The Role of Clinical Pharmacology in HCV Drug Development: Regulatory Experience

Transcription

1 The Role of Clinical Pharmacology in HCV Drug Development: Regulatory Experience Islam R. Younis, Ph.D. Team Leader Office of Clinical Pharmacology Center for Drug Evaluation and Research U.S. Food and Drug Administration

2 Disclaimer This presentation reflects the views of the presenter and not the position or policies of the Food and Drug Administration. 2 2

3 Landscape of HCV Therapy Modified from Florian et al, CPT,

4 Role of Clinical Pharmacology Dose Selection Shortening Trial Duration Pharmacogenomics Specific Populations DDI Biopharmaceutics Post-Marketing 4

5 Shortening Trial Duration (SVR12 vs SVR24) Retrospective analysis from 5 drug development programs: 15 phase II and phase III trials 3 Pediatric trials Database included 13,599 adult subjects 5

6 Shortening Trial Duration (SVR12 vs SVR24) Gastroenterology Jun;144(7):

7 Number of In Vitro and Phase I Studies Submitted to Approved HCV NME NDAs Drug-Drug Interactions (in vivo) 7 (3,32) Study Type Specific Populations Biopharmaceutics Human PK 3 (2,9) 3 (1,8) 6 (1,15) In Vitro 21 (7,63) Median Number of Studies Data do not include TQT studies or PD studies in healthy volunteers 7

8 Example 1: Pharmacogenomics Simeprevir HCV Q80K: Impact on SVR12 Rates Simeprevir- FDA Antiviral Drugs Advisory Committee Meeting (10/24/2013) 8

9 Example 1: Pharmacogenomics Simeprevir HCV Q80K Excerpt from simeprevir label approved on 11/22/2013 9

10 Example 2: Race- Based Dosing Simeprevir (East Asian) hepatocyte bile CYP3A diffusion OATP1B1/3 simeprevir metabolite systemic circulation Simeprevir- FDA Antiviral Drugs Advisory Committee Meeting (10/24/2013) 10

11 Example 2: Race- Based Dosing Simeprevir (East Asian) Simeprevir- FDA Antiviral Drugs Advisory Committee Meeting (10/24/2013) 11

12 Example 2: Race- Based Dosing Simeprevir (East Asian) All Subjects Asian Subjects Simeprevir- FDA Antiviral Drugs Advisory Committee Meeting (10/24/2013) 12

13 Example 2: Race- Based Dosing Simeprevir (East Asian) Excerpt from simeprevir label approved on 11/22/

14 Example 2: Race- Based Dosing Simeprevir (East Asian) Excerpt from simeprevir approval letter dated 11/22/

15 Example 2: Race- Based Dosing Simeprevir (East Asian) J Gastroenterol Hepatol May;31(5):

16 Example 2: Race- Based Dosing Simeprevir (East Asian) PL SMV 100 mg SMV 150 mg N Efficacy SVR12 76% 89% 91% Safety Any AEs 97% 95% 97% Rash 13% 16% 18% Pruritus 9% 13% 9% Photosensitivity 0% 1% 1% J Gastroenterol Hepatol May;31(5):

17 Example 2: Race- Based Dosing Simeprevir (East Asian) Excerpt from simeprevir label approved on 02/26/

18 Example 3: DDI Sofosbuvir/Velpatasvir-Omeprazole Data obtained from Epclusa Clinical Pharmacology Review 18

19 Example 3: DDI Sofosbuvir/Velpatasvir-Omeprazole Excerpt from Epclusa label approved on 06/28/

20 Example 4: Relative Bioavailability Based Approval Viekira XR TM Viekira Pak TM Viekira XR TM AM PAR/OMB/RTV PM PAR/OMB/DAS/RTV DAS DAS 20

21 Example 4: Relative Bioavailability Based Approval Viekira XR TM Viekira XR CDTL Review 21

22 Example 4: Relative Bioavailability Based Approval Viekira XR TM (Food Effecct) Viekira XR CDTL Review 22

23 Example 6:Post-Marketing Viekira Pak & Clopidogrel Dasabuvir is a substrate of CYP2C8 enzyme and is contraindicated with strong inhibitors of CYP2C8 due to an increased risk of QT prolongation associated with increased dasabuvir exposure 23

24 Example 6:Post-Marketing Viekira Pak & Clopidogrel Repaglinide Dasabuvir Primary Route of Metabolism CYP2C8 CYP2C8 Other Routes of Metabolism CYP3A4 CYP3A4 OATP Transporters OATP1B1 None Exposure Change in Presence of Gemfibrozil ~7-8 fold ~11-fold Exposure Change in Presence of Clopidogrel ~4-fold Not known Courtesy: Vikram Arya, FCP, Ph.D. 24

25 Example 6:Post-Marketing Viekira Pak & Clopidogrel Clinical Pharmacology & Therapeutics, Vol 99, Issue Supplement S1 25

26 Conclusions Clinical pharmacology plays a critical role in advancing the development of HCV DAAs. Clinical pharmacology plays a critical role in dose selection of HCV DAAs. Clinical pharmacology contributions span over the life cycle of HCV DAAs. Combination therapy contribute to the complexity of designing and reviewing HCV DAAs clinical pharmacology programs. 26

27 Acknowledgment Clinical Pharmacology Antiviral Team Members: Vikram Arya, Ph.D. Stanley Au, Pharm.D. Amal Ayyoub, Ph.D. Su-Young Choi, Pharm.D., Ph.D. Mario Sampson, Pharm.D. Shirley Seo, Ph.D. Jenny Zheng, Ph.D. 27