HCV Drug Resistance: Regulatory Perspective

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 DAAexperienced patients 3

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. 4

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. 5

Drug Resistant Virus Often Pre-Exists (Example from Rong, Perelson et al., 2010) HCV: 10 12 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. 6

Monotherapy with a Low Resistance Barrier Drug Selects for Resistance HCV RNA decline during monotherapy unmasks and enriches drug resistant virus Green=low dose, Pink=mid dose, Purple=high dose Dvory-Sobol et al., AAC 2012 Schiffer et al., Nat Med 2011 7

Examples of Early Low Resistance Barrier IFN-Free DAA Regimens GS-9256 + Tegobuvir (PI + Non-Nuc) GS-9256 + Tegobuvir + RBV (PI + Non-Nuc + RBV) Lok et al., NEJM 2012; 366:216-224 Zeuzem et al., Hepatology (2012) 55, 3: 749-58 8

Highly Effective (>90% SVR Rates) IFN- Free Regimens (HCV Treatment Guidelines Spring 2016) DAA Combination DAA Class(es) Sofosbuvir + RBV NS5B Nuc. Analogue Polymerase Inhibitor 2 Ledipasvir/Sofosbuvir ± RBV Ombitasvir/Paritaprevir/ ritonavir ± Dasabuvir ± RBV Daclatasvir + Sofosbuvir ± RBV Simeprevir + Sofosbuvir ± RBV NS5A Inhibitor/ NS5B Nuc. Analogue Polymerase Inhibitor NS5A Inhibitor/NS3 PI/ NS5B Non-Nuc. Polymerase Inhibitor NS5A Inhibitor/ NS5B Nuc. Analogue Polymerase Inhibitor NS3 PI/ NS5B Nuc. Analogue Polymerase Inhibitor Elbasvir/Grazoprevir ± RBV NS5A Inhibitor/NS3 PI 1, 4 Genotype Coverage 1, 4, 5, 6 1, 4 1, 2, 3 1 9

Impact of HCV Polymorphisms on Efficacy of DAA-based Regimens 10

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. 11

To screen or not to screen for polymorphisms... Favoring Screening Clear impact on efficacy Significantly impacts U.S. population Assay commercially available Reasonable alternative treatment options available (including waiting) Resistance consequences of failure Limited or no re-treatment options Clinical consequences of failure Screening Not Necessary No clear impact on efficacy Very low (<<5%) overall virologic failure rates in population No commercially available assay Alternative treatment options not available Minimal resistance consequences of failure Reasonable re-treatment options available Minimal clinical consequences of failure Factors Generally Not Considered Cost Complicating the treatment algorithm 12

Resistance testing is relatively simple Response-Guided Therapy Cirrhosis Determination in Trials (e.g.) Afdhal N, Reddy KR, Nelson DR, et al. N Engl J Med 2014;370:1483-93. Resistance Test Test: NS5A Substitution Detected: Y93H VA boceprevir treatment algorithm 13

To screen or not to screen for polymorphisms... Favoring Screening Clear impact on efficacy Significantly impacts U.S. population Assay commercially available Reasonable alternative treatment options available (including waiting) Resistance consequences of failure Limited or no re-treatment options Clinical consequences of failure Screening Not Necessary No clear impact on efficacy Very low (<<5%) overall virologic failure rates in population No commercially available assay Alternative treatment options not available Minimal resistance consequences of failure Reasonable re-treatment options available Minimal clinical consequences of failure Factors Generally Not Considered Cost Complicating the treatment algorithm 14

Simeprevir + P/R: GT1a NS3 Q80K D.Deming, FDA Clinical Virology review of simeprevir 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 15

Simeprevir + Sofosbuvir: GT1a Q80K Sarrazin C., 2016. J Hepatol. 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 Q80K 16

LDV/SOF: NS5A PMs and Relapse Rates 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) LDV/SOF 12W 2.3% (2/86) 22% (5/23) ION-2 (tx-exp.) 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) L.Naeger, FDA Clinical Virology review of ledipasvir/sofosbuvir 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 17

OBV/PTV/r + DSV (GT1a) P.Harrington, FDA Clin. Virology review of OBV/PTV/r+DSV 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) 18

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 P.Harrington, FDA Clin. Virology review of daclatasvir At the time, assay for screening was not commercially available and alternative treatment options were not ideal. 19

Elbasvir/Grazoprevir Impact of NS5A Resistance-Associated Amino Acid Polymorphisms on Efficacy of EBR/GZR ± RBV for HCV GT1a Infected Subjects T. Komatsu, FDA Clin. Virology review of elbasvir/grazoprevir 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) 20

EBR/GZR for HCV GT1a: NS5A Polymorphisms Favoring Screening Clear impact on efficacy Significantly impacts U.S. population Assay commercially available Reasonable alternative treatment options available (including waiting) Resistance consequences of failure Limited or no re-treatment options Clinical consequences of failure Screening Not Necessary No clear impact on efficacy Very low (<<5%) overall virologic failure rates in population No commercially available assay Alternative treatment options not available Minimal resistance consequences of failure Reasonable re-treatment options available Minimal clinical consequences of failure Factors Generally Not Considered Cost Complicating the treatment algorithm 21

EBR/GZR Label 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 22

Daclatasvir/Sofosbuvir ± RBV GT1a Impact of NS5A Polymorphisms Population SVR12 with Polymorphism(s) SVR12 without Polymorphism(s) Subjects with Child-Pugh A/B Cirrhosis 1 2/6 (33%) 38/39 (97%) Subjects without Cirrhosis 9/9 (100%) 72/72 (100%) Subjects Post-Transplant 2/2 (100%) 28/29 (97%) 1 No subjects with Child-Pugh C cirrhosis had NS5A resistance polymorphisms P. Harrington Clin. Virology review of daclatasvir 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 23

Daclatasvir Label (GT1) 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 ) 24

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 treatmentemergent 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

Elbasvir Concentration (nm) Daclatasvir Concentration (nm) 26 100 10 1 0,1 EBR Plasma C24 Phenotypic Impact of Clinically Relevant NS5A Polymorphisms 1000 100 10 1 0,1 DCV Plasma C24 0,01 0,01 0,001 GT1a EC50 GT1a EC50 (Serum-Adj) GT1a-L31M EC50 (Serum-Adj) 0,001 GT1a EC50 GT3a EC50 GT3a-Y93H EC50 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

Absolute Quantity of HCV Population (log) How can a polymorphism without a clinically relevant phenotype still be clinically relevant? No Resistance PM L31M (Sensitive) No NS3+NS5A resistant virus present NS5A Resistant (L31M + Other Subst) NS5A Resistant + NS3 PI Resistant Wild-type Predominant L31M Predominant What leads to failure 27

Re-Treatment Following DAA Failure 28

Re-Treatment Following DAA Failure Combination DAA Treatment Outcome Must Address These Challenges: 1. Baseline characteristics that reduced efficacy of 1 st 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 29

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 DAAresistant viruses: promising efficacy results emerging in DAA failure populations (including NS5A failures) 30

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 31

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 Debbie Birnkrant, MD, Division Director Jeffrey Murray, MD, MPH, Deputy Division Director 32