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

2. 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)

3. 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].

4. 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].

5. 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].

6. 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].

7. 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].

8. 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].

9. 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].

10. 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].

11. 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].

12. 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].

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

14. 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):

15. 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):

16. 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):

17. 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):

18. 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 μmol/L; p<0.001
Nevens, F. et al. NEJM. 2016;375(7):

19. 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):

20. 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):

21. 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.

22. Ocaliva™ - obeticholic acid References
Ocaliva [package insert]. New York, NY. Intercept Pharmaceuticals, Inc; 2016.
Nevens, F. et al. NEJM. 2016;375(7):