# Presentation: 739432

## Tipranavir NDA 21-814:Efficacy Evaluation

- Rafia Bhore, Ph.D.
- Statistician Reviewer
-    Division of Antiviral Drug Products
- Food and Drug Administration

- May 19, 2005		FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## 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

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## Study Design of RESIST* Trials 

- (Studies 1182.12 and 1182.48)
- *_R_andomized _E_valuation of _S_trategic _I_ntervention in Multi-Drug Re_S_istant Patients with _T_ipranavir

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## 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
- ?

- Screening
- Failure

****** ****2**
- mutations at
- codons
- 33, 82, 84,
- or 90 ?

**Genotype**
**Resistance**
**Testing**

**SCREENING**
- 3 ARV class and
- dual PI-experienced

- Enroll in Trial 1182.51

**Enroll in RESIST Trial**

- Go to
- A

**RESIST 1:  USA, Canada, Australia**
**RESIST 2:  Europe, Latin America**

- 4

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## Amendment # 2

***Open-label***

**Roll-over**
- Trial 1182.17

- Patients in comparator PI/RTVgroup with lack of initial
- virologic response or confirmed
- virologic failure will** ****roll-over to **
**TPV/RTV group**
- in** **Roll-Over Trial 1182.17

- NOTES:
- PI=Protease Inhibitor
- TPV=tipranavir, RTV=ritonavir
- APV=amprenavir, SQV=saquinavir
- IDV=indinavir, LPV=lopinavir

- 5

- Allowed patients with
- highly PI resistant virus
- to be treated with
- PI-based regimen.

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## Patient Disposition 

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## Patient Disposition

| Number of patients | TPV/r + OBR | CPI/r + OBR |
| --- | --- | --- |
| Total randomized and treated with 16 week data | 	746 | 	737 |
| 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% |

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## Demographics and Baseline Characteristics

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## 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)

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## 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)

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## Baseline Disease Characteristics

|  | RESIST 1(1182.12)
N=620 | RESIST 2(1182.48)
N=539 |
| --- | --- | --- |
| HIV RNA (log10 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/mm3)
	Mean (Range)
		<   200 cells/mm3
		>= 200 cells/mm3 | 
164 (0.5 to 1183.5)
67%
33% | 
224 (1.5 to 1893)
53%
47% |

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## 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% |

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## 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% |

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## Evaluation of Potential Biases due toOpen-Label Design

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## 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

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## Pre-determined vs Actual Background Regimen

- Total # of pre-determined regimen = 155
- Total # of actual regimen = 161
- Mismatches between Pre-determined vs Actual

| RESIST 1 |  |  | RESIST 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%  | 14%  |

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## 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%)

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## 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

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## 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.

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## 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.

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## Initial Lack of Virologic Response by Week 8

- Viral load has not dropped 0.5 log10 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 log10 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

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## Efficacy Evaluation

- Primary Efficacy (FDA Analysis)

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## 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

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## 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% |

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## 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% | 2% | 6% | 1% |
| Died | 0% | 0% | 0% | <1% |
| Discontinued due to adverse events | 1% | 0% | 1% | 1% |
| Discontinued due to other reasons | 1% | 1% | 0% | 0% |
| Discontinued while suppressed | 0% | 1% | 1% | 0% |

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## 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

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## Sensitivity AnalysisEfficacy Results

| Analysis type | TPV/r + OBR
N=582 | CPI/r + OBR
N=577 | Difference (TPV/r-CPI/r) (95% CI) |
| --- | --- | --- | --- |
| ITT | 234  (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%)**

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## Subgroup Analyses

- By T-20 stratum
- By Control Protease Inhibitors adjusting for Resistance and Experience

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## Subgroup-Analysis by T-20 use stratum

| Enfuvirtide (ENF, T-20) used? | TPV/r  | CPI/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%) |  |

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## 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 month or >=6 months
- Resistant
- Possibly resistant or Resistant according to TruGene or Virtual Phenotype assay regardless of prior duration of exposure to PI

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## Baseline Resistance Patterns in PI Strata

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## Confidence Intervals on Treatment Differences (TPV/r – CPI/r)

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## 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%.

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## 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.

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005

## 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

- FDA Antiviral Drugs Advisory Committee Meeting

- May 19, 2005