Potent Antiretroviral Effect of MK0518, a Novel HIV1 Integrase Inhibitor, as part of Combination ART

1
Potent Antiretroviral Effect of MK-0518, a Novel
HIV-1 Integrase Inhibitor, as part of Combination
ART in Treatment -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

2
Protocol 004 Study Team
Merck Research Laboratories
Investigators M. 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
3
MK-0518 Strand Transfer Inhibitor of HIV
Integrase

• 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 gt IC95
• No dose adjustment when used with other ARTs

4
Protocol 004 Study Design
Interim analysis of Part I before initiating
Part II
Part I Integrase Monotherapy for 10 days
Part II Combination Therapy
Total
8pts
30 pts
38 pts
MK-0518 600mg bid
MK-0518 600mg bid TFV/3TC
30 pts
38 pts
MK-0518 400mg bid
MK-0518 400mg bid TFV /3TC
8pts
30 pts
8pts
38 pts
MK-0518 200mg bid
MK-0518 200mg bid TFV/ 3TC
30 pts
8pts
38 pts
MK-0518 100mg bid
MK-0518 100mg bid TFV/3TC
30 pts
8pts
38 pts
MK-0518 placebo bid
Efavirenz 600mg TFV/3TC
Part I cohort Rx-naïve ptsstratified and
randomized to Integrase monotherapy or placebo
for 10 days
Part II cohort Rx-naïve ptsstratified and
randomized to combination therapy for 48 weeks
TFV tenofovir
HIV RNA ? of 1.7 2.2 log10 copies/mL
Morales-Ramirez et al, EACS 2005
IAC 2006 Abs THLB0214
5
Protocol 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 (lt7 days OK)
• HIV RNA 5000 copies/mL
• baseline stratification for HIV RNA or gt 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

6
Protocol 004 Baseline Characteristics
With TFV/3TC geometric mean
7
Protocol 004 Patient Status at Week 24 Analysis
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
8
Protocol 004 HIV RNA Change from Baseline
(log10 copies/mL) (95 CI)
assay LoQ 400 copies/mL
9
Protocol 004 Percent (95 CI) of Patients with
HIV RNA lt 400 copies/mL (NC F)
10
Protocol 004 Percent (95 CI) of Patients with
HIV RNA lt 50 copies/mL (NCF)
P lt 0.001 for MK-0518 at each dose vs. EFV
11
Protocol 004 Change from Baseline in CD4
(cells/mm3) (95 CI)
12
Protocol 004 Common (5) Drug Related Adverse
Experiences
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
13
Protocol 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

14
Conclusion

• 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 lt 50 copies/mL
• achieved viral suppression faster than EFV
• was generally well tolerated