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Future Applications of Antiretroviral Agents in Development

Future Applications of Antiretroviral Agents in Development. Kathleen E. Squires, MD Professor of Medicine and Director Division of Infectious Diseases Jefferson Medical College Philadelphia, PA. Ideal Characteristics Improve convenience Improve tolerability Reduce toxicity

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Future Applications of Antiretroviral Agents in Development

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  1. Future Applications of Antiretroviral Agents in Development Kathleen E. Squires, MD Professor of Medicine and Director Division of Infectious Diseases Jefferson Medical College Philadelphia, PA

  2. Ideal Characteristics Improve convenience Improve tolerability Reduce toxicity Improve activity Wild-type virus Resistant virus Penetrate reservoirs Exploit new targets Antiretroviral Drug Development Issues to Address Current Limitations • Adherence • Toxicity • Activity • Resistance

  3. Novel Agents in Clinical Development

  4. New Generation NNRTIs Etravirine (TMC125) • Novel NNRTI designed to have a high genetic barrier to development of resistance[1] • Potent in vitro antiviral activity against: • Wild-type and NNRTI resistant HIV-1[2] • Clinical isolates resistant against approved NNRTIs[2] • In a 7-day clinical trial, TMC125 monotherapy produced a median viral load change of –0.89 log10 copies/mL in patients on failing NNRTI therapy[3] • DUET 1 and 2 studies ongoing: etravirine vs placebo, with DRV/r and OBR in patients with both NNRTI and PI resistance • Expanded access just opened 1Vingerhoets J, et al. J Virol 2005 Oct;79(20):12773-12782. 2Andries K, et al. Antimicrob Agents Chemother 2004 Dec;48(12):4680–4686. 3Gazzard BG, et al. AIDS 2003 Dec 5;17(18):F49–F54.

  5. Active control* TMC125 400 mg BID + OBR† N = 199 TMC125 800 mg BID + OBR† 4 weeks 48 weeks Treatment Screening TMC125-C223Study Design • Primary Objective: • Proportion of patients with ≥ 1 log10 reduction in HIV RNA from baseline to Week 24 *Active control: best available regimen from licensed agents †Optimized background regimen: investigator selected NRTIs ± LPV/r ± T-20 Cohen C, et al. 12th Annual Conference of BHIVA; Mar 29-Apr 1, 2006; Brighton, UK. Abstract P2.

  6. 800 mg BID(n = 79) Active control (n = 40) 400 mg BID(n = 80) P < .001 23% P < .001 <50 copies/mL 22% 0% P = .036 28% P = .009 <400 copies/mL 30% 8% P = .016 31% ≥1 log reduction in HIV RNA P = .004 34% 8% 0 20 40 60 80 100 Percentage with response P-values versus active control * Time-to-Loss of Virologic Response (TLOVR) TMC125, Phase IIb formulation TF035 TMC125-C223Virologic Response* at Week 48 Cohen C, et al, XVI International AIDS Conference; Aug 13-18, 2006; Toronto, Canada. Abstract TUPE0061.

  7. TMC125 800 mgBID Baseline NNRTI mutations in TMC125 800 mg BID Activecontrol 3 0* 1 2 0 n = 30 n = 79 n = 40 n = 14 n = 19 n = 16 –0.14 –0.5 –0.54 –0.9 –1.0 Mean change in log10 VL –1.01 –1.38 –1.5 –1.67 –2.0 TMC125-C223Number of NNRTI Mutations and Virologic Response at Week 48 • Patients discontinuing the trial for any reason had their VL response imputed as no change from baseline (NC = F) *All patients had NNRTI mutations from prior genotyping Cohen C, et al. XVI International AIDS Conference; Aug 13-18, 2006; Toronto, Canada. Abstract TUPE0061. TMC125, Phase IIb formulation TF035

  8. Baseline NNRTI Mutations Associated With TMC125 FC >10 (Arbitrary Threshold) • No single NNRTI mutation was associated with mean FC >10 (arbitrary threshold) to TMC125 • Frequency of combinations of NNRTI mutations associated with mean TMC125 FC >10 was low (12%) • Each of the following mutations, always in combination with up to four other mutations, were associated with mean FC >10 • K101P, V179E, V179F, Y181I, Y181V, G190S, M230L • For V179E, V179F, G190S, M230L: additional mutations always included Y181C when FC >10 • These mutations were previously identified in vitro to be associated with increased FC to TMC125 TMC125, Phase IIb formulation TF035 1. Cohen C, et al. XVI International AIDS Conference; Aug 13-18, 2006; Toronto, Canada. Abstract TUPE0061. 2. Vingerhoets J ,et al. J Virol. 2005 Oct;79(20):12773-82.

  9. Attachment Inhibitors, Coreceptor Antagonists Fusion Inhibitor NRTIs, NNRTIs Targets for Antiretroviral Therapy EntryInhibitors PIs Reverse Transcriptase Inhibitors Integrase Inhibitors Protease Inhibitors Maturation Inhibitors

  10. HIV Entry Inhibitors • New class of therapy • Works early in life cycle of the HIV virus • Inhibits fusion of viral particle with cell • Subcutaneous injection • Potent antiviral, but need other active antivirals for best effect • Injection site reactions

  11. 48-week phase II study 3-class experienced (n=82) Treatment arms OBR vs. TNX-355 + OBR 15 mg/kg IV q2wks 10 mg/kg IV qwk x 8 wks, then 10 mg/kg q2wks CD4 response: OBR: +5 cells/mm3 10 mg/kg: +9 cells/mm3 15 mg/kg: +51 cells/mm3 Well tolerated, no serious ADR related to drug, no ISRs Results sustained to Wk 48 TNX-355 + OBR OBR Alone 15 mg/kg 10 mg/kg 0 -0.20 -0.4 Mean Change in HIV-1 RNA at Week 24 (log10 copies/mL) -0.8 -0.95(P = .003) -1.2 -1.16(P < .001) Phase II Study of TNX-355A Novel Entry Inhibitor Norris D, et al. 45th ICAAC. Washington, DC, 2005. Abstract LB2-26 Tanox Inc. News Release May 2, 2006.

  12. HIV Tropism and Disease Progression CXCR4-tropic HIV ↑ X4 R5 Mixed/Dual Dual-tropic HIV CD4 Cell Count Limit of tropism assay detection* Amount of Virus CCR5-tropic HIV Time * Less than 10% of a tropism is not detectable with current tropism assay Courtesy GSK interactive CD "Exploring an allosteric world: CCR5 entry inhibitors and HIV"

  13. 0 -0.5 Median VL Change From BL (log10 copies/mL) 100 mg BID Placebo 15 150 mg Fast Placebo 07 -1.0 150 mg Fed 25 mg QD 50 mg BID 300 mg QD 100 mg QD 300 mg BID -1.5 Dosing -2.0 0 5 10 15 20 25 30 35 40 Days CCR5 Inhibitors in Development Maraviroc • Randomization of 80 HIV infected patients with CCR5 tropic virus • CD4 >250 cells/mm3 • VL >5000 copies/mL 0.5 • Doses >100mg/d had > 1.0 log10 decrease • Small  CD4 count with all doses • 61/63 had CCR5 tropic virus at BL remained CCR5 tropic at follow up • 1 reverted to CCR5 topic at day 40 • 1 persisted >6 mo post study with no evidence of clinical progression Fatkenheuer G et al. XV IAC. Bangcock, Thailand. Abstract TuPeB4489

  14. OBT* + MARAVIROC (150 mg** BID) Screening and randomization OBT* + MARAVIROC (150 mg** QD) OBT* + Placebo 4-6 Weeks 0 48 Weeks 24 Primary efficacyendpoint Phase IIb Pilot Study Evaluating the Safety of Maraviroc in Patients with Non-R5 HIV-1 • Randomized, double-blind, placebo-controlled study • Selection criteria: • D/M-tropic, X4-tropic or indeterminate tropism phenotype • Antiretroviral experienced and/or multi-class resistance • At least one active drug in OBT *OBT = 3 to 6 ARVs (note PK boosting doses of RTV will not be counted as an ARV) **150 mg maraviroc with PIs provides equivalent dose to 300 mg without PIs

  15. Maraviroc: Efficacy Results OBT -optimized background therapy D/M - dual/mixed tropic *Primary endpoint **LOCF Mayer H, et al IAC 2006. Abstract THLB0215.

  16. On the HorizonIntegrase Inhibitors • Integrase inhibitors • MK-0518 • GS 9137

  17. Integrase Inhibitor (MK-0518)Phase IIa 10-Day Dosing Study • Phase IIa, placebo-controlled, monotherapy study • 35 treatment-naïve patients • Baseline HIV RNA • 4.53 to 4.97 log10 copies/mL • MK-0518 • Doses: 100, 200, 400, 600 mg bid • At day 10 • HIV RNA <400 copies/mL: >50% • No significant change in CD4 cell count from baseline • Most common adverse events • Headache, fatigue, and dizziness Morales-Ramirez JO, et al. EACS 2005. Abstract LBPS1/6.

  18. MK-0518: Phase IIb (Protocol 005) N=167 VL ≥ 5000 CD4 ≥ 50 Resistant to ≥ 1 NRTI, NNRTI, PI • Multicenter, randomized, double blind MK-0518 600mg bid + OBR N = 42 Placebo + OBR N = 43 MK-0518 400mg bid + OBR N = 42 MK-0518 200mg bid + OBR N = 40 • Mean VL: 4.6-4.8 log10 copies/mL • Use of ENF in OBR: 33% to 38% • Patients with no active PIs in OBR: 84% to 98% • Mean CD4: 220-283 cells/mm3 • Treatment arms similar at baseline • Mean duration of HAART: 9-11 yrs Grinsztejn B, et al. 13th CROI. Denver, 2006. Abstract 159LB.

  19. MK-0518Virologic Suppression Through Week 16 Grinsztejn B, et al. 13th CROI. Denver, 2006. Abstract 159LB.

  20. MK-0518: Adverse Events • ADRs: similar to placebo • Most common ADR • Diarrhea, nausea, fatigue, ISRs, headache, pruritus • Occurring in >5% of 2 patients per arm Grinsztejn B, et al. 13th CROI. Denver, 2006. Abstract 159LB.

  21. MK-0518: Study DesignPotent Activity of Integrase Inhibitor in Treatment-Naive Patients Part I Design • 8 patients each received MK-0518 at 600, 400, 200, or 100 mg bid or placebo for 10 days monotherapy • 30 patients in addition each received one of the MK-0518 doses plus TFV+3TC, or efavirenz plus TFV+3TC, for a total of 38 patients in each arm Part II Design • Part I patients continued at same dose in Part II ~150 additional patients randomized for Part II Endpoints • HIV RNA and CD4 counts

  22. MK-0518 vs EfavirenzHIV RNA < 50 copies/mL at Week 24 (NC = F) Markowitz M, et al. IAC 2006. Abstract THLB0214.

  23. Integrase Inhibitor (GS 9137)10-Day Monotherapy Study • Phase IIb, placebo-controlled, monotherapy study • 40 treatment-naïve and treatment-experienced patients • Baseline • HIV RNA: 4.75 log10 copies/mL • CD4: 442 cells/mm3 • At day 10 • >1 log10 reduction in HIV RNA • GS-9137: 83% • Placebo: 0% • No serious adverse events and no study drug discontinuations • Most common adverse events • Fatigue, diarrhea, headache, nausea *P<0.01 versus placebo. †P<0.05 versus 800 mg qd. DeJesus E, et al. 13th CROI. Denver, 2006. Abstract 160LB.

  24. Maturation InhibitorPA-457 • First maturation inhibitor • Data from a double blind, placebo controlled single dose study of 75mg, 150mg and 250mg and placebo (all n=6); naïve or of-treatment for >4 weeks; two subjects had MDR • Dose related response with median reduction at the highest dose of -0.51 log10 and a greatest decline of -0.73 log10. 8/12 in higher doses >0.3 log10 • Return to baseline was inhibited for at least 20 days in the 250mg dose arm Martin D, et al. CROI 2005. Abstract 159.

  25. Change in HIV RNA at Day 11 0.046 -0.174 Log10 Copies/mL -0.483 -1.05 25 50 100 200 PA-457 mg qd Maturation Inhibitor (PA-457)Phase II Dosing Study • Phase II, placebo-controlled, monotherapy study • 32 treatment-naïve patients • Baseline • HIV RNA: 4.73 log10 copies/mL • CD4: 441 cells/mm3 • Oral doses of PA-457 • 25, 50, 100, 200 mg qd • At day 11 • AUC and trough levels were significantly associated with antiviral response (P<0.01) Smith P, et al. 13th CROI. Denver, 2006. Abstract 52.

  26. New Antiretroviral AgentsConclusions • Newer drugs are needed to improve convenience, tolerability and activity (wild-type and resistant virus) • Promising agents are in development both in existing classes (NNRTI, PI) and new classes (e.g, entry and integrase inhibitors) • Further basic and clinical research is needed

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