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

Islam R. Younis, Ph.D. Team Leader

Office of Clinical PharmacologyCenter for Drug Evaluation and Research

U.S. Food and Drug Administration

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Disclaimer

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

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Landscape of HCV Therapy

Modified from Florian et al, CPT, 2015

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Role of Clinical Pharmacology

• Dose Selection• Shortening Trial Duration• Pharmacogenomics• Specific Populations• DDI• Biopharmaceutics • Post-Marketing

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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

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Shortening Trial Duration (SVR12 vs SVR24)

Gastroenterology. 2013 Jun;144(7):1450-1455.

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0 5 10 15 20 25

In Vitro

Human PK

Biopharmaceutics

Specific Populations

Drug-Drug Interactions(in vivo)

Median Number of Studies

Stud

y Ty

pe

Number of In Vitro and Phase I Studies Submitted to Approved HCV NME NDAs

7 (3,32)

3 (2,9)

6 (1,15)

3 (1,8)

21 (7,63)

Data do not include TQT studies or PD studies in healthy volunteers

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Example 1: PharmacogenomicsSimeprevir HCV Q80K: Impact on SVR12 Rates

Simeprevir- FDA Antiviral Drugs Advisory Committee Meeting (10/24/2013)

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Example 1: PharmacogenomicsSimeprevir HCV Q80K

Excerpt from simeprevir label approved on 11/22/2013

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Example 2: Race- Based DosingSimeprevir (East Asian)

systemic circulation

bile

hepatocyte

OATP1B1/3

CYP3A

simeprevirmetabolite

diffusion

Simeprevir- FDA Antiviral Drugs Advisory Committee Meeting (10/24/2013)

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Example 2: Race- Based DosingSimeprevir (East Asian)

Simeprevir- FDA Antiviral Drugs Advisory Committee Meeting (10/24/2013)

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Example 2: Race- Based DosingSimeprevir (East Asian)

Simeprevir- FDA Antiviral Drugs Advisory Committee Meeting (10/24/2013)

All Subjects

Asian Subjects

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Example 2: Race- Based DosingSimeprevir (East Asian)

Excerpt from simeprevir label approved on 11/22/2013

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Example 2: Race- Based DosingSimeprevir (East Asian)

Excerpt from simeprevir approval letter dated 11/22/2013

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Example 2: Race- Based DosingSimeprevir (East Asian)

J Gastroenterol Hepatol. 2016 May;31(5):912-20.

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Example 2: Race- Based DosingSimeprevir (East Asian)

PL SMV 100 mg SMV 150 mgN 152 153 152

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. 2016 May;31(5):912-20.

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Example 2: Race- Based DosingSimeprevir (East Asian)

Excerpt from simeprevir label approved on 02/26/2016

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Example 3: DDI Sofosbuvir/Velpatasvir-Omeprazole

Data obtained from Epclusa Clinical Pharmacology Review

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Example 3: DDI Sofosbuvir/Velpatasvir-Omeprazole

Excerpt from Epclusa label approved on 06/28/2016

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Example 4: Relative Bioavailability Based ApprovalViekira XRTM

Viekira PakTM Viekira XRTM

AM PM

PAR/OMB/RTV

DAS DAS

PAR/OMB/DAS/RTV

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Example 4: Relative Bioavailability Based ApprovalViekira XRTM

Viekira XR CDTL Review

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Example 4: Relative Bioavailability Based ApprovalViekira XRTM (Food Effecct)

Viekira XR CDTL Review

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Example 6:Post-MarketingViekira 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

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Example 6:Post-MarketingViekira Pak & Clopidogrel

Courtesy: Vikram Arya, FCP, Ph.D.

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

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Example 6:Post-MarketingViekira Pak & Clopidogrel

Clinical Pharmacology & Therapeutics, Vol 99, Issue Supplement S1

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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.

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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.