Safety and efficacy of etravirine in HIV-1-infected, treatment-experienced children

and adolescents: PIANO 48-week results

Gareth Tudor-Williams,1 Pedro Cahn,2 Kulkanya Chokephaibulkit,3 Jan Fourie,4 Christos Karatzios,5 Stephanie Dincq,6 Thomas Kakuda,7

Steven Nijs,6 Lotke Tambuyzer,6 Frank Tomaka7

1Imperial College, London, UK; 2Fundación Huesped, Buenos Aires, Argentina; 3Mahidol University, Bangkok, Thailand; 4Dr Jan Fourie Medical Practice, Dundee, KZN, South Africa; 5McGill University Health Centre, Montréal, Canada; 6Janssen Infectious Diseases BVBA, Beerse, Belgium; 7Janssen

Research & Development, LLC, Titusville, NJ, USA

Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

Pediatric study of Intelence as An

NNRTI Option (PIANO)

Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

Background

The efficacy and safety of the NNRTI etravirine (ETR, TMC125) has been demonstrated in the Phase III DUET trials in treatment-experienced, HIV-1-infected adult patients1–4

In pediatric patients, there is a need for additional antiretrovirals (ARVs) with unique resistance characteristics and with appropriate dose and formulations

Week 24 results of the PIANO (TMC125-C213; NCT00665847) trial showed that ETR 5.2mg/kg bid (maximum dose 200mg bid) demonstrated safety and efficacy in HIV-1-infected, treatment-experienced children and adolescents aged 6 to <18 years5

Safety, efficacy and pharmacokinetic results from the Week 48 analysis are presented 1. Madruga J, et al. Lancet 2007;370:29–38

2. Lazzarin A, et al. Lancet 2007;370:39–48 3. Katlama C, et al. AIDS 2009;23:2289–300

4. Katalama C, et al. Antiviral Ther 2010;15:1045–52 5. Tudor-Williams G, et al. 6th IAS 2011. Abstract TULBPE027

Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

Week 48 pooled DUET Phase IIIdata in adults1

0 2 4 8 12 16 20 24 32 40 48

61%

40%

p<0.0001*

100

90

80

70

60

50

40

30

20

10

0

Time (weeks)

Placebo + BR (n=604)

ETR + BR (n=599)

+98

+73

p=0.0006†

150

125

100

75

50

25

0

–25

0 2 4 8 12 16 20 24 32 40 48

Time (weeks)

Placebo + BR (n=604)

ETR + BR (n=599)

>90% of patients undetectable at 24 weeks were still undetectable at 48 weeks

Responders (% VL <50 c/mL; ITT-TLOVR) Mean change in CD4 cell count (ITT NC=F)

1. Katlama C, et al. AIDS 2009;23:2289–300 *Logistic regression model; †ANCOVA model

Res

pond

ers

(%)

± 95

% C

I

Mea

n ch

ange

in C

D4

cell

coun

tfr

om b

ase

line

(cel

l/mm

3)

± S

E

PIANO: trial design Phase II, open-label, single-arm trial in HIV-1-infected, treatment-experienced children

(6 to <12 years) and adolescents (12 to <18 years)

ETR 5.2mg/kg bid(maximum 200mg bid) + OBR

OBR = ritonavir-boosted PI plus N(t)RTIs and

optional enfuvirtide and/or raltegravir

Primary objective: safety and tolerability over 24 weeks

Screening6 weeks 48-week treatment period

Follow-up4 weeks

Week 24 primary analysis

Target 100 pediatric patients with

screening viral load ≥ 500 copies/mL

Week 48 analysis

Patients with evidence of ETR resistance (virco®TYPE HIV-1) were excluded The trial was not powered to make statistical comparisons between children and

adolescents

Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204OBR = optimized background regimen

Patient disposition

Children (6 to <12 years)

(n=41)

Adolescents (12 to <18 years)

(n=60)All patients

(N=101)

Screened, n 72 106 178

Treated, n 41 60 101

Completed, n (%) 34 (83) 42 (70) 76 (75)

Discontinued, n (%) 7 (17) 18 (30) 25 (25)

AE/HIV related 2 (5) 6 (10) 8 (8)

Non-compliance 3 (7) 5 (8) 8 (8)

Virologic failure 2 (5) 2 (3) 4 (4)

Other reasons 0 5 (8) 5 (5)

76 patients (75%) completed the trial, i.e. received ETR treatment for 48 weeks; most discontinuations were for adverse events (AEs) or trial non-compliance

Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

Baseline demographics

Parameter

Children (6 to <12

years) (n=41)

Adolescents (12 to <18

years) (n=60)All patients

(N=101)

Age, years, median (range) 10 (6–11) 15 (12–17) 12 (6–17)

Weight, kg, median (range) 27.0 (19–42) 51.8 (26–80) 39.0 (19–80)

Female, n (%) 27 (66) 37 (62) 64 (63)

Race, n (%)*

White 20 (50) 29 (49) 49 (49)

Black/African American 16 (40) 14 (24) 30 (30)

Asian 4 (10) 16 (27) 20 (20)

Country, n (%)

Thailand 4 (10) 16 (27) 20 (20)

Argentina 9 (22) 6 (10) 15 (15)

USA 3 (7) 12 (20) 15 (15)

South Africa 8 (20) 2 (3) 10 (10)

Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

*Race information not available for one child and one adolescent

Baseline disease characteristics

Parameter

Children (6 to <12

years) (n=41)

Adolescents (12 to <18

years) (n=60)All patients

(N=101)

Viral load, log10 copies/mL, median (range)†

3.6 (2–7) 4.0 (2–6) 3.9 (2–7)

CD4 cell count, cells/mm3, median (range)†

443 (39–1441) 356 (7–1345) 385 (7–1441)

Previous NNRTI use, n (%)

None 14 (34) 11 (18) 25 (25)

Efavirenz (EFV) 10 (24) 34 (57) 44 (44)

Nevirapine (NVP) 18 (44) 22 (37) 40 (40)

EFV or NVP 26 (63) 42 (70) 68 (67)

EFV and NVP 1 (2) 7 (12) 8 (8)

Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

†Actual value at the start of ETR treatment; if this value was missing, it was imputed with the screening value

Overview of adverse events

Children (6 to <12 years)

(n=41)

Adolescents (12 to <18 years)

(n=60)All patients

(N=101)

Treatment duration, weeks, median (range) 48.3 (1–96) 49 (1–97) 48.9 (1–97)

Any serious AE, n (%) 0 5 (8) 5 (5)

Any grade 3 or 4 AE*, n (%) 6 (15) 8 (13) 14 (14)

AEs leading to discontinuation, n (%) 2 (5) 6 (10) 8 (8)

Rash/maculo-papular rash 1 (2) 3 (5) 4 (4)†

Pregnancy 0 2 (3) 2 (2)

Drug resistance 0 1 (2) 1 (1)

Hypersensitivity 1 (2) 0 1 (1)

No deaths were reported

*Only two patients (both children) reported grade 4 AEs (thrombocytopenia) and three patients had a grade 3 AE considered at least possibly related to ETR (two children: one with rash maculo-papular and one with hypersensitivity; one adolescent with diarrhea); †Two patients discontinued due to a grade 2 rash (2%) and two due to a grade 3 rash (2%)

Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

Most common adverse events

AE, n (%)

Children (6 to <12 years)

(n=41)

Adolescents (12 to <18 years)

(n=60)All patients

(N=101)

Regardless of severity or causality*

Upper respiratory tract infection

10 (24) 17 (28) 27 (27)

Any rash† 6 (15) 17 (28) 23 (23)

Diarrhea 5 (12) 11 (18) 16 (16)

Cough 5 (12) 8 (13) 13 (13)

Vomiting 4 (10) 7 (12) 11 (11)

Nausea 3 (7) 7 (12) 10 (10)

At least possibly related to ETR (≥grade 2)‡

Any rash† 3 (7) 10 (17) 13 (13)

Diarrhea 0 3 (5) 3 (3)

*Occurring in ≥10% of patients overall; †grouped term including rash (not further specified), rash maculo-papular, rash generalized, rash erythematous, rash macular, rash papular, and rash pruritic; ‡occurring in ≥2% of patients overall. No cases of Stevens-Johnson Syndrome.

Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

Grade 3 or 4 treatment-emergent laboratory abnormalities

There were no consistent or clinically relevant changes in lipid parameters over time

AE, n (%)

Children (6 to <12 years)

(n=41)

Adolescents (12 to <18 years)

(n=60)All patients

(N=101)

Prolonged plasma PT 1 (2) 2 (3) 3 (3)

Decreased neutrophil count 1 (2) 2 (3) 3 (3)

Hyperbilirubinemia 0 2 (3) 2 (2)

Increased LDL-cholesterol* 0 1 (2) 1 (1)

Increased triglycerides* 0 0 0

Increased total cholesterol* 0 0 0

Decreased platelet count 1 (2) 0 1 (1)

Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

*Fasted values; LDL = low-density lipoprotein; PT = prothrombin time

0

10

20

30

40

50

60

70

80

90

100

<400 c/mL <50 c/mL

Children (n=41) Adolescents (n=60) All patients (N=101)

68%

48%

56%

28/41 29/60 57/101Pa

tien

ts w

ith H

IV-1

RN

A <

50

or

<4

00

co

pie

s/m

L a

t W

ee

k 4

8,

%

Overall, more than half of patients achieved viral load <50 HIV-1 RNA copies/mL response was similar at Week 48 compared to Week 24

Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

67%

68/101

Proportion of patients with viral load <50 or <400 HIV-1 RNA copies/mL at Week 48 (NC=F)

76%

62%

31/41 37/60

0 2 4 8 12 16 24 32 40 48

90

80

70

60

50

30

20

10

0

40

100

Children (6 to <12 years) (n=41)

Adolescents (12 to <18 years) (n=60)

All patients (N=101)

Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

Proportion of patients with viral load <50 HIV-1 RNA copies/mL over 48 weeks (ITT-TLOVR)

Time (weeks)

Res

pond

ers

(%)

± 95

% C

I

Children (6 to <12 years) (n=41)

Adolescents (12 to <18 years) (n=60)

All patients (N=101)

Mea

n (9

5% C

I) c

han

ge

from

ba

selin

e in

CD

4 ce

ll co

unt,

cel

ls/m

m3

0 2 4 8 12 16 24 32 40 48

Time (Weeks)

0

50

100

150

200

250

Change in CD4 cell count (NC=F)

Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

+178+156+141

Adherence to ETR

Pro

por

tion

of p

atie

nts,

%

46%

35%39%

17/37 18/52 35/89 27/39 35/57 62/96

69%61%

65%

Adherence was measured either by pill count ([actual amount taken / amount to be taken] x 100%) and questionnaire (‘have any doses been missed over the last 3 days?’)

Self-reported adherence was higher than adherence estimated by pill count

Adherence by pill count is an independent predictor of virologic response as determined by an exploratory multivariate logistic regression model

Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

Virologic failure and resistance

Children (6 to <12 years)

(n=41)

Adolescents (12 to <18 years)

(n=60)All patients

(N=101)

Virologic failure, n (%) 11 (27) 30 (50) 41 (41)

Non-responder 8 (20) 21 (35) 29 (29)

Rebounder 3 (7) 9 (15) 12 (12)

Most frequent treatment-emergent NNRTI RAMs at endpoint*

VFs with endpoint genotypic data, n

7 23 30

Any emerging NNRTI RAM, n† 3 15 18

Y181C 1 7 8

V90I 1 2 3

L100I 0 3 3

E138A 2 1 3

*Observed in at least three patients; †Y181C, V90I, L100I, and E138A are known ETR resistance-associated mutations (RAMs); endpoint = the last available on-treatment time point with a genotype after failure

Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

Tambuyzer L, et al. Antivir Ther 2012;17 Suppl 1: A58. Abstract 47

Box plots of AUC12h and C0h

AUC12h = area under the plasma concentration-time curve over 12 hours at steady-state and C0h = predose plasma concentration, both derived using population pharmacokinetic model

Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

Reference line indicates median AUC12h or median C0h, respectively, in adults in the DUET studies1

1. Kakuda TN et al. Clin Pharmacol Ther 2010;88:695–703

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1,000

100

1,000

100

10

1Children

n=41Adolescents

n=60AdultsN=575

C0

h (

ng/m

L)

AU

C1

2h (

ng•h

/mL)

100,000 10,000

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Childrenn=41

Adolescentsn=60

AdultsN=575

Conclusions ETR 5.2mg/kg bid (maximum dose 200mg bid)

demonstrated safety and efficacy in this treatment-experienced population of HIV-1-infected children and adolescents aged 6 to <18 years

While the trial was not designed for comparison between children and adolescents, there were numerically higher virologic responses in children than adolescents

– most likely due to less advanced disease, better adherence and less NNRTI use prior to treatment with ETR in children vs adolescents

There is an ongoing program evaluating the efficacy and safety of ETR in younger treatment-experienced children (IMPAACT; NCT01504841)

Tudor-Williams G, et al. XIX IAC 2012. Abstract TUAB0204

Acknowledgements We would like to express gratitude to

– the patients who participated in this trial and their families, the investigators and the trial centre staff

– Janssen R&D team members, in particular M Opsomer, J Verspeelt, A Vandingenen, J Vingerhoets and F Blancke, and for their input into this presentation, D Anderson, G De La Rosa, B Hadacek and E Wong

This trial was sponsored by Janssen R&D Ireland

Medical writing support was provided by I Woolveridge of Gardiner-Caldwell Communications, Macclesfield, UK; this support was funded by Janssen.

The authors have the following conflicts of interest to declare: GTW has served as chair or member of the Data Safety and Monitoring Board for GlaxoSmithKline (GSK) and Bristol-Myers Squibb (BMS), and as an advisory board member for ViiV Healthcare, and received funding for travel and accommodation from Janssen; PC has served as an advisory board member for Avexa, Gilead Sciences and Merck, Myriad, Pfizer, Pharmasset, Schering-Plough and Janssen, as an investigator for Abbott Laboratories, Avexa, Boehringer Ingelheim (BI), BMS, Gilead Sciences, GSK, Roche, Merck, Pfizer, Pharmasset, Schering-Plough and Janssen, as a speaker for Abbott Laboratories, BMS, BI, GSK, Merck, Pfizer and Janssen, and as a scientific advisor for Avexa, GSK, Merck Sharp & Dohme, Pfizer and Janssen; CK has served as a paid lecturer for Abbott Laboratories (2008–2009) and as a media representative for Janssen upon the approval and launch of darunavir in 2009; SD, SN, LT, TNK and FT are full time employees of Janssen. KC and JF declare they have no conflicts of interest.