Changes in HIV-1 Co-receptor Tropism for Patients Participating in the Maraviroc MOTIVATE 1 and 2 Clinical Trials

1
Changes in HIV-1 Co-receptor Tropism for Patients
Participating in the Maraviroc MOTIVATE 1 and 2
Clinical Trials

• E van der Ryst and M Westby
• Pfizer Global Research and Development, Sandwich,
  UK

47th ICAAC Chicago, USA, September 1720, 2007
2
MOTIVATE 1 and 2 Trial Design
Randomization 122 MOTIVATE 1 N601MOTIVATE
2 N474
OBT placebo
OBT maraviroc (150 mg QD)
OBT maraviroc (150 mg BID)
Screening(6 weeks)
Plannedinterim analysis
0
24w
48w

• Patient eligibility criteria
• R5 HIV-1 infection
• HIV-1 RNA 5,000 copies/mL

• Stable pre-study ARV regimen, or no ARVs for 4
  weeks
• Resistance to and/or 6 months experience with
  one ARVfrom three classes ( two for PIs)

• Patients stratified by
• Enfuvirtide use in OBT
• HIV-1 RNA lt and 100,000 copies/mL at screening

OBT optimized background therapy of 36 ARVs
(PK boosting doses of RTV not counted as an
ARV) Patients receiving a PI (except TPV)
and/or delavirdine in their OBT received 150 mg
dose of MVC, all other patients received 300 mg
dose of MVC
3
MOTIVATE 1 and 2 Summary of Week 24 Efficacy
Results
Includes all patients who received at least one
dose of study medication
Plt0.001 Difference 51(95 CI 33, 69)
Plt0.001 Difference 49(95 CI 31, 67)
Plt0.0001
Plt0.0001
Patients ()
Mean change from baseline in CD4 count
(cells/mm3)
HIV-1 RNA lt50 copies/mL
Mean Change from Baseline in CD4 Count
versus OBT alone HIV-1 RNA value imputed as
baseline if missing or if patient discontinued
before 24 weeks Last observation carried
forward
MOTIVATE 1 2-Week 24
van der Ryst, et al. 4th IAS 2007 Poster
WEPEB116LB
4
Characterization of Maraviroc Resistance in
MOTIVATE 1 and MOTIVATE 2 Study Overview

• OBJECTIVE To study changes in HIV-1 tropism in
  patients who experienced treatment failure in the
  MOTIVATE 1 and 2 studies

MOTIVATE 1 and MOTIVATE 2 Phase 3 studies in
treatment-experienced patients (N1,075)
Tropism determined for all patients at screening,
baseline, and all visits where VLgt500 c/mL
(Trofile assay, Monogram Biosciences)
Assessment of CD4 count at failure, time of
failure, and occurrence of Category C events by
tropism result
CCR5-using virus CXCR4-using virus
5
Patients With a Change in Tropism Result from R5
at Screening to D/M at Baseline had a Lower
Median CD4 Count

• Of the 1042 patients with R5 virus at screening,
  approximately 8 had a change in tropism result
  between screening and baseline to non-R5 virus,
  prior to a change in ARV regimen or
  administration of study drug
• This subgroup had a lower median CD4 count and
  higher mean HIV-1 RNA at screening

Tropism result, Screening ? Baseline OBT alone MVC QD OBT MVC BID OBT
Mean screening HIV-1 RNA (copies/mL)R5 ? R5R5 ? D/M or X4 4.825.09 4.845.16 4.865.07
Median screening CD4 count (cells/mm3)R5 ? R5R5 ? D/M or X4 18092 18259 17057
MOTIVATE 1 2
6
Outcome of Patients with non-R5 Virus at Baseline
(Week 24)
Includes all patients who received at least one
dose of study medication
HIV-1 RNA lt50 c/mL
CD4 Count Change
Mean change from baseline in CD4 count at failure, cells/mm3 Mean change from baseline in CD4 count at failure, cells/mm3 Mean change from baseline in CD4 count at failure, cells/mm3
OBT alone MVC QD OBT MVC BID OBT
15(n5) 54(n8) 26(n19)
Tropism result at baseline
D/M
R5
Patients ()
N 17 33 33 187 362 377
MOTIVATE 1 2-Week 24
7
CD4 Count Increase in Patients Failing Maraviroc
is Greater Even in Patients With D/M or X4 Virus
at Failure
Tropism result, Baseline ? Treatment Failure Mean change from baseline in CD4 count in patients with treatment failure (cells/mm3 ) Mean change from baseline in CD4 count in patients with treatment failure (cells/mm3 ) Mean change from baseline in CD4 count in patients with treatment failure (cells/mm3 )
Tropism result, Baseline ? Treatment Failure OBT aloneN209 MVC QD OBT N414 MVC BID OBTN426
All treatment failures 14 (n97) 49 (n68) 71 (n77)
R5 ? R5 15(n80) 61(n18) 138(n17)
R5 ? D/M or X4 67(n4) 37(n31) 56(n32)
Data excludes patients who had no tropism result
at time of failure Includes patients with
non-R5 tropism result at baseline
MOTIVATE 1 2
Lalezari J et al. CROI 2007 Abstract 104bLB
Nelson M et al. CROI 2007 Abstract 104aLB
8
Patients Failing Maraviroc With D/M or X4 Virus
Fail Earlier Than Those Failing with R5 Virus
Tropism result, Baseline ? Treatment Failure
R5 ? D/M or X4
R5 ? R5
Patients ()
Early failure ( day 70) (N82)
Late failure (gt day 70) (N59)

• Time to maraviroc treatment failure with a D/M or
  X4 virus was approximately 30 days shorter than
  for failure with R5 virus

MOTIVATE 1 2
9
No Association Between Category C Events and
Treatment-emergent D/M or X4 Virus

• The number of patients experiencing CDC Category
  C events in the study was low 14 (6.7) OBT
  alone, 26 (6.3) MVC QD and 18 (4.2) MVC BID
• There was no evidence of an increased rate of
  Category C events in patients receiving maraviroc
  OBT vs those receiving OBT alone despite the
  extended treatment duration on maraviroc1,2
• Only 5 patients with R5 virus at baseline who
  experienced a Category C event had D/M or X4
  virus at the time of the event (3 on MVC QD, 1 on
  MVC BID, and 1 on OBT alone)
• All 5 patients had a baseline CD4 count lt20
  cells/mm3 and were therefore at high risk of
  developing a Category C event
• Category C events were therefore not associated
  with treatment-emergent CXCR4-using virus

MOTIVATE 1 2
1. Lalezari J et al. CROI 2007 Abstract 104bLB
2. Nelson M et al. CROI 2007 Abstract 104aLB
10
Reversion to R5 after Cessation of Maraviroc
Treatment
Treatment N Tropism result at last follow-up for patients with DM or X4 virus at treatment failure Tropism result at last follow-up for patients with DM or X4 virus at treatment failure Tropism result at last follow-up for patients with DM or X4 virus at treatment failure Tropism result at last follow-up for patients with DM or X4 virus at treatment failure
Treatment N D/M or X4 virus at last follow-up D/M or X4 virus at last follow-up R5 virus at last follow-up R5 virus at last follow-up
of Patients Median Days of Patients Median Days
MVC All 44 14 16 30 203
OBT alone 3 2 22 1 20

• For maraviroc patients with D/M or X4 virus at
  treatment failure and with in-study off-drug
  (ISOD) follow-up data, virus in 68 of patients
  was R5 at last follow-up
• Time of follow-up was significantly shorter for
  patients with D/M or X4 virus at their last study
  visit
• Where follow-up gt1 month, virus in 30 out of 31
  patients reverted to R5 during ISOD follow-up

MOTIVATE 1 2
11
Viral Populations That May Exist Within a Patient
A) Pure
R5
X4
B) Mixed
12
Example of a Patient With Treatment-emergent D/M
Virus
Treatment start
Failure
Treatment end
Patient T6
R5
R5
DM
DM
DM
DM
DM
DM
R5
R5
6
5
4
HIV-1 RNA (log10 copies/mL)
3
CD4 Count (cells/mm3)
2
1
Time Since First Administration (Day)
Lewis M et al. XVI International HIV Drug
Resistance Workshop, June 2007, Abstract 56
13
CXCR4-using env Clones Were Detected at Low
Frequency in the Baseline Sample
Patient T6
R5
R5
DM
DM
DM
DM
DM
DM
R5
R5
6
5
4

• CXCR4-using clones detected at baseline (7)
• No CCR5-tropic clones on treatment

HIV-1 RNA (log10 copies/mL)
3
CD4 Count (cells/mm3)
2
1
Time Since First Administration (Day)
Lewis M et al. XVI International HIV Drug
Resistance Workshop, June 2007, Abstract 56
14
Selective Inhibition of R5 Viruses can Lead to a
Change in Tropism Result to D/M or X4

• Trofile (like all resistance tests) measures
  relative proportions (not absolute amounts) of
  different viruses (Panel A)
• Selective inhibition of a majority virus type,
  increases the sensitivity to detect the minor
  variant (Panel B)

A
B
MVC
R5
D/M
15
Selective Inhibition of R5 Viruses Can Lead to a
Change in Tropism Result to D/M or X4

• Maraviroc selectively inhibits R5 virus
• If maraviroc is administered as part of a
  sub-optimal regimen, pre-existing low
  (undetected) levels of D/M or X4 virus will
  emerge as the dominant viral population
• Since the D/M or X4 virus is pre-existing, time
  to failure is shorter than with R5 virus (where
  maraviroc resistance must be selected de novo)
• Similar to the rapid outgrowth of pre-existing
  (archived) drug-resistant virus when failed ARV
  therapy is reinitiated after treatment
  interruption
• After withdrawal of maraviroc, selective pressure
  on R5 virus is removed, allowing R5 virus to
  re-emerge as the dominant population
• Reversion to R5 takes approximately 16 weeks,
  consistent with loss of 3TC1 or enfuvirtide2
  resistance after withdrawal of these ARVs

1. Deeks S, et al. J Infect Dis 2005
1921537-44. 2. Deeks et al. J Infect Dis
2007195387-91.
16
Conclusions

• Tropism changes are associated with MVC treatment
  failure
• Patients failing MVC therapy had higher mean CD4
  count increases even in the context of emergence
  of D/M or X4 virus
• Time to failure was shorter for patients failing
  with D/M or X4 virus vs R5 virus
• Patients who failed MVC therapy with D/M or X4
  virus reverted to an R5 virus tropism result
  after cessation of MVC therapy
• There was no association between Category C
  events and treatment-emergent D/M or X4 virus
• These data are consistent with the selective and
  reversible suppression of R5 virus during MVC
  therapy, resulting in detection of D/M or X4
  virus at time of failure in two-thirds of failing
  patients

17
Acknowledgments

• Investigators and study site staff
• Patients who participated in the study
• Colleagues from Pfizer Howard Mayer, James
  Goodrich, Irina Konourina, Margaret Tawadrous,
  Marilyn Lewis, Paul Simpson, Ayman Ayoub, Andrew
  Bullivant and John Sullivan