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Efficacy and tolerability of TMC125 in HIV patients with NNRTI and PI resistance at 24 weeks: TMC125-C223
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Reported by Jules Levin
The study was reported a few weeks ago in Dublin.
HA Grossman, C Hicks, P Shalit, DT Jayaweera, M Thompson, G Blick, J Vingerhoets, E Voorspoels, M Peeters and B Woodfall
TMC125-C223: Introduction (1)
TMC125 is a novel NNRTI designed to have a high genetic barrier to the development of resistance1
In a 7-day trial, TMC125 monotherapy produced a mean change in viral load of - 0.9 log10 copies/mL in patients failing NNRTI-based therapy2
1) Andries et al. Antimicrob Agents Chemother 2004; 48:4680- 6
2) Study TMC125-C207 - Gazzard et al. AIDS 2003; 17:49- 54
TMC125-C223: Introduction (2)
A prior Phase II dose-escalation, double-blind, placebo-controlled trial (TMC125-C203) in triple-class-experienced patients:
Found that TMC125 was generally safe and well tolerated
--Grade 3/4 AEs - not substantially different from placebo
--Most common AEs were diarrhea, headache, rash and nausea
--Rashes were generally mild to moderate and caused treatment discontinuation in three patients (2%)
--No consistent or frequent neuropsychiatric syndrome associated with TMC125
Guided design of TMC125-C223 dose-finding study
TMC125: Moving forward
DUET 1 and 2
--Pivotal Phase III trials in treatment-experienced patients currently enrolling
New formulation of TMC125
--100 mg tablets with significantly improved bioavailability
--Dosage 200 mg bid:
---Comparable exposure to 800 mg bid of previous formulation
TMC125-C223: Study design
--Viral load >1,000 copies/mL
--Documented NNRTI resistance and ≥3 primary PI mutations
--Randomized 1:2:2 (Active control vs 400 mg bid vs 800 mg bid), partially blinded
Specific Grade 3/4 AEs in ≥3 patients in TMC125 or control :
--Pneumonia: 3% and 0
--Hypertriglyceridemia: 2% and 8%
-- Drug-related rash: 2% and 0
--Pancreatitis: 2% and 0
--5 Deaths: 4 (3%) in 400 mg bid and 1 (3%) in control
TMC125-C223: Rash
Overall incidence:
--Combined TMC125 group 31 (20%) vs. control group 3 (8%)
--No dose differentiation
Relatedness and severity:
--At least possibly related to TMC125: 15%
--Grade 3 rashes (no SAEs):
2 in 400 mg arm (one related to dapsone)
1 in 800 mg arm
Permanent trial discontinuation: 5 (3%)
Time to onset / duration (at least possibly related rashes):
--median time to onset 13 days and median duration 5 days
Most common Grade 3/4 lab abnormalities for TMC125 or
active control were:
-- Pancreatic amylase: 12 (8%) and 0 patients
-- Triglycerides: 10 (6%) and 4 (11%) patients
-- Neutropenia: 9 (6%) and 4 (11%) patients
--Creatinine: 5 (3%) and 0 patients
TMC125-C223: Safety - SAEs
SAEs were reported in 23% in the TMC125 groups with no dose differentiation
SAEs at least possibly related to TMC125
-- 3 in 400 mg group (cardiopulmonary failure, myocardial infarction, hemorrhagic stroke)
-- 1 in 800 mg group (pancytopenia)
*1 case possibly related; 1 case not related
TMC125-C223: Conclusions
Both doses of TMC125 showed significant and sustained efficacy in heavily pre-treated patients with substantial NNRTI and PI resistance
--Additional one log10 viral load decline compared with control
There were no dose-related effects on safety and tolerability
TMC125 is the first NNRTI to show significant activity in patients with prior NNRTI failure
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