Download obeticholic acid

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:
1. Appropriately recommend Ocaliva™ -
(obeticholic acid)
2. 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
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
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
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
19% [14%]
discomfort
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
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
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
Nevens, F. et al. NEJM. 2016;375(7):631-43.
Ocaliva™ - obeticholic acid
Literature Review
Patient Demographics
Characteristic
Placebo
Ocaliva 510 mg
Ocaliva 10
mg
Age (years)
56 ± 10
56 ± 11
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
68 (93%)
65 (93%)
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:
Ocaliva Ocaliva
Placebo
5-10 mg 10 mg
Pruritus
Nasopharyngitis
28 (38%)
13 (18%)
39 (56%)
17 (24%)
50 (68%)
13 (18%)
Headache
Fatigue
Arthralgia
13 (18%)
10 (14%)
3 (4%)
12 (17%)
11 (16%)
4 (6%)
6 (8%)
17 (23%)
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
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
Ocaliva™ - obeticholic acid
References
1.
https://ocaliva.com/ocaliva_pi.pdf.
2.
Ocaliva [package insert]. New York, NY. Intercept
Pharmaceuticals, Inc; 2016.
3.
Nevens, F. et al. NEJM. 2016;375(7):631-43.