Advanced scarring from fatty-liver disease has no approved treatment today. Three drugs are in late-stage trials to change that.
55%likely
Well sourcedNext check
Digging in
Why it is different
The differentiated bet is an F4-specific approval on a histologic surrogate from three named programs, despite shared fibrosis-endpoint risk.
Why it matters
Right now this ends in a transplant or death. A first approval creates a standard of care where none exists.
Next check · 31 Dec 2026
Does Novo Nordisk publish its SYNCHRONY Real-World Phase 3 headline result by 31 Dec 2026 with no new safety problem in the cirrhosis group?
How we scored it ·
from how similar cases went
If right, how big4/5How overlooked3/5Upside vs downside4/5Source trust4/5Independent sources5/5
The exact wording we score
By 31 Dec 2031, at least one drug from this set fixed on 28 Jul 2026 wins an FDA approval specific to compensated F4 MASH cirrhosis: - Efruxifermin (FGF21, Novo Nordisk via Akero) — SYNCHRONY Outcomes NCT06528314, primary completion Feb-2030. - Resmetirom (THR-β, Madrigal) — MAESTRO-NASH-OUTCOMES NCT05500222, primary completion Dec-2026 est. - Pegozafermin (FGF21, 89bio/Roche) — F4 program. Resolves YES if at least one named drug has that FDA indication at the cutoff; NO otherwise, including if FDA requires hard outcomes rather than histology. No drug may be added after the call.
PROOF
Evidence and provenance
The links below are the evidence recorded when this forecast was scored. Each note states source quality or bias; a citation is not an endorsement.
Recorded sources · 5 citations / 5 independent origins
2026-07-28 | sell-side: F4 approval remains a debated catalyst; mainstream press: acquisition coverage emphasises the contingent value right; priced market: the non-transferable $6 CVR is the defined payoff but has no clean public quote; specialist: hepatology evidence focuses on regulatory-pathway and outcomes risk | E3
Revision history4 entries
Probabilities and interpretations are never silently overwritten. This is the append-only record of what changed and why.
(3rd pass) — Claim raised to class level; P 40→55. The edge here is the race — F4 MASH going from graveyard to three-horse contest while consensus still prices a graveyard — but the claim scored only EFX's histology endpoint, so a Madrigal or 89bio win would have resolved this NO while proving the thesis right. The set is now the three verified F4 programs. EFX stays the expression, not the claim: the $6/share CVR is the convex instrument and remains in the Asymmetry section — separating what you believe from how you'd express it. Component arithmetic shown in the claim: P(FDA grants any F4-specific approval on histologic surrogate by 2031) ≈0.60 × P(≥1 of three delivers in time) ≈0.90 ≈ 0.55. The three are explicitly flagged as correlated, not independent shots — an FDA demand for hard outcomes kills all three at once, which is why this is nearer 0.55 than 1−Πp.
(2nd pass) — Reclassified refclass: phase3-attrition (shared base rate) rather than corrgroup (shared event). Asymmetric-checkpoint defect flagged: the Q4-2026 SYNCHRONY Real-World indicator asks only whether there is NO new safety signal in the F4 stratum, so a Phase 3 efficacy result in cirrhotics — the nearest catalyst, and one this morning's log flagged as 'not referenced anywhere in this signal' — cannot move the probability in either direction. An indicator that can only confirm is not a test. To be rewritten at the next review with an efficacy condition.
v2 rescore. P held at 40. A near-term catalyst this file missed: Novo Nordisk's Q1-2026 report lists 'Efruxifermin Phase 3 results (Fibrosis stage 1-4)' among anticipated Q4-2026 milestones — that is SYNCHRONY Real-World (NCT06161571, primary completion actual 2026-03-03), which enrols F1-F4 non-invasively-diagnosed patients. A 2026 EFX Phase 3 readout containing a cirrhotic subgroup, not referenced anywhere in this signal. Edge recorded as 4→3 (2026-07-23, on the 3-horse F4 race).
created, then deepened same day: corrected NCT, added Novo acquisition + NEJM + competitive field + Week-36 miss; edge→3, sources→5, timing re-anchored 2030–2031, status→investigating.
Method challenge
Adversarial review record
Admitted after revision
Structured internal role review tied to this frozen claim. It is not independent human peer review. Independent specialist review not yet performed
clinical-domain specialist
biostatistics and trial-design reviewer
regulatory reviewer
forecasting-method reviewer
Strongest specialist challenge
F4 histology is vulnerable to biopsy sampling and reader variability, and efruxifermin missed its designated Week 36 primary endpoint before a later signal emerged. The three programs share the same population and regulatory pathway, so they are not independent shots.
Outside view
Late-stage MASH success rates are more relevant than all-drug Phase 3 rates, but no approved precedent yet establishes compensated-cirrhosis histology as sufficient. The 55 percent class estimate correctly discounts the correlated regulatory pathway.
Causal rival
Apparent fibrosis regression can reflect sampling variability, differential dropout, background weight change, or reader effects rather than durable clinical benefit. FDA may require hard outcomes and delay all three programs together despite positive histology.
Measurement risk
The outcome is straightforward only if Drugs@FDA names a compensated F4 MASH cirrhosis indication for one of the three frozen drugs by the cutoff. General MASH approval, subgroup language, filing acceptance, or positive trial data does not count.
Residual risk
Resmetirom and pegozafermin program details are less fully represented in the evidence dossier than efruxifermin. The claim set is frozen, but subsequent review should add direct registry sources for every named program without changing eligibility.
COLDTELL