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Clinical trials landscape

TL;DR — On 2026-09-02, the exact ClinicalTrials.gov union query (MASLD OR NAFLD OR MASH OR NASH OR "steatotic liver disease") held 2,056 studies, including 181 interventional and recruiting and 112 phase 3 across all statuses; 17 phase 3 studies were recruiting. The pipeline has three distinct layers. The first is the outcome layer: resmetirom's MAESTRO-NASH continues to 2028 (NCT03900429, n=1,759) and MAESTRO-NASH OUTCOMES runs in well-compensated MASH cirrhosis to December 2026 (NCT05500222, n=845), while semaglutide's ESSENCE runs to April 2029 (NCT04822181, n=1,205). The second is a crowded phase 3 field of FGF21 analogues, incretins and lanifibranor. The third is precision medicine: HSD17B13 and PNPLA3 silencers and AstraZeneca's completed AZD2693 phase 2 (NCT05809934, n=220). Accelerated-approval readouts remain histology-based, but confirmatory and newer phase 3 programmes include hard clinical composites.

All NCT records in this page were retrieved from the ClinicalTrials.gov v2 API on 2026-09-02.

Scale of the field

Query (ClinicalTrials.gov v2 API, 2026-09-02) Count
query.cond=(MASLD OR NAFLD OR MASH OR NASH OR "steatotic liver disease") 2,056
…plus AREA[OverallStatus]RECRUITING AND AREA[StudyType]INTERVENTIONAL 181
…plus AREA[StudyType]INTERVENTIONAL AND AREA[Phase]PHASE3 112
…plus AREA[OverallStatus]RECRUITING AND AREA[StudyType]INTERVENTIONAL AND AREA[Phase]PHASE3 17

Seventeen actively recruiting phase 3 studies against 112 registered ones is the number that characterises this field better than the headline 2,056: the pipeline is broad at registration and narrow at the point where patients are actually being enrolled into pivotal trials.

The outcome trials that will decide the approvals

NCT Agent Phase Status n Start Primary completion Sponsor
NCT03900429 Resmetirom (MAESTRO-NASH) 3 Active, not recruiting 1,759 2019-03-28 2028-01 Madrigal
NCT05500222 Resmetirom, clinical outcomes in well-compensated MASH cirrhosis 3 Active, not recruiting 845 2022-08-26 2026-12 Madrigal
NCT04951219 Resmetirom, safety and biomarkers (MAESTRO-NAFLD-OLE) 3 Active, not recruiting 810 2021-07-09 2027-03 Madrigal
NCT04822181 Semaglutide (ESSENCE) 3 Active, not recruiting 1,205 2021-04-01 2029-04-25 Novo Nordisk

Both approved drugs were licensed on interim histological analyses of these trials (resmetirom and thyromimetics, GLP-1 and incretin therapy). Their conversion to full approval depends on the outcome phases, the earliest of which completes in December 2026.

Phase 3 pipeline, by mechanism

FGF21 analogues — the most crowded class, and the one with the largest reported phase 2 fibrosis effects.

NCT Agent Population n Status Primary completion
NCT06215716 Efruxifermin non-cirrhotic MASH 1,650 Recruiting 2033-02
NCT06528314 Efruxifermin compensated cirrhosis due to MASH 2,150 Recruiting 2030-02
NCT06161571 Efruxifermin non-invasively diagnosed MASH 700 Active, not recruiting 2026-03-03
NCT06318169 Pegozafermin MASH with fibrosis 1,350 Recruiting 2029-02
NCT06419374 Pegozafermin compensated cirrhosis 762 Recruiting 2028-06
NCT07221188 Efimosfermin alfa safety/tolerability 1,250 Recruiting 2028-03-24
NCT07221227 Efimosfermin alfa biopsy-confirmed 1,200 Recruiting 2028-03-29
NCT07701993 Efimosfermin alfa pivotal 1,740 Recruiting 2033-07-27
NCT07704892 Efimosfermin alfa — 380 Recruiting 2030-10-16

Incretins and multi-agonists

NCT Agent Population n Status Primary completion
NCT06632444 Survodutide (LIVERAGE) MASH/NASH 1,800 Recruiting 2031-12-27
NCT06632457 Survodutide (LIVERAGE-Cirrhosis) cirrhosis 1,590 Recruiting 2029-06-05
NCT07165028 Tirzepatide and retatrutide, master protocol MASLD 4,500 Recruiting 2030-08
NCT07795164 Pemvidutide MASH 1,800 Recruiting 2028-12
NCT06884293 IBI362 vs semaglutide Chinese adults with overweight/obesity and MASLD 479 Active, not recruiting 2026-12-31

Other mechanisms

NCT Agent n Status Primary completion
NCT04849728 Lanifibranor (pan-PPAR agonist) 1,000 Active, not recruiting 2027-09-30
NCT07265297 Hydroxychloroquine 210 Recruiting 2030-12-31
NCT04833140 Transdermal estradiol in postmenopausal women with NASH 50 Active, not recruiting 2027-07-09
NCT06461208 Encapsulated faecal microbiota transplantation in cirrhosis 300 Recruiting 2028-01-31

The Eli Lilly master protocol (NCT07165028, n=4,500) is the largest study in the field and the first to test multiple agents under one protocol, which will produce internally comparable arms — something the cross-trial comparisons in this condition badly lack.

Precision medicine: genotype-directed trials

NCT Agent Target Phase n Status Sponsor
NCT05519475 ALN-HSD (rapirosiran) HSD17B13 siRNA 2 120 Recruiting Regeneron
NCT05648214 ALN-PNP PNPLA3 siRNA 1/2 172 Recruiting Regeneron
NCT07527910 ALN-PNP ± tirzepatide PNPLA3 siRNA + GLP-1/GIP 2a 204 Recruiting Regeneron
NCT05809934 AZD2693 PNPLA3 antisense 2 220 Completed 2025-07-14 AstraZeneca
NCT04142424, NCT04483947, NCT05107336, NCT05919069 AZD2693 PNPLA3 antisense 1 73 / 74 / 44 / 35 Completed AstraZeneca
NCT06322628 VSA006 siRNA 2 48 Active, not recruiting Visirna

This is the only part of the pipeline where trial eligibility is defined by genotype rather than histology. AZD2693's phase 2 (n=220) completed in July 2025 with results not yet retrieved in the published literature; the phase 1 programme is reported in Armisen 2025 (PMID 39798707). NCT07527910 is the first trial to combine a genotype-directed silencer with an incretin — the combination question that GLP-1 and incretin therapy identifies as untested. See genetics.

The failures, and what they cost

NCT Agent Phase n Outcome
NCT02548351 Obeticholic acid (REGENERATE) 3 2,477 Terminated 2023-09-15 (interim results published: Younossi 2019, PMID 31813633)
NCT02704403 Elafibranor (RESOLVE-IT) 3 2,157 Terminated 2020-10-28
NCT03053063 Selonsertib (STELLAR-4) 3 883 Terminated 2019-05-06 (published: Harrison 2020, PMID 32147362)
NCT06594523 Denifanstat 3 0 Withdrawn before enrolment, despite a positive phase 2b (Loomba 2024, PMID 39396529)

Roughly 5,500 participants were enrolled into the three terminated phase 3 programmes. The denifanstat withdrawal is the more instructive case: a phase 2b that met both primary endpoints (38% vs 16% for ≥2-point NAS improvement, p=0.0035) did not proceed, which is a commercial-landscape decision rather than a scientific one now that two drugs are approved.

The surrogate-endpoint problem

Accelerated-approval efficacy readouts in pivotal MASH trials use one or both of two histological endpoints defined by the NASH CRN system. Several confirmatory and newer phase 3 programmes also include hard clinical composites: NCT05500222, NCT06632457 and NCT07165028 use clinical outcomes as primary endpoints, while NCT03900429, NCT04822181, NCT06215716, NCT06528314 and NCT07795164 pair histology with later event-based assessment.

  1. Resolution of steatohepatitis with no worsening of fibrosis (often with a NAS reduction ≥2).
  2. Fibrosis improvement ≥1 stage with no worsening of steatohepatitis or NAS.

Three problems compound:

  • The endpoint is not the prognostic variable. Fibrosis stage predicts outcomes; steatohepatitis, as histologically diagnosed, adds little once fibrosis is known (natural history; Hagström 2017, PMID 28803953; Akbari 2024, PMID 38293684). Yet MASH resolution is a co-primary endpoint in nearly every trial.
  • The endpoint is noisily measured. Inter-rater κ is 0.45–0.56 for lobular inflammation and ballooning versus 0.84 for fibrosis, and NAS ≥5 misclassifies steatohepatitis in both directions (histology and biopsy; Kleiner 2005, PMID 15915461; Brunt 2011, PMID 21319198).
  • Surrogate validity has never been demonstrated as treatment-effect transfer. Taylor's systematic review concluded that further studies are needed to establish that change in fibrosis stage is a valid trial endpoint (PMID 32027911), and that conclusion has not been superseded.

Meanwhile, non-invasive tests can match or outperform histology in selected cohorts for predicting the events the surrogate is standing in for: 5-year tAUC 0.76 for LSM-VCTE versus 0.72 for histology (Mózes 2023, PMID 37290471), and ANTICIPATE-NASH C statistic 0.93 versus 0.67 for histology in F3–F4 (Aceituno 2026, PMID 41212130). Digital pathology is being developed explicitly to address the limitations of conventional histology in drug development (Sanyal 2024, PMID 37789057).

The recruitment bottleneck, and the biomarkers meant to relieve it

The practical constraint on this field is not ideas but biopsies. Trials enrol on histology, so most screened patients are biopsied and then rejected — the screen-failure rate is the hidden cost of every programme. The LITMUS consortium measured how far non-invasive markers could relieve it, comparing 17 biomarkers and multimarker scores against paired liver histology in 966 participants from the European NAFLD Registry across 13 countries (335 [35%] with at-risk NASH, 271 [28%] with advanced fibrosis) (Vali 2023, PMID 36958367):

Target condition Result
At-risk NASH (NAS ≥4 and F≥2) No single biomarker or score significantly cleared the prespecified AUC 0.80 acceptability threshold; point estimates ran from 0.61 (0.54–0.67) for FibroScan CAP to 0.81 (0.75–0.86) for SomaSignal, mostly similar to FIB-4
Advanced fibrosis (F≥3) SomaSignal AUC 0.90 (0.86–0.94); ADAPT 0.85 (0.81–0.89); FibroScan LSM 0.83 (0.80–0.86) — all acceptable
Screen-failure reduction With 11 of 17 markers, histological screen failures fall to 33% if only marker-positive patients are biopsied
Number needed to test to find one true positive (at-risk NASH) SomaSignal 4 (4–5); ADAPT 6 (5–7); MACK-3 7 (6–8); PRO-C3 9 (7–11)

The asymmetry is the finding: three markers cleared the study's accuracy criterion for advanced fibrosis, while none significantly cleared it for at-risk NASH. As prescreening tools, 11 markers reduced biopsy screen failures to 33%; the study did not support replacing biopsy for the combined activity-and-fibrosis target.

Getting any of these formally accepted is a separate problem. LITMUS has published its regulatory experience explicitly so the field can learn from it, noting that despite the potential of biomarkers to accelerate development, improve safety and enable personalised medicine, few have been approved through the biomarker qualification pathways of the regulatory agencies (Rasmussen 2023, PMID 36526000). A qualified biomarker, in their framing, is what allows a decision everyone understands and supports within one framework — and MASLD does not yet have one.

What the enrolled population actually looks like. ESSENCE's design and baseline paper describes its first 800 randomised participants: 250 (31.3%) had F2 and 550 (68.8%) F3; mean age 56 (SD 11.6); 57.1% female; mean BMI 34.6 (7.2) kg/m²; 55.5% had type 2 diabetes (Newsome 2024, PMID 39412509). MASLD cardiometabolic criteria were not an enrolment requirement, yet >99% met at least one. This supports substantial overlap between the NASH-enrolled ESSENCE population and MASLD criteria; it does not establish coverage of every trial-eligible population. The trial is two-part, with Part 1 histological and Part 2 based on clinical outcomes.

Placebo response, and why cross-trial comparison fails

Trial Placebo MASH resolution Placebo fibrosis improvement
MAESTRO-NASH (resmetirom) 9.7% 14.2%
ESSENCE (semaglutide) 34.3% 22.4%
SYNERGY-NASH (tirzepatide) 10% 30%
Survodutide phase 2 14% 22%
ENLIVEN (pegozafermin) 2% 7%
HARMONY 96 weeks (efruxifermin) — 19%
NATIVE (lanifibranor) 22% 29%
Denifanstat phase 2b 11% (with ≥2-point NAS) —

Placebo MASH resolution ranges from 2% to 34.3% and placebo fibrosis improvement from 7% to 30% — a spread wider than most drug effects. Cross-trial rankings, including network meta-analyses (Souza 2025, PMID 39903735), are built on top of this variance and should be read as hypothesis-generating. The Lilly master protocol (NCT07165028) is the field's first structural answer.

What is not being trialled

  • A completed screening or care-pathway trial with clinical outcomes. A cluster-randomised VA primary-care trial is underway, but its primary endpoint is diagnosis plus fibrosis-risk stratification rather than liver events (Godwin 2025, PMID 40325466; NCT06671886).
  • A cardiovascular-outcome trial in MASLD, despite cardiovascular disease being the leading cause of death (cardiovascular and extrahepatic outcomes).
  • An HCC surveillance trial in non-cirrhotic MASLD, where a large minority of tumours arise (MASLD-related hepatocellular carcinoma).
  • A completed head-to-head comparison of surgery against incretin therapy with histological endpoints; one 120-person trial is recruiting (NCT06374875) (bariatric and metabolic surgery).
  • Paediatric registration trials for either approved drug.

Open questions

  • Can at-risk MASH be identified without a biopsy at all? Across 17 markers in one histologically characterised cohort, none reached the prespecified AUC 0.80 for at-risk NASH, while three exceeded it for advanced fibrosis (PMID 36958367). Until a marker for the activity component exists, every registration trial must biopsy to enrol, and the best available prescreening still leaves a 33% screen-failure rate.
  • Why has no MASLD biomarker been formally qualified? LITMUS has interacted with regulators in both the US and EU and reports that few biomarkers clear the qualification pathways in any indication (PMID 36526000). Whether the obstacle is the evidence, the pathway, or the absence of an agreed context of use has not been analysed for this disease specifically.
  • Will the outcome phases confirm the surrogates? MAESTRO-NASH OUTCOMES completes December 2026 (NCT05500222) and ESSENCE April 2029 (NCT04822181). If either fails, the accelerated-approval framework for this disease has a problem no post-hoc analysis will fix.
  • Can the field afford nine concurrent phase 3 FGF21 trials? Eight are recruiting (four efimosfermin, two efruxifermin and two pegozafermin), while a third efruxifermin study is active but not recruiting; the eight recruiting studies seek more than 10,000 participants.
  • Do genotype-directed trials need genotype-matched controls? ALN-PNP and AZD2693 enrol by PNPLA3 genotype (NCT05648214, NCT05809934). Whether their effect sizes generalise to unselected MASH is unknown, and no trial has randomised genotype-directed against unselected treatment.
  • Why was denifanstat's phase 3 withdrawn after a positive phase 2b? NCT06594523 shows 0 enrolled with a start date of March 2025 (PMID 39396529 reports the positive phase 2b). The registry records the fact and not the reason.
  • Which combinations should be tested? Combination therapy is not absent: a randomised phase 2 study tested semaglutide with cilofexor and/or firsocostat (Alkhouri 2022, PMID 35439567); NCT07527910 combines a genotype-directed silencer with tirzepatide; and NCT07570810 tests CS0159 plus semaglutide. The 2026 global consensus does not recommend upfront combination (PMID 41950980), and no trial of the specific resmetirom-plus-semaglutide combination was found in a live ClinicalTrials.gov search on 2026-09-02.

References

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  2. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. N Engl J Med. 2025;392(21):2089-2099. PMID 40305708 (NCT04822181)
  3. Loomba R, Hartman ML, Lawitz EJ, et al. Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis. N Engl J Med. 2024;391(4):299-310. PMID 38856224 (NCT04166773)
  4. Sanyal AJ, Bedossa P, Fraessdorf M, et al. A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. N Engl J Med. 2024;391(4):311-319. PMID 38847460 (NCT04771273)
  5. Loomba R, Sanyal AJ, Kowdley KV, et al. Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH. N Engl J Med. 2023;389(11):998-1008. PMID 37356033 (NCT04929483)
  6. Noureddin M, Frias JP, Neff GW, et al. Safety and efficacy of once-weekly efruxifermin versus placebo in metabolic dysfunction-associated steatohepatitis (HARMONY): 96-week results. Lancet. 2025;406(10504):719-730. PMID 40818852 (NCT04767529)
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