1. Novel Classes of Antiretrovirals: Update on CCR5 Antagonists and Integrase Inhibitors This program is supported by an educational grant from

2. Clinical Data and Development of Agents in Novel Antiretroviral Classes Joseph J. Eron, Jr., MD University of North Carolina School of Medicine Chapel Hill, North Carolina

3. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors Development of Novel Antiretroviral Classes  Clinical steps in drug development  Clinical trial data on antiretrovirals in novel classes  Pharmacokinetic considerations with new agents

4. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors Clinical Steps in Drug Development  Phase I –Usually single dose then multiple doses in seronegative volunteers –Pharmacokinetics including bioavailability, dosing interval, food effects –Tolerability and toxicity—define maximum tolerated dose, sentinel side effects, target organ toxicity –Early drug-drug interactions –May be done in HIV-infected volunteers (phase I/II)  Phase IIa –Initial assessment of activity or proof-of-principle study –Several doses, short course of monotherapy or functional monotherapy –May include randomized dosing and control or may be dose escalating –PK, dose response, tolerability, and toxicity

5. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors Clinical Steps in Drug Development  Phase IIb –HIV-infected patients, longer-term dosing, almost always in combination with other agents –Usually several doses and a control arm –Longer-term tolerability and toxicity—important outcome –May be done in more than 1 target population (eg, treatment naive, highly treatment–experienced, etc)  Phase III –Typically the large randomized studies that are the centerpiece of submission for regulatory approval –Usually a single dose—blinded if possible –HIV-1 RNA response endpoint—now likely to be proportion with viral load below the limit of detection even in very experienced patients

6. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors Novel Antiretrovirals in Clinical Development TNX-355 CCR5 inhibitors CXCR4 inhibitors PA-457 MK-0518 GS-9137 Entry inhibitors Reverse transcriptase inhibitors Mature virus Protease inhibitors Integrase inhibitors

7. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors Current Status of Novel Agents in Clinical Development Novel AgentStage of Development Entry inhibitors MaravirocPhase III study in treatment-naive and treatment-experienced patients VicrivirocPhase IIB study in treatment-experienced patients AMD 070Phase IIa TNX-355Phase II study demonstrated activity in multiclass-experienced patients; phase III study planned Integrase inhibitors MK-0518Phase IIb; enrolling phase III GS-9137Phase IIa; starting phase IIb Maturation inhibitors PA-457Short-term activity in proof-of-principle phase IIa study Phase IIb study in treatment-experienced patients planned

8. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors Development of Novel Antiretroviral Classes  Clinical steps in drug development  Clinical trial data on antiretrovirals in novel classes  Pharmacokinetic considerations with new agents

9. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors HIV Entry Inhibitors  Possible Advantages –Work early in virus life cycle –Prevention or postexposure –Lack of cross-resistance with existing drug classes –Lack of “cellular resistance” –Typically cellular targets  Possible Disadvantages –Targets (such as gp120) may be highly variable –Inhibition of cellular targets may cause mechanism-related toxicity –Mode of delivery

10. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors TNX-355: Novel Entry Inhibitor  Anti-CD4 monoclonal Ab blocks HIV entry by binding CD4 receptor –Delivered by IV infusion  Phase II randomized trial in 82 triple-class–experienced patients [1] –TNX-355 + OBR or OBR alone –TNX-355 doses –15 mg/kg IV every 2 wks –10 mg/kg IV every wk x 8 wks, then 10 mg/kg every 2 wks  Active against R5- and X4-tropic HIV in vitro [2] 1. Norris D, et al. ICAAC 2005. Abstract LB2-26. 2. Godofsky E, et al. ICAAC 2005. Abstract LB26. -0.8 -0.4 0 -1.2 Mean Change in HIV-1 RNA at Week 24 (log 10 copies/mL) OBR Alone 15 mg/kg 10 mg/kg -0.20 -0.95 (P =.003) -1.16 (P <.001) TNX-355 + OBR

11. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors CCR5 Inhibitors in Development 1. Pozniak AL, et al. ICAAC 2003. Abstract H-443. 2. Schurmann D, et al. CROI 2004. Abstract 140LB. 300 mg BID 150 mg fast 150 mg fed -1.5 -0.5 0 0.5 Days Placebo 15 Placebo 07 25 mg QD 50 mg BID 100 mg QD 100 mg BID 300 mg QD Maraviroc (UK-427857) [1] Dosing Median VL Change From BL (log 10 copies/mL) 0510152025303540 -2.0 0.5 0 -0.5 -1.5 051015202530 Days Vicriviroc (SCH-417690) [2] Median VL Change From BL (log 10 copies/mL) 10 mg BID Placebo 25 mg BID 50 mg BID Dosing

12. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors CCR5 Inhibitors in Development  Maraviroc –Phase II → III studies in treatment-naive and treatment- experienced patients ongoing –Once-daily arm in treatment-naive patients stopped  Vicriviroc –Comparative study in treatment-naive patients stopped by DSMB due to decreased efficacy vs EFV-based therapy –Placebo-controlled, phase II study in treatment-experienced patients ongoing

13. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors CCR5 Inhibitor: Vicriviroc  Phase IIb, randomized, placebo-controlled trial Greaves W, et al. CROI 2006. Abstract 161LB Response After 14 Days of Monotherapy Median Change From Baseline, log 10 copies/mL Placebo (n = 24)-0.07 Vicriviroc 25 mg QD (n = 23)-0.83* Vicriviroc 50 mg QD (n = 22)-1.18* Vicriviroc 75 mg QD (n = 23)-1.34* *P <.001 vs placebo Treatment-naive subjects CCR5-tropic virus CD4+ > 150 cells/mm³ HIV-1 RNA ≥ 3000 copies/mL No baseline resistance to study drugs (N = 92) 2480 Placebo Vicriviroc 50 mg QD Vicriviroc 25 mg QD Vicriviroc 75 mg QD Add ZDV/3TC ZDV/3TC + EFV Week

14. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors Late Virologic Breakthrough With Vicriviroc Plus ZDV/3TC  Median follow-up: 31.8 weeks (1-53.8) –All patients with evaluable genotypes had M184V/I at breakthrough (22/22); 1 had M41L –No change in vicriviroc IC 50 with virologic breakthrough  DSMB ended this study Greaves W, et al. CROI 2006. Abstract 161LB Virologic Breakthrough by Study ArmHIV-1 RNA > 50 copies/mL, % P Value vs Control Efavirenz + zidovudine/lamivudine (n = 24)4-- Vicriviroc 25 mg + zidovudine/lamivudine (n = 23)56.001 Vicriviroc 50 mg + zidovudine/lamivudine (n = 22)41.003 Vicriviroc 75 mg + zidovudine/lamivudine (n = 23)17.188

15. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors CCR5 Inhibitors  Advances –One agent in phase II and one in phase III –Short-term activity clear –Intraclass cross-resistance may not be the “rule” –Likely synergy with entry inhibitors  Setbacks –Timing of availability unclear –Potency and PK may not be as favorable as anticipated –Optimal clinical settings for the use of these agents are not defined –Utility in patients with dual/mixed variants uncertain –Longer-term toxicity still an open question –Tied to tropism phenotype assay?

16. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors CXCR4 Inhibitors  Difficult compounds to formulate  AMD 3100 –Discontinued development—suggestion of anti-X4 activity  AMD 070 –Dose-ranging, phase I study in seronegative volunteers –2 phase IIa studies ongoing –Preliminary results suggest X4 activity in HIV-infected patients

17. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors On the Horizon: New Classes  Integrase inhibitors –MK-0518 –Results of phase IIb study presented at CROI –Phase III trial enrolling (2006) –GS-9137 –Results of phase IIa study presented at CROI –Phase IIb studies in development  Maturation inhibitors –PA-457 –Proof-of-principle study demonstrated short-term activity

18. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors Integrase Inhibitor: MK-0518  MK-0518, novel integrase inhibitor –Active against HIV resistant to current antiretrovirals  Phase IIa 10-day monotherapy trial of MK-0518 vs placebo in treatment-naive patients –BL VL: 4.53-4.97 log 10 copies/mL –BL CD4+: 256-569 cells/mm 3  Good response seen with 10-day monotherapy –No dose response  All doses generally well tolerated Morales-Ramirez JO, et al. EACS 2005. Abstract LBPS1/6. Day on Therapy Change From Baseline in HIV-1 RNA (log 10 copies/mL) 12345810 MK-0518 100 mg BID (n = 7) MK-0518 200 mg BID (n = 7) MK-0518 400 mg BID (n = 6) MK-0518 600 mg BID (n = 8) Placebo (n = 7) -3 -2 0 1

19. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors MK-0518: Phase IIb Study  Multicenter, double-blind, randomized, phase IIb study  Patient characteristics –Mean duration of HAART: 9-11 yrs – Mean VL: 4.6-4.8 log 10 copies/mL –Use of ENF in OBR: 33% to 38% – Mean CD4+: 220-283 cells/mm 3 –Patients with no active PIs in OBR: 84% to 98% –PSS = 0: 40% to 57% Grinsztejn B, et al. CROI 2006. Abstract 159LB. 160 Triple-class resistance by genotype/phenotype CD4+ > 50 cells/mm 3 HIV-1 RNA > 5000 copies/mL (N = 167) Placebo + OBR (n = 43) MK-0518 400 BID + OBR (n = 42) MK-0518 200 BID + OBR (n = 40) MK-0518 600 BID + OBR (n = 42) Weeks

20. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors MK-0518: Virologic Suppression Through Week 16 (Observed Data*) Grinsztejn B, et al. CROI 2006. Abstract 159LB.

21. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors MK-0518: Adverse Events  MK-0518 was generally well tolerated  Adverse events similar to placebo –Most adverse events mild to moderate  2 discontinuations –Lack of efficacy (1), death (1) Grinsztejn B, et al. CROI 2006. Abstract 159LB.

22. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors Integrase Inhibitor: GS-9137  Phase IIa, 10-day monotherapy study of GS- 9137 vs placebo –N = 40 HIV+ patients –Naive or off treatment  GS-9137 dosing –200, 400, 800 mg BID –800 mg QD –50 mg + RTV 100 mg QD  Dose-dependent response –RTV boosting allowed lower, once-daily GS-9137 dosing  No serious adverse events  Once-daily dosing with ritonavir to be investigated in phase II trial with experienced patients DeJesus E, et al. CROI 2006. Abstract 160LB.

23. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors Maturation Inhibitor: PA-457  PA-457 first in new class called maturation inhibitors –Targets late step in HIV life cycle –Blocks cleavage of capsid precursor CA-SP1 to mature p24  Randomized, double-blind, placebo-controlled study –6 HIV+ patients per arm: placebo vs single-dose PA-457 75, 150, or 250 mg –CD4+ cell count ≥ 200 cells/mm 3, VL 5000-250,000 copies/mL  8/12 in 150/250 mg arms had > 0.3 log 10 reduction in HIV-1 RNA  Activity observed in 2 patients with NRTI + NNRTI or NNRTI + PI resistance mutations  All doses well tolerated Martin D, et al. CROI 2005. Abstract 159.

24. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors PA-457: Virologic Response to Novel Maturation Inhibitor Monotherapy  Phase IIa, 10-day monotherapy study of PA-457 vs placebo in 32 HIV-infected patients [1]  PA-457 dosing –25, 50, 100, 200 mg QD  Median 1 log 10 VL reduction with PA-457 200 mg/day  Generally well tolerated  No resistance seen to date in clinical studies [2] –In vitro resistance studies confirm mechanism of action 1. Beatty G, et al. ICAAC 2005. Abstract H-416d. 2. Adamson C, et al. CROI 2006. Abstract 156. -0.8 -0.4 0 -1.2 Median Change in HIV-1 RNA at Day 10 (log 10 copies/mL) PL (n = 8) 25 (n = 6) 50 (n = 6) 100 (n = 6) 200 (n = 6) PA-457 Dose (mg/day) +0.03 +0.05 -0.17 (P =.02) -0.48 (P =.004) -1.03 (P <.0001)

25. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors Development of Novel Antiretroviral Classes  Clinical steps in drug development  Clinical trial data on antiretrovirals in novel classes  Pharmacokinetic considerations with new agents

26. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors PK Interactions: Maraviroc  Maraviroc metabolized by cytochrome P450 system  No interaction between MVC and tipranavir/ritonavir [1]  Maraviroc AUC doubled with lopinavir/ritonavir [2] –↓ MVC dose by 50% when given with most PIs  Maraviroc AUC ↓ ~ 50% with efavirenz [2] –↑ C max with NVP 1. Abel S, et al. EACS 2005. Abstract LBPE4.3/15. 2. Muirhead G, et al. CROI 2005. Abstract 663. Mean MVC Concentration (ng/mL) 1000 100 10 1 02468 12 MVC + TPV/r (500/200) MVC + placebo Time postdose (Hours)

27. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors PK Interactions: Vicriviroc  Vicriviroc metabolized by cytochrome P450 system  Vicriviroc ↑ with RTV (LPV/RTV), ↓ with EFV 1. Sansone A, et al. PK Workshop 2005. Abstract 85. 2. Sansone A, et al. PK Workshop 2005. Abstract 84. 3. Saltzman M, et al. IAS 2005. Abstract TuPe3.1B05. 4. Saltzman M, et al. IAS 2005. Abstract TuPe3.1B08. Coadministered Antiretroviral in Healthy Volunteers Effect on Vicriviroc Levels C max (ng/mL) AUC (ng*hr/mL) Tenofovir [1] ↔+5%-6% Zidovudine/lamivudine [2] ↔-8%-9% Ritonavir [3] ↑+254%+528% Lopinavir/ritonavir [3] ↑+238%+417% Efavirenz [4] ↓-67%-81% Efavirenz + ritonavir [4] ↑+196%+384%

28. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors PK Interactions: Integrase Inhibitors  MK-0518 –Metabolized by glucuronidation –Potential interaction with atazanavir –Not a CYP450 metabolite or inhibitor; no expected significant interactions with most antiretrovirals, cannot be boosted by ritonavir  GS-9137 –Metabolized by CYP3A4 –↑ ↑ concentration with ritonavir [1] –Boosted 20-fold with 100 mg ritonavir, allowing once-daily dosing –Other PI interactions not yet known 1. DeJesus E, et al. CROI 2006. Abstract 160LB.

29. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors Timeline for New Antiretrovirals PA-457 PIs NNRTI NRTI Maturation inhibitors CCR5 inhibitors Integrase inhibitors TMC278 Etravirine Dexelvu- citabine Darunavir Brecanavir Integrase inhibitors Entry inhibitors (anti-gp120, CCR5) CXCR4 inhibitors 20052006200720082009

30. clinicaloptions.com/hiv Novel Antiretroviral Classes: Update on CCR5 Antagonists and Integrase Inhibitors For more information on this important clinical topic, go online to: www.clinicaloptions.com/novelclasses www.clinicaloptions.com/novel  CME-certified On-demand Webcast with presentation and discussion by Joel E. Gallant, MD, MPH, on novel antiretroviral classes  More downloadable slidesets –Joel E. Gallant, MD, MPH: Strategies for future use of agents in novel classes, including case studies –Daniel R. Kuritzkes, MD: Why do we need new antiretroviral drugs in novel classes and how do they work?  CME-certified didactic educational module summarizing data on the need and potential future use of novel antiretroviral classes in HIV management strategies