tipranavir resistance
DESCRIPTION
Tipranavir Resistance. Lisa K. Naeger, Ph.D. Kimberly Struble, Pharm.D. Division of Antiviral Drug Products Food and Drug Administration. FDA Antiviral Advisory Committee Meeting. May 19, 2005. TPV In Vitro Resistance Profile. - PowerPoint PPT PresentationTRANSCRIPT
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Tipranavir Resistance
Lisa K. Naeger, Ph.D.Kimberly Struble, Pharm.D.
Division of Antiviral Drug ProductsFood and Drug Administration
May 19, 2005 FDA Antiviral Advisory Committee Meeting
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During selection of resistant viruses by serial in vitro passage, breakthrough mutations arose in this sequence:
L33F I84V K45I I13V V32I V82L M36I A71V L10F I54V
Fold IC50
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
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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.
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Clinical Resistance
• Baseline genotype/phenotype and virologic outcome analyses
• Development of resistance on TPV treatment
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Clinical Resistance
• Baseline genotype/phenotype and virologic outcome analyses
• Development of resistance on TPV treatment
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Baseline Genotype/Phenotype and Virologic Outcome Analyses
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Endpoints
• Proportion of Responders (confirmed 1 log10 decrease)
• Median DAVG24
• Median change in HIV RNA from Baseline at Week 2, 4, 8, 16, 24
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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
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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 datawho were censored in the primary endpoint analysis
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Baseline Outcome Analyses
• Number of Baseline PI Mutations
• Type of Baseline PI Mutation
• Baseline TPV Phenotype
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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
# BaselineFDA PI Mutations
TPV/rN=531
CPI/rN=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)
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Response by #Baseline PI Mutations Median Change from Baseline: Overall
-2.5
-2
-1.5
-1
-0.5
0
TPV 1 to 4
TPV 5+
CPI 1 to 4
CPI 5+
2 4
Week
8 16 240
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Response by #Baseline PI Mutations Median Change from Baseline: No T20
2 4
Week
8 16 240-2.5
-2
-1.5
-1
-0.5
0
TPV 1 to 4
TPV 5+
CPI 1 to 4
CPI 5+
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Response by #Baseline PI Mutations Median Change from Baseline: +T20 Use
2 4
Week
8 16 240
-2.5
-2
-1.5
-1
-0.5
0
TPV 1 to 4TPV 5+CPI 1 to 4CPI 5+
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Baseline Outcome Analyses
• Number of Baseline PI Mutations
• Type of Baseline PI Mutation
• Baseline TPV Phenotype
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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)
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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)
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Baseline Outcome Analyses
• Number of Baseline PI Mutations
• Type of Baseline PI Mutation
• Baseline TPV Phenotype
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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)
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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)
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Mutations Developing on TPV Treatment
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Mutations that Developed on TPV: RESIST 1 and 2
MutationNumber 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%)
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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.
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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