HCV Drug Resistance:

Regulatory Perspective

Patrick Harrington, PhD

Senior Clinical Virology Reviewer

Division of Antiviral Products, FDA/CDER

2016 HIV and Hepatitis Clinical Pharmacology Workshop

Washington, D.C.

Disclosures: none

1

Disclaimer

The views expressed in these slides are those of the

presenter and do not necessarily represent official

policy of the Food and Drug Administration.

2

Presentation Outline

• Review of basic HCV antiviral drug resistance

concepts

• Impact of HCV polymorphisms on treatment

efficacy in DAA clinical trials, and considerations

for pre-treatment resistance testing

• Perspective on re-treatment for DAA-

experienced patients

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HCV Drug Resistance Basic Concepts and Definitions (1)

Baseline polymorphism

Major natural genetic variant that is present in the viral population of a

minority of infected individuals.

“Major” means detectable by Sanger population sequencing or at a

comparable sensitivity level by Next Generation Sequencing (generally at

least 10-15% of sequence reads).

Not to be confused with a low abundance minority variant present in viral

quasispecies.

Treatment-emergent substitution

Amino acid change that emerged or became enriched in the viral

population with treatment.

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HCV Drug Resistance Basic Concepts and Definitions (2)

Resistance-associated polymorphism or substitution

Amino acid variant that is associated with treatment failure with a DAA or

regimen, or associated with phenotypic resistance to a DAA.

The presence of a resistance-associated polymorphism or substitution in a

viral population does not necessarily mean a drug is ineffective.

Drug resistance barrier

Describes the potential for drug resistance selection.

Generally reflects the number and type of viral genetic changes that confer

resistance to a clinically relevant concentration of the drug.

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Drug Resistant Virus Often Pre-Exists(Example from Rong, Perelson et al., 2010)

• HCV: 1012 virions produced each day in an individual.

• Replication error rate: 10-5 to 10-4 per nucleotide (i.e., 0.1 to 1 change per

genome per round of replication).

• Do the math→ all possible single and combinations of double

nucleotide mutant viruses preexist in the quasispecies before

treatment, and additional mutations arise early during therapy.

• Many early generation HCV DAAs have a low barrier to resistance:

impacted by single amino acid changes in the target protein.

• Drug resistant virus preexists and is rapidly selected by monotherapy.

• Combinations of drugs with non-overlapping resistance mechanisms

prevent drug resistance selection because they collectively have a higher

resistance barrier than the individual drugs.

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Monotherapy with a Low Resistance Barrier

Drug Selects for Resistance

Schiffer et al., Nat Med 2011

Dvory-Sobol et al., AAC 2012

HCV RNA decline during monotherapy “unmasks” and enriches drug resistant virus

Green=low dose, Pink=mid dose,

Purple=high dose

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Examples of Early Low Resistance

Barrier IFN-Free DAA Regimens

8Zeuzem et al., Hepatology (2012) 55, 3: 749-58

GS-9256 + Tegobuvir(PI + Non-Nuc)

GS-9256 + Tegobuvir + RBV(PI + Non-Nuc + RBV)

Lok et al., NEJM 2012; 366:216-224

Highly Effective (>90% SVR Rates) IFN-

Free Regimens(HCV Treatment Guidelines Spring 2016)

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DAA Combination DAA Class(es)Genotype

Coverage

Sofosbuvir + RBV NS5B Nuc. Analogue Polymerase Inhibitor 2

Ledipasvir/Sofosbuvir ± RBV NS5A Inhibitor/

NS5B Nuc. Analogue Polymerase Inhibitor

1, 4, 5, 6

Ombitasvir/Paritaprevir/

ritonavir ± Dasabuvir ± RBV

NS5A Inhibitor/NS3 PI/

NS5B Non-Nuc. Polymerase Inhibitor

1, 4

Daclatasvir + Sofosbuvir ±

RBV

NS5A Inhibitor/

NS5B Nuc. Analogue Polymerase Inhibitor

1, 2, 3

Simeprevir + Sofosbuvir ±

RBV

NS3 PI/

NS5B Nuc. Analogue Polymerase Inhibitor

1

Elbasvir/Grazoprevir ± RBV NS5A Inhibitor/NS3 PI 1, 4

Impact of HCV Polymorphisms on

Efficacy of DAA-based Regimens

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Impact of HCV Polymorphisms on

Efficacy of DAA-based Regimens

• Many IFN-free DAA combinations can be impacted by the presence

of polymorphisms in drug target genes.

• The clinical impact of HCV polymorphisms is influenced by other

factors that also impact treatment efficacy, such as patient disease

characteristics (e.g., cirrhosis), the activity and resistance barrier for

other drugs in the regimen, and treatment duration.

• The presence of a DAA resistance-associated polymorphism does

not preclude the use of the DAA.

• Optimized/intensified DAA regimens (e.g., additional DAAs, ribavirin,

and/or longer treatment duration) can overcome the presence of

polymorphism(s) in drug target genes.

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To screen or not to screen for

polymorphisms...Favoring Screening Screening Not Necessary

Clear impact on efficacy No clear impact on efficacy

Significantly impacts U.S. populationVery low (<<5%) overall virologic failure

rates in population

Assay commercially available No commercially available assay

Reasonable alternative treatment options

available (including waiting)

Alternative treatment options

not available

Resistance consequences of failure Minimal resistance consequences of failure

Limited or no re-treatment options Reasonable re-treatment options available

Clinical consequences of failure Minimal clinical consequences of failure

Factors Generally Not Considered

Cost

Complicating the treatment algorithm

Resistance testing is relatively simple

Response-Guided Therapy

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Cirrhosis Determination in Trials (e.g.)

Resistance Test

Test: NS5A

Substitution Detected: Y93H

Afdhal N, Reddy KR, Nelson DR, et al. N Engl J Med 2014;370:1483-93.

VA boceprevir treatment algorithm

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To screen or not to screen for

polymorphisms...Favoring Screening Screening Not Necessary

Clear impact on efficacy No clear impact on efficacy

Significantly impacts U.S. populationVery low (<<5%) overall virologic failure

rates in population

Assay commercially available No commercially available assay

Reasonable alternative treatment options

available (including waiting)

Alternative treatment options

not available

Resistance consequences of failure Minimal resistance consequences of failure

Limited or no re-treatment options Reasonable re-treatment options available

Clinical consequences of failure Minimal clinical consequences of failure

Factors Generally Not Considered

Cost

Complicating the treatment algorithm

Key factors that contributed to label recommending screening for Q80K:

• GT1a Q80K polymorphism substantially reduces efficacy of SMV + P/R

• High prevalence of Q80K in U.S. (48% of GT1a)

• Resistance consequences of failure: Emergence of R155K (or others)

• Boceprevir and telaprevir not impacted and represented alternative treatments

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Simeprevir + P/R: GT1a NS3 Q80K

D.Deming, FDA Clinical Virology review of simeprevir

• Q80K associated with reduced efficacy in non-cirrhotic GT1a patients for 8-week duration

but not with 12-week duration

Longer treatment duration reduces impact of Q80K

• Q80K associated with reduced efficacy in cirrhotic GT1a patients treated for 12 weeks

Disease status influences clinical impact of Q80K16

Simeprevir + Sofosbuvir: GT1a Q80K

Sarrazin C., 2016. J Hepatol.

• Relapse rates -2% to +20% in those with baseline PMs versus those without

• Greatest efficacy impact associated with use of “less intense regimens”, presence of

multiple key NS5A polymorphisms, and/or presence of polymorphisms that reduce LDV

activity by >100-fold (Zeuzem et al., AASLD 2015).

• Impact of PMs minimized with regimens recommended in labeling: 12 weeks for most

patients, 24 weeks for cirrhotic tx-exp.; 8-weeks considered if low BL HCV RNA

L.Naeger, FDA Clinical Virology review of ledipasvir/sofosbuvir

LDV/SOF: NS5A PMs and Relapse Rates

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Trial (GT1) Regimen No NS5A PM With NS5A PM

ION-3

(tx-naïve)

LDV/SOF 8W 4.8% (8/167) 6.3% (3/48)

LDV/SOF 12W 1.9% (3/158) 0% (0/56)

LDV/SOF + RBV 8W 3% (5/167) 8.2% (4/49)

ION-2

(tx-exp.)

LDV/SOF 12W 2.3% (2/86) 22% (5/23)

LDV/SOF 24W 0% (0/90) 0% (0/19)

LDV/SOF + RBV 12W 3.4% (3/89) 4.5% (1/22)

LDV/SOF + RBV 24W 0% (0/91) 0% (0/19)

OBV/PTV/r + DSV (GT1a)

• Low estimated impact (~0-8%) of NS3 Q80K or NS5A polymorphisms in Phase 2b/3 trials

• Label-recommended regimens maximize efficacy for all subjects regardless of baseline

polymorphisms: 2-3% VF rate overall for GT1a

Recent retrospective analyses showed NS5A polymorphisms and NS3 Q80K did not

impact efficacy of label-recommended regimens (Sulkowski et al., CROI 2016)

P.Harrington, FDA Clin. Virology review of OBV/PTV/r+DSV

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Daclatasvir + Sofosbuvir (GT3)

• Clear impact of Y93H polymorphism

• Low or no NS5A inhibitor resistance consequence of failure

– No other major NS5A resistance-associated substitutions emerged in failures

who already had the Y93H polymorphism

– Y93H alone confers >3,000-fold reduction in DCV activity

• At the time, assay for screening was not commercially available and

alternative treatment options were not ideal.

P.Harrington, FDA Clin. Virology review of daclatasvir

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Elbasvir/Grazoprevir

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Impact of NS5A Resistance-Associated Amino Acid Polymorphisms on Efficacy

of EBR/GZR ± RBV for HCV GT1a Infected Subjects

• Clear impact of NS5A polymorphisms (present in ~10-12% of GT1a subjects),

although impact variable by NS5A position

• Nearly all virologic failures with these NS5A polymorphisms gained additional

treatment-emergent, resistance-associated substitution(s) in NS3 and/or NS5A

• No signal of virologic failure among subjects w/ or w/o NS5A polymorphisms

treated with EBR/GZR + RBV for 16 weeks (small #s w/ polymorphisms, but

challenging group)

T. Komatsu, FDA Clin. Virology review of elbasvir/grazoprevir

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EBR/GZR for HCV GT1a:

NS5A PolymorphismsFavoring Screening Screening Not Necessary

Clear impact on efficacy No clear impact on efficacy

Significantly impacts U.S. populationVery low (<<5%) overall virologic failure

rates in population

Assay commercially available No commercially available assay

Reasonable alternative treatment options

available (including waiting)

Alternative treatment options

not available

Resistance consequences of failure Minimal resistance consequences of failure

Limited or no re-treatment options Reasonable re-treatment options available

Clinical consequences of failure Minimal clinical consequences of failure

Factors Generally Not Considered

Cost

Complicating the treatment algorithm

EBR/GZR Label

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• First example where pre-treatment screening for resistance-associated

polymorphisms is recommended to guide optimal use of an IFN-free regimen

• AASLD/IDSA treatment guidelines consistent with prescribing information

Daclatasvir/Sofosbuvir ± RBV GT1aImpact of NS5A Polymorphisms

• Signal that NS5A polymorphisms (same 4 NS5A positions as EBR/GZR) may impact

treatment efficacy in HCV GT1a infected subjects with cirrhosis, although very few subjects

• Additional tx-emergent NS5A and/or NS5B substitutions in 3 of 4 virologic failures

• Evidence from other trials/populations that DCV-based regimens impacted by NS5A PMs

• Evidence from other trials that disease status can influence the impact of BL PMs

• Not a well-supported alternative to EBR/GZR-12W for GT1a compensated cirrhotic patients

with NS5A polymorphisms

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P. Harrington Clin. Virology review of daclatasvir

Population

SVR12 with

Polymorphism(s)

SVR12 without

Polymorphism(s)

Subjects with Child-Pugh A/B Cirrhosis1 2/6 (33%) 38/39 (97%)

Subjects without Cirrhosis 9/9 (100%) 72/72 (100%)

Subjects Post-Transplant 2/2 (100%) 28/29 (97%)

1No subjects with Child-Pugh C cirrhosis had NS5A resistance polymorphisms

Daclatasvir Label (GT1)

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• Not consistent with AASLD/IDSA guidelines for HCV GT1a infected patients with compensated cirrhosis, which recommend a longer DCV/SOF ± RBV duration of 24 weeks irrespective of NS5A polymorphisms (“Alternative regimen”)

Clinical Relevance of BL Phenotype (?)• Baseline phenotypic resistance may be associated with

reduced clinical efficacy, but lack of a baseline phenotype

does not preclude clinical relevance.

• Two NS5A examples illustrate relationship between

baseline phenotype, clinical impact, and treatment-

emergent substitutions

– Elbasvir/Grazoprevir 12W: GT1a L31M

• SVR rate: 38% (5/13)

• 0.5-fold impact in stable replicon assay, 10-fold in transient assay

• “High fold-change” according to AASLD/IDSA tx guidelines

– Daclatasvir/Sofosbuvir 12W: GT3a Y93H

• SVR rate: 54% (7/13)

• 3,733-fold impact on activity 25

Phenotypic Impact of Clinically

Relevant NS5A Polymorphisms

0,001

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GT1a EC50 GT1a EC50(Serum-Adj)

GT1a-L31M EC50(Serum-Adj)

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EBR/GZR treatment failure in GT1a

subjects with NS5A PMs associated with

additional emergent NS5A substitutions

DCV/SOF treatment failure in GT3 subjects

with Y93H generally not associated with

additional emergent NS5A substitutions

0,001

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GT1a EC50 GT3a EC50 GT3a-Y93HEC50

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DCV Plasma

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How can a polymorphism without a clinically

relevant phenotype still be clinically relevant?

Wild-type Predominant L31M Predominant

No Resistance PM

L31M (Sensitive)

NS5A Resistant(L31M + Other Subst)

NS5A Resistant +NS3 PI Resistant

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Absolu

te Q

uantity

of H

CV

Popula

tion (

log)

What leads to failure

No NS3+NS5A resistant virus

present

Re-Treatment Following

DAA Failure

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Re-Treatment Following DAA Failure

Combination DAA Treatment Outcome

Must Address These Challenges:

1. Baseline characteristics that reduced efficacy of 1st line DAA regimen, such as:

Poor IFN/immune status and IL28B unfavorable genotype

HCV GT 1a or GT3

High HCV RNA levels

Natural drug resistance polymorphisms

Advanced disease

Poor drug PK

Poor adherence or tolerability

2. AND…

Treatment-emergent DAA resistance

(possibly across multiple classes)

Any further disease progression or

other comorbidities

Effective Strategies for

DAA Re-treatment• More potent, non-cross-resistant regimen (e.g.,

Sofosbuvir + NS5A inhibitor ± RBV in P/R + PI Failures)

• Intensified regimen (e.g., add RBV or additional DAA,

longer duration)

• Combinations of novel DAAs with activity against DAA-

resistant viruses: promising efficacy results emerging in

DAA failure populations (including NS5A failures)

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Remaining Questions

• Impact of resistance-associated polymorphisms/

substitutions and need for resistance testing in DAA

combination regimen failures

• Optimal re-treatment for HCV GT3 infected patients who

failed an NS5A inhibitor

• Scope of GT4 and GT6 subtype diversity and impact on

DAA efficacy

• Optimal treatment for patients with advanced cirrhosis +/-

resistance-associated polymorphisms/substitutions

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Thanks to the following FDA/DAVP

HCV DAA review team members...

Clinical Virology Reviewers

Damon Deming, PhD

Eric Donaldson, PhD

Takashi Komatsu, PhD

Lalji Mishra, PhD

Lisa Naeger, PhD

Jules O’Rear, PhD, Team Leader

Clinical Reviewers

Sarita Boyd, PharmD

Wendy Carter, DO

Sarah Connelly, MD

Russ Fleischer, PA-C,MPH, Acting TL

Poonam Mishra, MD, Dep. Dir. Safety

Adam Sherwat, MD, Team Leader

Kim Struble, PharmD, Team Leader

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Debbie Birnkrant, MD, Division Director

Jeffrey Murray, MD, MPH, Deputy Division Director