nevirapine tomorrow

Nevirapine Tomorrow

Joseph C Gathe, Jr, MD, FACP, FIDSATherapeutic Concepts, PA

Houston, TX, [email protected]

Disclosures

Received funding and/or honoraria from all major pharmaceutical companies working in virology

Nevirapine Tomorrow

Can twice daily nevirapine be improved?Historical perspectiveAvailable data

Basic science Clinical science

Conclusions

Adherence To HAART

Adherence correlated with viral suppression, reduced rates of resistance, increased survival, and improved QoL

Predictors of poor adherence:

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

Low levels of literacy

Age-related challenges (eg vision

loss, cognitive impairment)

Active substance abuse

Stigma

Difficulty taking medication (eg trouble

swallowing pills)

Adverse drug effects

Treatment fatigue

Complex regimens (eg pill burden, dosing

frequency, food requirements)

Psychosocial issues (eg depression,

inadequate social support)

Adherence With QD vs More Frequent Dosing

Boyle et al. HIV Clin Trials 2008;9:164–176

% p

atie

nts

Correct adherence following switch to a qd regimen (EFV/3TC/D4T XR) vs continued use of a bid or more

frequent ARV regimen

Correct adherence = % days with the correct number of doses taken, evaluated with Medication Event Monitoring System (MEMS) caps

Nevirapine Tomorrow

Can twice daily viramune be improved?Historical perspectiveAvailable data


Conclusions

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!!!

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

Nevirapine is not currently indicated for qd dosing in Europe.

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

van Leth et al. Lancet 2004;363:1253–63


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

Nevirapine Tomorrow

Can twice daily viramune be improved?Historical perspectiveAvailable data – once daily nevirapine


Conclusions


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


The Basics Of Nevirapine XR: Target PK

Hours

NVP

pla

sma

conc

entr

atio

n (µ

g/m

L)

0

2

4

6

8

0 4 8 12 16 20 24

NVP IR (bid)NVP XR (qd)

Steady state Cmin 3 µg/mL (>30 fold higher than IC90 of wild type virus*)

Cmax/Cmin ratio <1.5

Nevirapine is not currently indicated for qd dosing in Europe.*IC90 for wild type virus = 100 ng/mL

IC90

Nevirapine XR: Overview Of Development

Phase Ia (single dose)

~10 prototypes, healthy

volunteersQ1–Q3 2006

Phase Ib: ERVIR multiple-dose PK (to steady state), NVP IR-

pretreated HIV patients switched to NVP XR

Q4 2006–Q2 2007

Phase III, VERXVE 48-wk final NVP XR formulation vs NVP IR (bid)

Q4 2007–Q3 2009

Phase III, TRANXITION48-wk transition study from NVP IR to XR

Q4 2008–Q3 2010

Colonic absorption

Q2–Q4 2005


Nevirapine XR: Overview Of Development





pretreated HIV patients switched to XR

Q4 2006–Q2 2007


Q4 2007–Q3 2009


Q4 2008–Q3 2010

Colonic absorption

Q2–Q4 2005


The Basics Of Nevirapine XRPhase Ib: ERVIRObjectives:

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

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


ERVIR Results: NVP XR vs NVP IR 400 mg Formulation A

-4 0 4 8 12 16 20 24Time (h)(day)

Mea

n N

VP p

lasm

a co

nc. (

ng/m

L) ±

SD

0

2000

4000

6000

8000

10000 IR 400 mg

XR 400 mg fastedXR 400 mg fed



IC90

*IC90 for wild type virus = 100 ng/mL

n=24

Pharmacokinetic data: relative bioavailability

Fasted Fed0

102030405060708090

100100 100

80

94Nevirapine IRNevirapine XR

Bio

avai

labi

lity

(%)

Relative to nevirapine (100%) The bioavailability for nevirapine XR under fasted conditions was 80% The bioavailability for nevirapine XR under fed conditions was 94%


FedFasted

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 Tomorrow

Can twice daily viramune be improved?Historical perspectiveAvailable data


Conclusions

Nevirapine XR: overview of clinical development




Phase Ib: ERVIR multiple dose PK (to steady state), NVP IR-


Q4 2006–Q2 2007


Q4 2007–Q3 2009


Q4 2008–Q3 2010

Colonic absorption

Q2–Q4 2005


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

VERXVE: Objectives And Study Design

• Objective:– To evaluate the efficacy and safety of NVP XR 400 mg qd

vs 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)

Eligible patient

Screening

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

VERXVE Study Schema


VERXVE: Study Endpoints

• 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



Total

Baseli

ne H

IV-R

NA >100

,000 c

/mL

Baseli

ne H

IV-R

NA <100

,000 c

/mL

020406080

10076 71 7981 73

86

NVP IRNVP XR

Pro

porti

on o

f Viro

logi

c R

espo

nder

s (F

AS

; %)

AD 4.9%95% CI: −0.1%, 10.0%

AD 2.3%95% CI: −6.6%, 11.1%

AD 6.6%95% CI: 0.7%, 12.6%

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

FAS: full analysis setAD: adjusted difference

n=506 n=505 n=203 n=194 n=303 n=311

VERXVE: Virologic Response at Week 48


Weeks

Mea

n do

se tr

ough

NVP

(µg/

mL)

10th percentile trough concentration for Viramune XR

0

1

2

3

4

5

6

4 6 8 12 16 24 32 40 48

NVP IR (4.11 µg/mL)NVP XR (3.35 µg/mL)

(~38-fold higher)

IC90 for wild type HIV-1 virus*

VERXVE: Multiple Dose Trough Concentrations NVP IR and NVP XR

Geometric Mean, µg/mL

Boehringer Ingelheim: Data on file

Nevirapine is not currently indicated for qd dosing in Europe.*IC90 for wild type virus = 100 ng/mL

Selected AEs Of Interest During The Randomisation Phase (Post-NVP IR Lead-In)

NVP IR, n (%) NVP XR, n (%)

Treatment-related rash (all grades)

25 (4.9) 29 (5.7)

Grade 3 rash 3 (0.6) 3 (0.6)

Stevens Johnson Syndrome

3 (0.6)* 0 (0.0)

Any hepatic event 46 (9.1) 28 (5.5)

Symptomatic hepatic events

22 (4.3) 14 (2.8)

*2 grade 3 and 1 grade 4 cases. No instances of SJS or grade 4 rash in the nevirapine XR group


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


Nevirapine XR: Overview Of Clinical Development






Q4 2006–Q2 2007

Phase III, VERXVE 48-wk final XR formulation vs NVP IR (bid)

Q4 2007–Q3 2009


Q4 2008–Q3 2010

Colonic absorption

Q2–Q4 2005


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 NVP IR

Study design: Open-label, randomised, parallel group study

Subjects: Adults with HIV RNA <50 copies/mL Randomised 2:1 to NVP XR 400 mg qd vs 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


Arasteh et al. JIAS 2010;13(Suppl 1):abstract P45 and poster

TRANXITION Study Schema

NVP IR 200 mg bid regimen ≥18 wks

HIV-RNA <50 copies/mL

Randomisation (2:1)

NVP XR 400 mg qd+ background ARV

Continued NVP IR 200 mg bid + background ARV



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



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.

nevirapine tomorrow

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