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A Double-blind Placebo-controlled Study in HIV-1-infected Subjects on the Safety, Pharmacokinetics, and Antiviral Effect of Cyclophilin A targeting DEBIO-025
D Steyn1, D Richman2, C Aeschlimann3, J M Dumont3, P Grosgurin3, B Rosenwirth4, C Loveday5, H Porchet3, V Nicolas3, and Pietro Scalfaro*3
1Univ of the Free State, Bloemfontain, South Africa; 2Univ of California, San Diego, La Jolla, US; 3Debiopharm, Lausanne, Switzerland; 4Biomed Primate Res Ctr, Rijswijk, The Netherlands; and 5Intl Clin Virology Ctr, High Wycombe, UK
Background: DEBIO-025 is
a first-in-class non-immunosuppressive cyclosporin targeting
host cell protein cyclophylin A (CypA),
which is being evaluated in man against HIV-1. Its action is documented in vitro, in particular against multidrug-resistant HIV-1 isolates and in vivo in the SCID/hu mouse model. It
was well tolerated in healthy subjects.
Methods: A 10-day course of once-daily oral DEBIO-025
or placebo was administered to 4 randomized groups of HIV+ ART-naïve
subjects (n = 48: placebo, 50, 400,
or 1200 mg/day). CD4 counts were ≥250/mL and plasma viral load ≥5000 copies/mL. Pharmacokinetics were investigated
over 30 days. HIV RNA load changes between day –1, Day 10, and recovery period were
compared by ANOVA using SAS PROC MIXED. Safety was assessed on incidence of
adverse events, changes in vital signs, electrocardiograms, and laboratory.
Results: DEBIO-025 was safe and well
tolerated. Pharmacokinetics in plasma and whole blood was best described by a
3-compartment model with saturable binding to blood
cells and was linear in plasma: 9
subjects showed a ≥0.5 log10 viral load reduction, 2 of which
>1.0 log10 (see the figure); 27 subjects had no relevant changes.
Mean reduction was not significantly different between groups (p >0.05): –0.24 (placebo), –0.41 (50 mg), –0.55 (400 mg),
and –0.44 (1200 mg). Genotyping did not reveal drug-resistance inducing substitutions
pattern within the capsid CypA-binding
site (V86P/H87Q/I91V/M96I).
HIV-1 group means (RNA
copies/mL): ♦ = non-responders (n = 27), ■ = placebo (n = 12), ▲ = responders (n = 9). Individual values: X = female 13 (400 mg); *= female 18 (1200
mg). X-axis: study day.
Conclusions: Repeated oral doses of DEBIO-025 showed
limited anti-HIV-1 activity in some subjects and were safe and well tolerated. Longer
duration studies are needed to fully establish the potential of DEBIO-025. Unknown
host or viral factors may explain the difference between responders and non-responders.
Such factors will direct the development of DEBIO-025 as a potential treatment
for HIV-1 infection.
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