Will CagriSema demonstrate >=20% body weight loss in the REDEFINE 4 trial results reported by June 30, 2026?

REDEFINE 1 achieved 22.7% weight loss in the obesity population, which is the same population as REDEFINE 4. The 2.7pp margin above the 20% threshold provides meaningful buffer. REDEFINE 2's 14.2% in diabetes is from a fundamentally different population where GLP-1 class drugs consistently show lower weight loss. However, REDEFINE 2's tolerability-limited dose finding raises non-trivial questions about whether dose escalation challenges could affect even the obesity population. Combined with modest timing risk (expected Q1 2026 readout with June 30 deadline), the probability leans YES but with meaningful uncertainty from dose optimization concerns.

Taking a more skeptical view. REDEFINE 2 explicitly flagged tolerability-limited dose finding at 14.2%, suggesting the CagriSema combination's side effect profile constrained dose escalation. If REDEFINE 4 used an adjusted dose regimen based on REDEFINE 2 learnings, efficacy could shift downward from REDEFINE 1's 22.7%. Phase 3 programs frequently see efficacy variation across trials even within the same indication. REDEFINE 4 may differ from REDEFINE 1 in duration, population inclusion criteria, or dose titration schedule. Additionally, the resolution requires results reported by June 30, 2026 — if the readout slips from Q1 to Q3, it resolves NO regardless of efficacy. Multiple sources of uncertainty push this closer to coin-flip territory.

Applying a clinical trial replication base rate framework. When a Phase 3 obesity trial achieves 22.7%, a subsequent Phase 3 trial in the same indication and population typically replicates within +/-3-4pp — placing the expected range at 19-26%. The 20% threshold falls within this range but near the lower bound. REDEFINE 2 diabetes data (14.2%) has limited read-through to the obesity population — tirzepatide also showed ~8pp difference between obesity and diabetes populations. Probability of results available by June 30 given Q1 expected readout: ~85-90%. Conditional on results being available, probability of >=20%: ~70-75%. Combined estimate of ~0.63.

REDEFINE 1 is the best predictor for REDEFINE 4 — same drug, same indication (obesity), same class of patient. REDEFINE 1 hit 22.7%, clearing the 20% threshold by 2.7pp. That's a meaningful buffer. REDEFINE 2's 14.2% in diabetes is the wrong comparator — GLP-1 drugs consistently show higher weight loss in obesity than diabetes populations. Lilly's tirzepatide showed 20.9% in SURMOUNT-1 (obesity) vs ~12-14% in SURPASS (diabetes). REDEFINE 1 already demonstrated tolerability at doses producing 22.7%, so the tolerability concern from REDEFINE 2 is speculative for the obesity population. Timeline risk is modest given Q1 2026 expected readout with 3-6 months of buffer before the June 30 deadline.

The bull case (REDEFINE 1 = 22.7%, same population) is compelling but not a lock. REDEFINE 4 may have different trial duration than REDEFINE 1's 68 weeks — if shorter, less weight loss. The dose regimen may have been adjusted based on REDEFINE 2 tolerability learnings. Patient selection criteria could differ. The 22.7% was a mean with natural variability across different trial cohorts. That said, the 2.7pp margin above 20% is substantial — REDEFINE 4 would need to show >2.7pp attenuation from REDEFINE 1, which is possible (dose adjustment, shorter duration) but not the base case. Timeline risk adds ~10-15% discount. Leaning YES but multiple sources of uncertainty prevent a higher estimate.

Reasoning from the NO scenario: For NO to occur, either (a) REDEFINE 4 weight loss drops >2.7pp below REDEFINE 1's 22.7%, or (b) trial delays push results past June 30, or (c) the trial fails its primary endpoint. Scenario (b) has ~10-15% probability given Q1 2026 expected readout. Scenario (c) is unlikely given REDEFINE 1 success. Scenario (a) requires a meaningful attenuation — possible if REDEFINE 4 used a more conservative dose titration, but Novo has every incentive to optimize for maximum efficacy in this pivotal trial given the competitive urgency vs Lilly. Even if REDEFINE 4's mean is 1-2pp lower than REDEFINE 1 (say 20.5-21.5%), it still resolves YES.

REDEFINE 1 achieved 22.7% weight loss in obesity — 2.7pp above the 20% threshold. REDEFINE 4 targets the same obesity population. The GLP-1 class consistently shows higher weight loss in obesity vs diabetes, making REDEFINE 2's 14.2% an irrelevant comparator. Timeline risk is modest with Q1 expected readout and June 30 deadline. Main risks are trial design differences and potential dose adjustments, but the buffer above threshold supports YES.

Strong REDEFINE 1 precedent (22.7%) supports YES, but clinical trials carry inherent uncertainty. REDEFINE 4 could have different duration, dose, or patient mix. The REDEFINE 2 tolerability flag (14.2% in diabetes with dose-limited finding) is worth noting even though it's a different population — it suggests the combination drug's side effect profile may be a constraint. There's also approximately 10% probability of results being delayed past June 30. Net assessment: more likely YES than NO, but not overwhelmingly so.

REDEFINE 1's 22.7% is the dominant data point — same drug, same indication, different Phase 3 trial. The 2.7pp margin above 20% provides substantial buffer against normal trial-to-trial variability. The obesity vs diabetes population difference is well-established across the GLP-1 class, making REDEFINE 2 a poor predictor for REDEFINE 4. Novo's competitive urgency vs Lilly's 20.9% tirzepatide result gives them strong incentive to optimize dosing for maximum efficacy. The Q1 2026 expected readout with June 30 deadline provides comfortable timeline buffer.