Safety and efficacy of maraviroc in CCR5-tropic HIV-1-infected children aged 2 to

Safety and efficacy of maraviroc in CCR5-tropic HIV-1-infected children

aged 2 to <18 years

C Giaquinto,1 L Keet,2 C Fortuny,3 A Fang,4 M Vourvahis,4 L McFadyen,5 SR Valluri,4 G Mukwaya,4 J Heera6

1Clinica Pediatrica, Centro AIDS Pediatrico, Padova, Italy; 2Department Pediatrics, University of the Free State, Bloemfontein, South Africa; 3Hospital Sant Joan de Deu, Barcelona, Spain; 4Pfizer Inc, New York, NY, USA; 5Pfizer Inc, Sandwich, Kent, UK; 6Pfizer Inc, Groton, CT, USA

7th IAS Conference on HIV Pathogenesis, Treatment and PreventionJune 30-July 3, 2013; Kuala Lumpur, Malaysia

Country Investigator/institution Country Investigator/institution

Brazil Marinella Della Negra, Instituto de Infectologia Emilio Ribas, São Paulo

Thailand Kulkanya Chokephaibulkit, Siriraj Hospital, Mahidol University, Bangkok noi, Bangkok

Italy Carlo Giaquinto, Clinica Pediatrica, Centro AIDS Pediatrico, Padova

Virat Sirisanthana, Chiang Mai University, Muang, Chiang Mai

Portugal José Gonçalo Marques, Centro Hospitalar de Lisboa Norte, EPE, Hospital Santa Maria, Lisboa

Pope Kosalaraksa, Khon Kaen University, Muang, Khon Kaen

Flora Candeias, Hospital D. Estefânia -Serviço de Imunologia, Lisboa

Jintanat Ananworanich, The HIV Netherlands Australia Thailand Research Collaboration, The Thai Red Cross AIDS Research Centre, Bangkok

Maria João Virtuoso, Hospital Distrital de Faro, EPE, Faro

USA Carina Adriana Rodriguez, University of South Florida, Children's Research Institute, St Petersburg, FL

Puerto Rico

Midnela Acevedo-Flores, San Juan Research Hospital, Puerto Rico Medical Center, Rio Piedras

Antonio Carlos Arrieta, Children's Hospital of Orange County, Orange County, CA

South Africa

Ismail Haroon Mitha, Benmed Clinic, Benoni, Gauteng

Suzanne Renee Lavoie, Virginia Commonwealth University, Richmond, VA

Jan Fourie, Dr. J Fourie Medical Centre, Dundee, KwaZulu Natal

Joseph August Church, Children's Hospital Los Angeles, Los Angeles, CA

Muthuhadini Patience Mawela, University of Limpopo, Pretoria, Gauteng

Stephen Cole Eppes, Alfred I. DuPont Hospital for Children, Wilmington, DE

Lizelle Keet, Iatros International, Westdene, Bloemfontein

Charles Debeaux Mitchell, University of Miami Miller School of Medicine, Miami, FL

Spain Claudia Fortuny, Hospital Sant Joan de Deu, Barcelona

Natella Yurievna Rakhmanina, Children's National Medical Center - Infectious Disease, Washington, D.C.

Daniel Blazquez Gamero, Hospital Universitario 12 de Octubre,

Study A4001031: participating sites (23 sites from 8 countries)

Introduction

• Maraviroc (MVC) is a selective CCR5 antagonist and is the first of this class of oral agents approved for treatment of CCR5-tropic HIV-1 in adults

• Preliminary data from 31 children have previously been presented at IAS 2011

• Here we present updated safety and efficacy findings from 94 subjects who received at least one dose of study medication with a data cut-off of March 12, 2013– Efficacy data is reported until Week 48– All safety data is included as of the cut-off date of March 12,

2013 • Pharmacokinetic (PK) and dose-finding data from Stage 1 are

presented in poster MOPE044,1 also at this meeting1. Vourvahis et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract #MOPE044.

7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 3, 2013; Kuala Lumpur, Malaysia

Study A4001031: Ongoing, open-label, two-stage, age-stratified, non-comparative study to evaluate PK, safety, and efficacy of MVC with

optimized background therapy (OBT) in treatment-experienced children and adolescents infected with CCR5-tropic HIV-1

Screening Day 1

Baseline

Cohort 1: ≥2–<6 years (liquid)

Cohort 2: ≥6–<12 years (tablet)

Cohort 3: ≥6–<12 years (liquid)

Cohort 4: ≥12–<18 years (tablet)

End of study

Weeks4–6

weeks 48 weeks 240 weeks (5 years)

S1 Follow-up5 years after initial MVC exposure

On or off MVC

S2

S2

Screening

S1, Stage 1: intensive PK for dose finding (4-12 weeks): Minimum of 12 (cohort 1) and 10 children (in each of cohorts 2-4) to complete stage 1, prior to entering stage 2.S2, Stage 2: safety/efficacy. Following the minimum numbers being reached for stage 1, all new patients then directly enter stage 2


Methods• Subjects infected with CCR5-tropic HIV-1 (as detected by

Phenotypic assay, ESTA) were enrolled into one of four age/formulation cohorts

• Eligibility criteria included: – HIV-1 RNA >1000 copies/mL at screening– On stable or no pre-study antiretroviral (ARV) regimen for >4 weeks

prior to screening visit– Previous experience/intolerance >6 months (sequential or cumulative)

with at least two ARV drug classes

• OBT choice was guided by resistance test results and consisted of ≥3 ARVs in addition to MVC

• MVC dose based on body surface area and co-medications1

• Safety, viral load and CD4 counts were evaluated at all study visits

• Statistical analyses are descriptive in nature1. Vourvahis et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract #MOPE044.


MVC doses by BSA on entry and OBT

BSA, m2Dose in absence of potent

CYP3A4 inhibitors/inducers

Dose with potentCYP3A4 inhibitors

Dose with CYP3A4 inducers (in absence of

potent CYP3A4 inhibitors)

<0.22 40 mg BID 10 mg BID 40 mg BID

0.220.43 100 mg BID 25 mg BID 100 mg BID





>1.73 300 mg BID 150 mg BID 600 mg BID

Subject baseline characteristics (N=94)

Cohort 1(N=13)

Cohort 2(N=27)

Cohort 3(N=12)

Cohort 4(N=42)

Sex, males/females 9/4 13/14 6/6 16/26Race, White/Black/Asian/Other 1/8/2/2 5/18/3/1 1/11/0/0 9/26/6/1

Body surface area, m2 (median [range])

0.7 (0.5 – 0.7)

1.0 (0.6–1.4)

0.9 (0.6–1.6)

1.3 (0.9–1.8)

Age, years(median [range])

3.0 (2.0–5.0)

10.0 (6.0–11.0)

9.0 (6.0–11.0)

14.0 (12.0–17.0)

Median baseline plasma HIV-1 RNA (log10, copies/mL [range])

4.6 (3.9–5.6)

4.3 (3.2–5.5)

4.7 (3.5–5.3)

4.4 (2.9–5.9)

Median baseline CD4 counts (μ/L [range])

894.5 (131.5–1768.5)

467.8 (5.5–1120.5)

414.0 (192.5–1341.0)

371.0 (29.0–847.5)

Median duration of study treatment (days) [range]

226(45 – 1321)

526(92 – 1316)

240(2 – 1373)

261(14 – 1234)


Study disposition through Week 4875/94 children were followed up for 48 weeks (26 discontinued MVC; 49 still on treatment)

Cohort 1 (N=13)

Cohort 2 (N=27)

Cohort 3 (N=12)

Cohort 4 (N=42)

Screened(N=262)

Screen failure (N=164)Viral load <1000 copies/mL (n=40)PSGT was non-reportable (n=4)Not CCR5-tropic (n=71)Tropism not reportable (n=36)Other (n=13)In screening (N=4)

Enrolled(N=94)


*Other includes discontinuation (DC) due to withdrawal of consent, non-compliance, lost to follow-up; all virological failures had confirmed poor compliance with study medication; 3 virological failures had non-R5 tropism at failure

Cohort 1 (N=13)

Cohort 2 (N=27)

Cohort 3 (N=12)

Cohort 4 (N=42)

DC prior to Week 48 (n=4)• Virological failures

(n=3)• Other* (n=1)


(n=2) • Other* (n=1)

DC prior to Week 48 (n=18)• Virological failures (n=11) • Adverse events (n=1)• Other* (n=6)

Screened(N=262)

DC prior to Week 48 (n=1)• Other* (n=1)


Enrolled(N=94)


Cohort 1 (N=13)

Cohort 2 (N=27)

Cohort 3 (N=12)

Cohort 4 (N=42)


(n=3)• Other* (n=1)


(n=2) • Other* (n=1)

DC prior to Week 48 (n=18)• Virological failures (n=11) • Adverse events (n=1)• Other* (n=6)

Completed Week 48 (n=5)




Screened(N=262)

DC prior to Week 48 (n=1)• Other* (n=1)


Enrolled(N=94)

Ongoing Pre-Week 48 (n=7)




*Other includes discontinuation (DC) due to withdrawal of consent, non-compliance, lost to follow-up; all virological failures had confirmed poor compliance with study medication; 3 virological failures had non-R5 tropism at failure


Percentage of subjects with HIV-1 RNA <400 copies/mL at 24 (N=84) and 48 weeks (N=75)*

*Efficacy was evaluated using the missing/discontinuation = failure approachNumerator=Number of responding subjectsDenominator=Includes all subjects who completed week 48 or discontinued prior to week 48

0102030405060708090

100

Cohort 1 Cohort 2 Cohort 3 Cohort 4

Week 24Week 48

7/104/6

22/26

15/236/10 5/8

21/38

15/38

% o

f sub

ject

s w

ith H

IV-1

RN

A <4

00 c

opie

s/m

L67% at 24 weeks and 52% at 48 weeks had VL < 400c/mL


Percentage of subjects with HIV-1 RNA <48 copies/mL at 24 (N=84) and 48 weeks (N=75)*

0102030405060708090

100


Week 24Week 48

2/10

3/6 14/26

10/23

6/104/8

17/38

13/38

% o

f sub

ject

s w

ith H

IV-1

RN

A <4

8 co

pies

/mL

*Efficacy was evaluated using the missing/discontinuation = failure approachNumerator=Number of responding subjectsDenominator=Includes all subjects who completed week 48 or discontinued prior to week 48

46% at 24 weeks and 40% at 48 weeks had VL < 48 c/mL


Median CD4% at baseline, Week 24, and Week 48

11

CD4%

6 4 26 23 15 11 9 5 36 23 19

n = children with available CD4 data at Week 24 and Week 48

n =



Summary of all-causality adverse events*Subjects n (%)

With adverse events 60 (63.8) Serious adverse events 16 (17) Grade 3 or 4 adverse events 10 (10.6) Death 0

Discontinued due to adverse events 3 (3.2)Most frequently reported (>10%) adverse events by system organ class, n (%)

Gastrointestinal disorders 34 (36.2)Infection and infestations 46 (48.9)Nervous system disorders 13 (13.8)Reproductive system and breast disorders 12 (12.8)Skin and subcutaneous tissue disorders 11 (11.7)

*All data included as of the cut-off date of March 12, 20137th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 3, 2013; Kuala Lumpur, Malaysia

Adverse events (>Grade 2) in each cohort, n (grade)

Cohort 1(N=13)

Cohort 2(N=27)

Cohort 3(N=12)

Cohort 4(N=42)

Gastritis (1, G3) Pneumonia (1, G3) TB drug-induced liver injury (1, G4)

Vomiting (1, G3) Pneumonia (1, G3)

Otitis media (1, G3) H1N1 influenza (1, G3)

Transaminases increased (1, G4)

Hepatic enzyme abnormal (1, G3)

Bipolar disorder (1, G3)

None of these events were attributed to maraviroc by the study investigators


Conclusions

• These data suggest that in HIV-1-infected, treatment-experienced children aged 2 − <18 years, MVC (administered twice-daily) in addition to OBT was:– Generally well-tolerated– Effective at 48 wks, with 52% and 40% of subjects achieving

HIV-1 RNA < 400 copies/mL and < 48 copies/mL, respectively• Virological failure was associated with non adherence

and was more frequent in adolescents (Cohort 4)• Enrolment is continuing with collection of additional

data, including OBT resistance, out to 5 years


Acknowledgments

• We would like to thank all study participants, care-givers, DMC members, and investigators

• This ongoing study is being conducted by Pfizer Inc and is funded by ViiV Healthcare

• Editorial support was provided by Complete Medical Communications and was funded by ViiV Healthcare


Documents

Safety and efficacy of maraviroc in CCR5-tropic HIV-1-infected children aged 2 to