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INTELENCE (Etravirine) UPDATE

INTELENCE (Etravirine) UPDATE. Rekha Sinha, MD January 30, 2009. Global Clinical Research. Overview of Presentation. Etravirine (ETR) Safety and Tolerability - Pooled Data from Phase III Trials - Short-term safety in Pediatric Population Planned Trials with Etravirine

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INTELENCE (Etravirine) UPDATE

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  1. INTELENCE (Etravirine) UPDATE Rekha Sinha, MD January 30, 2009 Global Clinical Research

  2. 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

  3. Clinical Data: Previous Human Experience Phase I (57 trials) Total N=1167 (healthy) 96 (HIV-1 infected) • Additional ongoing trials • Worldwide Expanded Access and CU • (9000) • DUET rollover trial (N - 300) • -------------------Pediatric StudyPhase I completed • N= 41 • Phase II ongoing • N= 100 Phase IIa (POP) 3 trials Total N=48 Phase IIb 6 trials Total N= 442 Phase III (Pivotal) DUET: 2 trials (C206 and C216) Total N=599 FDA approval January 2008 NDA 2007

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

  5. Screening 6 weeks Follow up 4 weeks 600 patients target per trial Design and Major Inclusion Criteria 48-week treatment period with optional 48-week extension • 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 24-week primary analysis TMC125 + BR* Placebo + BR* *BR = darunavir/ritonavir with optimized NRTIs and optional enfuvirtide *From extended list of 41 NNRTI RAMs (Tambuyzer et al. Abstract 67 EHDRW 2007); BR = background regimen; RAM = resistance-associated mutation

  6. 0 2 4 8 12 16 20 24 32 40 48 Response (<50 copies/mL) at Week 48 (ITT-TLOVR) • 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) Placebo + BR (n=604) ETR + BR (n=599) 100 90 80 70 61% 60 p<0.0001 Patients with viral load <50 copies/mL at Week 48 (%)(± 95% CIs) 50 40% 40 30 20 10 0 Time (weeks) 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., 15th CROI 2008. Abstract 791

  7. Overview of AEs (regardless of causality) • 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., 15th CROI 2008. Abstract 791

  8. Rash (1) 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

  9. Nervous system* & Psychiatric disorders *Selected based on the nervous system events commonly associated with approved NNRTIs. • 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

  10. Hepatic AEs and laboratory abnormalities Hepatic disorders: similar incidence to placebo, low severity, infrequently led to discontinuation ALT = alanine aminotransferase; AST = aspartate aminotransferase.

  11. 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

  12. Safety in Pediatric population • Phase I trial in children (6-17 years)

  13. 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 Stage II 20 subjects (10/Group) Dose: 5.2 mg/kg b.i.d Interim analysis Stable ARV: LPV/rtv and a minimum of 2 NRTIs +/- ENF

  14. Most Common AEs *10.0% in TMC125 group

  15. 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 on5.2 mg/kg b.i.d.

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

  17. 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

  18. 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

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

  20. ETR Resistance

  21. Table 1. Overview ofthe NNRTI mutations No. of patientswithmutation at baseline No. ofpatientswith <50 cps/mLat Week 24 Response rate (<50 cps/mL) in pooledDUET (%) ETR FC insingle SDM Mutation V90I 22 11 50.0 1.5 A98G 59 29 49.2 2.5 A98S 38 26 68.4 0.4 • 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) L100I 34 18 52.9 1.8 K101E 53 24 45.3 1.7 K101H 26 11 42.3 1.3 K101P 9 4 44.4 6.2 K101Q 35 20 57.1 3.4 K101R 5 3 60.0 0.7 K103N 118 82 69.5 0.7 K103R 9 2 22.2 0.8 K103S 16 12 75.0 0.9 V106I 24 9 37.5 NA V108I 66 42 63.6 0.5 E138A 12 6 50.0 2.0 E138Q 10 8 80.0 5.1 V179D 5 2 40.0 2.6 V179F 7 1 14.3 0.1 V179I 97 60 61.9 0.8 V179T 8 3 37.5 0.8 Y181C 110 50 45.5 3.9 Y181I 8 4 50.0 12.5 Y181V 6 2 33.3 17.4 Y188L 32 24 75.0 0.9 V189I 24 13 54.2 0.8 ETR RAMs 2008 G190A 115 58 50.4 0.8 G190S 14 3 21.4 0.2 Response rate below threshold (<51.9%) H221Y 35 23 65.7 2.5 P225H 5 3 60.0 1 ETR FC >3.0 F227L 20 13 65.0 0.4 M230L 4 2 50.0 3.4 K238T 10 9 90.0 2.4 Y318F 13 10 76.9 1.4 N348I 60 35 58.3 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

  22. Figure 1. Effect of the ETR RAMs 2008(n=17) on virologic response 80 70 60 75% of response in patients without NNRTI RAMs 50 Patients with confirmed VL HIV-1 RNA <50 copies/mL (%) 40 30 20 10 7 52 34 115 22 12 8 4 59 110 53 9 26 5 24 8 6 14 52 34 115 22 12 8 4 59 110 53 9 26 5 24 8 6 14 7 0 V90l L100l Y181l A98G V106l V179T Y181V Y181C K101E K101P V179D V179F G190S G190A M230L E138A K101H *No mutation *No detectable baseline NNRTI RAM from the list of 44; Mutations in the ETR RAM list of 2008 but not 2007 are underlined

  23. Etravirine Weighted Genotype Score to Predict Response ETR FC in the subset of HIV-1 clinical isolates with 1 ETR RAM (n=1,619), regardless of the Prevalence (%) presence of other NRTI or in the panel of Effect on FC ETR FC in NNRTI RAMs* 4,248 HIV-1 in linear Weight a single Median Q1–Q3 n SDM Mutation clinical isolates model factor Y181I 1.5 42.0 34 12.5 High 3 23.2–129.7 Y181V 0.9 10.4 28 17.4 High 3 3.9–60.6 K101P 2.6 22.3 65 6.2 High 2.5 5.6–42.9 L100I 8.4 6.7 264 1.8 Medium 2.5 2.7–17 Y181C 32.0 4.4 552 3.9 Medium 2.5 2.1–11.6 M230L 1.1 4.3 20 3.4 High 2.5 2.7–10.5 E138A 2.5 2.9 44 2.0 Medium 1.5 1.4–10.6 V106I 4.4 2.6 63 NA Low 1.5 1.4–5.2 G190S 3.7 0.8 32 0.2 Low 1.5 0.6–1.7 § V179F 0.7 – 0 0.1 Medium 1.5 – V90I 6.8 2.0 97 1.5 Low 1 0.8–3.6 V179D 2.1 1.7 33 2.6 Low 1 1.0–4.7 K101E 9.9 1.5 24 1.7 Low 1 0.8–2.5 K101H 2.2 1.1 8 1.3 Low 1 0.6–2.8 A98G 9.5 1.0 127 2.5 Low 1 0.5–1.9 V179T 0.6 0.9 2 0.8 Low 1 0.7–1.2 G190A 23.3 0.8 226 0.8 Low 1 0.5–1.5 *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)

  24. 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

  25. Hatched bars indicate virologic response for the entire category 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 Figure 6. Relation between the weighted score and the virologic response (<50 copies/mL) Highest response Intermediateresponse Reduced response Response category 74.4% 52.0% Patients with confirmed VL HIV-1 RNA <50 copies/mL (%) 37.7%  Weighted score for the 17 ETR RAMs 2008

  26. 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%) ·  

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