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. 2024 Nov 1;80(5):1291-1300.
doi: 10.1097/HEP.0000000000000864. Epub 2024 Mar 22.

Primary biliary cholangitis drug evaluation and regulatory approval: Where do we go from here?

David E J Jones  1 , Ulrich Beuers  2 , Alan Bonder  3 , Marco Carbone  4 , Emma Culver  5   6 , Jessica Dyson  7 , Robert G Gish  8   9 , Bettina E Hansen  10   11   12 , Gideon Hirschfield  13 , Rebecca Jones  14 , Kris Kowdley  15   16 , Andreas E Kremer  17 , Keith Lindor  18 , Marlyn Mayo  19 , George Mells  20 , James Neuberger  21 , Martin Prince  22 , Mark Swain  23 , Atsushi Tanaka  24 , Douglas Thorburn  25 , Michael Trauner  26 , Palak Trivedi  27   28 , Martin Weltman  29 , Andrew Yeoman  30 , Cynthia Levy  31
Affiliations

Primary biliary cholangitis drug evaluation and regulatory approval: Where do we go from here?

David E J Jones et al. Hepatology. .

Abstract

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The management landscape was transformed 20 years ago with the advent of ursodeoxycholic acid. Up to 40% of patients do not, however, respond adequately to ursodeoxycholic acid and therefore still remain at risk of disease progression to cirrhosis. The introduction of obeticholic acid as a second-line therapy for patients failing ursodeoxycholic acid has improved outcomes for patients with PBC. There remains, however, a need for better treatment for patients at higher risk. The greatest threat facing our efforts to improve treatment in PBC is, paradoxically, the regulatory approval model providing conditional marketing authorization for new drugs based on biochemical markers on the condition that long-term, randomized placebo-controlled outcome trials are performed to confirm efficacy. As demonstrated by the COBALT confirmatory study with obeticholic acid, it is difficult to retain patients in the required follow-on confirmatory placebo-controlled PBC outcome trials when a licensed drug is commercially available. New PBC therapies in development, such as the peroxisome proliferator-activated receptor agonists, face even greater challenges in demonstrating outcome benefit through randomized placebo-controlled studies once following conditional marketing authorization, as there will be even more treatment options available. A recently published EMA Reflection Paper provides some guidance on the regulatory pathway to full approval but fails to recognize the importance of real-world data in providing evidence of outcome benefit in rare diseases. Here we explore the impact of the EMA reflection paper on PBC therapy and offer pragmatic solutions for generating evidence of long-term outcomes through real-world data collection.

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Conflict of interest statement

David E.J. Jones consults, is on the speakers’ bureau, and received grants from Intercept. He consults and is on the speakers’ bureau for GlaxoSmithKline and Ipsen. He consults for Advanz and CymaBay. He is on the speakers’ bureau for Dr Falk. Ulrich Beuers consults for Abacus and CSL Behring. He is on the speakers’ bureau for GlaxoSmithKline and Zambon. He received grants from the Amsterdam UMC Foundation and ZonMW. He is employed by AASLD and EASL. Alan Bonder consults and received grants from Chemomab, CymaBay, Ipsen, and GlaxoSmithKline. He consults for GuidePoint and Intercept/Alfasigma. He received grants from CARA Therapeutics, GENFIT, Gilead, Intercept, and Mirium. He has other interests with AASLD and Pfizer. Marco Carbone consults and advises CymaBay and Ipsen. He consults for Advanz, Calliditas, Intercept, and Mayoly Spindler. Emma Culver consults, advises, and is on the speakers’ bureau for Dr Falk, Horizon, Ipsen, and Zenus. She consults and advises Moderna and Sanofi. She advises and is on the speakers’ bureau for Intercept. She is on the speakers’ bureau and received grants from Janssen. She consults for AstraZeneca, Avicenna, Gilead, and Mirum. She is on the speakers’ bureau for Advance, GlaxoSmithKline, and Intercept. Jessica Dyson is on the speakers’ bureau and received grants from GlaxoSmithKline and Ipsen. She consults for Umecrine and NICE. She is on the speakers’ bureau for Dr Falk and Intercept. Robert G. Gish consults, advises, and is on the speakers’ bureau for AbbVie, Genentech, and Intercept. He consults, advises, and owns stock in Genlantis, HepQuant, and HepaTx. He consults and advises Arrowhead, Dynavax, Enyo, Gilead, Helios, Janssen, Merck, and Pfizer. He consults and is on the speakers’ bureau for AstraZeneca, Eisai, and Ipsen. He consults and owns stock in Abacus, Eiger, JBS Science, and Virion. He consults for Abbott, Albireo, Aligos, Altimmune, Antios, Audentes, Corcept, Effectus, Fibronostics, Fujifilm/Wako, Gerson Lehrman Group, GlaxoSmithKline, Kinnate Bio, Perspectum, Precision BioSciences, Quest, Seres, Sonic Incytes, Topography Health, Tune, and Venatorx. He advises CymaBay, Durect, Kezar Life Sciences, Prodigy, Sagimet, and Takeda. He is on the speakers’ bureau for Bristol Myers Squibb, Diasorin, Mallinckrodt, and VBI Vaccines. He owns stock in AngioCrine. Bettina E. Hansen consults, advises, and received grants from Ipsen. She consults and advises Advanz. She advises and received grants from CymaBay. She consults for Albireo, Calliditas, Chemomab, Enyo, Intercept, and Mirum. She advises Pliant. She received grants from Calliditas. Gideon Hirschfield consults for Advanz, CymaBay, Dr Falk, Escient, GlaxoSmithKline, Intercept, Ipsen, Kowa, Mirum, and Pliant. Kris Kowdley consults, is on the speakers’ bureau, and received grants from Gilead and Intercept. He consults and received grants from 89bio, CymaBay, GENFIT, GlaxoSmithKline, Ipsen, Madrigal, Mirum, NGM, Pfizer, and Zydus. He consults and owns in stock in Inipharm. He consults for Enanta and HighTide. He is on the speakers’ bureau for AbbVie. He received grants from Boston, Corcept, Hanmi, Janssen, Novo Nordisk, Pliant, Terns, and Viking. He received compensation from UpToDate. Andreas E. Kremer consults, advises, and is on the speakers’ bureau, and received grants from Intercept. He consults, advises, and is on the speakers’ bureau for Advanz, CymaBay, Dr Falk, GlaxoSmithKline, Ipsen, and Mirum. He consults and advises Escient. Marlyn Mayo consults and received grants from CymaBay, GlaxoSmithKline, and Ipsen. She consults for Intra-Sana Laboratories. She received grants from Intercept and Mirum. George Mells received grants from Advanz and Intercept. James Neuberger consults for Umecrine. He is on the speakers’ bureau for Advanz and GlaxoSmithKline. Mark Swain consults, advises, and received grants from GlaxoSmithKline, Ipsen, and Novo Nordisk. He consults and advises Advanz. He consults and is on the speakers’ bureau for Abbott. He advises Abbott. He received grants from AbbVie, Altimmune, AstraZeneca, Axcella, Bristol Myers Squibb, Calliditas, CymaBay, Galectin, Gilead, GlaxoSmithKline, Intercept, Ipsen, Kowa, Madrigal, Merck, Novartis, Novo Nordisk, Pfizer, and Roche. Atsushi Tanaka advises GlaxoSmithKline, EA Pharma, and Kowa. He is on the speakers’ bureau for Gilead. Douglas Thorburn consults and is on the speakers’ bureau for Ipsen. He consults for Chemomab and Pliant. He is on the speakers’ bureau for Advanz. Michael Trauner consults, is on the speakers’ bureau, and received grants from Albireo, Dr Falk, Gilead, Intercept, and MSD. He consults and is on the speakers’ bureau for Janssen and Madrigal. He consults and received grants from AbbVie, CymaBay, and GENFIT. He consults for BiomX, Boehringer Ingelheim, HighTide, Novartis, Phenex, Pliant, Rectify, Regulus, Siemens, and Shire. He is on the speakers’ bureau for Bristol Myers Squibb and Roche. He received grants from Alnylam, Takeda, and Ultragenyx. He holds intellectual property rights on the medical use of norUDCA filed by the Medical Universities of Graz and Vienna. Palak Trivedi consults, advises, is on the speakers’ bureau, and received grants from Advanz and Albireo/Ipsen. He consults, advises, and received grants from GlaxoSmithKline. He consults and advises CymaBay and Pliant. He received grants from Bristol Myers Squibb, LifeArc, Medical Research Foundation, NIHR, and Regeneron. Martin Weltman advises Chiesi. Andrew Yeoman consults, advises, and is on the speakers’ bureau for Advanz and Falk. He consults and advises Ipsen. Cynthia Levy consults and received grants from Calliditas, CymaBay, GlaxoSmithKline, Intercept, Ipsen, Kowa, and Mirum. She received grants from Escient and Zydus. She is on the editorial board for AASLD. The remaining authors have no conflicts to report.

References

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