NORTHWEST AIDS EDUCATION AND TRAINING CENTER
Rilpivirine (Edurant): A New NNRTI
David Spach, MD
Clinical Director, Northwest AETC
Professor of Medicine, University of Washington
Presentation Prepared by:
David Spach, MD
Last Updated: July 8, 2011
ANTIRETROVIRAL THERAPY
Rilpivirine (Edurant)
ANTIRETROVIRAL THERAPY
Rilpivirine (Edurant)*
• Class: non-nucleoside reverse transcriptase inhibitor
• Approval: FDA-approved May 20, 2011
• Indication: in combination with other ARVs for treatment-naïve adults
• FDA Approved Dose/Formulation^: 25 mg tablet (with a meal)
• Co-Formulation (in development): Tenofovir-Emtricitabine-Rilpivirine
• Metabolism: primarily in liver via cytochrome P450 (CYP 3A4) enzymes
• Pregnancy : category B
• Adverse Events (low): depression, insomnia, headache, and rash
* Formerly TMC-278
^The dosage form contains rilpivirine hydrochoride 27.5 mg (equivalent to 25 mg of rilpivirine)
Summary of Key Rilpivirine (Edurant) Studies
• Phase 2b Trial
- C204 Dose Ranging Study: Rilpivirine versus Efavirenz
• Phase 3 Trials
- ECHO (TMC278-C209): Rilpivirine versus Efavirenz
- THRIVE (TMC278-C215): Rilpivirine versus Efavirenz
Rilpivirine vs. Efavirenz
TMC-278-C204 Dose-Ranging Study
ANTIRETROVIRAL THERAPY
Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive
TMC-278-C204: Study Design
Rilpivirine: 25 mg qd
Study Features
Protocol
- N = 368 randomized and treated
- Phase 2b randomized trial
- Age > 18
- ARV-naïve
- HIV RNA > 5,000 copies/ml
- No baseline NNRTI mutations
- Randomized to one of 4 arms
- All given 2 NRTIs*
(n = 93)
Rilpivirine: 75 mg qd
(n = 95)
1x
Rilpivirine: 150 mg qd
(n = 91)
Efavirenz: 600 mg qd
(n = 89)
*2 NRTIs: Zidovudine + Lamivudine (75%); Tenofovir + Emtricitabine (25%)
Source: Pozniak AL, et al. AIDS. 2010;24:55-65.
ANTIRETROVIRAL THERAPY
Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive
TMC-278-C204: Week 96 Results
48 and 96 Week Data: Virologic Response ( ITT)
All regimens included 2 NRTIs: Zidovudine + Lamivudine (75%); Tenofovir + Emtricitabine (25%)
Source: Pozniak AL, et al. AIDS. 2010;24:55-65.
ANTIRETROVIRAL THERAPY
Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive
TMC-278-C204: Conclusion
• Conclusion: “All TMC278 doses demonstrated potent and sustained
efficacy comparable with efavirenz in treatment-naive patients over 96
weeks. TMC278 was well tolerated with lower incidences of
neurological and psychiatric adverse events, rash and lower lipid
elevations than those with efavirenz. TMC278 25 mg once daily was
selected for further clinical development.”
Source: Pozniak AL, et al. AIDS. 2010;24:55-65.
Rilpivirine vs. Efavirenz
ECHO and THRIVE Studies
ANTIRETROVIRAL THERAPY
Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive
ECHO and THRIVE: Study Design
Rilpivirine: 25 mg qd + TDF/FTC
(n = 346)
Study Features
Protocol
- Randomized, double-blind trial
- Phase 3
- N = 690 (ECHO) and 678 (THRIVE)
- Age > 18
- ARV-naïve
- HIV RNA > 5,000 copies/ml
- No baseline NNRTI mutations
- Randomized to one of 2 arms
- All given 2 NRTIs*
ECHO
1x
Efavirenz: 600 mg qd + TDF/FTC
(n = 344)
Rilpivirine: 25 mg qd + 2NRTIs*
(n = 340)
THRIVE
1x
*2 NRTIs:
ECHO: Tenofovir + Emtricitabine (TDF/FTC)
THRIVE: Tenofovir + Emtricitabine; Zidovudine + Lamivudine;
Efavirenz: 600 mg qd + 2NRTIs*
(n = 338)
Abacavir + Lamivudine
Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.
ANTIRETROVIRAL THERAPY
Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive
ECHO and THRIVE: Week 48 Results
48 Week Data: Virologic Response ( ITT-TLOVR)
All regimens included 2 NRTIs
Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.
ANTIRETROVIRAL THERAPY
Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive
ECHO and THRIVE: Week 48 Results
Pooled ECHO and THRIVE: Virologic Response ( ITT-TLOVR)
84.3%
82.3%
2NRTIs+ Rilpivirine (n = 686)
2NRTIs+ Efavirenz (n = 682)
Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.
ANTIRETROVIRAL THERAPY
Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive
ECHO and THRIVE: Week 48 Results
Virologic Response with Baseline HIV RNA > 100,000 copies/ml
All regimens included 2 NRTIs
Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.
ANTIRETROVIRAL THERAPY
Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive
ECHO and THRIVE: Week 48 Results
Virologic Response with Baseline HIV RNA < 100,000 copies/ml
All regimens included 2 NRTIs
Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.
ANTIRETROVIRAL THERAPY
Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive
ECHO and THRIVE: Results
48 Week Data: Virologic Failure
All regimens included 2 NRTIs
Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.
ANTIRETROVIRAL THERAPY
Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive
ECHO and THRIVE: Results
48 Week Data: Discontinuation Due to Adverse Effects
All regimens included 2 NRTIs
Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.
ANTIRETROVIRAL THERAPY
Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive
ECHO and THRIVE: Results
Resistant Associated Mutations (RAMs)
Rilpivirine
(N = 686)
Efavirenz
(N = 682)
62 of 72
28 of 39
No NNRTI or NRTI RAMs
29%
43%
Emergent NNRTI RAMs
63%
54%
E138K
K103N
68%
32%
M184I
M184V
Resistance Data with Virologic Failure
Most Frequent NNRTI RAMs
Emergent NRTI RAMs
Most Frequent NRTI RAMs
NOTE: 31 (50%) of 62 rilpivirine failure isolated were phenotypically resistant to rilpivirine
Of these, 90% phenotypically cross-resistant to etravirine
Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.
ANTIRETROVIRAL THERAPY
Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive
ECHO and THRIVE: Results
Conclusions:
• Rilpivirine demonstrated high response rate
• Rilpivirine virologic failure rate higher than efavirenz (9.0% vs 4.8%)
• Rilpivirine had significant tolerability advantage over efavirenz
Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.
ANTIRETROVIRAL THERAPY
Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive
ECHO and THRIVE: Resistance Results
Most Frequent NNRTI Resistance Associated Mutations (RAMs)
Source: Rimsky L, et al. 50th ICAAC. 2010:H-1810.
ANTIRETROVIRAL THERAPY
Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive
ECHO and THRIVE: Resistance Data
Most Frequent NRTI Resistance Associated Mutations (RAMs)
Source: Rimsky L, et al. 50th ICAAC. 2010:H-1810.
ANTIRETROVIRAL THERAPY
Rilpivirine Active Against Wild-Type and
NNRTI-Resistant HIV-1
• Sensitivity not affected by most single NNRTI resistance-associated
mutations: 100, 103, 106, 138,179,188,190, 221, 230, 236
• Decreased activity associated with: K101P, Y181I/V
From: Azijn H, et al. Antimicrob Agents Chemother. 2010;54;718-27.
ANTIRETROVIRAL THERAPY
Rilpivirine (Edurant)
Key Summary Points
• Overall has performed equally with Efavirenz
• Better tolerated than Efavirenz
• Higher virologic failure rate than with Efavirenz-based regimens
• Rilpivirine virologic failure often results in cross resistance to Etravirine
• Efficacy of Rilpivirine for patients with Efavirenz failure unknown
• Co-formulation in development: Tenofovir-Emtricitabine-Rilpivirine