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TMC278, new NNRTI, 7-day study results
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Reported by Jules Levin
TMC278 reduced HIV viral load by -1.2 log in antiretroviral-naïve patients in a 7-day proof-of-concept study....all doses had similar activity....study authors reported the drug was safe & well tolerated....a multinational phase IIB dose-finding study (TMC278-C204) in antiretroviral-naïve patients will start in March 2005.
At the "New Drugs" session Tibotec also presented on a new type of compound they are developing called an NcRTI: nucleotide-competitive RT inhibitor. It is structurally different from nucleoside RTIs & functionally different from NNRTIs. They called it "compound X" saying it represents a novel class of HIV RT inhibitors. See more at the end of this report.
"With three antiretrovirals in full development (TMC114, TMC125 and TMC278), and a TB compound (TMC207, also known as R207910) in clinical trials, we are demonstrating our commitment to providing new therapeutic options for patients with high unmet medical need," said Dr. Paul Stoffels, president of Tibotec.
Frank Goebel reported an oral talk on TMC278 in the last day's "New Drug" session: "TMC278: Potent Anti-HIV Activity in Antiretroviral Therapy-Naïve Patients"
Goebel reported:
--278 is a Potent NNRTI
--it has a high genetic barrier to resistance development
--278 is active against NNRTI resistant HIV
--it has favorable pharmacokinetics, including QD dosing
--there is potential for combined formulations with other ARVs
TMC278 is a DAPY* compound (*diarylpyrimidine).
Potency: wild-type HIV- EC50=0.5 nM (0.19ng/ml).
Selectivity index= 16,000
Half-life: 38 hours
Strong binding
Conformational flexibility
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Study TMC278-C201
Phase IIA, exploratory proof-of-principle trial in antiretroviral-naïve, HIV-1 infected subjects
--randomized
--double-blind
--placebo-controlled
--dose-escalating (25, 50, 100, or 150 mg)
TMC278 oral solution was given once daily as monotherapy for 7 days, 9 sites in 3 countries
Study objectives: HIV-RNA changes, safety & tolerability, pharmacologic profile, phenotypic/genotypic patterns.
Inclusion criteria: CD4 75-500 cells; HIV RNA >5,000 copies/ml; no resistance at screening.
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47 HIV-1 infected male Caucasians were enrolled.
Median viral load was 4.5 log (3.5 to 5.9).
Median CD4 count was 293 (29 to 590).
There was reported no difference between treatment arms.
There was confirmed phenotypic sensitivity to all ARVs, based on resistance testing at screening.
MEDIAN VIRAL LOAD REDUCTION: -1.2 log at Day 7
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There were small increases in CD4 counts in all treatment groups.
Trough plasma concentrations in all subjects were reported to be well above the EC50 corrected for protein binding.
No selection of NNRTI-resistance associated mutations in the course of treatment with TMC278 was reported: population sequencing at day 8.
SAFETY & TOLERABILITY
--Number of subjects reporting any AE:
22 (61%) in combined TMC278 groups
7 (64%) in placebo
--No dose relationship
--Almost all events were Grade 1 in severity
One Grade 3 event occurred (nausea)
--One Grade 1 rash on day 3
Resolved by day 7 with continued dosing
--No discontinuations due to AEs
--No serious adverse events (SAE)
MOST FREQUENT ADVERSE EVENTS
At least possibly related to treatment (in>1 subject)
| TMC278 (n=36) | Placebo (n=11) | | Events | | | | N(%) | | | | Headache | 3 (8.4%) | 1 (9.1%) | | Fatigue | 2 (5.6) | 0 | | Nausea | 2 (5.6) | 0 | | Somnolence | 2 (5.6) | 0 |
COMPOUND X
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