Resistance and Tropism - Maraviroc

1
Resistance and Tropism - Maraviroc

• Lisa K. Naeger, Ph.D.
• Division of Antiviral Products
• Food and Drug Administration

FDA Antiviral Advisory Committee Meeting
April 24, 2007
2
Maraviroc Resistance and Tropism

• Novel Target
• host receptor
• Unique Resistance Issues
• resistance to MVC
• tropism switching
• outgrowth of CXCR4-tropic virus

3
Baseline Analyses Studies 1027 and 1028

• Genotypic susceptibility scores (GSS) and
  phenotypic susceptibility scores (PSS) were
  balanced across treatment groups
• median GSS 1
• median PSS 2
• Heavily treatment-experienced population
• 67 had overall susceptibility scores lt2
• 30 had one potentially active drug in their OBT
• 14 had no potentially active drug in their OBT

4
Tropism at Baseline

• 2560 screened 56 were CCR5-tropic
• 90 of enrolled subjects had CCR5-tropic virus at
  Baseline
• 4 had Dual-mixed tropic virus
• 5 had non-typable virus

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Why Did Subjects Fail MVC Treatment in Studies
1027 and 1028?

• CCR5 to CXCR4 co-receptor switch through virus
  mutation
• Outgrowth of MVC resistant CCR5-tropic viruses
• Outgrowth of CXCR4-tropic viruses undetected at
  baseline
• Resistance to Optimized Background Therapy
• Host CCR5 genotype

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FDA Censored Dataset for As-Treated Analyses
Studies 1027 and 1028
Overall Number of subjects in Pfizer virology dataset 1050
Overall number of subjects in virology dataset from FDA 962
FDA Censored 88

• FDA Censored
• Subjects who
• Discontinued while suppressed (lt400 copies/mL)
• Discontinued with gt400 copies/mL between
  Baseline and Week 4
• Discontinued between Baseline and Week 8 with at
  least
• 0.5 log decrease and no rebound (previous 2
  log decrease
• with 1 log increase)

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Tropism at Failure
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Tropism at Time of Failure
Percentage of Virologic Failures (gt400 copies/mL)
with CCR5-tropic and CXCR4-tropic virus at Week 24
Tropism MVC QD n154 MVC BID n143 Placebo n146
CCR5 47 34 84
Dual-Mixed 31 43 8
CXCR4 12 14 1
NR/NP 10 10 8
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Resistance to Optimized Background Therapy
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Responders (lt400 copies/mL) by Susceptibility
Score at Baseline
Overall Susceptibility Score
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Optimized Background in Treatment Failures
QD N154 BID N143 Placebo N143
No Susceptible Drugs at Baseline 29 29 27
Changes in OBT on therapy 43 42 46
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Enfuvirtide Use inTreatment Failures
QD N154 BID N143 Placebo N143
ENF Use 45 45 45
ENF Resistance Mutations at Failure 71 52 74
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Overall Susceptibility Scores of Treatment
Failures by Tropism
OSS CXCR4-tropic n29 CCR5-tropic n163 Dual/Mixed n94 All n320
0-1 80 55 63 60
2 17 24 23 23
3 3 19 11 15
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Virology Sub-Studies

• Comprehensive analysis requested
• Treatment failures and/or
• Change in HIV co-receptor tropism

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Failure with CCR5-Tropic Virus

• Determine maraviroc susceptibility in cell
  culture
• Nucleotide sequence analysis of the gp120 region
  to identify amino acid substitutions
• Nucleotide sequence analysis of protease and RT
  regions

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Failure with CXCR4-Tropic Virus

• Baseline and on-treatment clonal evaluation of
  virus to determine the relative number of
  CXCR4-tropic and CCR5-tropic viral isolates.
• Nucleotide sequence analysis of the gp120 region
  to identify amino acid changes that may
  contribute to a co-receptor switch to CXCR4
• Phylogenetic analysis to determine the
  relationship of emerging CXCR4-tropic virus to
  the CCR5-tropic virus at baseline
• Nucleotide sequence analysis of protease and RT

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Virology Subgroup Analysis

• Selected 267 subjects on blinded therapy from
  Studies 1027 and 1028

38 failures with CCR5-tropic virus (13 MVC 25
PLC)
20 failures with CXCR4- tropic virus (16 MVC 4
PLC)
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Virology Subgroup Analysis

• Selected 267 subjects on blinded therapy from
  Studies 1027 and 1028

38 failures with CCR5-tropic virus (13 MVC 25
PLC)
20 failures with CXCR4- tropic virus (16 MVC 4
PLC)
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Subjects Failing with CCR5-Tropic Virus

• Virus from 2 subjects had 3-fold shifts in MVC
  susceptibility at failure
• All other subjects on maraviroc had EC50 FC
  values lt2-fold within the normal range of the
  Monogram assay (0.32-1.95)

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Subjects Failing with CCR5-Tropic Virus

• Viruses from 5 subjects showed evidence of a
  lower plateau in maximum percentage inhibition
• All had novel amino acid changes in the V3 loop
  at time of failure

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Genotypic Changes on Maraviroc in gp120

• V3 loop sequences were heterogeneous
• with multiple substitutions
• Changes at either amino position 13 or 26 were
  seen in the V3 loop in 5/5 subjects with
  MVC-associated lower plateaus in MPI

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Role of the V3 Loop Amino Acid Substitutions in
MVC Resistance

• Site-Directed Mutagenesis
• In 2 subjects
• Mutating amino acids in baseline clones resulted
  in the MVC resistance phenotype of lt95 MPI
• Back-mutation of the amino acid changes of the
  failure clones resulted in a MVC-sensitive
  phenotype

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Some Subjects had No Phenotypic Markers of MVC
Resistance

• 7 subjects receiving MVC showed no phenotypic
  markers of MVC resistance
• 5/7 had evidence of reduced susceptibility to 1
  or more drugs in OBT at screening and/or failure

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Virology Subgroup Analysis

• Selected 267 subjects on blinded therapy from
  Studies 1027 and 1028

38 failures with CCR5-tropic virus (13 MVC 25
PLC)
20 failures with CXCR4- tropic virus (16 MVC 4
PLC)
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Clonal Evaluation
Pink R5 Green X4 Blue dual/mixed
One subject
192 pre-treatment clones
48 on-treatment clones
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20 Treatment Failure Subjects with CXCR4-Tropic
Virus

• 14 subjects
• CXCR4-tropic on-treatment clones shared a
  common ancestor with a pre-treatment CXCR4-tropic
  virus.
• 6 subjects
• CXCR4-tropic on-treatment clones were
  genetically distinct from both the
  pre-treatment and on-treatment R5 population.
  
• The V3 loop sequences differed by 7-17 amino acid
  residues from the nearest R5 sequence on the
  phylogenetic tree.

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Greatest Proportion of MVC Failures had
Dual-Mixed or CXCR4-Tropic Virus

• Mutation from a CCR5 progenitor -Tropism switch
• Outgrowth of undetected CXCR4-virus at screening

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Why Did Subjects Fail Treatment in MVC Studies
1027 and 1028?

• Outgrowth of CXCR4-using viruses not detected at
  screening
• CCR5-using viruses some are resistance to MVC
• Resistance to OBT
• CCR5 receptor genotype?

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What is the Outcome of Failures who had
CXCR4-Tropic Virus Emerge on MVC Treatment?

• Evolution to a CXCR4-utilizing HIV may result in
  a more virulent virus
• Concern that MVC use will result in worse
  outcomes for patients because of outgrowth of
  CXCR4-tropic virus

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CD4 Cell Counts
Mean (median) Change in CD4 counts from Baseline
LOCF24
Tropism at Failure QD N154 BID N143 Placebo N146
R5 123 (93) N72 128 (110) N48 38 (11) N122
CXCR4 60 (33) N18 52 (31) N20 76 N1
Dual-Mixed 47 (25) N48 63 (58) N61 43 (14) N11
NR/NP 70 (70) N16 99 (103) N14 63 (29) N12
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Follow-Up on Failures with CXCR4-Tropic Virus

• Viral load
• CD4 cell counts
• HIV co-receptor tropism
• AIDS defining events

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Follow-Up Data (n20)

• 2/3 had changed tropism back to CCR5 or
  dual-mixed
• For the subjects with CCR5- or dual/mixed-tropic
  virus at end of follow-up, the median time to
  last follow-up was approximately 5 months (range
  18 days to 8 months).
• In contrast, the follow-up time for the subjects
  who remained CXCR4-tropic at the last follow-up
  visit was one month or less (median time was
  approximately 11 days).

Number X4-tropic Virus at Follow-up Decreased CD4 cells Mean change CD4 cells
20 35 (7) 50 (10) -21
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Follow-Up Data (n20)

• Viral loads remained similar to the value at
  treatment failure
• No new category C AIDS-defining events were
  reported
• 4 subjects went on a new ARV treatment
• viral loads decreased
• CD4 cell count increased

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Tropism Summary

• 50-60 subjects failed with CXCR4- or
  dual/mixed-tropic virus in the MVC arms
• Prominent reason for failure in these studies was
  outgrowth of a minor CXCR4-tropic virus
  population not detected at screening

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Resistance Summary

• Maraviroc treatment failure with CCR5-tropic
  virus also occurred
• phenotypic and genotypic resistance to MVC
• resistance to Optimized Background Therapy
• CCR5 host receptor genotype?

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Maraviroc Resistance

• Lower plateaus in MPI were detected in viruses
  from 5 subjects failing maraviroc regimens
• Changes in the V3 sequence of gp160 correlated
  with the presence of lower plateaus and maraviroc
  resistance

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Back-Up Slides

• Lisa K. Naeger, Ph.D.
• Division of Antiviral Products
• Food and Drug Administration

FDA Antiviral Advisory Committee Meeting
April 24, 2007
38
Failures with D32 Deletion/WT or CCR5 Promoter
Haplotypes
QD BID Placebo
D32/WT 8 (13/154) 3 (5/143) 6 (9/143)
WT/WT 84 (130/154) 89 (127/143) 85 (122/143)
P1 46 (71/154) 41 (59/143) 46 (31/143)
P4 11 (17/154) 12 (17/143) 12 (143)
P1/P4 33 (51/143) 34 (49/143) 31 (45/143)