Our team recently attended two leading forums focused on the future of MASH research and treatment: the 2026 Paris MASH Meeting and the 10th MASH Drug Development Summit in Boston. Together, the conferences brought perspectives from clinical practice, drug development, translational science, biomarkers, and regulatory strategy.

Across discussions about treatment differentiation, combination strategies, trial feasibility, non-invasive testing, patient identification, and precision development, one message was clear: MASH is entering a new phase of maturity. With disease-directed pharmacotherapy now established, the question is no longer simply whether MASH can be treated. It is how therapies will be differentiated, combined, and matched to the patients most likely to benefit.

Here are five key takeaways our team brought home from Paris and Boston.

1. The expanding treatment landscape is increasing the need for personalization

The arrival of the first pharmacologic options for non-cirrhotic MASH with moderate-to-advanced fibrosis has fundamentally changed the development and commercial environment. With a diverse pipeline of liver-directed therapies, incretin-based agents, FGF21 analogues, pan-PPAR agonists, RNA-based approaches, and other mechanisms, differentiation will require more than demonstrating MASH resolution or fibrosis improvement.

Sponsors will increasingly need to define which patient phenotypes are most likely to benefit, which disease drivers a therapy addresses, and how it fits alongside other MASH and cardiometabolic treatments. Practical considerations such as dosing, monitoring, tolerability, and access will also influence a therapy’s position in the market.

Combination therapy was a prominent part of the conversation. Because different therapies target different disease mechanisms, MASH care may move toward an add-on model in which treatments are combined to address complementary drivers. Sponsors will therefore need to establish not only whether a therapy works on its own, but how safely and effectively it can be used with incretins and other treatments.

Tolerability and persistence will be particularly important in a population that is often asymptomatic. Patients may be reluctant to remain on therapies that cause persistent side effects or create a substantial treatment burden. MASH therapies will therefore need to demonstrate value within a broader metabolic-treatment ecosystem that includes obesity, diabetes, cardiovascular risk management, metabolic surgery, and emerging combination regimens.

2. Patient identification is becoming a defining constraint on trial feasibility

Another clear takeaway was the difficulty of identifying and enrolling the right patients for MASH trials. Restrictive eligibility criteria, dependence on biopsy, limited disease recognition outside specialist care, and competition for the same sites and patient populations all contribute to high screen-failure rates.

Long follow-up periods, evolving use of incretin therapies, reluctance to join placebo-controlled studies, and trial fatigue create additional pressure on recruitment and retention. These challenges are not simply operational. Slow enrollment can delay readouts and launch timing, while narrow eligibility criteria can produce a study population that is difficult to identify after approval. A development strategy that depends on a complex, invasive, or difficult-to-scale screening pathway may create commercial challenges even when the therapy is effective.

Sponsors will need stronger patient-finding strategies across primary care, endocrinology, obesity medicine, cardiology, and other settings where high-risk patients already receive care. Broader site networks, centralized screening support, realistic background-therapy policies, and data-driven pre-screening can also help reduce unnecessary procedures and improve qualification rates.

Patient identification can no longer be treated as an enrollment issue addressed after the protocol is finalized. It must be considered from the beginning, with a clear connection between trial feasibility and the diagnostic pathways likely to exist after launch.

Related resource: Reducing operational risk in MASH trials
Patient identification, screening strategy, site selection, and standardized execution can all influence whether a promising therapy demonstrates a clear treatment effect. Read How CROs Help Sponsors Reduce the Operational Risks of MASH Clinical Trials for practical considerations related to patient qualification, screen failures, and data quality.

3. Moving beyond biopsy remains a priority, but NIT validation must keep pace

The desire to reduce reliance on liver biopsy was one of the clearest themes across the two conferences. Biopsy is invasive and costly, and it can create challenges at nearly every stage of development. Patients may decline the procedure, tissue samples provide only a limited snapshot of the liver, and reader variability can affect both eligibility and endpoint assessment. Repeat biopsies place further pressure on recruitment and retention.

Non-invasive tests, or NITs, could help address these challenges, but their intended uses must be distinguished. A test that can identify or stage disease is not automatically validated to predict progression, monitor disease, measure treatment response, or serve as a surrogate endpoint. Each use requires progressively stronger evidence, including clinically meaningful thresholds, analytical reproducibility, biological plausibility, and performance across diverse patient populations.

Therapeutic progress may help accelerate that validation. As more effective drugs generate clearer treatment signals, researchers may be better able to determine which non-invasive measures reliably reflect treatment response and future clinical benefit.

Validated NIT strategies could reduce unnecessary biopsies and screen failures, expand participation beyond major hepatology centers, improve recruitment and retention, and support more efficient longitudinal monitoring. They could also help create a scalable pathway for identifying and monitoring high-risk patients after launch.

Even when histology remains the immediate registration endpoint, high-quality longitudinal NIT data should be considered essential. These data may ultimately influence regulatory strategy, patient finding, treatment monitoring, payer evidence, and the commercial scalability of a therapy.

Explore our MASH clinical development expertise
Download our MASH Clinical Development Fact Sheet to learn how P95 Julius Clinical combines scientific leadership, specialized site networks, patient-identification strategies, and operational expertise to support complex MASH trials.

4. Biomarkers, multi-omics, and AI could improve translational confidence

Discussions about biomarkers, multi-omics, artificial intelligence, and machine learning reflected a broader challenge: connecting disease biology, preclinical findings, patient selection, and clinical outcomes more effectively.

MASH is not driven by a single pathway. Metabolic dysfunction, hepatic injury, inflammation, fibrosis, genetics, comorbidities, and environmental factors contribute differently across patients. This heterogeneity may help explain why an approach that appears promising in an animal model or laboratory experiment does not always produce the expected benefit in humans.

Integrated biomarker and computational approaches could help identify meaningful patient subgroups, predict progression or treatment response, improve pre-screening, and guide the selection of therapies or combinations. AI and machine learning may also help integrate imaging, laboratory results, clinical records, genomics, transcriptomics, proteomics, and other data to support target discovery and development decisions.

However, computational sophistication cannot replace clinical validation. Models must perform reliably across populations, sites, data sources, and care settings, and their outputs must be interpretable enough to inform decisions by investigators, regulators, clinicians, and payers.

The opportunity is not simply to generate more data. It is to translate complex biological signals into actionable decisions about whom to enroll, what to measure, and which therapy or combination is most likely to benefit a particular patient.

5. Evidence generation must reflect the complexity of real-world MASH care

The conferences also reinforced the limitations of studying MASH as a uniform disease within narrowly controlled trial populations. In clinical practice, patients have different combinations of metabolic dysfunction, fibrosis, cardiovascular risk, alcohol exposure, comorbidities, and background therapies. Development programs must account for this heterogeneity and generate evidence that remains useful beyond initial regulatory approval.

Metabolic Dysfunction–Associated Alcohol-Related Liver Disease (MetALD) offers one example. Rather than representing a clear dividing line between metabolic and alcohol-associated liver disease, alcohol exposure may act as a disease modifier whose contribution varies among patients. Metabolic dysfunction and alcohol can interact, genetic factors may influence their effects, and drinking patterns may change over time. Self-reported intake may also provide an incomplete picture.

Routinely excluding these patients from trials could leave sponsors without evidence for a meaningful part of the real-world population. Including them without adequate characterization, however, could introduce variability. More precise and repeated assessment of alcohol exposure may therefore be needed to determine which patients should be included and how their results should be interpreted.

Real-world evidence will become increasingly important as additional therapies reach clinical practice. Placebo-controlled trials can establish efficacy under defined conditions, but clinicians, payers, and health systems will also want to understand which therapies work best for particular patients, when treatment should begin, how therapies should be combined or sequenced, and whether benefits persist in routine care.

These questions also reflect a broader shift across cardiometabolic development. Differentiation is increasingly based not only on improvements in weight or individual disease markers, but on durable cardiovascular, renal, metabolic, and patient-centered outcomes. Sponsors must also generate evidence in populations that reflect the multimorbidity commonly seen in clinical practice. Explore this changing evidence landscape in Beyond Weight Loss: Why the Next Phase of Cardiometabolic Innovation Will Be Defined by Outcomes.

Head-to-head randomized trials may not always be practical. Pragmatic studies, indirect comparisons, external control arms, and carefully designed target-trial emulations may help address remaining evidence gaps. This will require fit-for-purpose data, strong epidemiologic expertise, transparent methodology, and evidence plans established before launch.

What this means for MASH sponsors

MASH is moving from proof of concept toward precision development and increasingly individualized care. The next phase will be shaped by how effectively sponsors can:

  • Match treatments and mechanisms to the patients most likely to benefit
  • Establish a clear position for individual therapies and combination strategies
  • Identify high-risk patients through scalable pathways that reduce screen failures and reliance on biopsy
  • Translate biological, computational, and real-world insights into evidence that supports treatment selection, access, and long-term outcomes

A differentiated mechanism will remain important, but it will not be sufficient on its own. Successful programs will also require scalable diagnostic pathways, realistic protocols, thoughtful management of background therapies, and evidence strategies designed for a complex real-world population.

The field has moved beyond proving that MASH is treatable. For sponsors, the next challenge is to develop and position the right therapy or combination for the right patient while generating evidence that translates into meaningful long-term benefit.

Advance your MASH clinical development program

At P95 Julius Clinical, we help sponsors translate emerging MASH science into effective development strategies, from patient identification and feasibility planning to endpoint strategy and global trial delivery. Connect with our MASH experts to discuss how we can support your next clinical development program.