PSC Partners Seeking A Cure 2019 Conference

1. PSC Partners Seeking A Cure 2019 Conference Management of PSC and Quality of Life David N. Assis, MD Assistant Professor of Medicine Yale University School of Medicine June 22, 2019

2. Disclosures • Site sub-investigator for autoimmune liver disease trials sponsored by: TARGET-PBC, Genkyotex, HighTide, Cymabay, Novartis.

3. Outline • Pharmacologic Management • Endoscopic Management • Cancer Monitoring • Bone Health • Symptoms and Quality of Life • Patient Reported Outcome Measures (PROMs)

4. Pharmacologic Management • Currently there is no proven pharmacotherapy for the treatment of PSC that is able to reduce disease progression or improve mortality. • Multiple clinical trials underway • Bile acid modulation has been the most common treatment approach

5. Pharmacologic Management • Ursodeoxycholic acid (UDCA) has been studied in PSC for several decades. • Moderate Dosing (15 mg/kg/day) • Improvement in liver tests and quality of life • No proven mortality benefit in PSC • High dose UDCA (>28 mg/kg/day) • Randomized Study (2009): increased adverse events and negative outcomes • AASLD 2010 guidelines: recommend against UDCA • Equivocal recommendation from other society guidelines Lindor KD. New Engl J Med. 1997;336:691-5. Harnois D, et al. Am J Gastro. 2001;96:1558-62. Lindor KD, et al. Hepatology 2009;50:808-14. Chapman R, et al. Hepatology 2010;51:660-78.

6. Pharmacologic Management • Prospective study evaluating withdrawal of UDCA in PSC patients: • Deterioration in serum liver test findings and Mayo risk score • Increased incidence of pruritus, reduced quality of life. Wunsch et al. Hepatology 2014 Sep;60(3):931-40.

7. Pharmacologic Management My personal practice approach to UDCA: • Not to initiate UDCA for new patients with PSC, unless the patient has elevated liver tests and/or symptoms and is not eligible or interested in clinical trials • Careful consideration about stopping UDCA if already started

8. Pharmacologic Management Increased interest in manipulating the microbiome for the management of PSC

9. Pharmacologic Management Increased interest in manipulating the microbiome for the management of PSC • Oral Vancomycin • Reduced ALP in small studies (peds and adults) • May be associated with improvement in colitis symptoms • A randomized, placebo-controlled clinical trial is pending. High Dose Low Dose Abarbanel et al. J Clin Immunol. 2013;33:397-406. Tabibian et al. Aliment Pharmacol Ther. 2013;37:604-12.

10. Pharmacologic Management • Concurrent management of PSC and IBD? • Vedolizumab • A humanized monoclonal antibody that selectively blocks the α4β7 integrin. • FDA approved for treatment of UC and Crohn’s disease.

11. Pharmacologic Management • Concurrent management of PSC and IBD? • Vedolizumab • A humanized monoclonal antibody that selectively blocks the α4β7 integrin. • FDA approved for treatment of UC and Crohn’s disease. • International PSC Study Group (IPSCSG) • Retrospective analysis (N=102) • Liver tests increased in some patients • No evidence of safety issues • It is possible that certain subgroups of patients may benefit Lynch et al, Clin Gastroenterol Hepatol 2019 (in press).

12. Pharmacologic Management • Concurrent management of PSC and IBD? • Anti-TNF agents • Effect on the liver in PSC remains unclear. • Recent case series suggests reduced ALP in patients who received adalimumab after 6-8 months (but not at 12-24 months) Tse et al. Aliment Pharmacol Ther 2018;48:190-5.

13. Endoscopic Management • Over time, many patients with strictures will require ERCP for symptomatic disease, including cholangitis from acute obstruction, right upper quadrant pain, or pruritus. Dominant stricture • A stenotic area with a diameter of 1.5 mm or less in the common bile duct or 1 mm or less in the hepatic duct • Frequency as high as 50% in PSC • Can be associated with cholangiocarcinoma • Endoscopic treatment includes balloon dilation and stenting in the setting of symptoms or liver test changes.

14. Endoscopic Management • Prospective study of balloon dilatation (N=31) vs. short-term stents (N=34) in patients with PSC and dominant strictures • Followed for 24 months • Outcome: recurrence-free patency • Study terminated early: • No difference in outcomes • Difference in adverse events: • Stent group (45%) > Balloon group (6.7%) Ponsioen CY et al. Gastroenterology 2018 Sep;155(3):752-759.

15. Endoscopic Management • Routine endoscopic intervention for stricture management remains controversial. • Evidence is not clear that endoscopic intervention itself can change the natural history of PSC.

16. Endoscopic Management • 30-year study of a single-center practice • Scheduled (Yearly) vs. On-Demand ERCP • Strictures were treated even if asymptomatic, normal LFTs • Survival was higher in the scheduled group compared with the on-demand group • 30.2 years vs. 22.5 years, p<0.001 • Reduced bacterial cholangitis • Scheduled 17.3% vs on-demand 34.6%, p=0.001 • No difference in complication rates • Benefit of scheduled ERCP was only in those who eventually developed dominant strictures Rupp et al. Gut 2019 (in press).

17. Endoscopic Management Acute Cholangitis • Sudden pain, fever, chills from bacterial infection of biliary tract • Urgent labs, initiation of antibiotics, and evaluation for obstruction and need for ERCP • Pill-in-pocket approach in some cases -- initiate oral antibiotics early while obtaining labs and imaging

18. Cancer Surveillance Management • Cholangiocarcinomais one of the leading causes of death in PSC • Most centers perform imaging-based surveillance and guidelines suggest it though evidence to support this has traditionally been lacking

19. Cancer Screening Management • Benefit of imaging: 5-year overall survival: 68% (surveillance) vs. 20% (no surveillance) p<0.001 Ali et al. Hepatology. 2018 Jun;67(6):2338-2351.

20. Fibrosis Monitoring • Transient Elastography (TE) – non invasive measure of fibrosis • Marker of PSC disease progression and prognosis? • Ongoing prospective study of TE (FICUS study) • MR Elastography (MRE) may be even better Corpechot et al. Gastroenterology. 2014;146:970–979

21. Bone Health Management • Chronic cholestasis prevents normal absorption and processing of vitamins: • A, D, E, K • Vitamin D deficiency may contribute to risk of osteoporosis

22. Bone Health Management • Bone Density scan at diagnosis and every 1-3 years • Regular Exercise • Good nutrition • Minimize/eliminate alcohol intake • Calcium: 1000 - 1500 mg/day • Vitamin D: 800 - 1000 IU/day • Bisphosphonates in setting of osteoporosis

23. Management of PSC Symptoms • While some PSC symptoms, such as fatigue, are typically constant and stable over time, many other symptoms are episodic and fluctuating.

24. Management of PSC Symptoms PSC Partners Registry Study • More than half of patients had disease-associated symptoms • Abdominal pain (73%) • Pruritus (65%) • Fatigue (74%) • Depression (34%) • Mean number of missed weeks of school/work over the past year: 5.7 • Real-world impact! Kuo et al. Clin Gastroenterol Hepatol 2019.

25. Management of PSC Symptoms Itching (pruritus) • Can be mild, but can also be devastating! • New-onset pruritus: must verify that there is no new stricture, obstruction • Topical moisturizing creams (Eucerin) • Pharmacotherapy: • Cholestyramine 4 g, taken 20 minutes before meals • Refractory cases: rifampin, naltrexone, selective serotonin reuptake inhibitors, and plasmapheresis.

26. Management of PSC Symptoms • Symptoms of PSC significantly impact psychological wellbeing. • Asurvey of patients with PSC in Canada found a reduced quality of life (QoL) and a high frequency of anxiety in 75%of patients • No relationship between alkaline phosphatase and QoL Cheung AC et al. Dig Dis Sci. 2016 Jun;61(6):1692-9.

27. Patient Reported Outcome Measures (PROMs) • PROMsassess the symptomatic impact of disease by directly capturing the patient experience without additional interpretation from a provider, caregiver, or anyone else. • Disease-specific PROMs are needed to directly capture the patient’s experience and detect meaningful change in symptoms in response to current or emerging therapies. • Historically, quality of life studies in PSC used generic questionnaires

28. PROMs in PSC • PSC PRO is a new 42-item disease-specific instrument The PSC PRO Measures: (1) PSC symptoms and (2) Impact of symptoms on life functioning Younossi. Hepatology. 2018 Jul;68(1):155-165.

29. PROMs in PSC • PSC PRO is a new 42-item disease-specific instrument A few limitations: • Degree of patient input into its development (not ideal) • Not studied in relationship to IBD status and symptoms • Not studied in a diverse group of patients Younossi. Hepatology. 2018 Jul;68(1):155-165.

30. PROMs in PSC • There is a need for a critical evaluation of this new PSC PRO tool in a real-world set of patients of various backgrounds. • There is a need to develop PSC-specific PROMs that incorporate patient input during development and that can be used to assess changes in symptoms and to evaluate the efficacy of new drugs. • UK PRO Study (co-sponsored by PSC Partners Seeking a Cure)

31. Summary • Pharmacotherapeutic management of PSC is not yet adequately developed • Endoscopic management of dominant strictures is important and the practice is evolving • Monitoring for Fibrosis and Cancer Surveillance should be performed • Management of Bone Health is important for all PSC patients • Pruritus management should be treated in a personalized approach • PROMs are needed to better address symptoms and quality of life.

32. Thank you