IAC 2006 Abs# THLB0214

Potent Antiretroviral Effect of MK-0518, Potent Antiretroviral Effect of MK-0518, a Novel HIV-1 Integrase Inhibitor, as a Novel HIV-1 Integrase Inhibitor, as

part of Combination ART in Treatment part of Combination ART in Treatment -Naïve HIV-1 infected Patients-Naïve HIV-1 infected Patients

M. Markowitz1, B.-Y. Nguyen2, E. Gotuzzo3, F. Mendo4, W. Ratanasuwan5, C. Kovacs6, J. Zhao2, L. Gilde2, R. Isaacs2, H. Teppler2, and the Protocol

004 Part II Study Team

1Aaron Diamond AIDS Res. Ctr. New York, USA; 2Merck Res. Labs, West Point, USA; 3Hosp. Nac. Cayetano Heredia, Lima,

Peru; 4Hosp. Nac. Edgardo Rebagliati, Lima, Peru; 6Maple Leaf Med. Ctr, Toronto, Canada; 5Siriraj Hosp., Bangkok,

Thailand

IAC 2006 Abs# THLB0214

Protocol 004 Study TeamProtocol 004 Study Team

InvestigatorsM. Markowitz USA

E. Gotuzzo Peru

F. Mendo Peru

W. Ratanasuwan Thailand

C. Kovacs Canada

G. Prada Colombia

J. Morales-Ramirez Puerto Rico

A. Afani Chile

D. Cooper Australia

J. Perez Chile

S. Thitivichianlert Thailand

J. Cortes Colombia

R. Steigbigel USA

M. Bloch Australia

S. Little

USA

N. Bodsworth

Australia

R. Schwartz

USA

C Tsoukas

Canada

C. Workman

Australia

R. Liporace

USA

D. Baker

Australia

C. Hicks

USA

K. Tashima

USA

C. Crumpacker

USA

P. Kumar

USA

K. Lichtenstein

USA

J. Santana-Bagur

Puerto Rico

S. Brown

USA

H. Teppler

B.-Y. Nguyen

R. Isaacs

J. Zhao

J. Chen

L. Gilde

L. Wenning

M. Miller

D. Hazuda

J. Vacca

M. Rowley

V. Summa

M. Iwamoto

Merck Research Laboratories

IAC 2006 Abs# THLB0214

MK-0518: Strand Transfer Inhibitor of HIV MK-0518: Strand Transfer Inhibitor of HIV IntegraseIntegrase

• HIV integrase inhibition: a new mechanism of action• MK-0518: potent in vitro activity

• IC95 = 33 nM 23 nM in 50% human serum

• Preclinical evaluation favorable• Metabolism primarily via glucuronidation (UGT1A1)• Not a potent inhibitor or inducer of CYP3A4

• Does not require “ritonavir boosting”• Phase I and drug interaction data support:

– Dosing 100 - 800 mg po bid without regard to food

• At 100mg b.i.d, mean C12hr > IC95

– No dose adjustment when used with other ARTs

Part I cohort Rx-naïve ptsstratified and randomized to Integrase monotherapy

or placebo for 10 days

MK-0518 600mg bid

MK-0518 400mg bid

MK-0518 200mg bid

MK-0518 placebo bid

Protocol 004: Study Design

MK-0518 600mg bid + TFV*/3TC

MK-0518 400mg bid+ TFV* /3TC

Part I

Integrase Monotherapy for 10 days

Part II

Combination Therapy

Interim analysis of Part I before initiating Part II

*TFV = tenofovir

~ 8pts

~ 8pts

~ 8pts

~ 8pts

~ 30 pts

~ 30 pts

~ 30 pts

~ 30 pts

MK-0518 200mg bid+ TFV*/ 3TC

Efavirenz 600mg** + TFV*/3TC

MK-0518 100mg bid~ 8pts

~ 30 pts

MK-0518 100mg bid + TFV*/3TC

Part II cohort Rx-naïve ptsstratified and randomized to combination therapy for 48

weeks

Total

~ 38 pts

~ 38 pts

~ 38 pts

~ 38 pts

~ 38 pts

HIV RNA of 1.7 – 2.2 log10 copies/mL Morales-Ramirez et al, EACS 2005

IAC 2006 Abs# THLB0214

IAC 2006 Abs# THLB0214

Protocol 004: Part II DesignProtocol 004: Part II Design• Part I patients continued at same dose in Part II (pbo→efv)• ~150 additional patients randomized for Part II• Key inclusion criteria

– Susceptible to EFV, 3TC , TFV (by genotype)– No prior ART (<7 days OK) – HIV RNA ≥ 5000 copies/mL

• baseline stratification for HIV RNA ≤ or > 50,000 copies/mL

– CD4 ≥ 100 cells/mm3

• Endpoints– HIV RNA and CD4 counts, Adverse experiences

• Hypotheses: MK-0518 + TFV/3TC– will be generally safe and well tolerated – will have similar antiretroviral activity vs efavirenz +

TFV/3TC

IAC 2006 Abs# THLB0214

Protocol 004: Baseline CharacteristicsProtocol 004: Baseline CharacteristicsMK-0518 mg bid*

Efavirenz * 600mg qd

N=38100

N=39

200

N=40

400

N=41

600

N=40

Age-mean (yrs) 37 34 36 37 36

%Male 85 73 90 73 76

%Non-White 82 65 66 65 68

HIV RNA

copies/ml** (log10cp/ml)

58206

(4.8)

64715

(4.8)

43083

(4.6)

57919

(4.8)

67554

(4.8)

CD4 – mean (cells/ul)

314 296 338 271 280

% with AIDS 31 33 29 43 37

* With TFV/3TC ** = geometric mean

IAC 2006 Abs# THLB0214

Protocol 004: Patient Status at Week 24 Protocol 004: Patient Status at Week 24 AnalysisAnalysis

MK-0518* EFV*

Description

100 mg

n (%)

200 mg

n (%)

400 mg

n (%)

600 mg

n (%) n (%)

Total Enrolled

Treated

N = 41

39 (95)

N = 40

40 (100)

N = 41

41 (100)

N = 40

40 (100)

N = 41

38 (93)

Discontinued by Wk 24 0 5 (13) 1 (2) 2 (5) 2 (5)

- due to lack of efficacy 0 2 (5) 0 0 0

- due to AE 0 0 0 1 (3) 0

- other 0 3 (8) 1 (2) 1 (3) 2 (5)

* + TFV/3TC

n = Number of patients in each category; N = Total number of pts enrolled in each group

% = n/N for each category in each group

IAC 2006 Abs# THLB0214

Protocol 004: HIV RNA Change from Baseline*

(log10 copies/mL) (95% CI)

0 2 4 8 12 16 24Week

-3

-2

-1

0

Change F

rom

Ba

selin

e

in H

IV R

NA

(Log 10

Copie

s/m

L)

m518p4rna6 Aug. 10, 2006

MK-0518 100mg 38 39 39 39 39 39 25MK-0518 200mg 40 40 40 40 40 40 27MK-0518 400mg 40 41 41 41 41 41 27MK-0518 600mg 39 38 38 38 38 38 28Efavirenz 37 38 38 37 38 37 26

*assay LoQ 400 copies/mL

IAC 2006 Abs# THLB0214

Protocol 004 - Percent (95% CI) of Patients with HIV RNA < 400 copies/mL (NC = F)

0 2 4 8 12 16 24Week

0

20

40

60

80

100

Per

cent

of

Pat

ient

s w

ithH

IV R

NA

<40

0 co

pies

/mL

m518p4.r400.5 June 27, 2006

MK-0518 100mg 39 39 39 39 39 39MK-0518 200mg 40 40 40 40 40 40MK-0518 400mg 41 41 41 41 41 41MK-0518 600mg 40 40 40 40 40 40Efavirenz 38 38 38 38 38 37

IAC 2006 Abs# THLB0214

Protocol 004: Percent (95% CI) of Patients with HIV RNA < 50 copies/mL (NC=F)

0 2 4 8 12 16 24Week

0

20

40

60

80

100P

erce

nt o

f P

atie

nts

with

HIV

RN

A <

50 c

opie

s/m

L

*

*

m518p4.r50.5 Aug. 3, 2006

MK-0518 100mg 39 39 39 39 39 39MK-0518 200mg 40 40 40 40 40 40MK-0518 400mg 41 41 41 41 41 41MK-0518 600mg 40 40 40 40 40 40Efavirenz 38 38 38 38 38 37

* P < 0.001 for MK-0518 at each dose vs. EFV

IAC 2006 Abs# THLB0214

Protocol 004: Change from Baseline in CD4 (cells/mm3) (95% CI)

0 2 4 8 12 16 24Week

0

50

100

150

200

250C

hang

e fr

om B

asel

ine

in

CD

4 C

ell C

ount

m518p4.cd4.3a June 12, 2006

MK-0518 100mg 38 39 39 38 39 39

25

MK-0518 200mg 39 39 39 37 37 34

22

MK-0518 400mg 38 40 40 39 40 40

25

MK-0518 600mg 40 39 38 38 37 38

27

Efavirenz 36 37 37 36 37 37

24

IAC 2006 Abs# THLB0214

Protocol 004: Common (≥5%) Drug Related Adverse Protocol 004: Common (≥5%) Drug Related Adverse ExperiencesExperiences

MK 0518* (all doses) N=160

(%)

Efavirenz*

N=38

(%)

Nausea 11 13

Headache 9 24

Dizziness 8 26

Diarrhea 7 11

Insomnia 7 11

Abnormal dreams 6 18

Flatulence 6 -Additional AEs seen at ≥ 5% in efavirenz group:Nightmare (11%)Vomiting (8%)Malaise (8%)

Fatigue (5%)Disturbance in attention (5%)Lethargy (5%)Anxiety (5%)

* With TFV/3TC

IAC 2006 Abs# THLB0214

Protocol 004: SafetyProtocol 004: Safety

MK-0518 safety profile was similar to efavirenz (both with TFV/3TC)

• Most clinical adverse experiences (AE) were mild to moderate

• 8 serious adverse experiences overall (7/160 or 4% in the 4 MK groups, 1/38 or 3% in EFV group); none considered drug related

• One discontinuation for increased AST/ALT• Grade 3 / 4 lab abnormalities uncommon

IAC 2006 Abs# THLB0214

ConclusionConclusion

• MK-0518 is a promising new strand transfer inhibitor of HIV integrase with potent and durable antiretroviral effect.In treatment naïve patients with HIV RNA ≥ 5000 copies/ml and CD4 ≥ 100/mm3, MK-0518 at all doses studied for 24 weeks

• had potent antiretroviral activity

» 85-95% with HIV RNA < 50 copies/mL» achieved viral suppression faster than EFV

• was generally well tolerated