Paper # 49
Pharmacodynamics, Safety, and Pharmacokinetics of BMS-663068: A Potentially First-in-class Oral HIV Attachment Inhibitor
Richard Nettles*1, D Schurmann2, L Zhu1, M Stonier1, S-P Huang3, C Chien1, M Krystal4, M Wind-Rotolo3, R Bertz1, and D Grasela1
1Bristol-Myers Squibb, Hopewell, NJ, US; 2Charité-Univ Med Berlin, Germany; 3Bristol-Myers Squibb, Princeton, NJ, US; and 4Bristol-Myers Squibb, Wallingford, CT, US
Background: BMS-663068, a potential first-in-class
oral HIV attachment inhibitor (AI), is a prodrug for BMS-626529 which binds to
the viral envelope glycoprotein gp120 and interferes with attachment of virus
to the cellular CD4 receptor. In single and multiple dose studies with healthy
subjects, BMS-663068 was well-tolerated and had a pharmacokinetic (PK) profile
supportive of once or twice daily dosing.
Methods: The objectives of this randomized,
open-label, multiple-dose study were to evaluate the pharmacodynamics, safety,
and PK of BMS-663068 in clade B HIV-1-infected subjects. Men or women ≥18
years of age with CD4+ lymphocyte count ≥200 cells/μL and
with plasma HIV RNA ≥5000 copies/mL who have not been on ART for ≥8
weeks and who are either antiretroviral (ARV) experienced or naïve received
either A: BMS-663068 600 mg Q12H + RTV 100 mg Q12H, B: BMS-663068
1200 mg QHS + RTV 100 mg QHS, C: BMS-663068 1200 mg Q12H + RTV 100 mg
Q12H, D: BMS-663068 1200 mg Q12H + RTV 100 mg QAM, or E:
BMS-663068 1200 mg Q12H for 8 days (10 subjects [6 to 7 ARV naïve] per dose
group).
Results: The table below shows the changes in HIV
RNA and CD4+ lymphocyte count and PK exposures to BMS-626529.
Maximum viral load drops for most subjects were observed several days after the
last dose of BMS-663068. All BMS-663068 doses were well tolerated with no
deaths, serious adverse events or discontinuations due to adverse events (AE).
There were no clinically relevant effects on ECG, laboratory values, vital
signs, or physical exams. The most frequent AE included headache (22 of 50,
44%) and rash (8 of 50, 16%), the majority of which were mild.
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Dose Regimen
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A
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B
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C
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D
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E
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Median Maximal HIV RNA log10 Decline (range)
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1.6
(1.0 to 2.0)
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1.6
(1.0 to 2.4)
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1.8
(1.2 to 2.1)
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1.6
(0.3 to 2.3)
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1.2
(0.4 to 2.6)
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Median Day 8 Change in CD4 (range)
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130
(–299 to 474)
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86
(–33 to 240)
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102
(–77 to 281)
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38
(–241 to 259)
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23
(–98 to 276)
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Geometric Mean Day 8 AUC ng·h/mL (CV%)
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26,772 (49)
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22,946 (44)
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60,624 (27)
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55,170 (36)
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42,589 (21)
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Geometric Mean Day 8 Cmin ng/mL (CV%)
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438 (68)
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55 (101)
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749 (56)
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613 (62)
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524 (57)
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Conclusions: BMS-663068 is a potential
first-in-class oral HIV AI being developed for treatment of HIV-1 infection. It
is generally well tolerated, resulting in a substantial decline in HIV RNA with
increases in CD4+ lymphocytes over 8 days of dosing and a PK profile
that supports once or twice daily dosing with or without ritonavir. Longer term
clinical trials of BMS-663068 as part of a HAART regimen are warranted.
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