1. DPC 083 ATAC Meeting Seattle February 24, 2002 Nancy Ruiz, MD

2. DPC 083-201 A Phase II Double-Blind (DB) Comparison of 3 Once Daily Doses of the NNRTI DPC 083 vs 600 mg Efavirenz (EFV) in Combination with 2 NRTIs in HIV Anti- Retroviral (ARV Treatment-Naïve Patients Dr. Nancy Ruiz R.Nusrat, A.Lazzarin, K.Arasteh, F.D.Goebel, S.Audgnotto, A. Rachlis, J.R. Arribas, L.Ploughman, W. Fiske, D.Labriola, R.Levy, R.Echols for the DPc 083-201 study team.

3. Limitations of Current NNRTIs Single Point Mutations Confer Resistance –Efavirenz - K103N –Nevirapine - Y181C, K103N –(Delavirdine - not used - inferior efficacy) Inability to sequence NNRTIs –Patients failing nevirapine with Y181C cannot be successfully rescued with efavirenz Toxicities –Efavirenz: CNS effects, primate teratogenicity, rash –Nevirapine: rash, hypersensitivity, hepatotoxicity DPC 083-201

4. Goals for a second generation NNRTI Coverage of pan-class resistance mutations –Target K103N and viruses with multiple mutations –Maintain potency against wild-type virus Safety and tolerability no worse than efavirenz –Optimally reduce CNS and psychiatric side effects of efavirenz Maintain long-half life allowing once daily dosing with forgiveness for occasionally missed doses DPC 083-201

5. Design of Second Generation NNRTIs N H NH Cl O F 3 C DPC 083* Quinazolinone O Cl O F 3 C N H Efavirenz Benzoxazinone DPC 083-201 *BMS-561390

6. DPC 083* as a Second Generation NNRTI Potency –towards “wild-type” HIV-1 essentially identical to efavirenz – towards mutant HIV-1 is 2 to 11-fold better Free fraction (protein binding) –Free fraction is 5.3-fold higher than efavirenz Overall improvement (“Plasma IC90”) is >10-fold relative to efavirenz DPC 083-201 *BMS-561390

7. Study DPC 083-201 - Cohort 1 Design ARV Naïve Double-Blind DPC 083* 50 mg once daily + Combivir bid N=30 DPC 083* 100 mg once daily + Combivir bid N=30 DPC 083* 200 mg once daily + Combivir bid N=30 Efavirenz 600 mg once daily + Combivir bid N=30 Safety, PK analysis and dose selection at 8 weeks DPC 083-201 *BMS-561390

8. Study DPC 083-201 Objectives Compare the tolerability of the regimens –8 weeks considered adequate to assess potential CNS effects and rash Determine PK in HIV-1-infected patients Determine mutations arising in failures (if any) Select phase III dose based on tolerability and PK. Dose selection not to be based on efficacy which was expected to be comparable across doses DPC 083-201 *BMS-561390

9. Demographics Study DPC 083-201 Males 85% Median Age 35 yr Cauc 83% Black 8% Hisp. 5% *BMS-561390

10. Study DPC 083-201 Baseline Characteristics Mean Log 10 Plasma IV-RNA4.52 Mean CD4402 *BMS-561390

11. Study 201- On-Treatment Response Rates DPC 083-201*BMS-561390

12. Study 201 ITT (NC=F) Response Rates DPC 083-201*BMS-561390

13. Most Common Adverse Experiences DPC 083-201*BMS-561390

14. Frequency of Specific CNS and Psychiatric AEs 1% of Patients discontinued for CNS or Psychiatric Adverse Experiences DPC 083-201*BMS-561390

15. Further Details on Rash DPC 083-201*BMS-561390

16. Study DPC 083-201 Conclusions All DPC 083* doses adequately tolerated Tolerability equal or better than efavirenz except for rash at the 200 mg dose No significant laboratory abnormalities (data not shown) All doses highly effective 100 mg dose selected for Phase III for NNRTI naïve patients Potential benefit in reducing the frequency and severity of rash with prophylactic use of a non-sedating antihistamine will be explored in a 64 patient extension to Study 201 (cohort II) DPC 083-201*BMS-561390

17. Acknowledgements Stephen Kravcik, MD Anita Rachlis, MD Stephen Shafran, MD Chris Tsoukas, MD Sharon Walmsley, MD Stefan Esser, MD Keikawus Arasteh, MD Prof. Guido Gerken Frank-Detlef Goebel, MD Thomas Harrer, MD Martin Hartmann, MD Franz A. Mosthaf, MD Juergen Rockstroh, MD Gerd Faetkenheuer, MD Prof. Reinhold E. Schmidt Schlomo Staszewski, MD Albert Theisen, MD Philippa Easterbrook, MD Mark Nelson, MD Margaret Johnson, MD Prof. Giampiero Carosi Giovanni Di Perri, MD Andrea Antinori, MD Prof. Adriano Lazzarin Prof. Fredy Suter Prof. Fernando Aiuti Prof. Francesco Chiodo, MD Prof. L. Minoli José Ramón Arribas, MD Juan Gonzalez-Lahoz, MD Esteban Ribera, MD Refael Rubio, MD Lutwin Weitner, MD Prof. Gaetano Filice

18. DPC 083-203 A Phase II Comparison of 100 and 200 mg Once-Daily DPC 083 and 2 NRTIs in Patients Failing a NNRTI Containing Regimen Dr. Nancy Ruiz R. Nusrat, E. Lauenroth-Mai, D. Berger, C. Walworth, L.T. Bacheler, L. Ploughman, P.Tsang, D.Labriola, R. Echols, R. Levy and the DPC 083-203 study team.

19. Unmet Medical Need Growing number of these people are treated with ARV drugs Growing prevalence of viral mutations resistant to available ARV drugs seen in both treatment-experienced and -naïve patients Shift in proportion of patients given first-line therapy to second- line therapy and beyond Evolving practice of sequencing ARV drugs to maintain therapeutic options in treatment-experience patients Increasing demand for second-generation ARV drugs that are effective in suppressing mutant viral strains and provide simple regimens that facilitate adherence DPC 083-203

20. Future Goals of HIV Therapy DPC 083-203 Efficacy Wild-type virus Viral sanctuaries Mutant virus Quality of Life Tolerability Dosing interval Pill burden Sustained HIV Suppression Durable therapy Long-term patient survival ‘HIV is a manageable disease’

21. Plasma IC90 of DPC 083* Single Mutants L100IK101EK103NV106AV108IE138KY181CY188CG190SP225H 0 1000 2000 3000 4000 5000 6000 7000 8000 PLASMA IC90 DPC 083* PLASMA IC90 EFAVIRENZ Plasma IC90, nM Value > 20,000 nM DPC 083-203 *BMS-561390

22. Plasma IC90 of DPC 083* Double mutants K013N+V108I K103N+P225H K103N+Y181C K103N+K101E Y188L G190S K103N+L100I 1000 10000 100000 Plasma IC90 DPC 083* Plasma IC90 Efavirenz Plasma IC90, nM DPC 083-203 *BMS-561390

23. Study DPC 083-203* NNRTI-experienced, PI-naive Double -blind 200 mg DPC 083* + 2 NRTIs 100 mg DPC 083* + 2 NRTIs (N=75) FDA had prohibited 200 mg dose until after August 16 meeting Split into two studies, Non-IND study in Europe randomized patients DPC 083-203 *BMS-561390

24. Inclusion Criteria NNRTI experienced, virologic failure PI Naïve Screening Genotyping while on NNRTI Study DPC 083-203* *BMS-561390

25. Demographics Males93% Median age 37yr Cauc.77% Black16% Hisp. 3% Study DPC 083-203* *BMS-561390

26. Baseline Characteristics Mean Log 10 Plasma HIV-RNA3.84 Mean CD4518 Study DPC 083-203* *BMS-561390

27. Prior ARV Medications 100mg DPC 083*200 mg DPC 083* + ZDV / 3 TC _____________________________________________________________________________________________ No. of Subjects238 No. of Subjects who received medication23 (100)8 (100) _____________________________________________________________________________________________ Nevirapine15 (65.2)5 (62.5) Lamivudine12 (62.5)7 (87.5) Stavudine15 (65.2)4 (50.0) Efavirenz 8 (34.8)4 (50.0) Zidovudine 7 (30.4)4 (50.0) Lamivudine \ Zidovudine 7 (30.4)1 (12.5) Indinavir Sulfate 6 (21.7)0 ( 0.0) Didanosine 4 (17.4)0 ( 0.0) Ritonavir 4 (17.4)0 ( 0.0) Abacavir 2 ( 8.7)1 (12.5) Dideoxycytidine 3 (13.0)0 ( 0.0) Saquinavir Mesylate 1 ( 4.3)1 (12.5) Delavirdine Mesylate 1 ( 4.3)0 ( 0.0) Nelfinavir 1 ( 4.3)0 (0.0) Unknown Invest Agent (NOS) * 1 ( 4.3)0 ( 0.0) _____________________________________________________________________________________________ * Uknown Agent = Emtricibine / Placebo *BMS-561390

28. Number of New NRTIs at Baseline None10 One17 Two15 Study DPC 083-203* *BMS-561390

29. Premature Discontinuation 100mg DPC 083*200 mg DPC 083* +ZDV / 3TC +ZDV / 3TCTOTAL _____________________________________________________________________________________________ No. of Subjects23831 No. of Subjects who prematurely 9 (39.13)3 (37.50)12 (30.71) discontinued _____________________________________________________________________________________________ Reason for Premature Discontinuation: Adverse Experience4 (17.39)1 (12.50)5 (16.13) Protocol Violation13 (56)1 ( 12)14 ( 45) Withdrew Consent0 ( 0.00)1 (12.50)1 ( 3.23) Failed to return / Lost to follow-up1 ( 4.35)0 ( 0.00)1 ( 3.23) Unsatisfactory Thereputic Response 1( 4.35)0 ( 0.00)1 ( 3.23) Other1 ( 4.35)0 ( 0.00)1 ( 3.23) Unknown0 ( 0.00)1 (12.50)1 ( 3.23) _____________________________________________________________________________________________ *BMS-561390

30. On-Treatment Response Rate in Study DPC 083-203* Number of New NRTIs Includes only patients with data at week 8 or beyond and known choice of NRTIs Dose of DPC 083 remains blinded from patients not included in original analyses Maximum duration of treatment = 36 weeks DPC 083-203 *BMS-561390

31. B B B B B B B B J J J J JJ J 246812162024 0 10 20 30 40 50 60 70 80 90 100 N= 2117 111213 11105 N=7876 55 4 Percentage of Subjects with HIV-RNA < 400 Copies/mL (Observed Data) WEEKS * * U.S. Patients Only B 100mg J 200mg DPC083-203* DPC 083-203 *BMS-561390

32. B B B B B B B B J J J J JJ J 246812162024 0 10 20 30 40 50 60 70 80 N= 2117 111213 11105 N=7876 55 4 Percentage of Subjects with HIV-RNA < 50 Copies/mL (Observed Data) WEEKS * * U.S. Patients Only DPC083-203* B 100 MG J 200 MG DPC 083-203 *BMS-561390

33. B B B B B B J J JJ J 24681216 0 10 20 30 40 50 60 70 80 90 100 N= 23 132120 19 N=8888 8 Percentage of Subjects with HIV-RNA < 400 Copies/mL Non-Completer = Failure WEEKS * * U.S. Patients Only B 100mg J 200mg DPC083-203* DPC 083-203 *BMS-561390

34. B B B B B B JJ J JJ 24681216 0 10 20 30 40 50 60 70 80 90 100 N= 23 132120 19 N=8888 8 Percentage of Subjects with HIV-RNA < 50 Copies/mL Non-Completer = Failure WEEKS * * U.S. Patients Only B 100mg J 200mg DPC083-203* DPC 083-203 *BMS-561390

35. Adverse Experiences 100mg DPC 083*200 mg DPC 083* +ZDV / 3TC _____________________________________________________________________________________________ ADVERSE EVENTS _____________________________________________________________________________________________ Nervous System Disorder6 (27.3)4 (50.0) Headache NOS 3 (13.6)2 (25.0) Insomnia NEC3 (13.6)0 ( 0.0) Dizziness (Exc Vertigo) 1 ( 4.5)0 ( 0.0) Hypoaesthesia 1 ( 4.5)0 ( 0.0) Somnolence0 ( 0.0)1 (12.5) Tremor NEC0 ( 0.0)1 (12.5) Psychiatric Disorders5 (22.7)1 (12.5) Abnormal Dreams5 (22.7)0 ( 0.0) Anxiety NEC2 ( 9.1)0 ( 0.0) Depressed Mood0 ( 0.0)1 (12.5) Depression NEC1 ( 4.5)0 ( 0.0) _____________________________________________________________________________________________ *BMS-561390

36. Summary of Rash Events 100mg DPC 083*200mg DPC 083* *BMS-561390 Number of subjects228 Number of subjects with rash 6 (27.3%)0 Number of rashes 6 Maximum Intensity Mild 1 Moderate 5 Action Taken None 4 Study Drug Discontinued 2

37. Summary of Rash Events 100mg DPC 083* Onset of First Symptoms (days) Median13.5 Min, Max9,77 Duration (days**) Median 11 Min, Max5,96 Impact on Lifestyle None 2 Mild 1 Moderate 3 *BMS-561390 **Kaplan Meier estimates

38. Issues With DPC 083-203 Study 1) Heterogeneous patient population 2) Poor recruitment 3) 29% Premature discontinuations 4) Protocol violations eg. Prior PI 5) No clear dose response 6) Tolerability profile not well defined 7) No control arm *BMS-561390

39. Conclusions 1) DPC 083 (BMS-561390) appears to be well tolerated in most NNRTI experienced patients 2) Dose selection for NNRTI experienced patients not possible from this study. -Insufficient number of patients -Heterogeneous patient population -Insufficient data 3) Future Phase II study to determine tolerable and effective dose in NNRTI patients in planning.

40. Acknowledgements Daniel S. Berger, MD Prof. Pierre Dellamonica Dr. Pere Domingo Prof. Christine Katlama Keikawus Arasteh, MD Martin Hartmann, MD Franz A. Mosthaf, MD Albrecht Stoehr, MD Prof. Reinhold E. Schmidt Prof. Willy W. Rozenbaum Elke Lauenroth-Mai, MD Santiago Moreno, MD Hernando J. Knobel, MD Dr. Antonio Ocampo Prof. Francois Raffi Antonio Rivero, MD Jonathan Anderson, MD Norm Roth, MD Lutwin Weitner, MD Dr. Juergen Rockstroh Schlomo Staszewski, MD Prof. Jean-Francois Bergmann David Baker, MD David A. Cooper, MD Eliot W. Godofsky, MD Mark T. Bloch, MD Charles Farthing, MD Daniel Seekins, MD David Dalmau, MD Dr. Jean-Michel Molina