Presatovir (GS-5806) for Treatment of Respiratory...

IWCPAT 2017, Chicago

Presatovir (GS-5806) for Treatment of

Respiratory Syncytial Virus Infection

Polina German, Pharm.D.

Clinical Pharmacology, Gilead Sciences, Inc., Foster City, CA

Disclosures

I am an employee of Gilead Sciences, Inc.

2

Significant Unmet Medical Need of RSV Infection

RSV is a significant cause of morbidity and mortality among children <5 years old

– Worldwide: ~3.4 million hospitalizations with up to 200,000 deaths1

– US: ~60,000 hospitalizations among <24 month old infants2

• ~2 million annual outpatient and emergency visits

• Among <1 year olds: 9-fold more respiratory deaths than influenza

RSV infections also affect adults

– Elderly with underlying cardiopulmonary disease (prevalence 5–8%)

• Among >50 year olds: ~10,000 deaths each year3

– Immunocompromised: hematopoietic cell and lung transplant patients (prevalence 2–17%)

• ~25% of upper tract infections progress to lower tract4

• Mortality rate among lower tract infected is ~30%5

No effective treatment for RSV infection is available

RSV, respiratory syncytial virus.

1. Nair et al. Lancet. 2010;375:1545-55. 2. Hall et al. N Engl J Med. 2009;360:588-98. 3. Thompson et al. JAMA. 2003;289:179-86. 4. Kim et al. J Infect Dis.

2014;209:1195-204. 5. Seo et al. Biol Blood Marrow Transplant. 2013;19:589-96.3

RSV Development Challenges

No formal guidance available for development of agents to treat or prevent RSV

Establishing definition for RSV disease severity

– Lack of widely-accepted definition

Defining appropriate patient population

– Underlying patient factors, age and/or disease severity

Clinical endpoints

– Clinical outcome versus virologic endpoints

– Need to avoid endpoints that are influenced by health care system (eg, duration of

hospitalization)

• “MALRI”: medically attended lower respiratory illness endpoint (eg, physician visits, urgent care and

emergency visits, and hospitalization)

Agents in Development for RSV Treatment

5

RSV

VIRAL PARTICLE

(–) GENOME(+) ANTIGENOME

CYTOPLASM

Transcription

Protein synthesis

Entry via fusion

Assembly

HOST CELL

NUCLEUS

A

A

A

A

A

A

A

A

A

A

RNA replication

Fusion inhibitors

Presatovir, VP-14637,

JNJ-2408068, ALX-0171

RSV Polymerase

Inhibitors

ALS-8176, T-705

(influenza polymerase)

Presatovir Preclinical Characteristics

Allosteric inhibitor of F protein

– Blocks viral entry by inhibiting fusion of the viral envelope with the host cell membrane

In vitro antiviral effect

– Mean EC50 0.4 nM for 75 clinical RSV (types A and B) isolates

In vivo efficacy in a cotton rat model

Concentrates in the lung in Sprague-Dawley rats

– Lung tissue /plasma AUC ratio ~26, ELF/plasma AUC ratio ~9.4 in animal models

Favorable safety profile in toxicology studies

AUC, area under concentration-time curve; EC50, half-maximal concentration; ELF, epithelial lining fluid.6

7

Presatovir Preclinical Characteristics

Limited potential for clinically significant DDIs

Rates of presatovir metabolism by CYPs 1A2, 2B6, 2C8, 2C9 and 2C19 below limit of

quantification

No appreciable Phase II metabolism (eg UGT1A1)

Presatovir is not expected to be an inhibitor of CYP450- or UGT1A1 or an inducer via PXR

or AhR-mediated pathways

AhR, aryl hydrocarbon receptor; BCRP, breast cancer resistance protein; CYP, cytochrome p450; DDI, drug-drug interaction; MATE, multidrug and toxic

compound extrusion protein; OATP, organic anion-transporting polypeptide; P-gp, P-glycoprotein; PXR, pregnane X receptor; UGT, uridine 5’-diphospho-

glucuronosyltransferase.

Transporters / Enzymes Substrate Inhibitor

P-gp/BCRP and OATP1B1/3

MATE1/MATE 2-K —

CYP3A —

(weak)

(weak)

Clinical Program Overview

7 Phase 1 studies in healthy subjects

– SAD, MAD, mass balance, food effect, ethnic bridging, QT, ECHO, DDI studies

with inhibitors/inducers

Phase 2a challenge study in healthy subjects infected with RSV

4 Phase 2b efficacy and safety studies in adults with RSV

– Hospitalized adults with RSV

– HCT recipients with upper respiratory tract infection

– HCT recipients with lower respiratory tract infection

– Lung transplant recipients with RSV infection

ECHO, environmental influences on child health outcomes; HCT, hematopoietic cell transplantation; MAD, multiple ascending dose.8

Presatovir PK Data in Healthy Adults

Dose-proportional exposure increases across 25 mg to 800 mg

Low variability in PK (CV% 30–40%)

t1/2 ~33–35 hours%CV, % coefficient of variation; plasma-binding-adjusted effective concentration required for 95% inhibition.

Jin et al. ICAAC. September 2-6, 2014, Washington DC, USA.

Presatovir Single Oral Dose

0 1 2 2 4 3 6 4 8 6 0 7 2

1 0

1 0 0

1 0 0 0

1 0 0 0 0

Mean P

resato

vir

Co

ncen

tration

, ng

/mL (

±S

D)

25 mg

75 mg

150 mg

500 mg

300 mg

800 mg

Time, h

paEC95 for M37b strain

9

In vivo DDI Potential

– Presatovir may be administered with inhibitors of P-gp/BCRP, OATP1B1/1B3 or

CYP3A

– Moderate/strong CYP3A inducers should not be administered with presatovir

Presatovir may be administered without regard to food1

Lack of effect of race on the PK of presatovir1

10

Clinical Pharmacology

GLSM, geometric least-squares mean.

1. Xin et al. IDWeek 2015, abstr 765.

Object Perpetrator AUC Cmax

Presatovir

Cyclosporine OATP/P-gp/BCRP inhibitor ↑26% ↑11%

Cobicistat CYP3A inhibitor ↑122% ↑13%

Rifampin Strong CYP3A/P-gp inducer 80% 40%

Efavirenz Moderate CYP3A/P-gp inducer 56% 12%

90% CIs of the GLSM ratios extended above (↑) or below (↓) the predetermined equivalence boundaries of 70 to 143%.

Challenge Study in Adults: Treatment Model

The 5d 50/25 mg regimen targeted Cmin ~4x paEC95

Doses and regimens for Cohorts 5–7 (adaptive regimens) informed by interim efficacy/safety

analyses of Cohorts 1–4 (prespecified regimen)

*Included in safety but not efficacy analysis.11

Pretreatment Period Treatment Period

Day −2 2–50 12

CohortPresatovir, mg/d or placebo

1:1

4:1

4:1

4:1

50 25 25 25 251–45d 50/25 mg

53d 50/25 mg

6SD 100 mg

75d 10/5 mg

Admit to

quarantine

RSV

inoculation

Randomization

RSV+ Day 2–5

RSV− Day 5*

50 25 25

100

10 5 5 5 5

0

Discharge

Results: Reduction in Viral Load and Symptoms

DeVincenzo et al. N Engl J Med. 2014;371:711-22. 12

Reduced Viral Load

0

1

2

3

4

5

6

0 1 2 3 4 5 6 7 8 9 10

Post-Treatment, d

Me

an

(S

E)

Vira

l L

oa

d, lo

g1

0P

FU

e/m

L

Treatment start

(2–5 d after RSV

inoculation)

p <0.001 Reduced Respiratory Symptoms

-3

-2

-1

2

3

1 2 3 4 5 6 7 8 9 10

0

0

1

p=0.005

Me

an

Cha

ng

e (

SE

) F

rom

Ba

selin

e

Post-Treatment, d

Placebo

Presatovir

Reduced Nasal Mucus Production

0 1 2 3 4 5 6 7 8 9 1 0

0

1

2

3

4

5

6

p=0.03

Me

an

(S

E)

Da

ily T

ota

l, g

Post-Treatment, d

0

1

2

3

4

5

6

0 1 2 3 4 5 6 7 8 9 1 0

Post-Treatment, days

Mean V

L, lo

g10

PF

Ue

/mL (

SE

)

Treatment start

(2–5 days after RSV inoculation)

Presatovir 5d 50/25 mg (n=27)


Presatovir SD 100 mg (n=10)


Placebo (n=27)*

Placebo (n=36)†

Results: Viral Load With Shorter/Lower-Dose Regimens

*Cohorts 1–4; †Cohorts 5–7; p <0.05 for all arms vs placebo.

SE, standard error; VL, viral load.13

-3

-2

-1

0

2

3

1 2 3 4 5 6 7 8 9 100

1

0

1

2

3

4

5

6

1 2 3 4 5 6 7 8 9 1 00

Results: Similar Effects With Shorter/Lower-Dose Regimens

p <0.05 for all arms vs placebo, except GS-5806 5d 10/5 mg vs placebo for Mucus Weight (p=0.20).


Mucus Weight Total Symptom Diary Score

Me

an

Da

ily T

ota

l, g

(S

E)

Me

an

Ch

an

ge

(S

E)

Fro

m B

ase

line


Placebo (n=27)*

Placebo (n=36)†

5d 50/25 mg (n=27)

3d 50/25 mg (n=13)

SD 100 mg (n=10)

5d 10/5 mg (n=11)

Presatovir

14

Mechanistic Modeling

Characterization of the dynamics between viral load (VL), clinical symptom

score (CSS) and presatovir dose

Presatovir dosing simulations (N=100 subjects):

– 100 mg SD, 2 to 200 mg ascending QD dosing, 200 mg Q4D, and 200 mg LD

then 100 mg QD

– Dosing regimens modeled to initiate from 24 to 120 hours post-infection to

examine effect of time of drug initiation post-infection

Lutz J, et al. RSV Symposium 2016, 15

Presatovir Effect as a Function of Dose

Maximum VL and CSS suppression is predicted to occur at doses as low as 50 mg QD

Lutz J, et al. RSV Symposium 2016.16

2 4 4 8 7 2 9 6 1 2 0 1 4 4 1 6 8 1 9 2 2 1 6

-2

-1

0

1

2

3

4

2 4 4 8 7 2 9 6 1 2 0 1 4 4 1 6 8 1 9 2 2 1 6

1

2

3

4

0 5 0 1 0 0 1 5 0 2 0 0

-1 0 0

-8 0

-6 0

-4 0

-2 0

0

0 5 0 1 0 0 1 5 0 2 0 0

-1 0 0

-8 0

-6 0

-4 0

-2 0

0

Placebo

2 mg qd

3 mg qd

6 mg qd

2 4 4 8 7 2 9 6 1 2 0 1 4 4 1 6 8 1 9 2 2 1 6

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0

13 mg qd

25 mg qd

50 mg qd

100 mg qd

200 mg qd

Presatovir 24 h postinoculation

Presatovir Dose, mgPresatovir Dose, mg

Time, hTime, h

Lo

g10

VL

, P

FU

e/m

L

% D

ecre

ase

in

VL

AU

C0-2

16

CS

SF

ractio

na

l E

ffic

acy

Presatovir Effect as a Function of Time Post-Infection

Minimal VL and CSS suppression is predicted if presatovir is administered greater than 72 hrs post inoculation

Lutz J, et al. RSV Symposium 2016.17

2 4 4 8 7 2 9 6 1 2 0 1 4 4 1 6 8 1 9 2 2 1 6

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0

2 4 4 8 7 2 9 6 1 2 0 1 4 4 1 6 8 1 9 2 2 1 6

-2

-1

0

1

2

3

4

2 4 4 8 7 2 9 6 1 2 0 1 4 4 1 6 8 1 9 2 2 1 6

1

2

3

4

2 4 4 8 7 2 9 6 1 2 0

-1 0 0

-8 0

-6 0

-4 0

-2 0

0

2 4 4 8 7 2 9 6 1 2 0

-1 0 0

-8 0

-6 0

-4 0

-2 0

0

Placebo

24 h postinoculation





Presatovir 200/100 mg

Lo

g10

VL

, P

FU

e/m

L

% D

ecre

ase

in

VL

AU

C0-2

16

CS

S

Fra

ctio

na

l E

ffic

acy

Presatovir Initiation Time

Post-Inoculation, h

Presatovir Initiation Time

Post-Inoculation, h

Time, hTime, h

2 4 4 8 7 2 9 6 1 2 0 1 4 4 1 6 8 1 9 2 2 1 6

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0

2 4 4 8 7 2 9 6 1 2 0 1 4 4 1 6 8 1 9 2 2 1 6

-2

-1

0

1

2

3

4

18

Mechanistic Modeling: Presatovir Efficacy Intermittent Dosing

Administration of two 200 mg doses, staggered by 4 days, is predicted to achieve maximal

viral suppression

Lutz J, et al. RSV Symposium 2016.

Fra

ctional E

ffic

acy

Lo

g10 V

L,

PF

Ue

/mL

Time, hTime, h

Placebo

Presatovir 200mg Q4D x2






Phase 2b Hospitalized Adult Study

200 RSV+ hospitalized adults

Single-dose regimen

Primary endpoint: daily average change in VL (Day 5)

Secondary endpoints: symptoms, healthcare utilization

190 subjects enrolled (May 2017)

Presatovir 200-mg single dose

Day 1 5 2814

Viral load

Symptoms

n=100

Placebo single dosen=100

19

Phase 2b Bone Marrow Transplant Upper

and Lower Respiratory Tract Studies

Day 1 9 2822

Presatovir 200 mg q4d x5

Placebo q4d x5

Viral Load

Symptoms

56

Optional Extended Viral Follow-up

20

Upper Respiratory Tract Lower Respiratory Tract

RSV+ patients 200 outpatients 60 inpatients

Regimen Multidose Multidose

Primary endpoint Daily average change in VL (Day 9) Daily average change in VL (Day 9)

Secondary endpoints Progression, respiratory failure, mortality Respiratory failure, mortality

Subjects enrolled 188 (June 2017) 60 (May 2017)

Phase 2b Lung Transplant Study

60 RSV+ lung transplant patients

Primary endpoint: daily average change in VL (Day 7)

Secondary endpoints: lung function, symptoms

48-wk follow-up for development of BOS/graft failure after Day 28

61 subjects enrolled

BOS, bronchiolitis obliterans syndrome.

Day 1 7 2114

Presatovir 200 mg on Day 1; 100 mg/d on Days 2‒14

Placebo daily for 14 d

n=40

n=20

56

Optional extended viral follow-up

Symptoms Daily assessment

Spirometry

28

Viral load

21

Conclusions

Presatovir is a fusion inhibitor for treatment of RSV infection

Favorable clinical pharmacology profile (healthy volunteers)

Favorable safety profile (healthy adults and patients)

Potent antiviral effect that reduces clinical signs and symptoms of RSV

infection in challenge study

Currently being evaluated in 4 ongoing Phase 2b studies in both outpatient

and inpatient settings

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Acknowledgments

We extend our thanks to the study participants and study team. This study was funded by

Gilead Sciences, Inc.

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