SYNCHRONIZE-MASLD Phase 3 Trial Findings on Survodutide
Key Takeaways
- The co-primary endpoints were met, and mean body weight changed by -12.2% with survodutide versus -1.0% with placebo by the efficacy estimand.
- Broader liver-related and cardiometabolic improvements were observed across liver volume, VCTE liver stiffness, ELF, cT1, aminotransferases, waist circumference, blood pressure, glycemia, lipids, HOMA-IR, uric acid, and hsCRP.
- Gastrointestinal adverse events were most common during dose escalation.
SYNCHRONIZE-MASLD was a 48-week, randomized, double-blind, placebo-controlled phase 3 trial conducted at 31 sites in the United States and 1 site in Spain. Adults aged 18 years or older were randomized 2:1 to once-weekly subcutaneous survodutide 6.0 mg or placebo and were stratified by type 2 diabetes status. All participants received diet and exercise counseling.
The treated population included 216 adults, with 146 assigned to survodutide and 70 to placebo; mean baseline MRI-PDFF liver fat was 16.9%. Eligible adults had obesity, defined as BMI at least 30 kg/m2 or at least 27 kg/m2 with an obesity complication, and at-risk MASLD. At-risk MASLD required MRI-PDFF at least 8% plus noninvasive evidence of inflammation or fibrosis or recent biopsy-confirmed MASH, and the co-primary endpoints were at least 30% liver-fat reduction and percentage body-weight change.
By the treatment-regimen estimand, 68.5% receiving survodutide and 28.6% receiving placebo achieved 30% liver-fat reduction, with odds ratio 5.9, 95% CI 2.9 to 11.9, and P<0.0001. Mean body-weight change by the treatment-regimen estimand was -8.7% with survodutide and -1.4% with placebo, with an estimated treatment difference of -7.3%, 95% CI -9.4 to -5.2, and P<0.0001. Mean relative liver-fat change was -58.7% versus -9.5%, with estimated treatment difference -49.2%, 95% CI -61.7 to -36.7, and P<0.0001. A 5% or greater body-weight reduction occurred in 79.1% with survodutide and 14.3% with placebo. Results for the co-primary endpoints were consistent across both estimands.
Secondary measures also favored survodutide across several liver-related and cardiometabolic domains. Liver volume changed by -408.3 ml versus -17.3 ml, and VCTE liver stiffness fell 28.7% versus 9.2%, with estimated treatment difference -19.6%, 95% CI -31.9 to -7.2, and P=0.0021. ELF showed an estimated treatment difference of -0.28, and cT1 changed by -116.8 ms versus -23.9 ms, with 63.0% versus 21.4% reaching at least an 80 ms reduction. ALT changed by -36.8% versus -11.0%, AST by -27.9% versus -7.2%, and waist circumference by -11.1 cm versus -1.9 cm, with estimated treatment difference -9.3 cm. Blood-pressure differences were -7.4 mmHg systolic and -2.7 mmHg diastolic, while MRE liver stiffness showed no difference between groups.
Gastrointestinal adverse events, particularly nausea, vomiting, diarrhea, and constipation, were the most common events and arose mainly during the 24-week dose-escalation period. These events were largely mild to moderate, and 87.0% of participants receiving survodutide versus 78.6% receiving placebo reported at least one adverse event. Treatment discontinuation due to adverse events occurred in 19.9% with survodutide and 4.3% with placebo, while serious adverse events were more frequent in the placebo group.
No adjudication-confirmed drug-induced liver injury, acute pancreatitis, pancreatic cancer, or thyroid cancer occurred in the survodutide group.