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Nevirapine Tomorrow

Nevirapine Tomorrow. Joseph C Gathe, Jr, MD, FACP, FIDSA Therapeutic Concepts, PA Houston, TX, USA drgathe@josephgathe.com. Disclosures. Received funding and/or honoraria from all major pharmaceutical companies working in virology. Nevirapine Tomorrow.

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Nevirapine Tomorrow

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  1. Nevirapine Tomorrow Joseph C Gathe, Jr, MD, FACP, FIDSA Therapeutic Concepts, PA Houston, TX, USA drgathe@josephgathe.com

  2. Disclosures • Received funding and/or honoraria from all major pharmaceutical companies working in virology

  3. Nevirapine Tomorrow • Can twice daily nevirapine be improved? • Historical perspective • Available data • Basic science • Clinical science • Conclusions

  4. Adherence To HAART • Adherence correlated with viral suppression, reduced rates of resistance, increased survival, and improved QoL • Predictors of poor adherence: • Treatment fatigue • Low levels of literacy • Difficulty taking medication (eg trouble swallowing pills) • Psychosocial issues (eg depression, inadequate social support) • Complex regimens (eg pill burden, dosing frequency, food requirements) • Active substance abuse • Age-related challenges (eg vision loss, cognitive impairment) • Adverse drug effects • Stigma Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 10, 2011; 1–166

  5. Adherence With QD vs More Frequent Dosing Correct adherence following switch to a qd regimen (EFV/3TC/D4T XR) vs continued use of a bid or more frequent ARV regimen % patients Correct adherence = % days with the correct number of doses taken, evaluated with Medication Event Monitoring System (MEMS) caps Boyle et al. HIV Clin Trials 2008;9:164–176

  6. Nevirapine Tomorrow • Can twice daily viramune be improved? • Historical perspective • Available data • Basic science • Clinical science • Conclusions

  7. Can Twice Daily Nevirapine Be Improved? • Nevirapine immediate release (NVP IR) 200 mg twice-daily (bid) is a well established component of effective triple HAART therapy1,2,3 • A nevirapine preparation given once daily (qd) would be beneficial in providing dosing symmetry with the guideline recommended qd combination nucleoside therapies3,4 • Is this possible? YES!!! Nevirapine is not currently indicated for qd dosing in Europe. 1. Gazzard et al. HIV Med 2008; 9:563–6082. EACS Guidelines 2009 http://www.europeanaidsclinicalsociety.org/guidelinespdf/1_Treatment_of_HIV_Infected_Adults.pdf; 3. DHHS 2011 http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf; 4.Thompson A et al. JAMA 2010; 304:321–333

  8. Past Experience With Nevirapine • Safety • 2004 2NN study (D4T/3TC) + NVP daily or NVP bid or EFV daily or NVP/EFV • Suggested some AEs may be related to extremes of NVP pharmacokinetic (PK) parameters •  Lowering NVP Cmax may reduce common AEs Nevirapine is not currently indicated for qd dosing in Europe. van Leth et al. Lancet 2004;363:1253–63

  9. Past Experience With Nevirapine • Efficacy (2NN data) • Efficacy not predicted by PK at NVP 400 mg/day dose • Patients with lowest NVP trough plasma levels did as well as patients with the highest levels • Viral decay and 48-week data supported use of NVP 3 µg/mL steady state equivalent plasma exposure as target •  Median NVP Cmin of 3 µg/mL should be target van Leth et al. HIV Clin Trials 2005;6:254-261; Leth et al. AIDS Res Hum Retroviruses 2006:22:232–239

  10. Nevirapine Tomorrow • Can twice daily viramune be improved? • Historical perspective • Available data – once daily nevirapine • Basic science • Clinical science • Conclusions Nevirapine is not currently indicated for qd dosing in Europe.

  11. The Basics Of Nevirapine eXtended Release (XR) • NVP XR should ideally show: • qd dosing • No specific dietary requirements • Lower peak plasma levels without compromising efficacy • Comparable/improved safety and maintained efficacy vs bid dosing of NVP IR • Formulation: hydrophilic polymer matrix system, widely used in oral controlled release drug delivery Nevirapine is not currently indicated for qd dosing in Europe.

  12. The Basics Of Nevirapine XR: Target PK • Steady state Cmin 3 µg/mL (>30 fold higher than IC90 of wild type virus*) • Cmax/Cmin ratio <1.5 8 NVP IR (bid)NVP XR (qd) 6 4 NVP plasma concentration (µg/mL) 2 0 IC90 0 4 8 12 16 20 24 Hours Nevirapine is not currently indicated for qd dosing in Europe. *IC90 for wild type virus = 100 ng/mL

  13. Nevirapine XR: Overview Of Development Phase Ib: ERVIR multiple-dose PK (to steady state), NVP IR-pretreated HIV patients switched to NVP XR Q4 2006–Q2 2007 Phase Ia (single dose) ~10 prototypes, healthy volunteers Q1–Q3 2006 Colonic absorption Q2–Q4 2005 Phase III,VERXVE 48-wk final NVP XR formulation vs NVP IR (bid) Q4 2007–Q3 2009 Phase III,TRANXITION 48-wk transition study from NVP IR to XR Q4 2008–Q3 2010 Nevirapine is not currently indicated for qd dosing in Europe.

  14. Nevirapine XR: Overview Of Development Phase Ib: ERVIR multiple-dose PK (to steady state), NVP IR-pretreated HIV patients switched to XR Q4 2006–Q2 2007 Phase Ia (single dose) ~10 prototypes, healthy volunteers Q1–Q3 2006 Colonic absorption Q2–Q4 2005 Phase III,VERXVE 48-wk final NVP XR formulation vs NVP IR (bid) Q4 2007–Q3 2009 Phase III,TRANXITION 48-wk transition study from NVP IR to XR Q4 2008–Q3 2010 Nevirapine is not currently indicated for qd dosing in Europe.

  15. The Basics Of Nevirapine XRPhase Ib: ERVIR • Objectives: • To establish the steady state PK profile of 2 different NVP XR formulations (formulation A and formulation B) under fasting and fed conditions • To compare the steady state bioavailability of the 2 different NVP XR formulations with NVP IR (200 mg bid) • Open-label, multiple-dose, parallel group study: • 4 countries: Germany, Switzerland, France, USA • Enrolled HIV-infected patients (viral load <50 c/mL; n=92) treated for >12 weeks with a stable regimen based on NVP IR 200 mg bid • Plasma samples at steady-state after IR and XR collected over 24h Nevirapine is not currently indicated for qd dosing in Europe. Quinson A et al. ICAAC 2009, Poster, Abstract A1-1310; Battegay, M et al. 12th EACS, Nov 2009; HIV Med 10, Suppl 2: 76-77

  16. ERVIR Results: NVP XR vs NVP IR 400 mg Formulation A n=24 IR 400 mg 10000 XR 400 mg fed XR 400 mg fasted 8000 6000 Mean NVP plasma conc. (ng/mL) ± SD 4000 2000 IC90 0 -4 0 4 8 12 16 20 24 (day) Time (h) Nevirapine is not currently indicated for qd dosing in Europe. *IC90 for wild type virus = 100 ng/mL Quinson A et al. ICAAC 2009, Poster, Abstract A1-1310; Battegay, M et al. 12th EACS, Nov 2009; HIV Med 10, Suppl 2: 76-77

  17. Pharmacokinetic data: relative bioavailability Bioavailability (%) Fasted Fed • Relative to nevirapine (100%) • The bioavailability for nevirapine XR under fasted conditions was 80% • The bioavailability for nevirapine XR under fed conditions was 94% Quinson A et al. ICAAC 2009, Poster, Abstract A1-1310; Battegay, M et al. 12th EACS, Nov 2009; HIV Med 10, Suppl 2: 76-77

  18. The Basics Of Nevirapine XRCan Nevirapine Be Given QD? • Administration of NVP XR 400 mg qd resulted in extended absorption and reductions in peak levels at steady state while attaining similar troughs levels as NVP IR • NVP 400 XR formulation A exhibited better bioavailability and lower variability than other XR formulations • NVP XR formulations demonstrated similar rates of AEs and nearly all were mild • No virologic failures were observed •  NVP XR 400 mg formulation Aselected for Phase III studies Nevirapine is not currently indicated for qd dosing in Europe. Quinson A et al. ICAAC 2009, Poster, Abstract A1-1310; Battegay, M et al. 12th EACS, Nov 2009; HIV Med 10, Suppl 2: 76-77 Group A Group B

  19. Nevirapine Tomorrow • Can twice daily viramune be improved? • Historical perspective • Available data • Basic science • Clinical science • Conclusions

  20. Nevirapine XR: overview of clinical development Phase Ib: ERVIR multiple dose PK (to steady state), NVP IR-pretreated HIV patients switched to XR Q4 2006–Q2 2007 Phase Ia (single dose) ~10 prototypes, healthy volunteers Q1–Q3 2006 Colonic absorption Q2–Q4 2005 Phase III, VERXVE 48-wk final NVP XR formulation vs NVP IR (bid) Q4 2007–Q3 2009 Phase III,TRANXITION 48-wk transition study from NVP IR to XR Q4 2008–Q3 2010 Nevirapine is not currently indicated for qd dosing in Europe.

  21. Efficacy and safety of nevirapine extended-release once daily versus nevirapine immediate-release twice daily in treatment-naïve HIV-1 infected patients J Gathe, J Andrade-Villaneuva, S Santiago et al. Antivir Ther 2011;16: in press

  22. VERXVE: Objectives And Study Design • Objective: • To evaluate the efficacy and safety of NVP XR 400 mg qdvs NVP IR 200 mg bid, in ARV treatment-naïve, HIV–1-infected patients • Study design: • 48 week, double-blind, double-dummy, non-inferiority study • Subjects: • NVP eligible adult subjects with CD4/mm3 counts of 50–400 for men and 50–250 for women • Baseline viral load (VL) stratification (≤100,000 vs>100,000 copies/mL) Nevirapine is not currently indicated for qd dosing in Europe. Gathe et al. Antivir Ther 2011;16: in press (doi:10.3851/IMP1803)

  23. VERXVE Study Schema • Screening • Eligible patient • NVP IR 200 mg qd +TDF/FTC for 14 days • Randomisation • Group A (n=505) • 400 mg qd • NVP XR + TDF/FTC • Group B (n=506) • 200 mg bid • NVP IR + TDF/FTC Gathe et al. AntivirTher 2011;16: in press (doi:10.3851/IMP1803)

  24. VERXVE:StudyEndpoints • Primary endpoint: • Sustained virologic response at 48 weeks – defined as VL <50 copies/mL prior to and at week 48, without virologic rebound or change of ARV therapy • Secondary endpoints: • Time-to-loss of virologic response (TLOVR) • Time to new AIDS or AIDS-related progression event or death • AEs, SAEs, AEs leading to discontinuation; laboratory parameters • PK parameters – NVP plasma trough concentrations • Genotypic resistance associated with virologic failure Nevirapine is not currently indicated for qd dosing in Europe. Gathe et al. Antivir Ther 2011;16: in press (doi:10.3851/IMP1803)

  25. VERXVE:Virologic Response at Week 48 AD 2.3%95% CI: −6.6%, 11.1% AD 4.9%95% CI: −0.1%, 10.0% AD 6.6%95% CI: 0.7%, 12.6% Proportion of Virologic Responders (FAS; %) FAS: full analysis set AD: adjusted difference n=311 n=303 n=505 n=203 n=194 n=506 Virologic response was independent of age, gender, race or geographic regionMean CD4+ increase from baseline at Week 48: NVP IR 181 cells/mm3; NVP XR 192 cells/mm3 Gathe et al. AntivirTher 2011;16: in press (doi:10.3851/IMP1803)

  26. VERXVE:Multiple Dose Trough Concentrations NVP IR and NVP XR Geometric Mean, µg/mL 6 NVP IR (4.11 µg/mL) NVP XR (3.35 µg/mL) 5 (~38-fold higher) 4 3 Mean dose trough NVP (µg/mL) 2 10th percentile trough concentration for Viramune XR 1 IC90 for wild type HIV-1 virus* 0 4 6 8 12 16 24 32 40 48 Weeks Nevirapine is not currently indicated for qd dosing in Europe. *IC90 for wild type virus = 100 ng/mL Boehringer Ingelheim: Data on file

  27. Selected AEs Of Interest During The Randomisation Phase (Post-NVP IR Lead-In) *2 grade 3 and 1 grade 4 cases. No instances of SJS or grade 4 rash in the nevirapine XR group Gathe et al. AntivirTher 2011;16: in press (doi:10.3851/IMP1803)

  28. VERXVE: Conclusions • The VERXVE pivotal trial demonstrated: • Non-inferior efficacy for NVP XR compared withNVP IR independent of baseline viral load, age, race, gender, region, HIV-1 subtype or CDC class • No new AEs identified, reflecting similar safety and tolerability profiles for both formulations Gathe et al. Antivir Ther 2011;16: in press (doi:10.3851/IMP1803)

  29. Nevirapine XR: Overview Of Clinical Development Phase Ib: ERVIR multiple-dose PK (to steady state), NVP IR-pretreated HIV patients switched to XR Q4 2006–Q2 2007 Phase Ia (single dose) ~10 prototypes, healthy volunteers Q1–Q3 2006 Colonic absorption Q2–Q4 2005 Phase III, VERXVE 48-wk final XR formulation vs NVP IR (bid) Q4 2007–Q3 2009 Phase III, TRANXITION 48-wk transition study from NVP IR to XR Q4 2008–Q3 2010 Nevirapine is not currently indicated for qd dosing in Europe.

  30. TRANXITION: Objectives And Study Design • Objectives: • To assess the efficacy, safety and tolerability of switching HIV-1 infected patients from NVP IR to XR vs continued NVPIR • Study design: • Open-label, randomised, parallel group study • Subjects: • Adults with HIV RNA <50 copies/mL • Randomised 2:1 to NVP XR 400 mg qdvs NVP IR 200 mg bid • n=200 vs 100 patients • Stratified by background therapy and CD4+ count • Patients remain on previous background therapy • Treatment duration: 48 weeks Nevirapine is not currently indicated for qd dosing in Europe. Arasteh et al. JIAS 2010;13(Suppl 1):abstract P45 and poster

  31. TRANXITION Study Schema • NVP IR 200 mg bid regimen ≥18 wksHIV-RNA <50 copies/mL Randomisation (2:1) NVP XR 400 mg qd + background ARV Continued NVP IR 200 mg bid + background ARV Nevirapine is not currently indicated for qd dosing in Europe. Arasteh et al. JIAS 2010;13(Suppl 1):abstract P45 and poster

  32. TRANXITION: Endpoints • Primary endpoint: sustained treatment response at 24 weeks • Sustained treatment response: viral load <50 copies/mL for two consecutive visits prior to Week 24 • Secondary endpoints: • Virologic response after 48 weeks of treatment • Proportion of patients with viral load <50 copies/mL at each visit • Change in CD4+ cell count from baseline at each visit • Genotypic resistance associated with virologic failure • Incidence of AIDS progression or death Nevirapine is not currently indicated for qd dosing in Europe. Arasteh et al. JIAS 2010;13(Suppl 1):abstract P45 and poster

  33. Conclusions: Nevirapine Tomorrow • It remains important for health care professionals to have as many evidence-based treatment options for the millions of HIV infected patients worldwide • Once-daily regimens may make it easier for patients to accept and adhere to therapy • Nevirapine XR qd provides the potential for: • Dosing symmetry with preferred combination nucleoside analogues • A more convenient treatment regimen for patients compared with bid dosing Nevirapine is not currently indicated for qd dosing in Europe.

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