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Seeking Treatments for PSC Out of the Desert and into the Woods
Christopher L. Bowlus, MD Division of Gastroenterology and Hepatology University of California Davis
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PSC Clinical Trials Landscape - Past
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PSC Clinical Trials Landscape - Current
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Liver-related Death/Liver Transplantation
NATURAL HISTORY OF PSC Colitis Biliary Inflammation Elevated ALP Biliary Fibrosis Abnormal Cholangiogram Portal Hypertension Cirrhosis Variceal Bleeding Liver-related Death/Liver Transplantation Pre-Clinical PSC Competing Outcomes Cancers Bacterial cholangitis IBD Flares 10-20 years IMPAIRED Quality of Life Fatigue Pruritus Abdominal Pain
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Drug Approval Process Expensive Process High Rate of Failure
Phase 1 Small Number Open Label Single to Few Doses Pharmacokinetics Safety Phase 2 Intermediate Number Double-blind or Open Label Dose Ranging Efficacy and Safety Phase 3 Large number Double-blind Establish Clinical Efficacy Expensive Process Lack of support for repurposing of old drugs Vancomycin High Rate of Failure High bar for drug approval Slow Process Each phase takes years to complete
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FDA Terminology Clinical Benefit Intermediate Clinical Endpoint
A positive clinically meaningful effect of an intervention on how an individual feels, functions, or survives. Intermediate Clinical Endpoint Clinical outcome that can be measured earlier than an effect on irreversible morbidity or mortality (IMM) Reasonably likely to predict the medical product’s effect on IMM or other clinical benefit Accelerated Approval Regulatory mechanism by which new drugs can be approved based on clinical trials demonstrating an effect on a reasonably likely surrogate endpoint or a clinical endpoint other than survival or IMM. Reasonably Likely Surrogate Endpoint An endpoint supported by clear mechanistic and/or epidemiologic rationale but insufficient clinical data to show that it is a validated surrogate endpoint
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Myocardial Infarction
Example 1: Cholesterol is a validated surrogate endpoint for Heart Disease High Cholesterol Atherosclerosis Myocardial Infarction Death Statins Cholesterol Statins Death Epi High Cholesterol = High risk Mechanism Cholesterol forms plaques Mechanism Plaques lead to MI Surrogate Biomarker Intermediate Clinical Endpoint Irreversible Morbidity
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Example 2: Alk phos is a reasonably likely surrogate endpoint for PBC
High Alk Phos Fibrosis/Cirrhosis Liver Transplantation Death ? Urso Alk Phos Urso Death Epi Response in Alk Phos = Low risk Mechanism Bile duct damage leads to fibrosis Mechanism Fibrosis leads to liver failure Surrogate Biomarker Intermediate Clinical Endpoint Irreversible Morbidity
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PBC Surrogate Endpoints
Willem JL et al. Gastroenterol 2014;147:1338–1349.
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A reasonably likely surrogate endpoint for PSC
High Alk Phos Fibrosis/Cirrhosis Liver Transplantation Death ? Drug Alk Phos Drug Death Epi Low Alk Phos = Low risk Mechanism Bile duct damage leads to fibrosis Mechanism Fibrosis leads to liver failure Surrogate Biomarker Intermediate Clinical Endpoint Irreversible Morbidity
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Alkaline Phosphatase as a biomarker in PSC
Responder = ALP that was normal or reduced by ≥40% after 1 year in trial Lindstrom L, et al. Clin Gastroenterol Hepatol
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Urso Improves Liver Tests…
The trouble is… Urso Improves Liver Tests… …but not outcomes Lindor, K. et al. Hepatol. 2009;50:
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Phase of Clinical Development
Drug Pipeline for PSC Phase of Clinical Development Bile Acid Based Therapies OCA (Intercept) – OPEN TO ENROLLMENT NGM282 (NGM Biopharmaceuticals) – OPEN TO ENROLLMENT Nor-UDCA (Falk) - COMPLETED Intestinal Apical Sodium Bile Acid Transport (iASBT) inhibitors SHP625 (LUM001; Shire) - COMPLETED Anti-Fibrotic Simtuzimab (Gilead) – ENROLLMENT COMPLETED Immune-based Therapies Cenicriviroc (Tobira) - OPEN TO ENROLLMENT Microbiome Therapies Vancomycin (Stanford) – ENROLLMENT COMPLETED FMT (Mass General) - OPEN TO ENROLLMENT
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Criteria for PSC Trials
ALP IBD Biologic Liver Bx Small Duct OCA (Intercept) > 2 X ULN Mild Allowed Allowed No Not Allowed NGM282 (NGM Biopharmaceuticals) > 1.5 X ULN Simtuzimab (Gilead) Not required Mild allowed Yes Cenicriviroc (Tobira) Required, Mild only Other considerations: Advanced stage of disease; History of colectomy; Recent cholangitis; Colon dysplasia; Cholangiocarcinoma; Urso use
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NOR-URSO IMPROVES CHOLESTASIS IN PSC: PHASE II DOSE FINDING STUDY
Double-blind, placebo-controlled 12 weeks treatment 222 pts. screened 159 randomized 126 PP analysis Trauner, M. et al. J Hepatol. 2016;64:208A.
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PSC Clinical Trials Landscape
Challenges Recruitment Selection criteria excludes many patients Many patients feel well and do not want to participate Many patients are unaware of studies Travel, inconvenience, cost Endpoints What will FDA accept for a reasonably likely surrogate endpoint Opportunities Interest in PSC is HIGH! Industry – Researchers – Regulatory – Patients Targets have been identified Drugs are available
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PSC Clinical Trials Landscape - Future
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