1 / 29

Rationale for MVC + boosted PI regimen

48-week results of once-daily maraviroc (MVC) 150 mg in combination with ritonavir-boosted atazanavir (ATV/r) compared to emtricitabine/tenofovir (FTC/TDF) + ATV/r in treatment-naïve patients infected with R5 HIV-1 (Study A4001078).

kaelem
Download Presentation

Rationale for MVC + boosted PI regimen

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. 48-week results of once-daily maraviroc (MVC) 150 mg in combination with ritonavir-boosted atazanavir (ATV/r) compared to emtricitabine/tenofovir (FTC/TDF) + ATV/r in treatment-naïve patients infected with R5 HIV-1 (Study A4001078) Simon Portsmouth,1 Charles Craig,2 Anthony Mills,3Donna Mildvan,4 Daniel Podzamczer,5Gerd Fätkenheuer,6 Manuel Leal,7 Hernan Valdez,1SrinivasRao Valluri,1Jayvant Heera1 1Pfizer Inc., New York, NY, USA; 2Pfizer, Sandwich, Kent, UK; 3Anthony Mills MD, Los Angeles, CA, USA; 4Beth Israel Medical Center Division of Infectious Diseases, New York, NY, USA; 5HIV Unit, Infectious Disease Service, Hospital Universitari de Bellvitge, Barcelona, Spain; 6University Hospital of Cologne Köln, Germany; 7Laboratory of Immunovirology, Biomedicine Institute of Seville (IBIS), Infectious Disease Service, Virgen del Rocio University Hospital, Seville, Spain

  2. Rationale for MVC + boosted PI regimen • Potential for early use: prevalence of CCR5 tropic virus is greatest in treatment-naïve individuals1 • Nucleoside-sparing regimen • Good penetration of MVC in CSF and genital secretions2-4 • MOTIVATE and PK studies support use of MVC 150 mg QD with selected ritonavir-boosted PIs Study A4001078: an exploratory pilot study of a low pill burden QD dual-therapy regimen, MVC + ATV/r 1. Hoffmann, Eur J Med Res, 2007. 2. Tiraboschi et al, J Acquir Immune Defic Syndr, 20103. Dumond et al, J Acquir Immune Defic Syndr, 2009. 4. Brown et al, J Infect Dis, 2011

  3. Study designOpen-label, 48-week Phase 2b pilot study Randomization 1:1N=121 • Patient eligibility criteria • R5 HIV (ESTA) at screening • ≥16 years of age • HIV-1RNA ≥1000 copies/mL • CD4 ≥100 cells/mm3 • No evidence of resistance to ATV/r, TDF, or FTC • Study has iDMC • Ongoing study: USA, Spain, Germany • Extended to 96 weeks • Study is not powered to show a treatment difference and no formal comparative statistics will be performed FTC/TDF + ATV/r (300/100 mg QD) MVC (150 mg QD) + ATV/r (300/100 mg QD) Screening(6 weeks) 0 16 wk 24 wk 48 wk Interim analyses Primary analysis Week 2 First 15 US patients Serial PK of MVC *Sparse PK sampling on all patients at Weeks 2 (non-PK substudy), 12 and 24 (Vourvahis. Abstract 37 IWCPHIV, 2010)

  4. Study disposition Screening n=220 Enrolled into study n=121 MVC + ATV/r n=60 FTC/TDF + ATV/r n=61 • Discontinued n=7 • 2 AE (vomiting, jaundice) • 3 lost to follow-up • 1 withdrew consent • 1 insufficient clinical response (VL 934 copies/mL) • Discontinued n=7 • 2 lost to follow-up • 1 withdrew consent • 2 protocol violations • 1 pregnancy • 1 other: possible TDF-related kidney failure Continuing in study n=53 Continuing in study n=54 • Two patients in each arm experienced protocol defined treatment failure VL, HIV-1 RNA, viral load

  5. Summary of baseline characteristics

  6. HIV-1 RNA <400 copies/mL at Week 48 89.8% 86.9% Patients with HIV-1 RNA <400 copies/mL (%) MVC + ATV/r (N=59) FTC/TDF + ATV/r (N=61) Study week Intent-to-treat. Missing=failure

  7. HIV-1 RNA <50 copies/mL at Week 48 83.6% 74.6% Patients with HIV-1 RNA <50 copies/mL (%) MVC + ATV/r (N=59) FTC/TDF + ATV/r (N=61) Study week Intent-to-treat. Missing=failure

  8. HIV-1 RNA <50 copies/mL at Week 24 and Week 48 according to baseline viral load 100 MVC + ATV/r Patients with HIV-1 RNA <50 copies/mL (%) 94.9 FTC/TDF + ATV/r 90 37/39 81.3 81.4 80 77.3 35/43 13/16 17/22 70 60 50 40 30 20 10 0 Week 24 Week 48 Week 24 Week 48 <100,000 copies/mL ≥100,000 copies/mL Baseline HIV-1 RNA Intent-to-treat. Missing=failure

  9. HIV-1 RNA <50 copies/mL at Week 24 and Week 48 according to baseline viral load 100 MVC + ATV/r Patients with HIV-1 RNA <50 copies/mL (%) 94.9 FTC/TDF + ATV/r 90 37/39 87.2 81.3 81.4 34/39 80 77.3 76.7 77.3 35/43 13/16 17/22 17/22 33/43 70 68.8 11/16 60 50 40 30 20 10 0 Week 24 Week 48 Week 24 Week 48 <100,000 copies/mL ≥100,000 copies/mL Baseline HIV-1 RNA Intent-to-treat. Missing=failure

  10. HIV-1 RNA <400 copies/mL at Week 24 and Week 48 according to baseline viral load MVC + ATV/r 94.9 100 93.8 Patients with HIV-1 RNA <400 copies/mL (%) FTC/TDF + ATV/r 90.7 90.9 37/39 15/16 20/22 39/43 90 80 70 60 50 40 30 20 10 0 Week 24 Week 48 Week 24 Week 48 <100,000 copies/mL ≥100,000 copies/mL Baseline HIV-1 RNA Intent-to-treat. Missing=failure

  11. HIV-1 RNA <400 copies/mL at Week 24 and Week 48 according to baseline viral load MVC + ATV/r 94.9 100 93.8 93.8 Patients with HIV-1 RNA <400 copies/mL (%) FTC/TDF + ATV/r 90.7 90.9 37/39 88.4 15/16 15/16 87.2 86.4 20/22 39/43 90 38/43 34/39 19/22 80 70 60 50 40 30 20 10 0 Week 24 Week 48 Week 24 Week 48 <100,000 copies/mL ≥100,000 copies/mL Baseline HIV-1 RNA Intent-to-treat. Missing=failure

  12. Outcomes for all patients with VL >50 copies/mL at Week 48 HIV-1 RNA, copies/mL Week 48 Post Week 48 MVC+ATV/r AaBCDEFbGHI FTC/TDF+ATV/r JKL 69144578116787615158 5278055 497 (W84)<50 (W96)<50 (W72)<50 (W84)<50 (W96)274 (W96)<50 (W72)<50 (W84)<50 (W84) <50 (W84)<50 (W96)<50 (W84) aPatient discontinued at Week 84 due to insufficient clinical response bPatient discontinued at Week 96

  13. Change in median CD4+ cell count over time (LOCF) 187 173 Median change from baselinein CD4 cell count (cells/μL) MVC + ATV/r (N=59) FTC/TDF + ATV/r (N=61) Study week Intent-to-treat. LOCF, last observation carried forward

  14. No genotypic or phenotypic resistance observed through Week 48 • 3 patients in the MVC arm and 3 patients in the FTC/TDF arm were identified for virologic analysesa aPatients who discontinued from the study early with sufficient VL (≥500 copies/mL). Assays (ESTA, Monogram GenoSeq and/or PhenoSenseGT) performed at screening/baseline and at the last on-treatment time point were available

  15. Safety • 7 patients in the MVC + ATV/r group and 3 patients in the FTC/TDF group switched off of ATV/r therapy per protocol due to either tolerability or unconjugated hyperbilirubinemia *DAIDS grading

  16. Modern dual-therapy studies: 48-week results No. of patients with post-BL resistance mutations/no. of virologicfailuresa HIV-1 RNA <50 copies/mL ACTG 51421N=500 22/46 39/56 16/78 EFV + 2 NRTI EFV + LPV/r LPV/r + 2 NRTI COOL2N=143 EFV + TDF/3TC 0/03/3 EFV +TDF afrom evaluable samples BL, baseline % of patients 1. Riddler et al, N Engl J Med, 2008. 2. Girard et al, J Antimicrob Chemother, 2009.

  17. Modern dual-therapy studies: 48-week results No. of patients with post-BL resistance mutations/no. of virologicfailuresa HIV-1 RNA <50 copies/mL ACTG 51421N=500 22/46 39/56 16/78 EFV + 2 NRTI EFV + LPV/r LPV/r + 2 NRTI COOL2N=143 EFV + TDF/3TC 0/03/3 EFV +TDF SPARTAN3N=94 (2:1) 0/8 4/11 ATV/r QD + FTC/TDF ATV BID + RAL BID PROGRESS4N=206 LPV/r BID + FTC/TDF 1/3 1/4 LPV/r BID + RAL BID ACTG 52625N=112 DRV/r QD + RAL DRV/r QD + RAL BID 5/28 afrom evaluable samples BL, baseline % of patients 1. Riddler et al, N Engl J Med, 2008. 2. Girard et al, J Antimicrob Chemother, 2009. 3. Kozal THLBB204, IAS 2010. 4. Reynes MOAB0101, IAS, 2010. 5. Taiwo Abstract 551, CROI, 2011.

  18. Modern dual-therapy studies: 48-week results No. of patients with post-BL resistance mutations/no. of virologicfailuresa HIV-1 RNA <50 copies/mL ACTG 51421N=500 22/46 39/56 16/78 EFV + 2 NRTI EFV + LPV/r LPV/r + 2 NRTI COOL2N=143 EFV + TDF/3TC 0/03/3 EFV +TDF SPARTAN3N=94 (2:1) 0/8 4/11 ATV/r QD + FTC/TDF ATV BID + RAL BID PROGRESS4N=206 LPV/r BID + FTC/TDF 1/3 1/4 LPV/r BID + RAL BID ACTG 52625N=112 DRV/r QD + RAL DRV/r QD + RAL BID 5/28 VEMAN6N=37 0/0 0/0 LPV/r BID + FTC/TDF LPV/r BID + MVC QD 1078N=121 0/2 0/2 ATV/r QD + FTC/TDF ATV/r QD + MVC QD afrom evaluable samples BL, baseline % of patients 1. Riddler et al, N Engl J Med, 2008. 2. Girard et al, J Antimicrob Chemother, 2009. 3. Kozal THLBB204, IAS 2010. 4. Reynes MOAB0101, IAS, 2010. 5. Taiwo Abstract 551, CROI, 2011. 6. Nozza CDB325, IAS, 2011

  19. Conclusions • 48-week results of this pilot study of MVC + ATV/r support the antiviral activity of this once-daily, two-drug combination in treatment-naïve patients • No resistance nor change in phenotypic tropism was observed • No new unexpected safety events • A Phase III study (A4001095; NCT01345630) will start in Q3/4 2011 • MVC + DRV/r QD vs FTC/TDF + DRV/r QD • Estimated enrollment of 804

  20. Acknowledgments • Thanks to the patients and investigators who participated in this study • Editorial support was provided by Clemence Hindley of Complete Medical Communications and was funded by ViiV Healthcare

  21. Backups

  22. Creatinine clearance Study week Mean change from baseline in creatinine clearance (mL/min) MVC + ATV/r (N=60) FTC/TDF + ATV/r (N=61)

  23. Pharmacokinetics 10,000 * 1000 100 MVC concentration (ng/mL) 10 7.65 ng/mL (in vivo IC50)1 1 0 4 8 12 16 20 24 Hours • All 15 patients had plasma MVC concentrations above the in vivo IC50 across the dosing Interval (150 mg QD + ATV/r)2 • There were 139 sparse PK samples with full dose and time data collected at the 2,12 and 24 week visits yielding concentrations from 13.7 to 933 ng/mL with samples taken from 0-32 hours after dose3 1. Rosario et al, J Acquir Immune DeficSyndr, 2006.2. Vourvahis, Abstract 37 IWCPHIV, 2010. 3. Weatherley, Abstract P_05 IWCPHIV, 2011 * One patient accidentally dosed with MVC prior to the 24-hour sample draw

  24. Definition of Virologic Failure • HIV-1 RNA <1.0 log10 decrease from Baseline at Week 4 or thereafter (confirmed by a second measurement taken no more than 14 days after the first measurement); or • Failure to achieve HIV-1 RNA <400 copies/mL at Week 24, (confirmed by asecond measurement taken no more than 14 days after the first measurement); • An increase in HIV-1 RNA to detectable levels (1,000 copies/mL on 2 consecutive measurements taken no more than 14 days apart) in subjects previously confirmed to have undetectable levels of <400 copies/mL on 2 consecutive visits.

  25. Patients switching from ATV/r • 10 patients switched from ATV/r (7 in the MVC arm and 3 in the FTC/TDF arm) due to either tolerability issues or unconjugated hyperbilirubinemia • 8 switched to DRV/r • 2 switched to LPV/r • All 10 patients had reached HIV-1 RNA <50 copies/mL prior to switching

  26. HIV-1 RNA <50 copies/mL at Week 24 and Week 48 according to baseline CD4 count n/N 4/5 5/5 40/48 46/49

  27. Median CD4+ cell count over time (LOCF) Week 48MVC + ATV/r = 580 FTC/TDF + ATV/r = 580 Week 24MVC + ATV/r = 537 FTC/TDF + ATV/r = 536 Median CD4 cell count (cells/mm3) MVC + ATV/r (N=59) FTC/TDF + ATV/r (N=61) Study week Intent-to-treat. LOCF, last observation carried forward

  28. Responders at Week 24 but not Week 48 N/A, not available; W, week aPatient discontinued prior to Week 48 bResult of repeat test 13 days later was <50 copies/mL

  29. Responders at Week 24 but not Week 48 N/A, not available; W, week aPatient discontinued prior to Week 48 bResult of repeat test 13 days later was <50 copies/mL • 7/9 (MVC + ATV/r) and 3/3 (FTC/TDF + ATV/r) patients with HIV-1 RNA ≥50 copies/mL at Week 48 had HIV-1 RNA <50 copies/mL at their latest visit. HIV-1 RNA levels for the remaining 2 patients were 274 copies/mL (W96), and 497 copies/mL (W84)

More Related