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Preclinical and Early Clinical Evaluation of SPI-452, a New Pharmacokinetic Enhancer (PKE) S. Gulnik, M. Eissenstat, E. Afonina, D. Ludtke, J. Erickson, R. Dagger, B. Wynne, R. Guttendorf *
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Acknowledgements Wei Cao Dehui Duan Barbara Jaruga Weihua Ji Jason Rutledge Hiroko Yokoe Betty Yu
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Introduction • Protease inhibitors (PIs) are a cornerstone of HAART • Majority of PIs require PK boosting with ritonavir – Advantages • Increases drug exposure • Reduces dosing frequency and pill burden • Improves antiretroviral efficacy – Disadvantages • Increases GI side effects • Increases lipid levels • Risk of generating protease resistant mutants in non-PI containing regimens
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Goals of the Sequoia PKE Program • Develop a potent and selective inhibitor of CYP3A4 that lacks inherent antiviral activity • Enhance exposure of co-administered PIs comparable to ritonavir • Favorable safety and tolerability profile • Favorable metabolic/lipid profile • Stand alone or fixed dose combination
SPI-452 Lead Candidate from PKE Program • Discovered through a targeted internal PKE research program • Potent inhibitor of CYP3A – IC50 in microsomes ≈ 10-20 nM – Preferential inhibition of CYP3A4/3A5 • No anti-HIV activity • No alteration in anti-HIV activity of HAART drugs in vitro
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PK Enhancement of PIs In Vitro and In Vivo PI Enhancement in Human Liver Microsomes 6000
Without PKE WithSPI-452 With RTV
Maximum achievable levels
4000 3000 2000 1000 0
BPV
LPV
SQV
TPV
APV
ATV
NFV
(HCV)
PI AUC ratio • mean ± SD
AUC*
5000
DRV
IDV
*Based on percent of substrate remaining vs time
PI Enhancement in Animals (normalized for PKE AUC) 20 Rats
Dogs
SPI-452 Ritonavir
15 10 5 0 SQV
LPV
ATV
SQV
LPV
Study 0452-001: First Time in Humans Study Design (N=58) Phase 1* Cohort 1 SPI-452 25 mg Cohort 2 SPI-452 50 mg Cohort 3 SPI-452 100 mg Cohort 4 SPI-452 200 mg Cohort 5 SPI-452 400 mg Cohort 6 SPI-452 600 mg * Each cohort in Phase 1: • SPI-452 (n=6) • Placebo (n=2)
Study 0452-001: First Time in Humans Safety • SPI-452 was generally safe and well tolerated – No withdrawals due to study drug – No serious adverse events (SAEs) – Adverse events (AEs) • 19 subjects experienced ≥ 1 AE • Usually mild in severity • No pattern of body-system AEs • Headache (n=4) and pharyngitis (n=4) most common – No clinically relevant changes in ECG, vital signs, or clinical laboratory parameters
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Study 0452-001: First Time in Humans SPI-452 Mean Concentration-Time Profiles 25 mg SPI-452 200 mg SPI-452
Concentration (ng/mL)
10,000
50 mg SPI-452 400 mg SPI-452
100 mg SPI-452 600 mg SPI-452
1000 100 10 1 0.1 0
6
12
18
24 Time (h)
30
36
42
48
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Study 0452-001: First Time in Humans SPI-452 Enhances Saquinavir Exposure
Saquinavir Parameter ratio (with/without SPI-452)
Single Dose: Mean ± SEM 50
Cmax AUC
40 30 20 10 0
200 mg
50 mg SPI-452 dose
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Study 0452-002: Proof of Clinical Concept Study Design (N=67) Day -7
Day 16
ATV 300 mg (n=6)
SPI-452 Alone
SPI-452 + ATV
ATV
DRV 600 mg (n=6)
SPI-452 Alone
SPI-452 + DRV
DRV
SPI-452 Alone
SPI-452 + PI PBO
PI PBO
PBO
PBO + PI PBO
PI PBO
PI PBO (n=4)
Days 17 to 28
3 cohorts in the study. In each cohort: SPI-452 (n=18) or Placebo (n=4) • Cohort 1: SPI-452 25 mg QD • Cohort 2: SPI-452 50 mg QD • Cohort 3: SPI-452 200 mg QD
Washout
Day 15
Washout
Days 1 to 14
PI PBO (n=6)
Days -6 to -1
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Study 0452-002: Proof of Clinical Concept Safety • SPI-452 was generally safe and well tolerated – No withdrawals due to study drug – No SAEs – AEs • 45 subjects experienced ≥ 1 AE • Usually mild in severity • No pattern of body-system AEs • Headache (n=17), nausea/emesis (n=11), and diarrhea (n=7) most common AEs – No clinically meaningful changes in ECG or clinical laboratory parameters – No statistically significant changes in triglyceride and LDL levels compared to placebo
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Study 0452-002: Proof of Clinical Concept SPI-452 Enhances Darunavir Exposure
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Study 0452-002: Proof of Clinical Concept SPI-452 Enhances Darunavir Exposure (AUC)
AUC (0-24) ratio (day X/day -7)
Darunavir Mean AUC0-24 Enhancement
25 mg SPI-452 50 mg SPI-452 200 mg SPI-452
Dosing day
14
Study 0452-002: Proof of Clinical Concept SPI-452 Enhances Darunavir Exposure (C12) Darunavir Mean C12 Enhancement
Study 0452-002: Proof of Clinical Concept SPI-452 Enhances Atazanavir Exposure
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Study 0452-002: Proof of Clinical Concept SPI-452 Enhances Atazanavir Exposure (AUC)
AUC (0-24) ratio (day X/day -7)
Atazanavir Mean AUC0-24 Enhancement
25 mg SPI-452 50 mg SPI-452 200 mg SPI-452
Dosing day
17
Study 0452-002: Proof of Clinical Concept SPI-452 Enhances Atazanavir Exposure (C24) Atazanavir Mean C24 Enhancement
Atazanavir C24 (nM)
800
600 ATV alone 25 mg SPI-452
400
50 mg SPI-452 200 mg SPI-452
200 Day 15 0
Day 15
Day -7 Boosting Ratio:
3
5
Day 16 9
4
8
13
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Study 0452-002: Proof of Clinical Concept Summary •
SPI-452 was generally safe and well tolerated
•
No statistically significant changes in triglyceride and LDL levels compared to placebo
•
SPI-452 PK – Reached steady state by day 14 – Accumulation of SPI-452 was slightly greater than linear with multiple dosing
•
SPI-452 significantly enhanced systemic exposures of darunavir and atazanavir
•
Cmin is the parameter most sensitive to SPI-452 enhancement
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Conclusion SPI-452 achieved all PKE Program goals: • Potent and selective inhibitor of CYP3A4 that lacks inherent antiviral activity • Favorable safety and tolerability profile • Favorable metabolic/lipid profile • Enhances exposure of co-administered PIs comparable to ritonavir
SPI-452 is a promising new agent that may expand future treatment options and enhance current standard of care