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CCR5 Antagonist Maraviroc (Selzentry) It’s new, it’s novel, it’s niche?. Blake Max, PharmD RMR CORE Center Clinical Assistant Professor, UIC College of Pharmacy. Objectives. Describe the mechanism of action of CCR5 antagonist
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CCR5 AntagonistMaraviroc (Selzentry)It’s new, it’s novel, it’s niche? Blake Max, PharmD RMR CORE Center Clinical Assistant Professor, UIC College of Pharmacy
Objectives • Describe the mechanism of action of CCR5 antagonist • Understand the role and importance of the Trofile assay in relation to CCR5 antagonist use • Describe the significant clinical trials in tx-naïve and experienced patients • Infer optimal CCR5 antagonist dose when administered with other medications or patient populations
Introduction • 5 Classes of Antiretroviral Agents - NRTIs - NNRTIs - PIs - Integrase Inhibitors - Entry Inhibitors • August 2007 FDA approved maraviroc, a CCR5 co-receptor antagonist used in combination with other antiretroviral agents for treatment in adults (>16 y/o) infected with CCR5-tropic HIV.
Novel Mechanism of Action • HIV Entry Inhibitors Enfuvirtide- synthetic peptide that mimics amino acids of HIV transmembrane protein (gp41), which is critical for viral/CD4 cell membrane fusion. Maraviroc- HIV surface protein (gp120) binds to CD4 surface protein, acting as an anchor, then additional interaction with CD4 surface co-receptor allows for viral entry. HIV uses two co-receptors, CCR5 and CXCR4, maraviroc is a CCR5 antagonist. Vicriviroc- Not FDA approved, in clinical trials, same MOA as maraviroc.
HIV Attachment, Co-receptor Binding, and Fusion Targets for Inhibition CD4 Attachment Co-receptor Binding Virus–Cell Fusion Fusion inhibitors CCR5 antagonists CD4 attachmentinhibitors gp41 gp120 V3 loop CD4 Cell membrane CCR5 or CXCR4 Adapted from Moore JP, et al. Proc Natl Acad Sci USA 2003;100:10598–602
Approx. 50% of HIV Tropism is CCR5 in Treatment Experienced Patients
R5 Tropism Result is Strongly Associated with CD4+ Cell Count Categories in Treatment Experienced Patients South African Cohort (~94% clade C) MOTIVATE 1 and 2 (~96% clade B) R5 D/M X4 100 100 80 80 60 60 Percent of Tropism Results per CD4+ Category 40 40 R5* 20 D/M 20 0 X4 <50 0 >500 51–100 101–200 201–350 351–500 ≥500 (76) 0–49 (828) 50–99 (338) 100–199 (549) 200–299 (448) 300–399 (233) 400–499 (113) N= 22 25 68 56 119 11 N= Current CD4+ cell count (cells/mm3) Screening CD4+ Category (cells/mm3) * P<0.0001 for comparison of median screening CD4+ cell counts as a continuous variable Eng SM et al. 9th Intl Cong. on Drug Ther in HIV Infect.2008. Poster P198 Clax P et al. EI Wrkshp 2007. Abs 5
Tropism Testing • Trofile test should be used whenever the use of a CCR5 antagonist is being considered (HIV VL must be >1000 copies/ml) • An enhanced sensitivity tropism assay has been developed to increase detection of minor CXCR4-using virus. Second generation Trofile assay has improved detection of minor variants 10-fold. First generation assay was a limitation in early maraviroc studies. • This is critical to the success/failure of these drugs.
Typical HIV Tropism Patterns CCR5 tropic (R5) CXCR4 tropic (X4) Dual/mixed (D/M) Dual tropic Mixed tropism
Trofile Assay • Developed by Monogram Biosciences and made available when FDA approved maraviroc, no other similar test available. • Test is used to determine whether a patient’s HIV uses the CCR5 or CXCR4 co-receptor (or both) to enter CD4 cells. • Similar to phenotype technology used for detecting HIV drug resistance. Assay amplifies HIV envelop gene from patient’s blood sample, HIV particles are made with the envelop protein and used to infect cells that contain CCR5 or CXCR4 co-receptor on the cell surface. Viral replication is measured in-vitro determining the tropism of the patient’s virus.
Clinical Trials • Tx-naïve (MERIT Trial) • Tx-experience (MOTIVATE I-II)
MaravirocTreatment-naïve • Rationale: 80-90% of tx-naïve patients harbor R5 virus • MERIT Trial: Non-inferiority study CBV bid + MVC 300mg bid vs CBV bid + EFV 600 qd • 48-week analysis found MVC did not meet noninferiority vs EFV (VL < 50 copies/ml) • MVC associated with higher CD4 increases • Limitation with sensitivity/specificity of initial Trofile assay
Percentage of Patients with HIV-1 RNA <50 c/mL by Visit Includes all patients who were identified by the specified assay as R5 and received at least one dose of study medication; intent-to-treat (ITT) analysis MERIT 100 MERIT-ES 100 90 90 80 80 69% 68% 70 70 60 68% 60 64% 50 Patients (%) 50 40 40 EFV + CBV (N=361) EFV + CBV (N=303) MVC + CBV (N=360) 30 30 MVC + CBV (N=311) 20 20 10 10 0 0 0 4 8 12 16 20 24 28 32 36 40 44 48 0 4 8 16 32 40 48 24 Time (weeks) Time (weeks) Missing values classified as failures/non-responders Saag M, et al. ICAAC/IDSA 2008. Poster H-1232a MERIT Study – ESTA 48 weeks
Enhanced Phenotype Tropism Assay:In Vitro Validation • Original assay validated in clinical trials • Did not detect minor CXCR4 species comprising <10% of population • Sensitivity in detecting CXCR4 HIV • 100% when 10% of population is CXCR4 • 85% when 5% of population is CXCR4 • Enhanced phenotype tropism assay validated using in vitro HIV env clones • Sensitivity in detecting CXCR4 HIV • 100% when 0.3% of population is CXCR4 • 81% when 0.1% of population is CXCR4 Trinh L, et al. 48th ICAAC. Washington, DC, 2008. Abstract H-1219.
MERIT Week 48 Reanalysis by Enhanced Sensitivity Trofile Screening: Rationale and Methods • A more sensitive assay for the detection of CXCR4-using virus might better select a population of patients who would respond to maraviroc, decreasing the number of failures associated with emergence of CXCR4-using HIV-1 • The enhanced sensitivity Trofile assay was performed on stored env expression vectors pools from all 721 patients in MERIT who had an R5 tropism result by the original Trofile assay • Testing was performed by Monogram Biosciences’ Clinical Reference Laboratory Saag M, et al. ICAAC/IDSA 2008. Poster H-1232a MERIT Study – ESTA 48 weeks 20
Summary: MVC in Treatment-naive Patients with R5 Virus • As the original Trofile assay is no longer available, the MERIT-ES reanalysis, while retrospective, was critical to inform appropriate clinical practice • The enhanced Trofile assay reclassified approximately 15% of patients as non-R5 HIV at screening • In this retrospective analysis, the lower bound of the one-sided 97.5% CI for the treatment difference, for both the <400 and <50 copies/mL endpoints, was above –10% (the prespecified noninferiority margin) • However, as this is a retrospective analysis, the confidence intervals presented here are for descriptive purposes only 21
MOTIVATE 1 & 2: Trial Design Randomization 1:2:2 MOTIVATE 1 N=601MOTIVATE 2 N=474 OBT* + placebo 98/209 (46.9%)open-label MVC BID 239/414 (57.7%)open-label MVC BID OBT* + maraviroc (150 mg† QD) 259/426 (60.8%) open-label MVC BID OBT* + maraviroc (150 mg† BID) Screening6 weeks 0 Week 96 Week 48 Primary endpoint Patients were stratified by enfuvirtide use and HIV-1RNA < and ≥100,000 copies/mL • Patient eligibility criteria: • R5HIV-1 infection • HIV-1-RNA ≥5,000 copies/mL • Stable pre-study antiretroviral (ARV) regimen, or no ARVs for ≥4 weeks • Resistance to and/or ≥6 months’ experience with ≥one ARV from three classes (≥two for protease inhibitors [PIs]) Eligible patients (MVC non-failures, PBO failures or intolerance) were given the option to roll over to open-label MVC BID at end of blinded therapy (last patient week 48 visit). * OBT = optimized background therapy of 3–6 ARVs (PK boosting doses of ritonavir not counted as an ARV) † Patients receiving a PI (except tipranavir) and/or delavirdine in their OBT received 150 mg dose of MVC, all other patients received 300 mg dose of MVC MOTIVATE 1 and 2 Week 96 Safety and Efficacy Hardy WD et al. 9th Intl Cong. on Drug Ther in HIV Infection. Glasgow, UK, Nov 9-13 2008. Presentation O425
MVC BID + OBT (N=426) MVC QD + OBT (N=414) Placebo + OBT (N=209) MOTIVATE 1 & 2: Percentage of Patients with HIV-1 RNA <50 copies/mL at Week 96 Includes all patients who received at least one dose of study medication 100 90 Option to switch to open-label MVC BID 80 70 60 Patients (%) 46.5% 50 45.1% 41.3% 40 43.7% 43.5% 38.9% 30 20 23.0% 16.7% 10 7.2% 0 80 0 8 16 24 32 40 48 56 64 72 88 96 Time (weeks) In this analysis, non-completers were categorized as failures MOTIVATE 1 and 2 Week 96 MOTIVATE 1 and 2 Week 96 Efficacy Hardy WD et al. 9th Intl Cong. on Drug Ther in HIV Infection. Glasgow, UK, Nov 9-13 2008. Presentation O425
Mean Change from Baseline in CD4+ Cell Count in MOTIVATE 1 and 2 PBO + OBT (N=209) MVC QD + OBT (N=413) MVC BID + OBT (N=426) 140 124 120 116 100 80 Mean change from baseline CD4+ cell count (cells/mm3) 60 61 40 20 0 0 4 8 12 16 20 24 28 32 36 40 44 48 Time (weeks) PBO n = 186 205 206 206 206 206 206 206 206 206 MVC QD n = 362 399 405 407 407 407 407 407 407 407 MVC BID 418 n = 386 412 417 418 418 418 418 418 418 MOTIVATE 1 and 2- Week 48
100 Placebo + OBT 90 MVC QD + OBT 80 MVC BID + OBT 72 70 70 56 60 51 51 Patients (%) 50 40 33 33 30 20 17 10 0 0 N*= 76 81 41 87 113 35 41 78 77 wOBTSS <1 1-<2 ≥2 Virologic Response on Maraviroc-based Therapy is Greatest With a Background Regimen Containing Several Active Agents MOTIVATE 1 and 2:Patients receiving maraviroc with an unchanged OBT across their period of randomized therapy (non-virologic failures excluded) • wOBTSS: The Weighted OBTSusceptibility Score -- a measure of OBT virologic activity Valdez et al. ICAAC/IDSA 2008, poster H-1221
More Severely Immunosuppressed Patients Achieve 200 CD4+ Cell with Maraviroc Patients with BL CD4+ cell count <200 Who achieved >200 at Wk 481 Patients with BL CD4+ cell count between 200 and 349 Who achieved >350 at Wk 48 70 70 Placebo + OBT 61 59 MVC QD + OBT 60 60 MVC BID + OBT 50 47* 50 43 38 40 40 Patients (%) Patients (%) 32* 30 30 20 20 10 10 0 0 N= 118 235 250 N= 64 116 117 All treated patients with valid baseline and on-treatment measurements (LOCF) *P=0.007 for MVC BID compared to placebo Tressler R. 11th Annual Institute of Human Virology Meeting 2008 MOTIVATE 1& 2 – Week 48 26
MOTIVATE Immunologic Subanalysis Summary • In MOTIVATE 1 and 2, highly TE patients receiving MVC (QD or BID) + OBT experienced early, rapid,greater, and persistent CD4+ cell count increases vs those receiving PBO + OBT (P=0.0182) • The CD4+ cell count advantage of MVC over PBO was driven not only by those patients who achieved virologic suppression, but also by those who never achieved this goal • Since treatment group was found to be associated with CD4+ cell rises, these findings together suggest that MVC increases CD4+ cell counts above and beyond what is expected for a given viral load reduction • Predictors of CD4+ cell count rises among MVC-treated patients were similar to those observed among non-MVC-treated patients
Adverse Effects • Dose related: postural hypotension and dizziness • Long-term consequences of blocking chemokine receptor? - Hepatic abnormalities (aplaviroc) - Malignancies (vicriviroc study) • Most common reported SE higher than placebo were: diarrhea, fever, bronchitis, upper respiratory infection, back pain, dizziness, insomnia, cough, and rash.
MOTIVATE:Safety Summary • No new or unique safety findings emerged • Similar safety profile as OBT alone • Adverse events • Severe adverse events • Laboratory abnormalities (including grade 3/4 transaminase elevations) • AIDS-defining events • Not associated with treatment-emergent X4 virus • Discontinuations due to adverse events (5%-6%) • Maraviroc + OBT is not associated with excess mortality compared with OBT alone Gulick RM, et al. N Engl J Med. 2008;359:1429-1441. Fatkenheuer G, et al. N Engl J Med. 2008;359:1442-1455.
MOTIVATE 1 and 2 Pooled 48-week Safety Summary Tx = treatment; AEs = adverse events; SAEs = serious adverse events*Deaths reported up to 28 days after stopping study drug. No deaths were related to study drug according to the investigator MOTIVATE 1 and 2- Week 48
MOTIVATE 1 & 2: Incidence of LFT Abnormalities (Without Regard to Baseline) at Week 48 and End of Blinded Therapy MOTIVATE 1 and 2 Week 96 Safety ULN, upper limit of normalTotal patient-years of exposure to study drug at Week 48: Placebo + OBT 111; MVC QD + OBT 300; MVC BID + OBT 309 Total patient-years of exposure to study drug at at end of blinded therapy: Placebo + OBT 160; MVC QD + OBT 522; MVC BID + OBT 551
Summary: MVC in Treatment-experienced Patients with R5 Virus • Maraviroc (QD or BID) + OBT demonstrated significantly greater virologic suppression rates and increases from baseline in CD4+ cell counts at Weeks 24 and 48 compared to placebo + OBT in this combined analysis • Virologic suppression <50 copies/mL at Week 48 in the combined studies was preserved through Week 96 in 87% of patients receiving MVC BID + OBT • Maraviroc + OBT demonstrated a similar safety profile compared to placebo + OBT
Maraviroc Pharmacokinetics • Can be taken with or without food • Primarily metabolized by CYP3A4 to inactive metabolites. • Approx. 20% renally eliminated • Half-life ≈ 15 hours (bid dosing) • Substrate of CYP3A4 and p-glycoprotein, but not an inducer or inhibitor, therefore MVC does not effect the plasma concentrations of other drugs. • MVC PK are affected by CYP3A4 and p-glycoprotein inhibitors and inducers • Pregnancy category B (no harm in animal models, but should only be used in pregnancy if clearly needed)
MVC Dosing: Based on Two or Three Simple Questions Concomitant treatment Evening dose Morning dose Includes a potent CYP3A4/P-gpinhibitor For example: protease inhibitors +/- ritonavir (except tipranavir/r), elvitegravir/r*, delavirdine ketoconazole, itraconazole, clarithromycin, telithromycin, nefazadone NO Includes a CYP3A4/P-gp inducer without a CYP3A4/P-gp inhibitor For example: efavirenz, etravirine, rifampicin, carbamazepine, oxcarbazepine, phenobarbital, phenytoin NO NO CYP3A4/P-gp inhibitors or inducers For example: NRTIs, enfuvirtide, nevirapine, tipranavir/r, raltegravir, SMX/TMP, ethinyl estradiol, levonergestrel, midazolam Note: Agents specifically studied with MVC are shown in italics* If elvitegravir/r is co-administered with a ritonavir-boosted PI, then the MVC dose should be adjusted based on MVC dosing recommendations for co-administration with that PI/r YES Regardless of other agents in the regimen 150 mg 150 mg YES 300 mg 300 mg 300 mg 300 mg 300 mg 300 mg 34
Renal Dosing • Renal clearance accounts for 25% of total clearance
Advantages of CCR5 Antagonists • No cross resistance with other HIV medications, including enfuvirtide • Excellent option for treatment experienced pts • Co-receptor utilization (aka Viral Tropism) is associated with CD4 count (R5 more common when CD4>200) and antiretroviral treatment naïve patients. • Well tolerated • Immunologic benefit?
Disadvantages of CCR5 Antagonists • Requires test to determine co-receptor tropism ($2,000) • Only active in ≈ 50% of tx-experienced pts • Blocks biologic receptor (long-term consequences?) Δ 32 mutants (1%) show no deleterious effects • Dosing based on co-administration of other medications (important for pharmacist)