Navigating the complexities of drug development in hepatology: Leveraging insights from clinical practice

In the realm of medical research, liver disease remains a complex and often overlooked field. Despite the growing global burden of liver-related diseases, hepatology is still a relatively young specialty.

While our scientific grasp of liver disease mechanisms has paved the way for new treatments, these breakthroughs do not consistently attract the resources often dedicated to other diseases. This imbalance has led to a scarcity of treatment options, limited patient support, and slower research progress in tackling liver diseases.

The complexity of liver disease

Liver diseases pose complex challenges for medicine, and advances in the space have previously been hindered by low funding and industry investment. Established therapeutic modalities have often failed due to the challenging tractability of liver targets that modulate both inflammatory responses and tissue repair over a years-to-decades timespan, and clinical trials face difficulties in monitoring and establishing liver safety. Additionally, therapeutic nihilism and stigmatisation of liver diseases and the people that live with them further complicate matters. As a result, patient care is mainly limited to monitoring disease progression and recommending lifestyle changes.

The reality is that hundreds of millions globally are affected by liver diseases, including chronic hepatitis B (CHB) and C, immune-mediated conditions such as primary biliary cholangitis (PBC), and steatotic liver disease (SLD) – a broad term for liver diseases characterised by excessive fat accumulation in the liver, which can include both alcohol- and non-alcohol-related causes, and encompasses several subsets of disease (MASH/NASH/ALD). Globally, liver diseases are responsible for over two million deaths a year (4% of all deaths), through cirrhosis, liver failure, and liver cancer. In the USA alone, these accounted for over $30 billion in healthcare spending.¹

• CHB alone affects 254 million people across the world, although only about 13% of these people have a diagnosis and only 3% receive treatment^.2 

• PBC is a rare autoimmune liver disease in which the first line of treatment controls the disease in approximately 70% of patients, but does not reduce the severity or impact of cholestatic pruritus (relentless itch), a serious condition that can be debilitating, with patients experiencing sleep disturbance, fatigue, impaired quality of life, and even sometimes requiring liver transplantation in the absence of liver failure.^3,4

• SLD is increasing in prevalence globally and, although it is associated with calorie and alcohol excess, its impact is disproportionately higher in areas of social deprivation where it contributes to widening of health inequalities.

Pushing liver diseases down the list of public health priorities needs to change. The significant impact of both common and rare liver diseases highlights the urgent need to overcome challenges and advocate for a collaborative approach to innovation in drug development, clinical trial design, and patient care.

Challenges in scientific research that should be prioritised

As a physician treating liver diseases, I have experienced three important challenges in navigating these diseases:

1) The liver's resilience to injury can mean disease progression is not easily quantified on routine clinical assessment – progression can be variable over time and between patients and heterogenous within the liver, so, robust biomarker correlates for risk of serious clinical events are only just emerging. This has made clinical trials in early- and mid-stage disease slow, large, and consequently expensive. In contrast, late-stage disease has high mortality, which has raised concerns that by this stage the liver may be ‘too far gone,’ and that the bar for therapeutic efficacy and safety will be too high.

2) Current standards of care rely on limited or outdated data – the quality of life (QoL) for individuals with liver diseases can be severely impacted, yet treatment choices, eligibility, and monitoring are rarely based on patient experience. These standards have seen minimal innovation over the years, and we still risk missing the opportunity to help our patients feel better.

3) Stigma often leads to people living with liver diseases being blamed for their condition – this can influence the quality of patients’ interactions with healthcare systems.

Liver disease mechanisms are diverse, involving factors such as immunological responses, viral infections, genetic factors, and metabolic imbalances. Therefore, a single therapy may not be effective for all types. However, etiologies can co-exist, meaning more than one approach may be needed to improve outcomes for an individual.

The importance of following the science

Over the past 20 years, liver disease research has experienced significant fluctuations. While some successful drug development programmes have emerged, particularly in viral hepatitis and PBC, the field also expended considerable resources, repurposing drugs initially designed for other diseases, such as diabetes, dyslipidemia, or cancer. However, this approach often proceeds without deep investigation of the connection between these drugs' targets and the biology of liver disease in humans. Despite recent advances, a deeper understanding and a more comprehensive assessment of potential benefit-risk profiles, benchmarked to anticipated patient need, are imperative for continued progress.

As we follow the science for better outcomes in liver disease research, we are starting to see a shift from rodent to human tissue models for better insights into human-specific mechanisms. Advances in genetics and single-cell genomics are helping identify clinical targets, and novel therapeutic modalities like RNA interference are making previously intractable targets tractable, with fewer off-target effects. This, alongside large databases and advanced data analysis, is identifying novel disease-target pairings to meet future medical needs.

Growth of liver disease clinical research to meet the needs of patients will require a larger and more robust global network of study sites to offer trial participation to a large and diverse patient group representative of the eventual treatment population. Additionally, symptoms such as fatigue, driving restrictions, and work or caring responsibilities can make it challenging for people to attend frequent site visits, while populations with rarer diseases may be dispersed away from academic centres.

Through enhanced use of data and digital technology, we are starting to modernise the way we develop medicines. Offering patients the option to participate from home as part of a tech-enabled ‘decentralised’ trial site has aided study recruitment and allowed clinical research to parallel the innovations in clinical care closer to home. This has been a first for what we expect to be continued innovation in the clinical trials space as we work with patients, regulators, and physician colleagues to improve clinical development.

The role of collaboration and innovation

Ultimately, the key to overcoming these challenges lies in collaboration.

My journey as a medicine development leader began when GSK reached out to me as an external collaborator. As a treating physician, I had witnessed firsthand the unmet needs of patients with PBC, particularly those suffering from cholestatic pruritus.

By 2030, the number of people diagnosed with PBC is expected to reach 510,000 globally, with over 240,000 experiencing clinically significant itching that might benefit from treatment.^4,5,6,7

The collaboration investigated the potential of a new molecule to directly address the mechanisms that lead to pruritus in PBC. Through strategic partnerships with UK centres, advocacy groups, like the PBC-ers and PBC foundation, and global patient communities, we advanced clinical development and deepened our understanding of the disease burden, enabling efficient trial design and more meaningful data. We utilised a design-led approach where patient insights, such as the impact of itch on sleep, shaped the target profile, trial endpoints, and draft label, guiding scientific discussions with regulators and payers. The molecule is not yet approved, but it is this type of collaboration that enhances the lives of patients suffering from liver disease.

A call to action

The progress made in liver disease research to date presents an opportunity for further advancements in the near future. However, continued collaboration is essential to overcoming the challenges that remain.

Navigating the complexities of drug development in hepatology demands a powerhouse alliance between  patients, advocacy groups, hepatologists, scientists, pharmaceutical leaders, and the capabilities of advanced data and analytics platforms. These dynamic partnerships are essential to produce game-changing data that has the potential to redefine clinical care. By synchronising the discovery of cutting-edge therapeutics with progressive care practices, we can effectively steer through the intricate landscape of drug development and ensure that the full potential of these innovations is realised when they become available to patients.

The clock is ticking. It is time for decisive action to overhaul liver disease innovation and management to achieve lasting global improvements in patient outcomes.

References

1. Devarbhavi H et al. Global burden of liver disease: 2023 update; J Hepatol. 2023 Aug;79;516-537

2. World Health Organization. Global Hepatitis Report 2024: Action for access in low- and middle-income countries.

3. Carbone M, et al. Pre-treatment prediction of response to ursodeoxycholic acid (UDCA) in primary biliary cholangitis: the UDCA Response Score. Lancet Gastroenterol Hepatol. 2018 Jul 13;3(9):626–634.

4. Gungabissoon U, et al. Pruritus in primary biliary cholangitis is under-recorded in patient medical records. BMJ Open Gastroenterol. 2024 Mar 27;11(1):e001287.

5.    Lu M, et al. Increasing Prevalence of Primary Biliary Cholangitis and Reduced Mortality With Treatment. Clin Gastroenterol Hepatol. 2018 Aug;16(8):1342-1350.e1.

6. Sebode M, et al. Population-based study of autoimmune hepatitis and primary biliary cholangitis in Germany: rising prevalences based on ICD codes, yet deficits in medical treatment. Z Gastroenterol. 2020 May;58(5):431-438.

7. Tanaka A, et al. Increase trend in the prevalence and male-to-female ratio of primary biliary cholangitis, autoimmune hepatitis, and primary sclerosing cholangitis in Japan. Hepatol Res. 2019 Aug;49(4):881-889.

About the author

Stuart Kendrick is a hepatologist and clinician scientist who transitioned from academia to industry in 2014. He held leadership roles in drug discovery, clinical development, safety, and medical affairs. He is now VP medicine development lead for a liver programme in GSK’s Respiratory, Immunology and Inflammation Research Unit. He is an honorary consultant hepatologist at Cambridge University Hospitals, where he provides clinical care for liver outpatients one morning a week.