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Regulatory Perspective on HCV Drug Resistance

Patrick Harrington, Ph.D.

Clinical Virology ReviewerDivision of Antiviral Products

U.S. Food and Drug Administration

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DisclaimerThe views expressed in this presentation are those of the speaker and not necessarily official policy of the Food and Drug and Administration

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Outline1. Current Perspective on HCV Drug

Resistance

2. Drug Resistance Considerations in Drug Development and Protocol Design

3. FDA Analysis of Drug Resistance Data

42001 2012

Perspective on HCV Drug ResistanceR

esis

tanc

e C

once

rns

*

More drug classes/improvements to others P/R has some activity in null responders POC for IFN-free regimens Certain PI resistance substitutions may persist Predominance of resistance polymorphisms

for some patients

Few promising drugs/classes HIV mindset

52001 2012

Res

ista

nce

Con

cern

sPerspective on HCV Drug Resistance

More drug classes/improvements to others P/R has some activity in null responders POC for IFN-free regimens Certain PI resistance substitutions may persist Predominance of resistance polymorphisms

for some patients

Few promising drugs/classes HIV mindset

Optimized regimens w/SVR rates ~100% for DAA-naïve

Effective treatments for DAA-experienced

Future?

*

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Why Have Resistance Concerns Increased Recently?

No single reason in particular, but a combination of developments:• HCV genotype and subtype differences in DAA durability• Moving towards first-line regimens that do not include Peg-IFN• Poor responsiveness to P/R is associated with reduced efficacy of

IFN-free regimens– Overlapping factors impacting P/R and IFN-free regimens– Patients challenging to treat in IFN-era may remain challenging to treat

in DAA era• P/R add-on “rescue therapy” may have limited benefit for poor P/R

responders• Certain DAA resistance-associated substitutions can persist long

after drug exposure (across multiple classes)• Recent data indicating poor antiviral durability for certain regimens

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HCV Genotype and Subtype Differences in DAA Durability

• HCV subtype-related efficacy differences for regimens that include NS3/4A PIs, non-nucleoside NS5B inhibitors (multiple sub-classes) and NS5A inhibitors

• HCV subtype in the IFN-free era may be equivalent to HCV genotype in the P/R era– Different regimens, possibly different durations– Accurate HCV subtype identification in clinical trials and in

clinical practice will be critical for some regimens– Need to consider impact of non-Gt1 subtypes

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Future Treatment ParadigmTreat with IFN-free

DAA Regimen (P/R naïve, experienced,

intolerant, etc.)

Must Address These Challenges:1. Baseline characteristics that reduced

efficacy of 1st line DAA regimen, such as: Poorly IFN-responsive and IL28B

unfavorable Gt HCV Gt 1a High HCV RNA levels Natural drug resistance polymorphisms Advanced disease Poor drug PK Poor adherence or tolerability

2. AND at least for some patients… Enrichment of DAA resistance (possibly across multiple classes)

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Optimism that Resistance Challenges Will Be Addressed

• Identification of multiple combinations of drugs for first-line, IFN-free treatment with 90%+ efficacy for various populations (at least in small studies)

• Defining robust baseline predictors of efficacy • Dozens of potent drugs across several classes still

in active development• Trials in DAA-experienced and other difficult to treat

populations have begun or have been proposed

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Resistance Considerationsin Drug Development and Protocol Design

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Balancing Resistance Risks in Protocol Design

• What is the medical need for the study population?• Is the trial design scientifically justified, or is it just

studying what is convenient to test?• Are decisions being made based on SVR?• Will the trial be informative, and will data collection and

analysis be maximized to help guide future trial designs?• Does the trial include appropriate patient and arm futility

rules?• Is a feasible “rescue therapy” approach included?

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Treatment Arm Futility Rules

ExampleIf ≥5 of the first 10 subjects in a short duration arm experience virologic relapse, declare arm futile and extend treatment duration for other subjects who are still being treated in the arm.

Rationale• Help balance risk when “pushing the envelope”

– Have been triggered for multiple trials, and as a result, reduced # of subjects receiving suboptimal treatment

Considerations for Futility Rule Designs• Analyze different HCV genotypes/subtypes independently• Ensure results will remain interpretable• Validate and refine futility rules as clinical development progresses

wallbot.net

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Rescue Therapy for DAATreatment Failure

• Give patients best chance to achieve SVR• Consider emerging data and individual patient

characteristics– What seems like a “rescue” approach may actually be

futile for some patients• Collect and report data on efficacy of rescue

therapy approaches!– Clear data from a small number of patients may be

extremely valuable for future trial design and for clinical practice

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Rescue Therapy for DAATreatment Failure

BMS NS3+NS5A in P/R null responders– 6 GT 1a Patients

w/Virologic BT: add-on P/R for 48 weeks

– 2 of 6 subjects achieved SVR with rescue therapy

– Both SVR subjects had HCV RNA ~1,000 IU/mL at time of starting rescue therapy

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

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Trials in DAA-Experienced PatientsSome days I feel like Homer…

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• Currently, enough promising classes to construct reasonable regimens (+/- Peg-IFN) for most circumstances of first round DAA failure

• We strongly encourage cross-company collaboration when needed to construct a scientifically justified regimen

• Top priority for early trials: identify a highly effective treatment regimen– e.g., not the time to push the envelope on short treatment

duration

Trials in DAA-Experienced Patients: Protocol Design Considerations (1)

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• Should have proof-of-concept efficacy (i.e., SVR) in DAA-naïve patients– Ideally, in P/R null responders or other difficult to treat,

DAA-naive populations– Could be direct evidence, or extrapolated from studies

of individual components Drug A + Drug B + P/R never studied, but each increase SVR

rates when dosed individually with P/R (or other DAAs)

• Resistance screening may be necessary • Efficacy based on SVR12, confirm with SVR24

Trials in DAA-Experienced Patients: Protocol Design Considerations (2)

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Trials in DAA-Experienced Patients:Examples for Early POC Studies

1. BOC or TVR + P/R Experienced P/R + ≥ 2 “new” DAAs (neither are NS3/4A PIs) P/R + ≥ 1 “new” DAA + 1 NS3/4A PI, for first cohort

exclude those with detectable key resistance substitutions for the new PI*

IFN-free DAA combination that is highly effective in P/R null responders, w/o use of NS3/4A PI (PI can be added if hypothesized to enhance efficacy)

*Notes:- Sequencing assay sensitivity depends on emerging data. Currently recommend population-

based sequencing in most circumstances. - Resistance screening may not be necessary for second generation PIs with activity against

key HCV genotype 1a and 1b resistance pathways.

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Trials in DAA-Experienced Patients:Examples for Early POC Studies

2. IFN-free, Combination DAA Experienced P/R + ≥ 2 HCV DAAs, naïve to at least one class Peg-IFN-free, combination ≥ 2 DAA (+/- RBV) regimen

with demonstrated efficacy in DAA-naïve, Peg-IFN/RBV null responders or other difficult to treat populations

In both examples, the need for drug resistance screening depends on specific drug classes in the regimen and HCV DAA exposure history.

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Trials in DAA-Experienced Patients:Examples for Early POC Studies

3. Patients exposed to non-therapeutic DAA regimens, for example:

– Phase 1 monotherapy trials– Discontinued treatment early for tolerability/safety

reasons (while responding virologically)

Can be eligible for later Phase 2 or Phase 3 trials of regimens with proof-of-concept efficacy in DAA-naïve patients

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Trials in DAA-Experienced Patients:Retrospective Analyses

• All DAA-experienced subjects (even those exposed to short duration) should be identifiable in submitted efficacy and resistance datasets

• At minimum, for early studies of patients re-treated with the same DAA class, analyze the relationship between efficacy and the following: Prior treatment response (e.g., breakthrough, relapse) Time since prior DAA exposure Prevalence/quantity of DAA-resistant variants (e.g., based on

next-generation sequencing assay)

• Results should guide design of subsequent studies

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FDA Analysis of Drug Resistance Data

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What Do We Do with Resistance Data?

• Independent analysis– Confirm ‘known’ resistance-associated substitutions– Identify potentially novel substitutions– Recommend additional studies when needed– Publicize results from independent analysis, when appropriate

• Drug prescribing information – Based on totality of data, i.e., no specific criteria for calling something

‘resistance-associated’– Provides transparency and encourages further study

• Communicate ideas to reduce burden of analyses, e.g.:– Focus on NS3 protease domain if resistance pathways not detected in

NS3 helicase or NS4A in early studies– Due to technical burden and poor sensitivity, extensive population-

based phenotypic analyses usually not necessary

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Boceprevir Analysis ExampleTx-emergent subs. in non-SVR subjects in pooled Phase 3 trials

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Boceprevir Analysis ExampleTx-emergent subs. in non-SVR subjects in pooled Phase 3 trials

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Boceprevir Analysis ExampleTx-emergent subs. in non-SVR subjects in pooled Phase 3 trials

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Boceprevir Analysis ExampleEvidence of treatment selection in non-SVR subjects:D168N– Not previously reported for boceprevir or telaprevir– Position associated with resistance to NS3/4A PIs (non-covalent/macrocyclic)– Detected in 11 post-BL samples from 8 BOC-treated subjects– All subjects infected with HCV genotype 1a– R155T detected in all D168N samples; D168N detected in 11 of 13 R155T

samples– L. Naeger independently confirmed R155T + D168N emerged in telaprevir

treated subjects R155T + D168N selected by both boceprevir and telaprevir

V107I– No known previous reports– Emerged in 6 boceprevir-treated subjects and 0 control arm subjects (usually

in combination with other substitutions)– Emerged in a small number of boceprevir-treated subjects in Phase 2 studies

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Summary Our perspective on HCV drug resistance evolves as new

data emerge and new drugs are added to the pipeline. We remain optimistic that simple, tolerable, and highly

effective treatments for chronic HCV are on the horizon. We anticipate (and encourage) the development of

effective regimens for DAA-experienced patients and other difficult to treat populations.

We continue to encourage the collection and detailed analysis of drug resistance and other clinical virology data.

As always, we will independently review new data to understand the impact of drug resistance and help guide future trial design.

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AcknowledgmentsFDA Division of Antiviral ProductsDebra Birnkrant, M.D.Jeff Murray, M.D.Kim Struble, Pharm.D.and many others…

FDA Division of PharmacometricsJeff Florian, Ph.D.

FDA DAVP Clinical Virology TeamJules O’Rear, Ph.D., Team LeaderLisa Naeger, Ph.D.Narayana Battula, Ph.D.Damon Deming, Ph.D.Eric Donaldson, Ph.D.Takashi Komatsu, Ph.D.Lalji Mishra, Ph.D.Sung Rhee, Ph.D.

Study volunteersClinical investigators

Merck, Vertex, and other HCV drug developers

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For More Information...FDA Clinical Virology Reviews (via “Drugs@FDA”)Boceprevir:http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202258Orig1s000MicroR.pdf

Telaprevir:http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/201917Orig1s000MicroR.pdf

FDA Draft Guidance on HCV DAA Development(September 2010, currently being updated)http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfo

rmation/Guidances/UCM225333.pdf