1. Tipranavir NDA 21-814: Efficacy Evaluation Rafia Bhore, Ph.D. Statistician Reviewer Division of Antiviral Drug Products Food and Drug Administration May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting

2. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting2 Outline of Efficacy Presentation Study Design of Phase 3 Trials Patient Disposition Demographics and Baseline Characteristics Evaluation of Open-Label Design Efficacy Evaluation –Primary Efficacy (FDA Analysis) –Subgroup Analyses by PI resistance, T-20 use –Head-to-head comparison of TPV vs PIs Summary of Efficacy

3. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting3 Study Design of RESIST* Trials (Studies 1182.12 and 1182.48) *Randomized Evaluation of Strategic Intervention in Multi-Drug ReSistant Patients with Tipranavir

4. STUDIES 1182.12 (RESIST 1) and 1182.48 (RESIST 2) Open-label, Controlled, Highly ARV-experienced patients At least 1 primary protease resistance mutations at codons: 30N, 46I/L, 48V, 50V, 82 A/F/L/T, 84V, or 90 M ? Yes Screening Failure  2 mutations at codons 33, 82, 84, or 90 ? Genotype Resistance Testing SCREENING 3 ARV class and dual PI-experienced No Enroll in Trial 1182.51 No Yes Enroll in RESIST Trial Go to A RESIST 1: USA, Canada, Australia RESIST 2: Europe, Latin America 4

5. either or TPV 500 mg bid + RTV 200 mg bid + OBR PI + RTV + OBR APV/RTV SQV/RTV IDV/RTV LPV /RTV RANDOMIZE to Pre-select PI (Protease Inhibitor) based on genotypic resistance test Select OBR (OPTIMIZED BACKGROUND REGIMEN) based on screening genotype test and ARV medication history A Week 8Week 24Week 48Week 96 Open-label Roll-over Trial 1182.17 Patients in comparator PI/RTV group with lack of initial virologic response or confirmed virologic failure will roll-over to TPV/RTV group in Roll-Over Trial 1182.17 Week 8Week 24Week 48Week 96 NOTES: PI=Protease Inhibitor TPV=tipranavir, RTV=ritonavir APV=amprenavir, SQV=saquinavir IDV=indinavir, LPV=lopinavir 5 Amendment # 2 Allowed patients with highly PI resistant virus to be treated with PI-based regimen.

6. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting6 Patient Disposition

7. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting7 Patient Disposition Number of patientsTPV/r + OBRCPI/r + OBR Total randomized and treated with 16 week data746737 Randomized and treated with 24 week data (ITT)582 (100%)577 (100%) Completed Study through 24 weeks 82% 53% Prematurely discontinued before or at Week 24 17% 47% Discontinuations due to Virologic Failure or no Virologic response 3% 37% Adverse Events 8% 4%

8. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting8 Demographics and Baseline Characteristics

9. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting9 Demographics RESIST 1 (N=620) –USA (80%), Canada (13%), Australia (7%) RESIST 2 (N=539) –Europe (85%), Latin America (15%) France 26%, Germany 19%, Italy 16%, Spain 7%, Greece 4%, Belgium 3%, UK 3%, Denmark 3%, Portugal 2%, Netherlands 2%, Switzerland 1%, Sweden <1%, Austria <1%, Luxembourg <1% Argentina 14%, Brazil 2%, Mexico (not completed 24 weeks treatment yet)

10. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting10 Demographics (contd) Age [Mean (range)] –RESIST 1: 45 years (24 to 80 yrs) –RESIST 2: 43 years (17 to 76 yrs) Gender –RESIST 1: 91% male, 9% female –RESIST 2: 84% male, 16% female Race –RESIST 1: 77% Caucasian, 22% Black, 1% Asian –RESIST 2: 68% Caucasian, 5% Black, 1% Asian, 26% Missing (France)

11. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting11 Baseline Disease Characteristics RESIST 1 (1182.12) N=620 RESIST 2 (1182.48) N=539 HIV RNA ( log 10 copies/mL) Mean (Range) Prop w/ HIV RNA copies/mL < 10,000 >=10,000 to <100,000 >=100,000 4.7 (2.0 to 6.3) 16% 43% 41% 4.8 (2.9 to 6.8) 16% 46% 38% CD4 Cell Count (cells/mm 3 ) Mean (Range) < 200 cells/mm 3 >= 200 cells/mm 3 164 (0.5 to 1183.5) 67% 33% 224 (1.5 to 1893) 53% 47%

12. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting12 Baseline Disease Characteristics RESIST 1 (1182.12) N=620 RESIST 2 (1182.48) N=539 HIV infection stage Class A Class B Class C 24% 19% 57% 17% 27% 56% Hepatitis B positive Hepatitis C positive Hepatitis B and C co-infected 5% 7% 0.5% 5% 14% 0.9%

13. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting13 Protease Inhibitor Stratum RESIST 1 (1182.12) N=620 RESIST 2 (1182.48) N=539 Genotypic resistance to Pre-selected PIs Not resistant Possibly resistant Resistant (TruGene Assay) 8% 35% 57% (Virtual Phenotype or TruGene Assay) 20% 6% 74% Protease Inhibitor Stratum LPV APV SQV IDV 61% 14% 21% 4% 38% 40% 20% 3%

14. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting14 Evaluation of Potential Biases due to Open-Label Design

15. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting15 Pre-determined T-20 Stratum versus Actual T-20 use Pre-selected T-20 (No) but Actual T-20 (Yes) Pre-selected T-20 (Yes) but Actual T-20 (No) TPV/r N=427 CPI/r N=430 Total N=857 TPV/r N=155 CPI/r N=147 Total N=302 3%1%*2%5%16%*10% * McNemar’s test p-value <.001 Mismatches between Pre-determined vs Actual

16. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting16 Pre-determined vs Actual Background Regimen Total # of pre-determined regimen = 155 Total # of actual regimen = 161 Mismatches between Pre-determined vs Actual RESIST 1RESIST 2 TPV/r N=311 CPI/r N=309 Total N=620 TPV/r N=271 CPI/r N=268 Total N=539 9%12%11%13%14%

17. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting17 Commonly Used Background Antiretroviral Regimen Balanced across TPV/r and CPI/r groups –3TC + TDF (11%), –ddI + TDF (8%), –3TC + ddI + TDF (7%), –3TC + TDF + ENF (4%), –3TC + ddI + TDF + ENF (3%), 3TC + ABC + TDF (3%), d4T + TDF (3%)

18. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting18 Protocol Violations in RESIST 1 and RESIST 2 trials Unique patients with protocol violations –51% in TPV/r and 56% in CPI/r group Patients had 1 or more protocol violations of same or different type Types of protocol violations –Screening (Entry Criteria) violations –Treatment Regimen violations during study –Other violations with use of concomitant drugs

19. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting19 Screening Violations 29% TPV/r vs 32% CPI/r unique patients with screening violations –E.g., no protease gene mutations at codons 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, or 90M –Less than 2 PIs or less than 3 mos. of trt on historical therapy –Screening viral load < 1,000 copies/mL, etc.

20. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting20 Treatment Regimen Violations 24% TPV/r vs 25% CPI/r unique patients with treatment regimen violations –E.g., Dual-boosted PIs used –Randomized to CPI/r group and pre- specified PI not taken or changed –No new or recycled ARV in optimized background regimen, etc.

21. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting21 Initial Lack of Virologic Response by Week 8 Viral load has not dropped 0.5 log 10 HIV RNA copies/mL after 8 weeks of treatment Failure to achieve a viral load <100,000 copies/mL after 8 weeks, despite a 0.5 log 10 drop after 8 weeks of treatment Patients in CPI/r group may discontinue and roll-over to Study 1182.17 and receive tipranavir/ritonavir Escape clause may create bias in efficacy after Week 8

22. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting22 Efficacy Evaluation Primary Efficacy (FDA Analysis)

23. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting23 Efficacy Endpoint at 24 Weeks Proportion of patients with confirmed ≥1 log reduction from baseline in HIV RNA without prior evidence of treatment failure, i.e., –Death –Confirmed virologic failure –Permanent discontinuation of study drug –Introduction of a new ARV drug for reasons other than toxicity to background ARV

24. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting24 Efficacy Outcomes at 24 Weeks (Intent-to-Treat Analysis) RESIST 1 (1182.12)RESIST 2 (1182.48) TPV/r + OBR N=311 CPI/r + OBR N=309 TPV/r + OBR N=271 CPI/r + OBR N=268 Response (>=1 log reduction) 41%21%40%14% Virologic Failure 55%75%52%83% Initial Lack of Virologic Response at Week 8 35%53%35%66% Rebound Never suppressed through Week 24 13% 7% 13% 9% 10% 7% 10% 8%

25. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting25 Efficacy Outcomes at 24 Weeks (contd.) RESIST 1 (1182.12)RESIST 2 (1182.48) TPV/r + OBR N=311 CPI/r + OBR N=309 TPV/r + OBR N=271 CPI/r + OBR N=268 Added ARV drug 2% 6%1% Died 0% <1% Discontinued due to adverse events 1%0%1% Discontinued due to other reasons 1% 0% Discontinued while suppressed 0%1% 0%

26. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting26 Sensitivity Analyses addressing Open-Label Biases Bias at Week 8 due to initial lack of virologic response –incorporated into ITT analysis –Probability of response (>=1 log reduction in HIV RNA) was 0.5% in TPV/r vs 1.5% in CPI/r if lack of virologic response (>= 0.5 log reduction) by Week 8 Bias due to Wrong T-20 stratum Bias due to each type of protocol violation

27. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting27 Sensitivity Analysis  Efficacy Results Analysis type TPV/r + OBR N=582 CPI/r + OBR N=577 Difference (TPV/r-CPI/r) (95% CI) ITT234 (40%)103 (18%) 22% (17%, 27%) ITT adjusting wrong T-20 stratum 232 (40%)126 (22%) Per-Protocol (Exclude Treatment Regimen Violations) 215/507 (42%) 98/480 (20%) Per-Protocol (Exclude Screening Violations) 191/465 (41%) 82/457 (18%) 18% (13%, 23%) 22% (16%, 27%) 23% (17%, 29%)

28. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting28 Subgroup Analyses By T-20 stratum By Control Protease Inhibitors adjusting for Resistance and Experience

29. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting29 Subgroup-Analysis by T-20 use stratum Enfuvirtide (ENF, T-20) used?TPV/rCPI/r Difference in proportions (95% CI) P-value for treatment by subgroup interaction Yes (25%)48%19%29% (19%, 30%) 0.02 No (75%)29%13%16% (10%, 21%)

30. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting30 New Definition of Combined Resistance & Experience Patterns Susceptible Naïve –Not resistant and prior duration of exposure to PI is <=1 month Susceptible Experienced –Not resistant and prior duration of exposure to PI is 1- =6 months Resistant –Possibly resistant or Resistant according to TruGene or Virtual Phenotype assay regardless of prior duration of exposure to PI

31. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting31 Baseline Resistance Patterns in PI Strata

32. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting32 Confidence Intervals on Treatment Differences (TPV/r – CPI/r)

33. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting33 Summary of Efficacy FDA analysis confirmed that tipranavir was statistically significantly better than the control with respect to the surrogate endpoint of percent with at least 1 log decrease in viral load at 24 weeks. Efficacy of tipranavir/ritonavir was shown when the best available comparator protease inhibitor was sub- optimal. Sensitivity analyses adjusting for open-label biases in RESIST trials –Results were consistent with the efficacy shown –Net treatment benefit will range from 13% to 29%.

34. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting34 Summary of Efficacy (contd.) Efficacy of tipranavir/ritonavir was demonstrated regardless of T-20 use, but the efficacy was significantly greater when combined with T-20 Boosted tipranavir is not proven to be better than boosted lopinavir, or amprenavir, or saquinavir, if patients are naïve and not resistant to respective protease inhibitors. –No data available on indinavir on susceptible naïve patients.

35. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting35 Acknowledgment FDA colleagues –Greg Soon, Ph.D., Statistics Team Leader –Andrea James, M.D., Medical Reviewer –Rosemary Johann-Liang, M.D., Medical Team Leader –Tom Hammerstrom, Ph.D., Statistician Reviewer