Why Phase 3 Trials Have Not Proceeded for SYNERGY-NASH
The SYNERGY-NASH phase 2b trial for tirzepatide in MASH has not yet advanced to phase 3 primarily due to the extraordinarily high screen failure rate of 87%, which revealed fundamental challenges in patient identification and enrollment that must be addressed before committing to the substantial investment required for a definitive phase 3 trial 1.
The Core Problem: Screen Failure Rates
The SYNERGY-NASH trial screened 1,583 participants but only randomized 190 patients—an 87% screen failure rate 1. This means that for every 100 patients screened, only 13 qualified for the study. Even after implementing protocol amendments to improve patient selection (adding FAST score >0.35 and raising AST cutoff from >20 to >23 U/L), the qualification rate barely improved, moving from 27.5% to only 28.9% 1.
This level of inefficiency makes phase 3 trials operationally and financially prohibitive. Phase 3 trials require hundreds to thousands of patients to demonstrate clinical benefit, and with such poor enrollment efficiency, the timeline and cost become unsustainable.
Why This Matters for Phase 3 Advancement
Operational Feasibility
- Site burden: With qualification rates this low, sites must screen 7-8 patients for every one enrolled, creating massive operational strain
- Timeline extension: Poor enrollment efficiency can extend trial duration by years
- Cost escalation: Each screen failure represents wasted resources in terms of imaging, biopsies, and clinical assessments
Strategic Considerations
The field has learned hard lessons from previous failures. Multiple NASH drugs have failed in phase 3 despite promising phase 2 data 2. The STELLAR-3,4 trial of selonsertib and the RESOLVE-IT trial of elafibranor both failed to demonstrate therapeutic efficacy and were discontinued 2. The FDA rejected obeticholic acid for conditional approval despite showing histological improvement, citing that severe itching and increased cardiovascular risk from elevated LDL-C outweighed treatment benefits 2.
The Histological Endpoint Challenge
A critical issue revealed by SYNERGY-NASH and other trials is the fundamental problem with liver biopsy-based enrollment criteria:
Inter-reader Variability
The EMMINENCE trial demonstrated that approximately 25% of patients who initially qualified were found ineligible upon re-reading of the same digitized slides, and MASH diagnosis was not confirmed in 13% of cases 3. Inter-reader kappa values for key histological features were only moderate: 0.609 for steatosis, 0.484 for fibrosis, 0.328 for lobular inflammation, and 0.517 for ballooning 3.
Sequence Unmasking Issues
The seladelpar trial was prematurely halted due to misinterpretation of end-of-treatment histology when pathologists were not blinded to slide sequence 3. Features initially flagged as safety concerns were later found to be present at baseline and characteristic of MASH itself.
What Needs to Happen Before Phase 3
1. Optimize Patient Selection
The SYNERGY-NASH data showed that non-specialist sites (endocrinology) had better qualification rates (39.3-40.9%) compared to gastroenterology/hepatology sites (20-23.3%) after protocol amendments 1. This suggests:
- Site selection strategy needs refinement
- Non-invasive biomarkers need better validation
- FAST score cutoffs may need further optimization for different practice settings
2. Validate Surrogate Endpoints
The FDA's 2018 draft guidance requires either:
- Resolution of MASH without worsening fibrosis, OR
- Improvement in fibrosis by ≥1 stage without worsening MASH 3
However, the EMA requires BOTH endpoints to be met 3, creating regulatory divergence that complicates global trial design.
3. Address the Confirmatory Trial Requirement
Even if accelerated approval is obtained based on histological surrogates, confirmatory trials are mandatory to verify clinical benefit using time-to-event composite endpoints: histological progression to cirrhosis, decompensation events, liver transplant, MELD score changes, and all-cause mortality 3. These trials require 5-10 years of follow-up.
The Broader Context
Resmetirom became the first FDA-approved drug for MASH in 2024 based on the MAESTRO-NASH phase 3 trial 4. This approval provides a new benchmark and raises the bar for subsequent therapies. Companies must now demonstrate:
- Superiority or non-inferiority to resmetirom
- Differentiated safety profile
- Practical advantages in real-world use
Common Pitfalls to Avoid
Over-interpreting phase 2 data: Multiple NASH trials have shown promising phase 2 results that failed to replicate in phase 3 5, 6, 7
Inadequate phase 2 duration: Studies of 6 months are too short to demonstrate meaningful histological change 8. Most successful trials have been 18-24 months 9, 10
Multiplicity issues: Secondary endpoint analyses without proper statistical adjustment lead to false-positive signals 8
Ignoring site-specific variation: The 15-20 percentage point difference in qualification rates between specialist types cannot be ignored in phase 3 planning 1
The Path Forward
Before advancing to phase 3, sponsors typically need to:
- Refine enrollment criteria using pooled data from phase 2 to identify optimal biomarker cutoffs
- Validate digital pathology workflows with proper blinding and multiple readers
- Secure regulatory alignment between FDA and EMA on acceptable endpoints
- Establish feasibility through site qualification studies
- Optimize the risk-benefit profile based on emerging safety data
The decision not to immediately proceed to phase 3 after SYNERGY-NASH reflects appropriate caution given the 87% screen failure rate and the field's history of expensive phase 3 failures. Additional optimization work is likely underway to improve patient identification and enrollment efficiency before committing to a definitive trial.