Safety and Efficacy of MARAVIROC, a Novel CCR5 Antagonist, When Used in Combination with Optimized B

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Safety and Efficacy of MARAVIROC, a Novel CCR5
Antagonist, When Used in Combination with
Optimized Background Therapy for the Treatment of
Antiretroviral-Experienced Subjects Infected with
Dual/Mixed-Tropic HIV-1 24-Week Results of a
Phase 2b Exploratory Trial
Abstract number THLB0215XVI IAC, Toronto,
Canada, 13th-18th August 2006
H Mayer1, E van der Ryst2, M Saag3, B Clotet4, G
Fätkenheuer5, N Clumeck6, K Turner2, and JM
Goodrich1
Pfizer Global Research and Development, 1New
London, USA, and 2Sandwich, UK, 3University of
Alabama at Birmingham, USA, 4University Hospital
Germans Trias i Pujol, Barcelona, Spain,
5University of Cologne, Cologne, Germany, 6St
Pierre University Hospital, Brussels, Belgium
Study A4001029
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MARAVIROC (MVC, UK-427,857)

• Selective, reversible CCR5 (R5) antagonist
• Active in vitro versus R5-tropic HIV-1, MDR HIV-1
  but not X4-tropic or R5X4-tropic HIV-1
• Cross-clade activity ( 2 nM antiviral IC90)
• Phase 1/2a clinical trials
• Generally well tolerated in healthy volunteers
  and patients
• Maximum HIV-1 RNA reductions of gt1 log10
  copies/mL in all patients with R5 tropic HIV-1
  treated with MVC monotherapy at 100 mg BID

Dorr P et al. Antimicrob Agents Chemother
20054947214732 Macartney et al. 43rd ICAAC
2003 Poster H-875 Fätkenheuer G, et al. Nat Med.
20051111701172
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MARAVIROC Phase 2b/3 Program to Assess Safety and
Efficacy in Patients with R5-tropic HIV-1
ARV - antiretroviral, EFV - efavirenz
(Sustiva) LOQ - Limit of Quantification OBT
- optimized background therapy, VL - viral load
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Rationale for Studying MARAVIROC in Patients with
Dual/Mixed (D/M)-Tropic Infections

• Theoretical risk of outgrowth of X4-tropic HIV-1
  when a patient with D/M-tropic HIV-1 is treated
  with a CCR5 antagonist
• X4-tropic HIV-1 has been associated with more
  rapid CD4 cell depletion and progression to AIDS

Patient with D/M- tropic HIV-1who received
MARAVIROC 100 mg BID in Phase 2a study
X4-tropic HIV-1
R5-tropic HIV-1
160000
120000
Relative light units (RLU)
80000
40000
0
Off Treatment Day 40
Treatment Started Day 1
Treatment Stopped Day 11
Westby M, et al. J Virol. 2005 8049094920
Schuitemaker H, et al. J Virol 1992 661354-1360
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Phase 2b Pilot Study Evaluating the Safety of
MARAVIROC in Patients with Non-R5 HIV-1
OBT MARAVIROC (150 mg BID)
Screening and randomization
OBT MARAVIROC (150 mg QD)

OBT Placebo
4-6 Weeks
Weeks
0
24
48
Primary efficacy endpoint

• Randomized, double-blind, placebo-controlled
  study
• Selection criteria
• D/M-tropic, X4-tropic or indeterminate tropism
  phenotype
• Antiretroviral experienced and/or multi-class
  resistance
• At least one active drug in OBT

OBT 3 to 6 ARVs (note PK boosting doses of RTV
will not be counted as an ARV) 150 mg maraviroc
with PIs provides equivalent dose to 300 mg
without PIs
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Study Population
Randomised 190
Treated 186
D/M - dual/mixed tropic NP/NR - not phenotyped or
not reported OBT - 3 to 6 ARVs
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Optimized Background Therapy (OBT) Selected
Data for one patient missing from each
treatment arm
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OBT - optimized background therapy
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CD4 Count and Viral Load at Baseline
Mean of all pre-dose assessments D/M -
dual/mixed-tropic
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Efficacy Results
LOCF
OBT - optimized background therapy D/M -
dual/mixed tropic Primary endpoint,
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Changes in CD4 Cell CountPatients with
D/M-tropic HIV-1 at Screening
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D/M - dual/mixed-tropic, Data for 4 patients
is missing
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Summary of Clinical and Laboratory Adverse Events

• In general, MARAVIROC was well tolerated
• AEs, including those judged to be severe or life
  threatening (Grade 3/4), SAEs and
  discontinuations due to AEs were evenly balanced
  between treatment groups
• No cases of lymphoma or adenocarcinoma reported
• Thirteen category C events occurred
• MARAVIROC QD (7), MARAVIROC BID (3), Placebo (3)
  
• There were 7 deaths in patients on study drug and
  none were considered drug related
• MARAVIROC QD (2), MARAVIROC BID (2), Placebo (3)

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Grade 3/4 LFT Abnormalities (Without Regard to
Baseline)
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ULN Upper Limit of Normal
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Summary

• Over 24 weeks, in treatment-experienced patients
  with D/M-tropic HIV-1 and advanced disease
• MARAVIROC OBT was generally well tolerated
• No cases of hepatotoxicity, lymphoma or
  adenocarcinoma
• MARAVIROC OBT did not demonstrate superior
  reductions in HIV-1 RNA compared with placebo
  OBT
• MARAVIROC OBT was associated with greater
  increases in CD4 cell count than placebo OBT
• Patients receiving MARAVIROC OBT were more
  likely to fail with X4-tropic HIV-1 than those
  receiving placebo OBT
• However, patients treated with MARAVIROC and
  X4-tropic virus at treatment failure had
  increases in CD4 cell count consistent with the
  overall MARAVIROC-treated population

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Acknowledgements

• Patients who participated in the study
• Investigators and study site staff
• Colleagues from Monogram Biosciences J Whitcomb,
  E Coakley and C Petropoulos
• Colleagues from Pfizer S Felstead, M McHale, J
  Sullivan, D Lindell, D Paige, M Westby, S
  Nuttall
• Authors E van der Ryst, M Saag, B Clotet, G
  Fätkenheuer, N Clumeck, K Turner, JM Goodrich

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