1	Safety Presentation on NDA 21-814 Tipranavir Andrea N. James, M.D. Primary Medical Reviewer Division of Antiviral Drug Products Food and Drug Administration
2	Presentation Outline Safety Summary Data reviewed Summary of AEs, SAEs, AEs leading to discontinuation Safety Concerns Hepatotoxicity Rash Hyperlipidemia Clinical Progression AIDS Defining Illnesses, Death Summary of the Risk/Benefit Analysis of TPV/r Questions to the Committee
3	Data Reviewed Review of data submitted with original NDA Submitted December 22, 2004 Covers TPV/r development program through June 11, 2004 NDA Safety Update Submitted February 22, 2005 Covers TPV/r development program through September 30, 2004 NDA Safety Update confirms conclusions drawn from the original NDA submission
4	TPV/r Safety Summary
5	Safety Summary: RESIST trials
6	Tipranavir Safety Concerns
7	Hepatotoxicity ALT/AST DAIDS Toxicity Grading Scale Grade 1 1.25-2.5x ULN Grade 2 >2.5-5.0x ULN Grade 3 >5.0-10.0x ULN Grade 4 >10.0x ULN ALT ULN ranged from 32 - 52 U/L AST ULN ranged from 34 - 59 U/L
8	Hepatotoxicity 19% of healthy volunteers in 18 Phase 1 studies had drug induced ALT elevations (N = 631) 13% had ALT elevations above the ULN 4% Grade 3 ALT 2% Grade 4 ALT Median time to onset 16 days (range: 6- 46 days)
9	Study 1182.52: Dose Dependent Hepatotoxicity
10	Study 1182.52: Exposures Across Doses RTV and TPV
11	RESIST Trials: Treatment Emergent Hepatotoxicity
12	RESIST Trials: ALT/AST Grades 3 and 4 Maximum Values
13	RESIST Trials: Outcomes of Grade 3/4 ALT/AST Elevations
14	RESIST Trials: Hepatotoxicity Presentation Asymptomatic Median time to onset = 56.5 days (8 – 176 days)
15	RESIST Trials: Potential Risk Factors for Hepatotoxicity Baseline liver parameters ALT/AST Hepatitis status
16	RESIST Trials: Baseline ALT/AST Inclusion Criteria: < Gr 1 ALT/AST Subjects with ALT/AST Protocol Violations 3% TPV/r (N = 746) > Grade 1 at baseline 19 Grade 2 ALT/AST 2 Grade 3 ALT/AST 3% CPI/r (N = 737) > Grade 1 at baseline 22 Grade 2 ALT/AST 1 Grade 3 ALT/AST
17	RESIST Trials: Subjects With Baseline ALT/AST > Grade 1 TPV/r arm 5.0% (n= 1/21) of subjects developed a Grade 3 or 4 ALT/AST CPI/r arm 20% (4/23) of subjects developed a Grade 3 or 4 ALT/AST
18	RESIST Trials: Baseline Hepatitis as a Risk Factor for TPV Induced Hepatotoxicity
19	RESIST Trials: Baseline Hepatitis Status Not Sole Predictor
20	Hepatotoxicity Summary Transaminase elevations were common throughout the development program. ALT > AST Healthy volunteers, HIV+ subjects Presentation Asymptomatic and can occur at any time Outcome Majority resolve either on or off treatment Treatment limiting Risk factors Viral hepatitis ? ALT value at baseline Monitoring/Management Early Often
21	Rash Study 1182.22 Drug interaction study of Ortho-Novum 1/35 and TPV/r 52 predominately white healthy females enrolled (mean age = 35.2 years ) Randomized to TPV/r 500/100 mg or TPV/r 750/200 mg twice daily on d 4 – 16 and Ortho-Novum 1/35 on d 1 and d 16
22	Rash: Study 1182.22 33% (n = 17) of subjects developed rash An additional 18% of subjects had musculoskeletal symptoms or symptoms consistent with hypersensitivity. Study prematurely stopped ? Serum sickness
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25	Rash TPV is a sulfonamide
26	Rash and Sulfa Allergy
27	Rash Phase 1 trials 13% females (N=265) versus 4% males (N=345) developed rash Phase 2 trials 13% females (N=108) versus 8% males (N=733) developed rash. Study 1182.52 (N=216) Suggests rash may be dose-related Overall 8.6% of subjects developed rash 10% (n=7/73)TPV/r 500/100 mg 4% (n=3/72) TPV/r 500/200 mg 15% (n=11/71) TPV/r 750/200 mg
28	RESIST trials: Rash
29	Rash Summary TPV is a sulfonamide Cannot rule out relationship to rash Overall rash is not more common on the TPV/r arms Female subjects on TPV/r have a higher frequency of rash than male counterparts Rate is consistent throughout Phase 1-3 studies (13-14%) Few females in these studies ? Cause Immune mediated reaction Hormonally mediated
30	Hyperlipidemia
31	Hypertriglyceridemia Triglyceride toxicity scale Grade 2: 400-750 mg/dL Grade 3: 751-1200 mg/dL Grade 4: >1200 mg/dL
32	% of Treatment Emergent Hypertriglyceridemia
33	Hypercholesterolemia Cholesterol toxicity grading scale Grade 2 >300 – 400 mg/dL Grade 3 >400 – 500 mg/dL Grade 4 > 500 mg/dL
34	% of Treatment Emergent Hypercholesterolemia
35	Hyperlipidemia Summary TPV/r group has a much higher rate of hyperlipidemia than the CPI/r group 46% of TPV/r subjects had Grade 2-4 treatment emergent hypertryglyceridemia vs. 24% of CPI/r subjects 15% of TPV/r subjects had Grade 2-4 treatment emergent hypercholesterolemia vs. 5% of CPI/r subjects
36	Clinical Progression Events
37	RESIST Trials: Deaths Possible cause of similar mortality rate Advanced population studied Natural disease course Many comorbid diseases Many concomitant medications Study design Early loss of control subjects Time point too early to see a difference
38	TPV/r Risk/Benefit Assessment Efficacy Superior activity over a suboptimal control in 3 class experienced, advanced HIV-1 infected subjects Resistance profile Impact of TPV score and baseline PI mutations on treatment response PK profile Multiple drug-drug interactions High inter-patient variability in TPV exposure Safety profile Hepatotoxicity, rash and hyperlipidemia
39	Contributors Melisse Baylor, M.D. Neville Gibbs, M.D., MPH Rosemary Johann-Liang, M.D. Jenny J. Zheng, Ph.D. Susan Zhou, Ph.D.
40	Question 1 Do the data demonstrate that tipranavir/ritonavir (TPV/r) is safe and effective for the multi-drug resistant HIV-1 infected population? If no, what additional data are needed to provide evidence of safety and efficacy? If yes, please address the appropriate population for TPV/r use considering the following: limited inclusion criteria of the RESIST trials drug-drug interactions resistance information and patterns associated with optimal use safety considerations
41	Question 2 Given the data on transaminase elevations, please provide your recommendations for: TPV/r use in patients with underlying liver disease Monitoring and management of hepatotoxicity during clinical use Future studies
42	Question 3 The limited amount of data in females with HIV infection in the TPV program shows an increased incidence of rash in females. Please provide your recommendations for: Investigation of this safety signal in future studies with TPV
43	Question 4 Current information indicates the net effect of TPV/r on substrates of CYP1A2, CYP2C9, CYP2C19 and CYP2D6 is not known, and there are competing effects of TPV/r on CYP3A (inhibition) and P-glycoprotein (induction). Please comment on additional post-marketing drug interaction studies.
44	Question 5 Given the high inter-patient variability in TPV exposures following fixed doses and exposure (blood levels)-virologic response relationships, could a biomarker such as Cmin/IC50 be used for the individualization of TPV/r therapy? Please discuss the studies that would supplement the data presented today.
45	Question 6 Please provide your recommendations regarding the display of TPV/r resistance data/analyses in the TPV package insert that would be useful to clinicians.
46	Examples Baseline Outcome Analyses Baseline Number of PI Mutations Type of PI Mutation Baseline Phenotype TPV score Key mutations Endpoints Primary endpoint (proportion of responders) Change from Baseline (e.g. median, average) +/-T20 use
47	Response by Baseline Number of PI Mutations
48	Response by Baseline PI Mutations Median Change from Baseline - Overall
49	Question 7 Please discuss and recommend future study designs /data acquisition for the heavily pretreated population.