Ocaliva™ - obeticholic acid Manufacturer: Intercept Pharmaceuticals FDA Approval Date: 5/27/2016 Han Lin, PharmD Candidate

Ocaliva™ - obeticholic acid Objectives At the end of this presentation participants will be able to: Appropriately recommend Ocaliva™ - (obeticholic acid) Effectively educate patients on the purpose, proper use and potential adverse effects of Ocaliva™ - (obeticholic acid)

Ocaliva™ - obeticholic acid Clinical Application Indications: Treatment of primary biliary cholangitis (PBC) as monotherapy or in combination with ursodeoxycholic acid (UDCA) Place in therapy: Second line therapy in patients that are seeing inadequate response to UDCA UDCA - Decreases the cholesterol content of bile by reducing the secretion of cholesterol from the liver and the fractional reabsorption of cholesterol by the intestines. Mechanism of action in primary biliary cirrhosis is not clearly defined. Ocaliva [package insert].

Ocaliva™ - obeticholic acid Clinical Application Contraindications: Complete biliary obstruction Black Box warnings: None listed Warnings/Precautions: Liver – Related Adverse Reactions Severe Pruritus Reduction in HDL-C Ocaliva [package insert].

Ocaliva™ - obeticholic acid Clinical Application Pregnancy: Limited human data No fetal harm at 13 and 6 times max amount in rats and rabbits Lactation: No information on drug transfer Ocaliva [package insert].

Ocaliva™ - obeticholic acid Drug Facts Pharmacology: Farnesoid X Receptor Agonist Expressed in liver and intestine Suppresses CYP7A1, the rate-limiting enzyme in bile acid synthesis from cholesterol Nuclear receptors which up- or down-regulates the expression of certain genes. One of the primary functions of FXR activation is the suppression of cholesterol 7 alpha-hydroxylase (CYP7A1), the very first and rate-limiting enzyme in bile acid synthesis from cholesterol. Ocaliva [package insert].

Ocaliva™ - obeticholic acid Drug Facts Pharmacokinetics: A Cmax ~1.5 hrs. Follows linear kinetics. Food does not alter extent of absorption. D V = 618 L. >99% protein binding M Conjugation with glycine or taurine E 87% excretion in feces Ocaliva [package insert].

Ocaliva™ - obeticholic acid Drug Interactions Drug Interactions – Object Drugs: CYP1A2: potential for increased exposure to CYP1A2 substrates. 25 mg warfarin – 13%  systemic exposure 200 mg caffeine – 42%  AUC 20 mg omeprazole – 32%  AUC 20 mg rosuvastatin – 22%  AUC All interactions compared to concomitant 10 mg Ocaliva Ocaliva [package insert].

Ocaliva™ - obeticholic acid Drug Interactions Drug Interactions – Precipitant Drugs: 20 mg omeprazole – <1.2 fold  exposure. Determined to be not clinically significant. Ocaliva [package insert].

Ocaliva™ - obeticholic acid Adverse Effects Common Adverse Effects: (obeticholic acid%)[placebo%] Pruritus 70% [38%] Fatigue 25% [15%] Abdominal pain and discomfort 19% [14%] Rash 10% [8%] Ocaliva [package insert].

Ocaliva™ - obeticholic acid Monitoring Parameters Efficacy Monitoring: Improvement in lowering ALP. No current mortality or symptom relief benefits Toxicity Monitoring: LFTs, including alkaline phosphatase and bilirubin Lipid profile Pruritus ALP: a liver enzyme and biomarker used to track disease progression in PBC Ocaliva [package insert].

Ocaliva™ - obeticholic acid Prescription Information Dosing: Initial: 5 mg daily Max: 10 mg daily if adequate reduction not achieved in 3 months Cost: $6840 Source: Uptodate. Accessed 09/01/2016 Ocaliva [package insert].

Ocaliva™ - obeticholic acid Literature Review Nevens, F. et al. NEJM. 2016;375(7):631-43.

Ocaliva™ - obeticholic acid Literature Review Study Design: 12 month, double-blind, placebo controlled randomized phase 3 trial Inclusion Criteria: ≥ 18 YO diagnosed with PBC Alkaline phosphatase level ≥1.67x UL, or Abnormal total bilirubin < 2 times UL Alk Phos: 38 – 126 Tbili: 0.3 – 1.2 Nevens, F. et al. NEJM. 2016;375(7):631-43.

Ocaliva™ - obeticholic acid Literature Review Interventions: N=217 who had inadequate response to ursodeoxycholic acid (ursodiol) or unacceptable side effects Randomization into 1:1:1 Obeticholic acid 10 mg, 5 mg (titrating up to 10 mg as need), or Placebo Nevens, F. et al. NEJM. 2016;375(7):631-43.

Ocaliva™ - obeticholic acid Literature Review Primary Endpoint: Reduction of alkaline phosphatase level <1.67 times the upper limit of normal (reduction of at least 15%) AND Normal total bilirubin level at 12 months Secondary efficacy end points included levels of alkaline phosphatase, GGT, alanine aminotransferase, aspartate aminotransferase, total and conjugated bilirubin, and albumin; prothrombin time; international normalized ratio; plasma bile acid levels; level of fibroblast growth factor 19 (FGF-19), an enterokine released after FXR activation; inflammation, as assessed by high- sensitivity C-reactive protein (CRP) and tumor necrosis factor α (TNF-α) levels; interleukin-6 level; Nevens, F. et al. NEJM. 2016;375(7):631-43.

Ocaliva™ - obeticholic acid Literature Review Patient Demographics Characteristic Placebo Ocaliva 5-10 mg Ocaliva 10 mg Age (years) 56 ± 10 56 ± 11 Female no. (%) 68 (93%) 65 (93%) 63 (86%) White Race 66 (90%) 67 (96%) 70 (96%) Alk Phos 327 ± 115 326 ± 116 316 ± 104 Tbili 0.69 ± 0.42 0.6 ± 0.33 0.66 ± 0.39 Ursodiol use 67 (92%) Pruritus 47 (93%) 37 (53%) 44 (60%) Nevens, F. et al. NEJM. 2016;375(7):631-43.

Ocaliva™ - obeticholic acid Literature Review Results: Primary endpoint 5-10 mg; 10 mg; placebo 46% and 47% vs. 10%; p<0.001 Alkaline phosphatase level -113 and -130 vs. -14 U/L; p<0.001 Total bilirubin -0.3 and -0.9 vs. 0.12 μmol/L; p<0.001 Nevens, F. et al. NEJM. 2016;375(7):631-43.

Ocaliva™ - obeticholic acid Literature Review Adverse Effect: Placebo Ocaliva 5-10 mg Ocaliva 10 mg Pruritus 28 (38%) 39 (56%) 50 (68%) Nasopharyngitis 13 (18%) 17 (24%) Headache 12 (17%) 6 (8%) Fatigue 10 (14%) 11 (16%) 17 (23%) Arthralgia 3 (4%) 4 (6%) 7 (10%) Nevens, F. et al. NEJM. 2016;375(7):631-43.

Ocaliva™ - obeticholic acid Literature Review Conclusion: Obeticholic acid administered with ursodiol or as monotherapy resulted in significant decreases in alkaline phosphatase and total bilirubin levels There were more serious adverse events with obeticholic acid “Obeticholic acid administered with ursodiol or as monotherapy for 12 months in patients with PBC resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo.“ Nevens, F. et al. NEJM. 2016;375(7):631-43.

Ocaliva™ - obeticholic acid Summary Ocaliva™ - obeticholic acid is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (ursodiol) as monotherapy Obeticholic acid is a farnesoid X receptor agonist. Initial dosing for Ocaliva is 5 mg daily, titrated to 10 mg if adequate reduction not achieved in 3 months Child-Pugh B and C: 5 mg weekly This medication provides an alternative treatment option for PBC through a unique, novel mechanism of action.

Ocaliva™ - obeticholic acid References https://ocaliva.com/ocaliva_pi.pdf. Ocaliva [package insert]. New York, NY. Intercept Pharmaceuticals, Inc; 2016. Nevens, F. et al. NEJM. 2016;375(7):631-43.