Preclinical and Early Clinical Evaluation of SPI-452, a

Preclinical and Early Clinical Evaluation ... (PIs) are a cornerstone of HAART • Majority of PIs require PK boosting with ritonavir...
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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)

Phase 2** Cohort 1 Day -1 SQV 1000 mg or PBO

Day 1 SPI-452 50 mg + SQV 1000 mg SQV 1000 mg/ PBO PBO/PBO Cohort 2

Day -1 SQV 1000 mg or PBO

Day 1 SPI-452 200 mg + SQV 1000 mg/

** Each cohort in Phase 2: • SQVÆSPI-452 + SQV (n=6) • SQVÆ SQV + PBO (n=2) • PBOÆ PBO + PBO (n=2)

SQV 1000 mg/ PBO PBO/PBO

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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

Darunavir C12 (nM)

8000

6000 DRV alone 25 mg SPI-452 50 mg SPI-452 200 mg SPI-452

4000

2000

Day 15

Day -7 Boosting Ratio:

15

32

Day 16 37

11

20

34

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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

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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