# Presentation: 714589

## Tipranavir Resistance

**Lisa K. Naeger, Ph.D.**
**Kimberly Struble, Pharm.D.**
**Division of Antiviral Drug Products**
**Food and Drug Administration**

- May 19, 2005

- FDA Antiviral Advisory
- Committee Meeting

## TPV In Vitro Resistance Profile

-           **L33F  I84V  K45I  I13V  V32I  V82L  M36I  A71V  L10F  I54V**
**Fold IC****50**

**TPV In Vitro Resistance Profile**

-   A valine to isoleucine mutation at the P2 residue in the CA/P2
-    protease cleavage site and a serine to proline mutation in the
-    transframe region were also observed in variants at passage 39

**3X**

**16X**

** ****70X**

## Cross-Resistance In Vitro

- TPV showed <4-fold decreased susceptibility against 90% (94/105) of HIV-1 isolates resistant to APV, ATV,
-   IDV, LPV, NFV, RTV, or SQV.
- TPV-resistant viral molecular clones showed decreased susceptibility to all currently available protease inhibitors except SQV.

## Clinical Resistance

- Baseline genotype/phenotype and virologic outcome analyses
- Development of resistance on TPV treatment

## Clinical Resistance

- Baseline genotype/phenotype and virologic outcome analyses
- Development of resistance on TPV treatment

## Baseline Genotype/Phenotype and Virologic Outcome Analyses

## Endpoints

- Proportion of Responders (confirmed 1 log10 decrease)
- Median DAVG24
- Median change in HIV RNA from Baseline at Week 2, 4, 8, 16, 24

## FDA Reasons for Censoring Primary Endpoint Dataset

**FDA Censored:**
-  Subjects who discontinued while suppressed
-  Subjects who discontinued before confirmed suppression due
-   to an adverse event or other reasons
-  Subjects with no week 8-24 HIV RNA data (D/C weeks 0-4)
-  Subjects who added any new ARV or changed PI

| Overall Number of subjects in BI dataset | 1482 |
| --- | --- |
| Overall number of subjects in Resistance dataset from FDA  | 1015 |
| FDA Censored |   467 |

## FDA Reasons for Censoring DAVG24 Dataset

| Overall number of subjects in BI dataset | 1482 |
| --- | --- |
| Overall number of subjects in FDA resistance dataset  | 1409 |
| FDA censored |    73 |

**Added back the RESIST 2 subjects who did not **
**have week 24 data but had week 16 data**
**who were censored in the primary endpoint analysis**

## Baseline Outcome Analyses

- Number of Baseline PI Mutations
- Type of Baseline PI Mutation
- Baseline TPV Phenotype

## Response by Number of Baseline PI Mutations 

**Proportion of Responders **
**(confirmed **_**>**_**1 log decrease at Week 24) **

**# Any change at positions 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 and 90**

| # Baseline
FDA PI 
Mutations | TPV/r
N=531 |  |  | CPI/r
N=502 |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | All | No T20 | + T20 | All | No T20 | + T20 |
| Overall | 47%
(241/531) | 40%
(148/369) | 65%
(93/144) | 22%
(110/502) | 20%
(76/389) | 30%
(34/113) |
| 1 - 2 | 70%
(30/43) | 69%
(27/39) | 75%
(3/4) | 44%
(19/43) | 41%
(17/41) | 100%
(2/2) |
| 3 - 4 | 50%
(117/236) | 44%
(78/176) | 65%
(39/60) | 27%
(60/221) | 23%
(39/169) | 40%
(21/52) |
| 5+ | 41%
(94/231) | 28%
(43/151) | 64%
(51/80) | 13%
(31/236) | 11%
(20/178) | 19%
(11/58) |

## Response by #Baseline PI Mutations Median Change from Baseline: Overall

- 2

- 4

- Week

- 8

- 16

- 24

- 0

## Response by #Baseline PI Mutations Median Change from Baseline: No T20

- 2

- 4

- Week

- 8

- 16

- 24

- 0

## Response by #Baseline PI Mutations Median Change from Baseline: +T20 Use

- 2

- 4

- Week

- 8

- 16

- 24

- 0

## Baseline Outcome Analyses

- Number of Baseline PI Mutations
**Type of Baseline PI Mutation**
- Baseline TPV Phenotype

## Effect of Type of Baseline PI Mutation on the Primary Endpoint

|  | TPV/r Arm
(n=513) |  |  |
| --- | --- | --- | --- |
| Mutation | All | No T20 | +T20 |
| Overall | 47%
(240/513) | 40%
(147/369) | 65%
(93/144) |
| I13V/A/L/S | 40%
(69/171) | 27% 
(32/119) | 69%
(37/54) |
| V32I/L | 39%
(29/74) | 26%
(12/46) | 61%
(17/28) |
| M36I/A/V/L/N | 40%
(124/310) | 29%
(60/208) | 63%
(64/102) |
| I47V/A | 31%
(29/93) | 18%
(11/62) | 58%
(18/31) |
| Q58E | 38%
(28/74) | 27% 
(14/52) | 64%
(14/22) |
| D60E/K/A/N | 39%
(43/110) | 30%
(24/79) | 61%
(19/31) |

## Effect of Type of Baseline PI Mutation on the Primary Endpoint

|  | TPV/r Arm
(n=513) |  |  |
| --- | --- | --- | --- |
| Mutation | All | No T20 | +T20 |
| Overall | 47%
(240/513) | 40%
(147/369) | 65% 
(93/144) |
| V82 any 
change | 48%
(149/311) | 41%
(90/222) | 66%
(59/89) |
| V82A/T/C | 50%
(133/264) | 45%
(85/189) | 64%
(48/75) |
| V82S/F/I/L | 34%
(16/47) | 15%
(5/33) | 79%
(11/14) |
| I84V/A | 41%
(64/155) | 31%
(32/103) | 62%
(32/52) |
| V82 + I84V | 36%
(12/33) | 25%
(6/24) | 67% 
(6/9) |

## Baseline Outcome Analyses

- Number of Baseline PI Mutations
- Type of Baseline PI Mutation
**Baseline TPV Phenotype**

## Proportion of Responders by Baseline TPV Phenotype

| Baseline TPV Phenotype | TPV
 ALL | TPV
 No T20 | TPV
 + T20 |
| --- | --- | --- | --- |
| 0-3 | 54%
(120/223)  | 45%
(74/163) | 77%
(46/60) |
| >3-10 | 29%
(22/75) | 21%
(10/47) | 43%
(12/28) |
| >10 | 27%
(4/15) | 0%
(0/8) | 57%
(4/7) |

## Baseline TPV Phenotype: DAVG24

| Baseline TPV Phenotype | TPV 
ALL | TPV
No T20 | TPV 
+ T20 |
| --- | --- | --- | --- |
| 0-3 | -1.55 (237) | -1.31 (176) | -2.23 (61) |
| >3-10 | -0.53 (79) | -0.41 (49) | -1.30 (30) |
| >10 | -0.84 (20) | -0.24 (11) | -1.87 (9) |

## Mutations Developing on TPV Treatment

## Mutations that Developed on TPV: RESIST 1 and 2 

| 
Mutation | Number Developing (%)
(n = 59) |
| --- | --- |
| L10I/V/S | 17  (29%) |
| I13V | 9  (15%) |
| L33F/I/V | 15  (25%) |
| E34D/A/K/T/N/Q | 6  (10%) |
| E35D/G/N | 9  (15%) |
| M36V/I/A | 9  (15%) |
| I47V | 7  (12%) |
| I54V/A/M | 9  (15%) |
| K55R | 8  (14%) |
| A71V/I/L/F | 6  (10%) |
| V82T | 20  (34%) |
| V82L/C/S | 10  (17%) |
| I84V | 15  (25%) |
| L89M/V/W | 7  (12%) |

## Resistance Summary

- TPV is a protease inhibitor with antiviral activity against multi PI-resistant clinical HIV-1 isolates.
- The most common protease mutations that developed in >20% of isolates from treatment-experience subjects who failed on TPV/r treatment were
-   L10I/V/S, I13V, L33V/I/F, M36V/I/L, V82T or L, and I84V.
- The resistance profile in treatment-naive subjects has not yet been characterized.

## Resistance Summary

- Virologic response rates in TPV/r-treated subjects were reduced when:
- isolates with substitutions at positions **I13, V32, M36, ****I47****, Q58, D60 or I84** and substitutions **V82S/F/I/L** were present at baseline.
- the number of baseline PI mutations was **5** or more.
- Subjects taking T20 with TPV/r were able to achieve >1.5 log10 reductions in viral load through 24 weeks
- the baseline phenotype for TPV was **>3**.
- Consistent observations were made in each of the analyses conducted by multiple endpoints.
- 20% more responders in the TPV/r arm compared to CPI/r
- Greater reductions in viral load in TPV/r arm vs. CPI/r arm