redefining-what-success-looks-like-in-psc:-the-evolution-of-clinical-trial-endpoints
Redefining what success looks like in PSC: The evolution of clinical trial endpoints

Redefining what success looks like in PSC: The evolution of clinical trial endpoints

Posted inBiotechnology

By Jennifer Schranz, Senior Vice President, Head of Rare Diseases at Ipsen

Progress in rare diseases is rarely defined by a single breakthrough. Instead, it emerges through advances in how we understand disease biology, measure change and define meaningful outcomes for patients. In rare cholestatic liver diseases, the evolution of clinical trial endpoints is playing a central role in enabling this progress.

Knowing whether a treatment is working in slowly progressive diseases is a particular challenge. Clinical outcomes such as liver failure, transplantation or death are definitive but may take years to occur, making trials long and complex.1 

This has driven increasing focus on surrogate endpoints: measures that can help predict long-term clinical benefit. However, identifying and validating these requires deep biological understanding, robust longitudinal data and alignment across clinical, regulatory and patient communities.2

PSC: a continuing evolution in endpoint selection

Primary sclerosing cholangitis (PSC) is an example of why endpoint development remains such an important focus in rare cholestatic liver disease.1 PSC is a rare, progressive and heterogeneous condition, affecting around 7 in every 100,000 people worldwide and up to 50,000 people currently living with PSC in the US.3,4 PSC can lead to liver failure, transplantation or malignancy, yet the biology is still not fully understood and there are currently no approved therapies.1

Primary biliary cholangitis (PBC) is another rare cholestatic liver disease, but one with distinct biology and a different clinical course from PSC.5 A key milestone in PBC was the identification of alkaline phosphatase (ALP) as a biomarker associated with disease activity.2 Over time, reductions in ALP were shown to correlate with improved transplant-free survival, supporting its use as a surrogate endpoint.6 This enabled more feasible clinical trials and contributed to the emergence of new therapies; a clear example of how progress can tangibly be made when a meaningful biomarker is validated and linked to long-term outcomes.2,7

For PSC however, there is a lack of validated surrogate endpoints that can reliably predict outcomes. Therefore, a different approach to trial design is needed, accounting for complex biology, variable disease progression and the need for clinically meaningful measures of benefit.8

Evolving trial design: responding to the needs in PSC 

These challenges are shaping how PSC studies are designed. Ongoing efforts are focused on identifying new biomarkers, developing composite endpoints and integrating patient-reported outcomes.8,9

This shift is reflected in contemporary PSC studies, with event-driven designs focused on outcomes such as event-free survival. Such approaches prioritize clinically meaningful endpoints that reflect real-world priorities while recognizing current limitations in surrogate markers.8

However, this approach brings with it important considerations, most notably the willingness to commit to longer, more rigorous clinical trials, underpinned by the expertise to design trials that can truly advance scientific understanding. For a disease where research has historically been limited and no approved therapies exist, this strength of conviction is essential to robustly assess the effectiveness of new therapies and generate evidence that can meaningfully inform clinical practice.1,10

Looking beyond biomarkers: what is meaningful?

While biochemical markers remain important, the complexity of PSC shows why endpoints must extend beyond laboratory values. Increasingly, treatment benefit is also defined by how people feel and function in their daily lives.11 In cholestatic liver diseases, symptoms such as pruritus and fatigue can significantly affect quality of life, even when biomarkers appear stable.11

Efforts to develop disease-specific patient-reported outcome tools are gaining momentum, supported by collaboration with patient communities. These tools aim to capture aspects of disease burden not reflected in traditional measures, helping ensure trials evaluate outcomes that matter to patients.11

At the same time, advances in imaging, elastography and molecular profiling are expanding the range of potential endpoints.2,12 Increasingly, researchers are exploring composite approaches that combine biochemical, radiological and clinical measures to better reflect disease complexity.2

Looking ahead

The story of endpoint evolution in rare cholestatic liver disease is still being written. PBC shows what can become possible when biology, data and regulatory alignment converge. PSC now presents the next chapter: pioneers driving science forward, building the evidence, tools and partnerships needed to define meaningful measures of progress.

At Ipsen, we are committed to contributing to this effort, advancing endpoint science, supporting collaboration across the ecosystem, and helping to build the evidence needed to translate scientific insight into meaningful progress. In doing so, we have an opportunity to support effective clinical trials and move the field closer to better outcomes for people living with and impacted by rare cholestatic liver diseases. 

This article was funded by Ipsen.

This article is for scientific and educational purposes only and is not intended to provide medical advice, promote any product or imply benefit in any disease area.

© 2026 Ipsen Biopharmaceuticals, Inc. All rights reserved. 

NON-US-004666 | ALLSC-ALL-008898 | June 2026

References:

  1. Rabiee A, Silveira MG. Primary sclerosing cholangitis. Transl Gastroenterol Hepatol. 2021;6:29. Published 2021 Apr 5. doi:10.21037/tgh-20-266
  2. Jones DEJ, Beuers U, Bonder A, et al. Primary biliary cholangitis drug evaluation and regulatory approval: Where do we go from here? Hepatology. 2024;80(5):1291-1300. doi:10.1097/HEP.0000000000000864
  3. Olfatifar M, Rajabnia M, Sadeghi A, et al. The epidemiological trends and projected future of primary sclerosing cholangitis by 2040: An updated meta-analysis and modeling study. PLoS One. 2025;20(5):e0322479. doi:10.1371/journal.pone.0322479 
  4. Digestive Health Foundation. Primary Sclerosing Cholangitis (PSC). Available at: https://digestivehealthfoundation.org/research-area/primary-sclerosing-cholangitis-psc/. Accessed June 2026
  5. Marchioni Beery RM, Vaziri H, Forouhar F. Primary biliary cirrhosis and primary sclerosing cholangitis: a review featuring a women’s health perspective. J Clin Transl Hepatol. 2014;2(4):266-284. doi:10.14218/JCTH.2014.00024
  6. Lammers WJ, van Buuren HR, Hirschfield GM, et al. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow up study. Gastroenterology. 2014;147(6):1338-1349.e5. doi:10.1053/j.gastro.2014.08.029
  7. Makhija D, Rock M, Kim CH, et al. Investigating composite response definitions based on key surrogate markers for predicting clinical outcomes in primary biliary cholangitis: a systematic review and meta analysis. Value Health. 2025;28(12 Suppl 1):S73. doi:10.1016/j.jval.2025.09.258
  8. Ponsioen CY. Endpoints in the design of clinical trials for primary sclerosing cholangitis. Biochim Biophys Acta Mol Basis Dis. 2018;1864(4 Pt B):1410-1414. doi:10.1016/j.bbadis.2017.08.015
  9. Ponsioen CY, Chapman RW, Chazouillères O, et al. Surrogate endpoints for clinical trials in primary sclerosing cholangitis: review and results from an International PSC Study Group consensus process. Hepatology. 2016;63(4):1357-1367. doi:10.1002/hep.28256
  10. Fuchs J, Murtha-Lemekhova A, Pfeiffenberger J, et al. Generating evidence for diagnosis and therapy of RarE LIVEr disease: the RELIVE Initiative for systematic reviews and meta-analyses. Syst Rev. 2022;11(1):235. Published 2022 Oct 25. doi:10.1186/s13643-022-02105-0
  11. Marcus E, Stone P, Krooupa AM, Thorburn D, Vivat B. Quality of life in primary sclerosing cholangitis: a systematic review. Health Qual Life Outcomes. 2021;19(1):100. doi:10.1186/s12955-021-01739-3
  12. Wang WL, Lian H, Liang Y, Ye Y, Tam PKH, Chen Y. Molecular Mechanisms of Fibrosis in Cholestatic Liver Diseases and Regenerative Medicine-Based Therapies. Cells. 2024;13(23):1997. Published 2024 Dec 3. doi:10.3390/cells13231997