MAFLD and MASH: Clinical Research with Precision

Rethinking Early‑Phase MASLD Trials: A More Realistic Path Forward

The complexities of MASLD The landscape of fatty liver disease has changed rapidly, and the terminology has changed with it. What was once known as NAFLD or NASH is now recognised as MASLD—metabolic dysfunction‑associated steatotic liver disease. The new name reflects a deeper truth: this is not an isolated liver condition, but a metabolic disease that sits at the crossroads of obesity, diabetes, cardiovascular risk, and systemic inflammation. For many years, MASLD was under‑recognised by clinicians and almost invisible to patients. Most people who have it still do not know they do. Even among those with type 2 diabetes—where prevalence is extraordinarily high—awareness remains low. Yet the disease carries serious consequences. It can progress from simple steatosis to fibrosis, cirrhosis, and hepatocellular carcinoma, and it significantly increases cardiovascular risk. In fact, most people with MASLD do not die from liver complications, but from cardiovascular events. This combination of high prevalence, low awareness, and significant morbidity creates a unique challenge for drug developers. It also makes early‑phase clinical research more important—and more complex—than ever. A disease that is common, silent, and difficult to identify Text: One of the fundamental challenges in MASLD development is that the disease is both widespread and underdiagnosed. Traditional diagnostic tools are either too insensitive or too invasive to be practical for broad screening. Standard abdominal ultrasound only detects fatty liver once the disease is already advanced. MRI provides a far more accurate picture, but it is expensive and typically reserved for research settings. Transient elastography technologies such as FibroScan offer a sensitive, non‑invasive alternative, but the equipment is costly and not universally available.[FT1] [AI2] In recent years, clinical risk scores such as FIB‑4, the Agile score, and the MASLD Risk Score have emerged as practical first‑line tools to identify individuals who may warrant further evaluation. These scores are inexpensive, widely accessible, and useful for triaging large populations—but they are still imperfect. They can flag patients at risk, yet they cannot confirm disease stage or reliably distinguish steatosis from fibrosis without follow‑up imaging or elastography. As a result, sponsors still face a fragmented diagnostic landscape where no single tool offers both scalability and diagnostic precision. This diagnostic gap has real implications for early‑phase trials. Identifying suitable participants requires more than simply opening a study and waiting for referrals. It demands a deliberate strategy, an understanding of which tools are appropriate for which stage of disease, and the operational capability to screen efficiently without overwhelming patients or sites. Regulatory expectations are evolving—but not fast enough The scientific community has made significant progress in developing non‑invasive methods to assess liver fat, inflammation, and fibrosis. MRI‑based techniques, elastography, and advanced ultrasound methods offer a clearer, more reproducible view of the liver than traditional biopsy. Yet regulatory expectations have not fully caught up. Biopsy remains the standard requirement for many MASLD studies, particularly those aimed at demonstrating improvements in fibrosis. This creates a major barrier. Biopsies are invasive, uncomfortable, and carry a small but real risk of complications. Patients are understandably reluctant to undergo them repeatedly, and many physicians discourage their use outside of clear clinical necessity. The result is a tension between what science can measure and what regulators still require. Sponsors often feel compelled to design biopsy‑driven studies even when better tools exist, and this can make recruitment extraordinarily difficult. It is not unusual for programmes to struggle or stall simply because patients are unwilling to undergo multiple invasive procedures for research purposes. Why early‑phase MASLD trials are uniquely challenging MASLD sits at the intersection of several metabolic pathways, and its progression varies widely from person to person. This heterogeneity makes early‑phase design particularly sensitive. Developers must understand not only the mechanism of action of their drug, but also how that mechanism interacts with the broader metabolic environment. Early‑phase studies need to capture signals that are meaningful, feasible, and aligned with the eventual regulatory path. That means selecting the right biomarkers, choosing the right imaging modalities, and defining endpoints that reflect both biological plausibility and operational reality. It also means recognising that MASLD patients often carry multiple comorbidities—diabetes, hypertension, dyslipidaemia—that influence both disease progression and study outcomes. Without careful planning, early‑phase MASLD trials can become overburdened with assessments that are difficult to execute or interpret. The goal is not to replicate a Phase II study in miniature, but to generate early evidence that a mechanism is acting in the right direction and warrants further investment. The value of integrated early‑phase expertise Given the complexity of MASLD, early‑phase development benefits enormously from an integrated approach. The most effective environments are those that connect preclinical insights with clinical strategy, and clinical strategy with operational execution. This integration allows teams to identify the most appropriate markers, anticipate feasibility challenges, and design studies that generate meaningful early signals without overwhelming patients or sites. A strong early‑phase metabolic unit brings together several critical elements: experience with first‑in‑human and early patient studies, access to the right populations, specialised investigations that have been validated and refined over time, and the scientific expertise to interpret early data in context. This combination helps sponsors move from preclinical promise to clinical proof‑of‑concept with greater clarity and confidence. For smaller biotechs—many of whom are driving innovation in MASLD—this support can be transformative. They often arrive with compelling preclinical data but limited experience navigating the regulatory, operational, and scientific complexities of metabolic liver disease. Early guidance on study design, endpoints, diagnostic tools, and feasibility can prevent costly missteps and accelerate progress. A more realistic, more hopeful path forward MASLD remains a challenging area of drug development, but it is also one of the most important. As understanding of the disease deepens and diagnostic tools continue to improve, the opportunities for meaningful therapeutic impact are growing. The key is to approach early‑phase development with realism, scientific discipline, and a willingness to adapt to the evolving landscape. By grounding early‑phase studies in biology, aligning them with regulatory expectations, and designing them with operational feasibility in mind, sponsors can generate the evidence needed to move forward with confidence. The path is not simple, but it is navigable—and with the right expertise, it becomes not just feasible, but promising.