preclinical and early clinical evaluation of spi-452, a new … · 2016. 3. 7. · study 0452-002:...
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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 CaoDehui Duan
Barbara JarugaWeihua Ji
Jason RutledgeHiroko 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
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SPI-452Lead 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
0
5
10
15
20
LPVSQV ATV
PI A
UC
ratio
• m
ean
±SD
PI Enhancement in Animals(normalized for PKE AUC)
Rats
LPVSQV
Dogs
RitonavirSPI-452
PI Enhancement in Human Liver MicrosomesMaximum achievable levels
0
2000
3000
6000
LPV DRV
5000
AU
C*
APV
4000
1000
BPV(HCV)
SQV TPV ATV NFV IDV
Without PKEWithSPI-452With RTV
*Based on percent of substrate remaining vs time
Cohort 1
Day -1 Day 1
SQV 1000 mg
orPBO
SPI-452 50 mg + SQV 1000 mg
SQV 1000 mg/PBO
PBO/PBO
Cohort 2
Day -1 Day 1
SQV 1000 mg
orPBO
SPI-452 200 mg + SQV 1000 mg/
SQV 1000 mg/PBO
PBO/PBO
Phase 1* Phase 2**
Study 0452-001: First Time in HumansStudy Design (N=58)
Cohort 6 SPI-452 600 mg
Cohort 5 SPI-452 400 mg
Cohort 4 SPI-452 200 mg
Cohort 3 SPI-452 100 mg
Cohort 2 SPI-452 50 mg
Cohort 1 SPI-452 25 mg
* Each cohort in Phase 1:• SPI-452 (n=6) • Placebo (n=2)
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** Each cohort in Phase 2:• SQV SPI-452 + SQV (n=6) • SQV SQV + PBO (n=2)• PBO PBO + PBO (n=2)
Study 0452-001: First Time in HumansSafety
• 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 HumansSPI-452 Mean Concentration-Time Profiles
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0.1
1
10
100
1000
10,000
0 6 12 18 24 30 36 42 48Time (h)
Con
cent
ratio
n (n
g/m
L)
600 mg SPI-452100 mg SPI-452
400 mg SPI-45250 mg SPI-452
200 mg SPI-45225 mg SPI-452
0
10
20
30
40
50
50 mg
SPI-452 dose
Saqu
inav
ir Pa
ram
eter
ratio
(with
/with
out S
PI-4
52)
Single Dose: Mean ± SEM
200 mg
Cmax
AUC
Study 0452-001: First Time in HumansSPI-452 Enhances Saquinavir Exposure
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Study 0452-002: Proof of Clinical Concept Study Design (N=67)
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
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Day -7
Days-6 to -1
Days 1 to 14
Day 15
Day 16
Days 17 to 28
ATV 300 mg(n=6)
Washout
SPI-452Alone
SPI-452+
ATVATV
Washout
DRV 600 mg(n=6)
SPI-452Alone
SPI-452+
DRVDRV
PI PBO(n=6)
SPI-452Alone
SPI-452+
PI PBOPI PBO
PI PBO(n=4) PBO
PBO+
PI PBOPI PBO
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)
14
Dosing day
AU
C (0
-24)
ratio
(day
X/d
ay -7
)
25 mg SPI-45250 mg SPI-452
200 mg SPI-452
Darunavir Mean AUC0-24 Enhancement
15Study 0452-002: Proof of Clinical ConceptSPI-452 Enhances Darunavir Exposure (C12)
Boosting Ratio: 15 32 37 11 20 34
Dar
unav
ir C
12(n
M)
Darunavir Mean C12 Enhancement
Day -7
25 mg SPI-45250 mg SPI-452200 mg SPI-452
DRV alone
2000
4000
6000
Day 15 Day 16
8000
Study 0452-002: Proof of Clinical Concept SPI-452 Enhances Atazanavir Exposure
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Dosing day
Atazanavir Mean AUC0-24 Enhancement
AU
C (0
-24)
ratio
(day
X/d
ay -7
)
25 mg SPI-45250 mg SPI-452
200 mg SPI-452
Study 0452-002: Proof of Clinical Concept SPI-452 Enhances Atazanavir Exposure (AUC)
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Boosting Ratio: 3 5 9 4 8 13
18Study 0452-002: Proof of Clinical Concept SPI-452 Enhances Atazanavir Exposure (C24)
Atazanavir Mean C24 Enhancement
Ata
zana
vir C
24(n
M)
25 mg SPI-45250 mg SPI-452
200 mg SPI-452
ATV alone
Day -7 Day 15 Day 16
Day 150
200
400
600
800
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
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SPI-452 is a promising new agent that may expand future treatment options and enhance
current standard of care