Transcript Seeking Treatments for PSC Out of the Desert and into the Woods

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
PSC Clinical Trials Landscape - Past
PSC Clinical Trials Landscape - Current
NATURAL HISTORY OF PSC
Colitis
Pre-Clinical PSC
Biliary
• Elevated ALP
Inflammation
Biliary
Fibrosis
• Abnormal Cholangiogram
Competing Outcomes
Portal
Hypertension
• Cirrhosis
•
•
•
Variceal
Bleeding
IMPAIRED
Quality of Life
Fatigue
Pruritus
Abdominal Pain
Liver-related
Death/Liver
Transplantation
Cancers
Bacterial cholangitis
IBD Flares
Drug Approval Process
Phase 1
Phase 2
Phase 3
• Small Number
• Open Label
• Single to Few Doses
• Pharmacokinetics
• Safety
• Intermediate Number
• Double-blind or Open
Label
• Dose Ranging
• Efficacy and Safety
• Large number
• Double-blind
• Establish Clinical
Efficacy
• Safety
• 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
FDA Terminology
• Clinical Benefit
• 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
Example 1: Cholesterol is a validated surrogate
endpoint for Heart Disease
Statins 
Cholesterol
Statins 
Death
High Cholesterol
Epi
High
Cholesterol
= High risk
Atherosclerosis
Mechanism
Cholesterol
forms plaques
Myocardial
Infarction
Mechanism
Plaques lead
to MI
Surrogate Biomarker
Intermediate Clinical Endpoint
Irreversible Morbidity
Death
Example 2: Alk phos is a reasonably likely
surrogate endpoint for PBC
Urso 
Alk Phos
Urso 
Death
High Alk Phos
Epi
Response in
Alk Phos
= Low risk
Fibrosis/Cirrhosis
Mechanism
Bile duct
damage leads
to fibrosis
Liver
Transplantation
Mechanism
Fibrosis leads
to liver failure
Surrogate Biomarker
Intermediate Clinical Endpoint
Irreversible Morbidity
Death
PBC Surrogate Endpoints
Willem JL et al. Gastroenterol 2014;147:1338–1349.
A reasonably likely surrogate endpoint for PSC
Drug 
Alk Phos
Drug 
Death
High Alk Phos
Epi
Low Alk Phos
= Low risk
Fibrosis/Cirrhosis
Mechanism
Bile duct
damage leads
to fibrosis
Liver
Transplantation
Mechanism
Fibrosis leads
to liver failure
Surrogate Biomarker
Intermediate Clinical Endpoint
Irreversible Morbidity
Death
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. 2013.
The trouble is…
Urso Improves Liver Tests…
…but not outcomes
Alk Phos
Outcomes
Times ULN
Urso
Placebo
3.5
3
2.5
2
1.5
1
0.5
0
Placebo
Urso
0
20
40
60
Number of Events
0
12
24
Months
26
Death
Transplant
Listing
Cirrhosis
Varices
CCA
Lindor, K. et al. Hepatol. 2009;50:808-814.
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
1
2
3
4
Criteria for PSC Trials
CRITERIA
ALP
IBD
Biologic
Liver Bx
Small Duct
> 2 X ULN
Mild Allowed
Allowed
No
Not Allowed
NGM282 (NGM
Biopharmaceuticals)
> 1.5 X ULN
Mild Allowed
Allowed
No
Allowed
Simtuzimab (Gilead)
Not required
Mild allowed
Not Allowed
Yes
Not Allowed
> 1.5 X ULN
Required, Mild
only
Not Allowed
No
Not Allowed
OCA (Intercept)
Cenicriviroc (Tobira)
Other considerations: Advanced stage of disease; History of colectomy; Recent cholangitis; Colon dysplasia;
Cholangiocarcinoma; Urso use
NOR-URSO IMPROVES CHOLESTASIS IN PSC:
PHASE II DOSE FINDING STUDY
ALP (ITT)
• Double-blind, placebo-controlled
5
Placebo
• 12 weeks treatment
• 159 randomized
• 126 PP analysis
% Change from Baseline
• 222 pts. screened
0
-5
-10
500 mg/d
-15
1000 mg/d
-20
-25
1500 mg/d
-30
Trauner, M. et al. J Hepatol. 2016;64:208A.
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
PSC Clinical Trials Landscape - Future