15 to 30 percent, creating a significant overlap with GLP-1 therapy candidates.

Survodutide showed strong Phase 2 activity in a 48 week MASH trial with biopsy-confirmed disease. The trial reported MASH resolution without worsening fibrosis in 64 percent of participants on survodutide versus 14 percent on placebo, placing it among the most active investigational therapies in MASH. Boehringer is pursuing a direct MASH indication through the LIVERAGE Phase 3 program and is positioning survodutide as the first dual-indication metabolic therapy.

Regulatory endpoints for MASH drug approval are histological and include resolution of steatohepatitis without worsening fibrosis, improvement in fibrosis by at least one stage without worsening of steatohepatitis, and combined resolution with fibrosis improvement. These endpoints require paired liver biopsies at baseline and at treatment end, which limits enrollment but is regulatory standard.

Survodutide Phase 2 histological data indicated statistically significant improvement in both steatohepatitis resolution and fibrosis improvement endpoints, consistent with the hypothesis that glucagon receptor agonism contributes directly to hepatic fat oxidation and reduction in hepatic lipogenesis in addition to the weight-loss-mediated improvement in liver disease.

In Phase 2 obesity and MASH studies, survodutide showed an adverse event profile dominated by gastrointestinal symptoms consistent with the incretin class: nausea, vomiting, diarrhea, decreased appetite, and constipation, typically mild to moderate and concentrated during dose escalation. Adverse event-related discontinuations in the highest-dose Phase 2 arms were in the 20 to 25 percent range, higher than for semaglutide and tirzepatide at comparable timepoints, attributable at least in part to aggressive dose escalation in Phase 2 designs.

Glucagon receptor-related effects including small increases in resting heart rate and transient hepatic aminotransferase elevations were observed in a minority of participants but did not result in safety signals warranting program modification. Phase 3 dose titration protocols have been adjusted to improve tolerability compared with the Phase 2 regimens.

In the dual and multi-agonist landscape, survodutide (GLP-1/glucagon) sits alongside tirzepatide (GLP-1/GIP, marketed as Mounjaro and Zepbound), retatrutide (GLP-1/GIP/glucagon, Phase 3), CagriSema (semaglutide plus cagrilintide amylin analog, Phase 3), and mazdutide (GLP-1/glucagon, Chinese market Phase 3). The inclusion of glucagon receptor agonism is shared between survodutide, retatrutide, and mazdutide but differs from the GIP-containing tirzepatide.

The MASH dual indication is the most differentiated positioning for survodutide and provides a potential commercial advantage independent of the direct obesity efficacy comparison with tirzepatide or retatrutide. Boehringer has emphasized that the program is designed to deliver survodutide as a best-in-class option for patients with concurrent metabolic and liver disease.

Boehringer Ingelheim and Zealand Pharma announced that SYNCHRONIZE-1 readout is expected in 2026 to 2027, with regulatory submissions to the FDA and European Medicines Agency planned for the late 2027 to 2028 timeframe depending on readout timing and completion of the full Phase 3 dataset. The LIVERAGE Phase 3 in MASH is running in parallel with a planned histological endpoint readout in 2027.

For the research and industry community, the SYNCHRONIZE program is the most advanced Phase 3 dataset for dual GLP-1/glucagon agonism and will provide the most rigorous test of whether the dual mechanism confers differentiated efficacy in obesity and MASH compared with single GLP-1 and dual GLP-1/GIP approaches.