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DPC 083 ATAC Meeting Seattle February 24, 2002

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

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DPC 083 ATAC Meeting Seattle February 24, 2002

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  1. DPC 083ATAC MeetingSeattleFebruary 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. F F C C 3 3 N N H H Design of Second Generation NNRTIs Cl Cl NH O O O Efavirenz Benzoxazinone DPC 083* Quinazolinone 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. Study DPC 083-201 Demographics 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-RNA 4.52 Mean CD4 402 *BMS-561390

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

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

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

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

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

  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) *BMS-561390 DPC 083-201

  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 • 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’ DPC 083-203

  21. 8000 7000 PLASMA IC90 DPC 083* PLASMA IC90 EFAVIRENZ 6000 5000 4000 3000 2000 1000 0 L100I K101E K103N V106A V108I E138K Y181C Y188C G190S P225H Plasma IC90 of DPC 083* • Single Mutants Value > 20,000 nM Plasma IC90, nM DPC 083-203 *BMS-561390

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

  23. Study DPC 083-203* NNRTI-experienced, PI-naive Double-blind (N=75) 100 mg DPC 083* + 2 NRTIs (N=75) 200 mg DPC 083* + 2 NRTIs 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. Study DPC 083-203* Inclusion Criteria NNRTI experienced, virologic failure PI Naïve Screening Genotyping while on NNRTI *BMS-561390

  25. Study DPC 083-203* Demographics Males 93% Median age 37yr Cauc. 77% Black 16% Hisp. 3% *BMS-561390

  26. Study DPC 083-203* Baseline Characteristics Mean Log 10 Plasma HIV-RNA 3.84 Mean CD4 518 *BMS-561390

  27. Prior ARV Medications 100mg DPC 083* 200 mg DPC 083* + ZDV / 3 TC + ZDV / 3 TC _____________________________________________________________________________________________ No. of Subjects 23 8 No. of Subjects who received medication 23 (100) 8 (100) _____________________________________________________________________________________________ Nevirapine 15 (65.2) 5 (62.5) Lamivudine 12 (62.5) 7 (87.5) Stavudine 15 (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. Study DPC 083-203* Number of New NRTIs at Baseline None 10 One 17 Two 15 *BMS-561390

  29. Premature Discontinuation 100mg DPC 083* 200 mg DPC 083* +ZDV / 3TC +ZDV / 3TC TOTAL _____________________________________________________________________________________________ No. of Subjects 23 8 31 No. of Subjects who prematurely 9 (39.13) 3 (37.50) 12 (30.71) discontinued _____________________________________________________________________________________________ Reason for Premature Discontinuation: Adverse Experience 4 (17.39) 1 (12.50) 5 (16.13) Protocol Violation13 (56)1 ( 12) 14 ( 45) Withdrew Consent 0 ( 0.00) 1 (12.50) 1 ( 3.23) Failed to return / Lost to follow-up 1 ( 4.35) 0 ( 0.00) 1 ( 3.23) Unsatisfactory Thereputic Response 1( 4.35) 0 ( 0.00) 1 ( 3.23) Other 1 ( 4.35) 0 ( 0.00) 1 ( 3.23) Unknown 0 ( 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. Percentage of Subjects with HIV-RNA < 400 Copies/mL DPC083-203* (Observed Data) J 100 90 J J B J 80 B J B B J J 70 B B B 60 B 50 40 30 20 10 0 * 2 4 6 8 12 16 20 24 WEEKS 100mg N= 21 17 11 12 13 11 10 5 B 200mg N= 7 8 7 6 5 5 4 J * U.S. Patients Only DPC 083-203 *BMS-561390

  32. Percentage of Subjects with HIV-RNA < 50 Copies/mL DPC083-203* (Observed Data) 80 J J 70 J J 60 B J B 50 B 40 B B 30 J B J 20 B 10 B 0 * 2 4 6 8 12 16 20 24 WEEKS B 100 MG N= 21 17 11 12 13 11 10 5 200 MG N= 7 8 7 6 5 5 4 J * U.S. Patients Only *BMS-561390 DPC 083-203

  33. Percentage of Subjects with HIV-RNA < 400 Copies/mL DPC083-203* Non-Completer = Failure J 100 90 80 J 70 J J B 60 B J 50 B B B B 40 30 20 10 0 * 2 4 6 8 12 16 WEEKS 100mg B N= 23 23 13 21 20 19 200mg J N= 8 8 8 8 8 * U.S. Patients Only *BMS-561390 DPC 083-203

  34. Percentage of Subjects with HIV-RNA < 50 Copies/mL DPC083-203* Non-Completer = Failure 100 90 80 70 J 60 50 40 J J B 30 J J B B B 20 B 10 B 0 2 4 6 8 12 16 * WEEKS 100mg B N= 23 23 13 21 20 19 200mg J N= 8 8 8 8 8 * U.S. Patients Only DPC 083-203 *BMS-561390

  35. Adverse Experiences 100mg DPC 083* 200 mg DPC 083* +ZDV / 3TC +ZDV / 3TC _____________________________________________________________________________________________ ADVERSE EVENTS _____________________________________________________________________________________________ Nervous System Disorder 6 (27.3) 4 (50.0) Headache NOS 3 (13.6) 2 (25.0) Insomnia NEC 3 (13.6) 0 ( 0.0) Dizziness (Exc Vertigo) 1 ( 4.5) 0 ( 0.0) Hypoaesthesia 1 ( 4.5) 0 ( 0.0) Somnolence 0 ( 0.0) 1 (12.5) Tremor NEC 0 ( 0.0) 1 (12.5) Psychiatric Disorders 5 (22.7) 1 (12.5) Abnormal Dreams 5 (22.7) 0 ( 0.0) Anxiety NEC 2 ( 9.1) 0 ( 0.0) Depressed Mood 0 ( 0.0) 1 (12.5) Depression NEC 1 ( 4.5) 0 ( 0.0) _____________________________________________________________________________________________ *BMS-561390

  36. Summary of Rash Events 100mg DPC 083* 200mg DPC 083* Number of subjects 22 8 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 *BMS-561390

  37. Summary of Rash Events 100mg DPC 083* Onset of First Symptoms (days) Median 13.5 Min, Max 9,77 Duration (days**) Median 11 Min, Max 5,96 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 Santiago Moreno, MDHernando 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 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, MDProf. Reinhold E. Schmidt Prof. Willy W. Rozenbaum Elke Lauenroth-Mai, MD

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