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Merck Integrase Inhibitor: -1.8 log reduction in 10-day study
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Reported by Jules Levin
Susan Little reported publicly at the 12th CROI for the first time data from the study of the Merck integrase inhibitor in patients: "Antiretroviral Effect of L-000870810, a Novel HIV-1 Integrase Inhibitor, in HIV-1 Infected Patients". This is the precursor compound to the integrase inhibitor Merck will be developing in further studies in patients.
ANTIVIRAL ACTIVITY
IC95= 15 nM in 10% FBS
= 100 nM in 50% human serum
IC50= 3 -- 6 nM in 10% FBS
= 40-70 nM in 50% HS
STUDIES IN UNINFECTED SUBJECTS
--generally well tolerated in 153 uninfected subjects
--pharmacokinetics support twice daily dosing; C12hrplasma levels>IC95 at doses >100mg every 12 hrs
L-000870810 is fully active against both wild-type and multidrug resistant HIV-1.
In vitro resistance studies suggest high genetic barrier.
Resistant viruses exhibit impaired replication.
Viruses with integrase inhibitor resistance mutations remain fully sensitive to NRTIs, NNRTIs, & PIs.
STUDY DESIGN
This was a double-blind, randomized, placebo-controlled, multiple site study enrolling 30 HIV+ patients, both treatment-naïve & experienced. Treatment-experienced patients were off therapy for >3 months. Treatment (randomized 4:1 for drug"placebo) was given for 10 days with doses divided into two groups:
400 mg p.o. bid
200 mg p.o. bid
PK was performed with either high fat or moderate fat meal. The endpoints were safety, PK, & HIV RNA.
BASELINE CHARACTERISTICS were comparable between the 3 arms (400, 200, placebo). 17 patients received 400 mg bid, 7 received 200 mg bid & 6 received placebo. Mostly men. Age, 32-39. 75%+ were white. CD4 count ranged from 422-550. HIV RNA was about 4.5 log. TREATMENT NAÏVE: 7/17 in 400mg; 2/7 in 200mg; 3/6 in placebo. The remaining patients were treatment-experienced with all 3 classes of ART. Prior duration of ART was 24-38 months.
CLINICAL ADVERSE EVENTS
Most patients experienced 1 or more AEs: nausea, herpes simplex, URI, headache, lymphadenopathy. 40-60% of patients did not experience any AEs. Several patients experienced increased AST, ALT.
10-DAY PK RESULTS
No significant effect of fat in meal was observed in this study.
400mg bid: high fat, n=11, AUC 0-12h: 25.6 C12h nM: 413
400 mg bid: moderate fat, n=5, AUC 0-12h: 21.8, C12h nM: 540
200 mg bid: moderate fat, n=5, AUC 0-12h: 13.8, C12h nM: 217
MEAN HIV RNA CHANGES FROM BASELINE
After 10 days of treatment viral load reduction was -1.8 log for both doses. At day 10 6/16 (37%) in the 400 mg dose group had <400 copies/ml, while in the 200 mg dose group 1/5 (20%) had <400 copies/ml. 0/5 in the placebo group had <400 copies/ml.
Little summarixed:
The drug was generally well tolerated. Plasma concentrations above IC50 & IC95 were observed with doses of 200 & 400 mgf twice daily. The drug is potent in naïve & experienced patients. There was no evidence of resistance selection within 10 days. This study was a proof of concept for the antiviral activity of HIV-integrase as a new therapeutic class.
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