INTELENCE (Etravirine) UPDATE

Global Clinical Research Rekha Sinha, MD January 30, 2009

Overview of Presentation



Etravirine (ETR) Safety and Tolerability - Pooled Data from Phase III Trials - Short-term safety in Pediatric Population



Planned Trials with Etravirine



Etravirine Resistance

Clinical Data: Previous Human Experience

Phase I (57 trials)

Total N=1167 (healthy) 96 (HIV-1 infected )

Phase IIb

6 trials Total N= 442

Phase IIa (POP)

3 trials Total N=48

Phase III (Pivotal) DUET

: 2 trials (C206 and C216) Total N=599

NDA 2007 FDA approval January 2008 Additional ongoing trials

• Worldwide Expanded Access and CU (9000) • DUET rollover trial (N - 300) -------------------

Pediatric Study

Phase I completed N= 41 Phase II ongoing N= 100

ETR Safety and Tolerability: DUET Trials (TMC125-C206/C216)

Design and Major Inclusion Criteria

Screening 6 weeks 48-week treatment period with optional 48-week extension

24-week primary analysis

TMC125 + BR* Follow up 4 weeks 600 patients target per trial Placebo + BR*

*BR = darunavir/ritonavir with optimized NRTIs and optional enfuvirtide    DUET-1 and -2 differed only in geographical location; pooled analysis was pre-specified Major inclusion criteria: – – – Plasma viral load >5,000 HIV-1 RNA copies/mL and stable therapy for ≥8 weeks ≥1 NNRTI RAM*, at screening or in documented historical genotype ≥3 primary PI mutations at screening Patients recruited from Thailand, Australia, Europe and the Americas

*From extended list of 41 NNRTI RAMs (Tambuyzer et al. Abstract 67 EHDRW 2007); BR = background regimen; RAM = resistance-associated mutation

Response (<50 copies/mL) at Week 48 (ITT-TLOVR)

 100 90 80 70 60 50 40 30 20 10 0 0 2 4 ETR + BR (n=599) 8 12 16 20 24 32 Placebo + BR (n=604) 40

61% 40%

48 p<0.0001

Time (weeks) 61% of patients in the ETR group achieved a confirmed undetectable viral load (<50 copies/mL) compared with 40% in the placebo group (p<0.0001) ITT-TLOVR = intent-to-treat time-to-loss of virologic response; ETR = etravirine; BR = background regimen CIs = confidence intervals; p value from logistic regression model Modified from Johnson M et al., 15 th CROI 2008. Abstract 791

Overview of AEs (regardless of causality)

Parameter, %

Any AE (any cause) Grade 3 or 4 AE Serious AE Discontinuation due to AE Death (any cause)

Most common AEs

Rash (any type) Diarrhea

AEs of interest

Nausea Headache Nervous system disorders Psychiatric disorders Hepatic AEs

ETR + BR (n=599)

96 33 20 7 2 19 18 15 11 17 17 7

Placebo + BR (n=604)

96 35 23 6 3 11 24 13 13 20 20 6   There were no consistent or clinically relevant trends in laboratory, vital signs or ECG data The profile of laboratory abnormalities, including hepatic and lipid parameters, was generally similar between the ETR and placebo groups Johnson M et al., 15 th CROI 2008. Abstract 791

Rash (1)

Investigator assessment of cause of rash, %

Any cause

ETR group (n = 599)

19.2

Placebo group (n = 604)

10.9

Significance

P = 0.0001

 – – – –

In the ETR group early onset:

median 14 days

limited duration:

median 15 days

low severity:

mostly mild-to-moderate; 1.3% grade 3, no grade 4 ● mostly maculopapular; no mucosal involvement

infrequently led to permanent discontinuation:

2.2% of ETR group, 0% in placebo group ● mostly resolved with continued treatment

Rash with etravirine: usually mild-to-moderate and infrequently led to permanent discontinuation

Nervous system* & Psychiatric disorders

Most common Nervous system events (reported in ≥ 1.0% of patients in the ETR group) Headache 10.9

12.7

Dizziness Somnolence 3.2

1.8

4.3

2.3

*Selected based on the nervous system events commonly associated with approved NNRTIs.

Most common psychiatric events (reported in ≥ 1.0% of patients in the ETR group) Insomnia Depression Anxiety Sleep disorder 7.2

4.2

3.8

1.3

8.3

6.6

4.1

0.8

   No increased risk in patients with a history of psychiatric disorders Abnormal dreams/nightmares were similar in incidence to placebo (0.8% vs 1.0% for the ETR and Placebo groups respectively) No episodes of hallucinations, suicidal ideation, or manic symptoms in the ETR group

AEs: similar incidence to placebo, low severity, did not lead to discontinuation

Hepatic AEs and laboratory abnormalities

Hepatic AEs, %

Any cause or severity Grade 3/4 Leading to discontinuation Laboratory abnormalities ALT elevated (grade 3/4) AST elevated (grade 3/4)

ETR group (n = 599)

6.5

3.0

1.0

1.6/0.8

1.8/0.4

Placebo group (n = 604)

6.1

3.0

0.7

1.2/0.2

1.2/0.2

Hepatic disorders: similar incidence to placebo, low severity, infrequently led to discontinuation

ALT = alanine aminotransferase; AST = aspartate aminotransferase.

Safety conclusions

     Safety and tolerability of ETR were

generally comparable to placebo

, except for the incidence of rash (any type) Overall, most AEs were of low severity and

infrequently led to discontinuation Rash

, the only AE to occur more frequently with ETR – generally mild-to-moderate – – most often resolved with continuing treatment infrequently led to discontinuation Nature and incidence of

nervous system and psychiatric

AEs were similar to placebo ETR was not associated with any increase in laboratory abnormalities, including

hepatic

and

lipid

parameters

Safety in Pediatric population

•

Phase I trial in children (6-17 years)

TMC125-C126 Trial Design

40 treatment experienced children on a Stable ARV & Virologically suppressed



Group 1 6 to



12 years



Group 2 12 to



17 years Screening up to 28 days Treatment Phase 7 days Follow-up 1 month Stage I 20 subjects (10/Group) Dose: 4 mg/kg b.i.d

Interim analysis Stage II 20 subjects (10/Group) Dose: 5.2 mg/kg b.i.d

Stable ARV: LPV/rtv and a minimum of 2 NRTIs +/- ENF

Most Common AEs

AE regardless of causality*, N ( %) Infections and infestations

Rhinitis

TMC125-C126 Stage I Stage II N=21 4 (19.0)

2 (9.5)

N=21 3 (14.3)

2 (9.5)

Nervous system disorders

Headache

-------------------------------------------------------------- Gastrointestinal disorders

Diarrhoea Nausea

3 (14.3)

3 (14.3)

---------------------- 3 (14.3)

3 (14.3)

---------------------- 2 (9.5)

0 1 (4.8)

2 (9.5)

1 (4.8) 1 (4.8)

Skin and subcutaneous tissue disorders

Rash Rash maculopapular

2 (9.5)

1 (4.8) 1(4.8)

1 (4.8)

0 0

*



10.0% in TMC125 group

Conclusion

Based on the comparable exposures of TMC125 in children to that seen in adults from the DUET trials and the overall safety of TMC125 in Stage II of TMC125-C126 The recommended dose per weight band for children and adolescents aged between 6 and 17, inclusive, will be based on 5.2 mg/kg b.i.d.

Planned trials with ETR - New target population - New ARV regimen

ETR, RAL plus 3TC in HIV-infected Early Treatment-Experienced Patients

Phase IV Single arm open label design

Population:

First or Second line failure, VL > 500 c/mL, Sensitive to ETR, Naïve to integrase

N

= 50

ARV regimen:

ETR 200mg/ RAL 400mg/ lamivudine 150mg each b.i.d

Duration:

48 week study

Objective:

To assess the percentage of early treatment experienced HIV-infected patients that have achieved an HIV RNA <50 copies/mL at week 24

Study of Efavirenz Neuropsychiatric Symptoms versus Etravirine (SENSE)

Double blind, active controlled trial

Population:

Treatment naive, VL > 5000 cp/mL, sensitive to ETR and background regimen (2 NRTIs), no NNRTI resistance

N

= 150

ARV regimen:

ETR 400 mg q.d ( 4 ETR tablets 100 mg each) versus efavirenz 600 mg q.d

Duration:

48 week study

Objective:

To compare neuropsychiatric adverse event profile of ETR versus efavirenz in combination with 2 N(t)RTIs as assessed at Wk 12

ETR in a Nucleoside Sparing Regimen

Open label, active controlled trial

Population:

Treatment experienced, NNRTI resistant, VL > 500 cp/mL, sensitive to ETR and background regimen

N

= 520

ARV regimen:

N(t)RTIs ETR 200 mg b.i.d plus PI/rtv versus PI/rtv plus 2

Duration:

48 week study

Objective:

Efficacy of ETR given in a PI-containing N(t)RTI-sparing regimen in terms of the proportion of subjects achieving a plasma viral load < 50 HIV-1 RNA copies/mL at Week 24.

ETR Resistance

 

Table 1. Overview of the NNRTI mutations

The list of 44 NNRTI RAMs was expanded to 57 mutations by addition of all mutations at NNRTI resistance amino acid positions 17 NNRTI related mutations that blunt response to ETR identified based on the DUET analysis The frequency and virologic response in patients with the mutations at baseline is shown (if n  5), along with the ETR FC in a site-directed mutant (SDM)

ETR RAMs 2008 Response rate below threshold (<51.9%) ETR FC >3.0 Mutation

V90I A98G A98S L100I K101E K101H K101P K101Q K101R K103N K103R K103S V106I V108I E138A E138Q V179D V179F V179I V179T Y181C Y181I Y181V Y188L V189I G190A G190S H221Y P225H F227L M230L K238T Y318F N348I

No. of patients with mutation at baseline No. of patients with <50 cps/mL Response rate (<50 cps/mL) in pooled at Week 24 DUET (%)

50.0

49.2

68.4

52.9

45.3

42.3

44.4

57.1

60.0

69.5

22.2

75.0

37.5

63.6

50.0

80.0

40.0

14.3

61.9

37.5

45.5

50.0

33.3

75.0

54.2

50.4

21.4

65.7

60.0

65.0

50.0

90.0

76.9

58.3

11 29 26 18 24 11 4 20 3 82 2 12 9 42 6 8 2 1 60 3 50 4 2 24 13 58 3 23 3 13 2 9 10 35 22 59 38 34 53 26 9 35 5 118 9 16 24 66 12 10 5 7 97 8 110 8 6 32 24 115 14 35 5 20 4 10 13 60

ETR FC in single SDM

1.5

2.5

0.4

1.8

1.7

1.3

6.2

3.4

0.7

0.7

0.8

0.9

NA 0.5

2.0

5.1

2.6

0.1

0.8

0.8

3.9

12.5

17.4

0.9

0.8

0.8

0.2

2.5

1 0.4

3.4

2.4

1.4

NA The following mutations were present in <5 patients at baseline: K101N, K103H, K103T, V106A, V106M, E138G, E138K, V179A, V179E, V179G, Y181F, Y188C, Y188F, Y188H, G190C, G190E, G190Q, G190R, F227C, M230I, M230L, P236L, K238N and N348T

Figure 1. Effect of the ETR RAMs 2008 (n=17) on virologic response 80 70 60 50 40 30 20 10 0

75% of response in patients without NNRTI RAMs

*No detectable baseline NNRTI RAM from the list of 44; Mutations in the ETR RAM list of 2008 but not 2007 are underlined

Etravirine Weighted Genotype Score to Predict Response

Mutation

Y181I Y181V K101P L100I Y181C M230L E138A V106I G190S § V179F V90I V179D K101E K101H A98G V179T G190A

Prevalence (%) in the panel of 4,248 HIV-1 clinical isolates

1.5

0.9

2.6

8.4

32.0

1.1

2.5

4.4

3.7

0.7

6.8

2.1

9.9

2.2

9.5

0.6

23.3

42.0

10.4

22.3

6.7

4.4

4.3

2.9

2.6

0.8

– 2.0

1.7

1.5

1.1

1.0

0.9

0.8

ETR FC in the subset of HIV-1 clinical isolates with 1 ETR RAM (n=1,619), regardless of the presence of other NRTI or Median NNRTI RAMs* Q1 –Q3

23.2

–129.7

3.9

–60.6

5.6

– 42.9

2.7

–17 2.1

– 11.6

2.7

– 10.5

1.4

– 10.6

1.4

– 5.2

0.6

– 1.7

– 0.8

– 3.6

1.0

– 4.7

0.8

– 2.5

0.6

– 2.8

0.5

– 1.9

0.7

– 1.2

0.5

– 1.5

n

34 28 65 264 552 20 44 63 32 0 97 33 24 8 127 2 226

ETR FC in a single SDM Effect on FC in linear model

12.5

17.4

6.2

1.8

3.9

3.4

2.0

NA 0.2

0.1

1.5

2.6

1.7

1.3

2.5

0.8

0.8

High High High Medium Medium High Medium Low Low Medium Low Low Low Low Low Low Low

Weight factor

3 3 2.5

2.5

2.5

2.5

1.5

1.5

1.5

1.5

1 1 1 1 1 1 1 *Median (Q1 –Q3) FC for all isolates was 3.0 (1.1–9.3); § V179F was never present as single ETR RAM (always with Y181C)

Effect of ETR FC Increasing ETR FC was associated with a gradual loss in virological response

 CCOs as defined by Tibotec: FC = 3 and FC = 13 Modified from Peeters, M, et al. IHDRW 2008. Poster 121

Figure 6. Relation between the weighted score and the virologic response (<50 copies/mL) 100

Highest response Intermediate response Reduced response

Response category

80

74.4%

60 40 20 0

52.0% 37.7%

N 115/148 37/53 6/11 11/15 32/59 2/7 19/36 1/5 14/27 3/9 4/9 4/13 1/3 2/11

Weighted score for the 17 ETR RAMs 2008 Hatched bars indicate virologic response for the entire category

Understanding Etravirine Susceptibility

The virologic response is a function of the number and weight of the baseline ETR RAMs  Among the 17 ETR RAMs, Y181I and Y181V had the highest weight, followed by L100I, K101P, Y181C and M230L  Among the 17 ETR RAMs, mutations with the highest weight had a low prevalence Weighted mutation score of 0-2 Highest response rates (74%) Weighted mutation score of 2.5-3.5 Intermediate response rates (52%) Weighted mutation score of >/=4 Reduced response rates (74%) ·