Early Safety, Tolerability and Pharmacokinetic

Profile of GSK2838232, a Novel 2nd Generation HIV

Maturation Inhibitor, as Assessed in

Healthy Subjects

1,7Johnson, M; 1Jewell RC; 2Peppercorn, A; 1 Gould E; 3Xu, J; 1,4Lou, Y; 5Davies, M; 6Baldwin, S; 1,7Tenorio, A; 8Burke, M and 1Johns, B

1GSK, RTP, NC; 2GSK, Cambridge, MA; 3GSK, Collegeville, PA; 4Parexel, RTP, NC; 5GSK Stockley Park,

UK; 6GSK Ware, UK; 7ViiV Healthcare, RTP, NC; 8GSK King of Prussia, PA

18th International Workshop on Clinical Pharmacology of Antiviral Therapy

June 14th-16th, Chicago

Conflicts of Interest Disclaimer

2

18th International Workshop on Clinical

Pharmacology of Antiviral Therapy

This study was sponsored and funded by GSK. All authors are/were

employees of and owned stock in GSK.

18th International Workshop on Clinical Pharmacology of Antiviral Therapy June 14th-16th, Chicago

HIV Viral Lifecycle and Maturation Inhibitor Drug Targets

18th International Workshop on Clinical Pharmacology of Antiviral Therapy June 14th-16th, Chicago 3

3

Protease

Inhibitors

RT

Inhibitors

Integrase

STrand

Inhibitors

Attachment,

entry & fusion

Inhibitors

Maturation

Inhibitors

GSK2838232: Preclinical Profile

MW 809.6

18th International Workshop on Clinical Pharmacology of Antiviral Therapy June 14th-16th, Chicago 4

• Low/moderate bioavailability; low permeability, low solubility

• CYP/transporter profile

• Does not inhibit CYP1A2, 2C9, 2C19, 2D6, or 3A4 (IC50 > 33 M) in vitro

o Has potential to cause metabolism-dependent inhibition of CYP3A4

• No drug interaction risk was identified for co-administrated substrates of UGT1A1, 1A3, 1A6,

1A9, 2B7, and 2B15, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2

• Cleared predominantly by CYP3A4 oxidative metabolism (some N-dealkylation,

glucuronidation, and other minor routes)

o RTV (CYP3A4 inhibitor) “boosts” GSK2838232 AUC, Cmax, and Ctau - which is then

cleared via Phase II conjugation

• Preclinical Toxicology

• Successful completion of reproductive toxicology studies; WOCBP can be included

• NOAELs established in rat/dog chronic toxicology studies

GSK2838232: Virology Profile

18th International Workshop on Clinical Pharmacology of Antiviral Therapy June 14th-16th, Chicago 5

Modified from Jeffrey et al 2015 CROI Poster #538

GSK2838232

Bevirimat (BVM)

Potency, Effect of protein

MT4 wt EC50 0.8 nM

MT4 V370A EC50 0.7 nM

*EC90 (minimum clinical Cmin target) 6.4 nM (5 ng/mL)

Protein binding >99.9%

*Fold shift with 40% human serum 1 (no shift) to 5-fold

GSK2838232: Clinical Program

• Objectives of early clinical program

– Safety/tolerability

– Pharmacokinetics of single/repeat doses +/-RTV and the impact of formulation and food

18th International Workshop on Clinical Pharmacology of Antiviral Therapy June 14th-16th, Chicago 6

Study Design Formulation/Dose N

HMI116787 Single escalating dose (SAD) and

assessment of RTV

SDD, PiB

5-100 mg and 10 mg+RTV, Placebo

17

200912 Continuation of SAD (Part 1) and

RBA of API then API+RTV (Part 2)

SDD, API, PiB 200 mg (Part 1),

100 mg API/SDD RBA then 20 mg API+RTV (Part 2)

20

200207 Multiple ascending dose (MAD) SDD

20 mg, 50 mg, 10mg+RTV (single dose), Placebo

24

204953Clinical phase

completed;

preliminary data

Continuation of SAD/MAD and RBA

of capsules (+food effect)

50-250 mg/r SAD PiB

20-50mg/r MAD PiB, 100-200 mg/r MAD Capsule

100 mg capsule/r vs PiB/r RBA +food

200mg capsule + food BID

63

Total 124

PiB Powder in Bottle; API Active Pharmaceutical Ingredient; SDD Spray Dried Dispersion

GSK2838232: Safety and Tolerability

– 124 healthy subjects exposed to GSK2838232 or placebo

– Mostly Male, 9 Female subjects

– 18-55 yrs, Body weight 50 kg (110 lbs.) for men and 45 kg (99 lbs) for women and

body mass index (BMI) within the range 18.5-31.0 kg/m2 (inclusive).

– Safety

– No study discontinuations or grade 3/4 labs related to GSK2838232

– One SAE (NSVT) on continuous telemetry/Holter. Unlikely to be drug-related:

– Occurred after 50 mg GSK2838232 QD dosing (39 hours after last dose) when

plasma concentrations were <1 ng/mL

– Similar event appeared on repeat Holter 17 weeks after last dose

– No increase between GSK2838232 and placebo in frequency of CV events

– No other clinically meaningful or significant changes in AE profile, ECG, blood

pressure, heart rate, or safety labs

– All formulations well tolerated with or without food

18th International Workshop on Clinical Pharmacology of Antiviral Therapy June 14th-16th, Chicago 7

GSK2838232: Single Dose Pharmacokinetic Profile

18th International Workshop on Clinical Pharmacology of Antiviral Therapy June 14th-16th, Chicago 8

Single doses up to 200 mg, from Studies HMI116787 and 200912; SDD PiB fasted

Time (h)

0 12 24 36 48 60 72

Me

dia

n G

SK

28

38

23

2 C

once

ntr

atio

n (

ng

/mL

)

0

5

10

15

20

25

30

5 mg

10 mg

20 mg

50 mg

100 mg (HMI116787)

100 mg (200912)

200 mg

Dose

(mg)

n Cmax

(ng/mL)

tmax1

(h)

AUC(0-)

(ng.h/mL)

t½

(h)

C241

(ng/mL)

5

(HMI116787)

8 1.52

(1.02-2.27)

2.24

(1.50-8.00)

ND ND 0

(0-0.60)

10

(HMI116787)

8 3.49

(2.98-4.09)

1.76

(1.50-4.00)

ND ND 0.63

(0-0.86)

20

(HMI116787)

8 8.09

(6.28-10.4)

1.75

(1.00-4.02)

104

(78.8-136)

14.1

(10.5-18.9)

1.54

(0.92-2.91)

50

(HMI116787)

6 13.1

(8.14-21.1)

2.02

(1.50-4.00)

195

(154-246)

17.4

(13.3-22.8)

3.11

(2.03-4.49)

100

(HMI116787)

6 23.7

(15.7-35.6)

2.75

(1.50-4.00)

385

(299-496)

18.8

(15.6-22.6)

5.93

(3.92-9.81)

100

(200912)

12 18.7

(12.0-29.2)

2.75

(1.00-4.00)

265

(179-391)

16.9

(13.6-20.9)

3.87

(1.30-10.6)

200

(200912)

6 29.3

(26.3-32.7)

1.75

(1.00-3.50)

381

(290-501)

16.6

(12.7-21.6)

5.18

(3.84-9.16)

ND = not determined 1 Median (minimum-maximum)

– Lower bioavailability than predicted from preclinical studies

– Broadly dose proportional through 100 mg

Median Plasma GSK2838232

Concentration-time Profiles

Summary of GSK2838232 PK Parameters:

geometric mean (95% CI)

GSK2838232: Boosting with RTV

RTV administered for 12 days, GSK2838232 SDD PiB administered on Day 10

18th International Workshop on Clinical Pharmacology of Antiviral Therapy June 14th-16th, Chicago 9

Dose

(mg)

n Cmax

(ng/mL)

tmax1

(h)

AUC(0-t)

(ng.h/mL)

AUC(0-)

(ng.h/mL)

t½

(h)

C241

(ng/mL)

10

(HMI116787)

8 3.49

(2.98-4.09)

1.76

(1.50-4.00)

26.8

(19.8-36.2)

ND ND 0.63

(0-0.86)

10/r

(HMI116787)

6 9.10

(6.85-12.1)

4.00

(2.48-6.00)

289

(213-393)

389

(285-531)

33.7

(27.3-41.5)

4.64

(3.48-8.64)

ND = not determined1 Median (minimum-maximum)

– RTV boosts GSK2838232 AUC by ~10-fold but only ~3-fold increase in Cmax

– Prolonged t½, consistent with reduced metabolic clearance

Time (h)

0 12 24 36 48 60 72

Med

ian

GS

K28

3823

2 C

once

ntra

tion

(ng/

mL)

0

2

4

6

8

10

10 mg

10 mg/r

Time (h)

0 12 24 36 48 60 72

Me

dia

n G

SK

28

38

23

2 C

onc

ent

ratio

n (n

g/m

L)

0.01

0.1

1

10

100

10 mg

10 mg/r

Median Plasma GSK2838232 Concentration-time Profiles

GSK2838232 PK Parameters:

geometric mean (95% CI)

GSK2838232 + RTV: Single Dose Pharmacokinetic Profile

Study 204953: Single RTV-Boosted Doses of up to 250 mg (48 hr RTV pre-dosing)

18th International Workshop on Clinical Pharmacology of Antiviral Therapy June 14th-16th, Chicago 10

Time (h)

0 20 40 60 80 100 120

Me

dia

n G

SK

28

38

23

2 C

once

ntr

atio

n (

ng

/mL

)

0

10

20

30

40

50

60

50 mg/r

100 mg/r

250 mg/r

Dose

(mg)

n Cmax

(ng/mL)

tmax1

(h)

AUC(0-t)

(ng.h/mL)

AUC(0-)

(ng.h/mL)

t½

(h)

C241

(ng/mL)

50/r 8 15.7

(10.9-23.4)

3

(2.5-6)

401

(300-558)

434

(334-583)

22.4

(19.4-26.0)

7.26

(3.18-9.61)

100/r 6 24.7

(19.8-30.5)

5

(2.5-12)

854

(681-1061)

874

(702-1079)

17.9

(15.3-20.7)

13.2

(8.64-17.4)

250/r 5 59.3

(43.7-77.6)

4

(2-12)

1658

(1101-2321)

1678

(1111-2352)

17.2

(15.9-18.6)

24.0

(16.0-32.0)1 Median (minimum-maximum)

– RTV-boosted GSK2838232 API PK is generally dose proportional

– All doses provide trough concentrations above target

– t½ values underestimated as a result of discontinuation of RTV dosing

GSK2838232 Preliminary PK Parameters:

geometric mean (95% CI)Median Plasma GSK2838232

Concentration-time Profiles

GSK2838232: Formulation and Food Effect, with RTV

18th International Workshop on Clinical Pharmacology of Antiviral Therapy June 14th-16th, Chicago 11

Parameter Comparison N Ratio of Geometric Least

Square Means

90% CI of Ratio

AUC(0-) Capsule/r:PiB/r 12 1.43 (1.194, 1.702)

Cmax Capsule/r:PiB/r 12 1.58 (1.312, 1.900)

Relative bioavailability – RTV-boosted PiB and capsule

Time (h)

0 12 24 36 48 60 72 84 96 108 120

Med

ian

GS

K28

3823

2 C

once

ntra

tion

(ng/

mL)

0

20

40

60

80

100 mg/r PiB, fasted

100 mg/r Capsule, fasted

100 mg/r Capsule, fed

Study 204953: API PiB vs API capsules, plus food effect (48 hr RTV pre-dosing)

Preliminary pharmacokinetic results:

– Geometric mean AUC(0-) and Cmax 43 and 58% higher after administration as capsule

compared to oral suspension from powder-in-bottle and ~60% higher in the fed state versus fasted

– API [50 mg] capsules, administered with food (with RTV) suitable treatment for repeat dose

Median Plasma GSK2838232

Concentration-time ProfilesSummary of GSK2838232 Preliminary

PK Parameter Comparisons

GSK2838232: Repeat Dose Pharmacokinetic Profile

Study 204953: Repeat doses +/- RTV for 11 days

18th International Workshop on Clinical Pharmacology of Antiviral Therapy June 14th-16th, Chicago 12

Preliminary pharmacokinetic results:

– RTV-boosted GSK2838232 appeared dose proportional through 200 mg QD

– RTV-boosted GSK2838232 doses achieved IQ values between 3 and 30 (assuming 5 ng/mL target)

– GSK2838232 200 mg BID PK profile similar to RTV-boosted 50 mg QD and also achieved target (IQ ~10)

5 ng/mL

4xPA-IC90

(20 ng/mL)

5 ng/mL

4xPA-IC90

(20 ng/mL)

Median Plasma GSK2838232

Concentration-time Profiles

Predicted PK Profiles for Evaluation in HIV-Infected Patients

– Predicted steady-state GSK2838232 concentration-time data ± SD based on Study 204953 results

18th International Workshop on Clinical Pharmacology of Antiviral Therapy June 14th-16th, Chicago 13

– GSK2838232/r doses achieve IQ values between 3 and 30 (assuming 5 ng/mL)

– Factoring in PK variability, GSK2838232 doses ≥50 mg/r QD are predicted to meet target exposures

– Caveat: Cobicistat substituted for RTV in PoC

4xPA-IC90 (20 ng/mL)

5 ng/mL

Conclusions

GSK2838232 was generally safe and well tolerated in healthy subjects up to

single doses of 250 mg + RTV and repeated daily doses of 200 mg QD +

RTV or 200 mg BID for 11 days

RTV increased AUC, Cmax, and C24 (Ctau) in single and repeated doses

Formulation and food (normal fat content, i.e., 30%) together had a

significant positive impact on overall GSK2838232 bioavailability

PK profile is consistent with the proposed therapeutic strategy of maintaining

plasma concentrations >PA-IC90 for all HIV-infected subjects

GSK2838232, boosted with cobicistat, is currently being assessed in a

Phase IIa 10-day monotherapy study in HIV patients that will support Phase

IIb evaluation in 2018

18th International Workshop on Clinical Pharmacology of Antiviral Therapy June 14th-16th, Chicago 14

Acknowledgements

The authors wish to sincerely thank:

o The subjects who took part in these studies, without which none of

this would be possible

o The Principal Investigators Dr. Azra Hussaini, Dr. Ron Goldwater,

Co-investigator Arthur Gapasin, and all the wonderful staff

at PXL, Baltimore

18th International Workshop on Clinical Pharmacology of Antiviral Therapy June 14th-16th, Chicago 15

Co-authors