Fortovase: maximizing power, maintaining safety

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Fortovase maximizing power, improving safety
Sharon Walmsley
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Saquinavir evolution of a protease inhibitor
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1995
1998
2002
2004
Saquinavir launched worldwide for HIV infection
worlds first protease inhibitor
Soft-gel capsules launched
Boosted saquinavir improved pharmacokinetics,
convenience and safety
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Saquinavir plasma concentrations are
significantly boosted by low-dose ritonavir
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8000
7000
Saquinavir 1600 mg ritonavir 100 mg
6000
5000
Saquinavir concentration (ng/ml)
4000
Saquinavir 1200 mg ritonavir 100 mg
3000
2000
Saquinavir 1200 mg
1000
0
0
5
10
15
20
25
Time after evening dose (hours)
Day 13 data. Adapted from Kilby et al.
Antimicrobial Agents and Chemotherapy
2000442672-2678
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The ideal dosage of saquinavir/ritonavir is
1000/100 mg twice daily
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• Convenient twice-daily dosage
• Proven anti-HIV efficacy in major clinical trials
• Very well tolerated
• No major organ toxicities
• Little effect on plasma lipid levels

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The ideal dosage of saquinavir/ritonavir is
1000/100 mg twice daily
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SQV/r 1000/100 mg full-fat breakfast
4000
3000
SQV/r 1000/100 mg normal breakfast
SQV plasma concentration (ng/ml)
2000
1000
0
0
2
4
6
8
10
12
Time (h)
Veldkamp et al. J A I D S 200127344-349
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Other boosted protease inhibitors
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• Amprenavir/ritonavir 600/100 mg bid
• Indinavir/ritonavir 800/100 mg bid
• Lopinavir/ritonavir 400/100 mg bid
• The best way to compare them is through
  head-to-head clinical trials

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MaxCmin1 the first head-to-head comparison of
boosted protease inhibitors
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Clinical indication for ritonavir-boosted PI
treatment
PI-naivePI failurePI intolerance
Randomization 11
Indinavir/r800/100 mg bid 158 patients
Saquinavir/r1000/100 mg bid 148 patients
Castagna et al. 9th CROI, 2002 abstract 450-W
and oral presentation
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MaxCmin1 baseline characteristics
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Antiretroviral-naive
25
PI-naive
14
PI-experienced
61
Castagna et al. 9th CROI, 2002 abstract 450-W
and oral presentation
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MaxCmin1 patient disposition at 24 weeks
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Miscellaneous
100
Virological failure
Adverse events
80
60
Still on randomized therapy
patients
73
83
40
20
0
Saquinavir/r 1000/100 mg bid (n 148)
Indinavir/r 800/100 mg bid (n 158)
Miscellaneous lost to follow-up, withdrawn
consent, other
Adapted from Castagna et al. 9th CROI, 2002
poster 450-W
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MaxCmin1 grade 3 or 4 adverse eventsLess common
in saquinavir/r patients at 24 weeks
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Organ system
IDV/r
SQV/r
Nervous system 6 3Pulmonary 4 1Cardiovascular 2
0Renal 10 0Gastrointestinal 18 14Skin and
hair 10 6Fatigue and/or fever 3 3Laboratory 15 1
6Other 7 2 Total 75 45
Some patients experienced gt1 grade 3 or 4
adverse event
Adapted from Castagna et al. 9th CROI, 2002
poster 450-W
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Wider spectrum of adverse events in
indinavir/ritonavir patientsClinical non-fatal
adverse events leading to withdrawal
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(ITT/exposed)
Indinavir/r
Saquinavir/r
Nervous system
Cardiovascular
Severity Grade I 6 Grade II 13 Grade III 13 Grade
IV 5 Not available 6
Renal
Gastrointestinal
Skin
Other
0
2
4
6
8
10
Adapted from Castagna et al. 9th CROI, 2002
poster 450-W
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Saquinavir/r is at least as effective as
indinavir/r over 24 weeks
lt400 copies/ml at 24 weeks ITT/exposed,
discontinuationfailure
100
80
76
60
61
patients
40
20
0
Saquinavir/r 1000/100 mg bid (n 148)
Indinavir/r 800/100 mg bid (n 158)
Adapted from Castagna et al. 9th CROI, 2002
poster 450-W
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Saquinavir/r is at least as effective as
indinavir/r over 24 weeks
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Increases in CD4 count from baseline
100
80
Saquinavir/r 1000/100 mg bid
60
Cells/mm3
40
Indinavir/r 800/100 mg bid
20
0
Baseline
Week 4
Week 12
Week 24
Adapted from Castagna et al. 9th CROI, 2002
poster 450-W
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MaxCmin1 24-week summary
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SQV/r
IDV/r
ITT HIV-RNA lt400 c/ml 76 61 ITT
HIV-RNA lt100 c/ml 68 56 Grade
3/4 adverse events 45 75
Discontinuation (AE) 8
20 analysis includes all patients who
received randomized medication discontinuation
of randomized therapy failure
Adapted from Castagna et al. 9th CROI, 2002
poster 450-W
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MaxCmin1 24-week summary
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• The first randomized comparison of two boosted
  protease inhibitors
• Saquinavir/r 1000/100 mg bid was highly potent in
  suppressing viral replication
• Saquinavir/r 1000/100 mg bid appears to be better
  tolerated than indinavir/r

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• MaxCmin1 final 48-week results
• XIV International AIDS Conference

Wednesday, 10 July 2002 Hall 21 11.15 - 11.30
a.m. Abstract number WeOrB1265
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The next head-to-head comparison of boosted PIs
MaxCmin2
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SQV 1000 mg bid RTV 100 mg bid
PI resistance failures PI toxicity or adherence
failures First-line PI
randomize
LPV 400 mg bid RTV 100 mg bid
LPV lopinavir
14 countries 40 centres 339 patients
SQV saquinavir RTV ritonavir
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Triglyceride elevations with lopinavir/r increase
with previous treatment experience
45
41
39
40
35
30
30
22
25
Patients () with triglyceride
levels gt750 mg/dl
20
13
15
11
10
5
0
ART naive
Single PI
Multiple PI
experienced
experienced
Dosage range 400/100, 400/200 or 533/133 mg bid
Stryker et al., Johnson et al., Feinberg et al.
and Rockstroh et al. 5th Int Cong Drug Ther HIV
Infection, 2000
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Saquinavir 1000/100 mg bid efavirenz in highly
treatment-experienced patients (n 32)
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Lipid profile
8
Cholesterol
7
6
5
Level (mmol/L)
4
3
2
Triglycerides
1
0
0
24
48
Time (weeks)
1 mmol/L cholesterol 38.6 mg/dl 1 mmol/L
triglyceride 88.5 mg/dl
Piketty et al. 1st IAS Conf Pathogen Treat HIV
Infect, 2001 poster 508
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Patients switching to saquinavir/r1000/100 mg
bid may experience improvements in plasma lipid
levels
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SQVRTV 400/400 mg bid 2NRTI ? 3 months HIV RNA
lt400 copies/ml
Randomization 11
n 11
n 10
SQVRTV 400/400 mg bid same 2NRTIs
SQV/r 1000/100 mg bid same 2NRTIs
OBrien et al. 3rd Int Workshop Clin Pharmacol
HIV Ther, 2002 poster 2-1
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Patients switching to saquinavir/r1000/100 mg
bid may experience improvements in plasma lipid
levels
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Stayed on 400/400
Switched to 1000/100
50
27
25
0
Change in median plasma lipid level, baseline to
24 weeks (mg/dl)
-32
-50
Cholesterol
Triglycerides
-100
-150
-159
-200
OBrien et al. 3rd Int Workshop Clin Pharmacol
HIV Ther, 2002 poster 2-1
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Summary
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• Saquinavir/r 1000/100 mg bid is effective and
  well tolerated in HIV infection
• Saquinavir/r 1000/100 mg bid is better tolerated
  than indinavir/r 800/100 mg bid
• Saquinavir/r 1000/100 mg bid is likely to have
  less effect on plasma lipids than other boosted
  PIs