1. The Unique Resistance Profile of Tipranavir Dr Kevin Curry Boehringer Ingelheim, Bracknell, UK

2. Tipranavir BI 1182.2 Background First non-peptidic protease inhibitor (NPPI) First non-peptidic protease inhibitor (NPPI) – Flexible molecule adjusts to protease binding pocket – Binds tightly to protease site by hydrogen bonding Potent activity against wild-type HIV-1 and HIV-2 Potent activity against wild-type HIV-1 and HIV-2 – Protein-adjusted IC 90 for wild-type HIV-1  1.0  M Active against HIV-1 resistant to available PIs Active against HIV-1 resistant to available PIs – Target plasma levels for PI-resistant HIV-1 strains  20  M (~10X the protein-adjusted IC 90 ) TPV exposure is markedly enhanced by RTV TPV exposure is markedly enhanced by RTV – Allows for reduced pill burden

3. Tipranavir--In Vitro Phenotypic Data IntermediateSensitiveResistant TPV= 95 TPV= 8 TPV= 2 IDV RTV NFV SQV TPV < IC 50 x 4 IC 50 x 4-10> IC 50 x 10

4. Tipranavir--Mean IC 50 for 105 Multiple PI-Resistant Isolates Tipranavir--Mean IC 50 for 105 Multiple PI-Resistant Isolates Larder BA et al. AIDS 2000;14:1934-1948. Larder BA et al. AIDS 2000;14:1934-1948. Mean Increase in IC 50

5. 10 20 30 40 50 60 70 80 90 100 1020243036464748505471737782 848890 Amino Acid Residue % Mutant 0 Tipranavir--Mutations Seen in 10 HIV Isolates with 4-Fold Reduced Susceptibility

6. Tipranavir BI 1182.2 Study design Open-label, randomized, parallel groups Open-label, randomized, parallel groups HIV-1–positive, NNRTI-naive adults HIV-1–positive, NNRTI-naive adults Patients with two or more PI-containing regimens Patients with two or more PI-containing regimens – No washout, must be on PI regimen at entry – No genotype or phenotype eligibility criteria Primary end point Primary end point – Mean plasma HIV-1 RNA reduction at 48 weeks

7. Tipranavir BI 1182.2 Study design (cont’d) Low Dose High Dose TPV HFC 1200 mg BID + RTV 100 mg BID TPV HFC 2400 mg BID + RTV 200 mg BID TPV SEDDS 500 mg BID + RTV 100 mg BID + EFV 600 mg QD + 1 new NRTI TPV SEDDS 1000 mg BID + RTV 100 mg BID + EFV 600 mg QD + 1 new NRTI Most patients initially took TPV 300 mg (HFC), then switched to TPV 250 mg soft-gel capsules (SEDDS) when this formulation became available. 7/41 received SEDDS alone.

8. Tipranavir BI 1182.2 Baseline characteristics Plasma HIV-1 RNA, log 10 copies/mL CD4+ T-cell count, cells/mm 3 4.51(3.87–5.21) 314(38–1067) 4.46(3.68–5.47) 290(41–610) Low dose High dose Number of subjects 19 22 Percent male 79 77 Mean age, years 44 41

9. Tipranavir BI 1182.2 Prior PI exposure 32% 95% 53% 63% 55% 91% 68% 50% 44% 93% 61% 56% 0 20 40 60 80 100 IDVSQVNFVRTV Percent prior experience (N = 41) Low doseHigh doseTotal

10. Tipranavir BI 1182.2 48-Week viral load response ITT-LOCF and AT -2.34 log 10 -1.71 log 10 -2.23 log 10 -2.72 log 10

11. Tipranavir BI 1182.2 Median viral load change at 48 weeks stratified by number of baseline mutations -0.46 -1.89 -2.56 -1.77 -3 -2.5 -2 -1.5 -0.5 0 3–5 (n = 2) 6–10 (n = 13) 11–15 (n = 14) 16–20 (n = 8) Log 10 change from baseline (copies/mL) ITT-LOCF

12. Tipranavir BI 1182.2 Baseline susceptibility to TPV At baseline, 40/41 isolates from the study population were fully susceptible to TPV At baseline, 40/41 isolates from the study population were fully susceptible to TPV No patients had isolates with 4–10-fold change in IC 50 at baseline No patients had isolates with 4–10-fold change in IC 50 at baseline High-level resistance to TPV (a >10-fold increase in the IC 50 ) was detected in the isolate from 1/41 (2.4%) patients at baseline (subject 111) whose virus had 17 protease gene mutations at entry High-level resistance to TPV (a >10-fold increase in the IC 50 ) was detected in the isolate from 1/41 (2.4%) patients at baseline (subject 111) whose virus had 17 protease gene mutations at entry

13. Tipranavir BI 1182.2 Baseline susceptibility to tipranavir IC50 fold change relative to wild type reference

14. Tipranavir BI 1182.2 Baseline susceptibility (Median Fold-Change) to PIs and TPV

15. Tipranavir BI 1182.2 Baseline susceptibility to indinavir IC50 fold change relative to wild type reference Patients (n)

16. Tipranavir BI 1182.2 Baseline susceptibility to nelfinavir IC50 fold change relative to wild type reference Patients (n)

17. Tipranavir BI 1182.2 Baseline susceptibility to ritonavir IC50 fold change relative to wild type reference Patients (n)

18. Tipranavir BI 1182.2 Baseline susceptibility to saquinavir IC50 fold change relative to wild type reference Patients (n)

19. Tipranavir BI 1182.2 Baseline susceptibility to amprenavir IC50 fold change relative to wild type reference Patients (n)

20. Tipranavir BI 1182.2 Emergence of resistance to TPV Through 48 weeks of treatment: Through 48 weeks of treatment: – 35/41 (85.4%) patients had either undetectable viral load or virus which was susceptible to TPV – 5/41 (12.2%) patients had HIV isolates with 4- 10 fold (average 7-fold) changes in TPV IC 50 – One patient (subject 111) had TPV resistant virus with a 10.1-fold change in TPV IC 50 (was 23.7 at baseline)

21. Tipranavir BI 1182.2 Effect of TPV/RTV treatment on phenotype Change in IC 50 pre- and post-TPV/RTV treatment* *median IC 50 fold change relative to wild type reference for the total study population 28.7045.70 30.45 30.4513.952.002.256 Week 24 8.40 8.4013.30 10.70 10.70 6.60 6.602.002.103 Week 72 2.00 2.00 4.30 4.30 8.60 8.60 1.40 1.402.700.505 Week 80 5.40 5.4028.55 6.30 6.30 4.90 4.900.952.504 Week 48 7.30 7.3018.5524.108.301.700.8040 Day 1 SQVRTVNFVIDVAPVTPVNTime

22. Tipranavir 1182.2 Susceptibility of TPV-resistant isolates before and after treatment Patient Before treatment After treatment SQVRTVIDVNFVAPVTPVSQVRTVIDVNFVAPVTPV 151 34.3 169. 0 3.331.21.42.340.2 197. 7 26.829.02.86.3 1142 39.695.534.061.94.61.340.2 197. 7 71.449.59.67.9 211 43.8 207. 0 88.751.316.31.836.5 147. 7 57.242.24.27.3 261 37.169.134.954.92.30.333.127.07.733.35.67.1 262 10.614.36.59.51.01.140.2 125. 5 32.513.90.74.6 111 48.1 161. 0 41.161.916.823.735.4 127. 2 10.561.935.810.1

23. Tipranavir BI 1182.2 Treatment-emergent mutations HIV-1 protease gene mutations at last patient visit.

24. Tipranavir BI 1182.2 Location of TPV-selected mutations in HIV protease K45 M46 I13 A71 L90 M36 V82 L33 I84 V32

25. Patient 151 T12I, G16A, S37D, R41K, K43T, Q61E, L63P, A71V, V82T, L90M 1142 I13V/I, L33F/L, E35D, M36I, I62V, A71T, V82T 211* L10IV, K20IML, L24IML, L33IVL, Q61K, L63P, K70KI, G73S, V82T, I84V, L89V 261* L24M, L33I, E34D, S37D, K55R, I64V, V82T 262*L33I, S37ND, I54V, A71V, V82T, I84IV Emergent Mutations Fold TPV R 6X 7X 4.6X 10X Tipranavir BI 1182.2 Genotypic changes in post-treatment isolates with reduced susceptibility to TPV *Patients receiving high-dose TPV/RTV. Baseline PI mutations (N) 16 14 13 17 18

26. Tipranavir BI 1182.2 Treatment-emergent PI-resistance mutations Mean 10.8 protease gene mutations at baseline in 33 isolates which remained fully susceptible to TPV at 48 weeks Mean 10.8 protease gene mutations at baseline in 33 isolates which remained fully susceptible to TPV at 48 weeks Mean 16.2 protease gene mutations at baseline in 6 isolates which developed a mean 7-fold reduced susceptibility to TPV Mean 16.2 protease gene mutations at baseline in 6 isolates which developed a mean 7-fold reduced susceptibility to TPV History of exposure to all 4 protease inhibitors at study entry was associated with development of reduced susceptibility to TPV History of exposure to all 4 protease inhibitors at study entry was associated with development of reduced susceptibility to TPV

27. Tipranavir BI 1182.2 Conclusions Isolates from 40/41 multiple PI–experienced patients susceptible to TPV at baseline Isolates from 40/41 multiple PI–experienced patients susceptible to TPV at baseline TPV/RTV remained effective against most HIV isolates with up to16 protease mutations at baseline TPV/RTV remained effective against most HIV isolates with up to16 protease mutations at baseline No evidence of emergence of high-level resistance to TPV during 48 weeks of treatment No evidence of emergence of high-level resistance to TPV during 48 weeks of treatment One patient whose virus had 23.7-fold resistance at baseline decreased to 10.1-fold change One patient whose virus had 23.7-fold resistance at baseline decreased to 10.1-fold change

28. Tipranavir BI 1182.2 Conclusions Isolates from 5/41 patients who were susceptible at baseline developed decreased (average 7-fold) susceptibility to TPV during 48 weeks of treatment Isolates from 5/41 patients who were susceptible at baseline developed decreased (average 7-fold) susceptibility to TPV during 48 weeks of treatment 16+ protease mutations at baseline or prior exposure to all 4 PIs was associated with development of reduced TPV susceptibility 16+ protease mutations at baseline or prior exposure to all 4 PIs was associated with development of reduced TPV susceptibility Viruses from heavily pre-treated patients that developed reduced susceptibility to TPV usually had 16 mutations with 3 of the following mutations L33I/F/V, V82T, I84V, L90M. Viruses from heavily pre-treated patients that developed reduced susceptibility to TPV usually had 16 mutations with 3 of the following mutations L33I/F/V, V82T, I84V, L90M.