HIV
and Hepatitis.com Coverage of the 14th
Annual Conference on Retroviruses and Opportunistic Infections (14th CROI) February
25 - 28, 2007, Los Angeles, CA
TMC278
Demonstrates Equally Potent and Durable Efficacy, Less Rash, Better Lipid Profile,
and Fewer Nervous System Effects than Efavirenz
The widespread use of HAART in the developed
world has resulted in a significant increase in survival time and a substantial
decrease in morbidity among HIV positive individuals. However, there is a pressing
need for the development of new, improved anti-HIV therapies due to the emergence
of drug-resistant viruses in patients on HAART and to the increasing transmission
of these resistant viruses to recently-infected individuals.
In addition,
there is also a need for new treatments that are better tolerated than existing
therapies, in particular in the anti-HIV drug class known as non nucleoside reverse
transcriptase inhibitors (NNRTIs), which are important components of present day
HAART due to their potency. The use of the currently available NNRTI, efavirenz
(EFV; Sustiva) and nevirapine (NVP; Viramune) has been limited by the sometimes
rapid emergence of resistance to the entire drug class and by the adverse effects
of these drugs.
TMC278 is a novel new NNRTI developed by Tibotec, a subsidiary
of Johnson and Johnson. The drug has a higher genetic barrier to the emergence
of resistance compared with the currently available NNRTI. In addition, it is
potent and highly active against wild type HIV and retains activity against NNRTI-resistant
HIV strains in vitro.
At the 14th CROI in Los Angeles (February 25-28,
2007), Anton Pozniak of Chelsea and Westminster Hospital in London presented preliminary
results of an ongoing study in 368 treatment-naïve HIV patients to evaluate
the efficacy and safety of three different once-daily doses of TMC278 (25, 75
or 150 mg) compared with efavirenz (600 mg once daily). Both drugs were used in
combination with zidovudine/lamivudine (ZDV/3TC; Combivir) or tenofovir/emtricitabine
(TDF/FTC; Truvada).
The primary objective of the study is to determine
the best TMC278 dose to be used in future trials of the drug. The primary endpoint
was the proportion of patients with confirmed viral load <50 copies/mL ((time
to loss of virologic response (TLOVR) definition, non-completer = failure) at
48 weeks.
Results
•
368 individuals (33% female) were randomized to TMC 278 25, 75 or 150 mg once
daily or EFV 600 mg once daily.
•
76% used Combivir and 24% used Truvada.
•
Baseline median log10 viral
load was 4.85 copies/mL and median CD4 cell count was 203 cells/mm3.
•
48-week results for the intent-to-treat
population (TLOVR) are shown in the table.
•
There was no statistically
significant difference in the efficacy results between any of the treatment arms.
•
The most common adverse events
were nausea (TMC278 doses combined 35% vs EFV 29%) and headache (18% vs 16%).
•
Nervous system disorders and
psychiatric events were less frequent with TMC278 (28% and 13%, respectively)
compared with EFV (48% and 16%, respectively).
•
Rash events were also less
frequent for TMC278 (8%) vs EFV (19%).
•
Mean (SD) changes from baseline
of total and LDL cholesterol were 5 mg/dL (30) and 0 mg/dL (24) with TMC278 versus
31 mg/dL (30) and 16 mg/dL (26), respectively with EFV.
•
In patients treated with Combivir,
anemia, or neutropenia led to switches off zidovudine (ZDV; Retrovir) in 6% of
TMC278 subjects and 1% of EFV subjects.
•
For TMC278 and EFV, respectively,
the incidence of grade 3 or 4 adverse events was 25% vs 16%; serious adverse events
was 10% vs 9%; and grade 3 or 4 lab abnormalities was 22% vs 20%.
Most
common AEs at least possibly related to TMC278 or efavirenz
%
25mg
n=93
75mg
n=95
150mg
n=91
All
TMC278 n=279
EFV
600mg n=89
Nausea
15.1
25.3
20.9
20.94
18.0
Headache
6.5
11.6
5.5
7.9
7.9
Dizziness
5.4
5.3
5.5
5.4
27.0
Vomiting
3.2
7.4
3.3
4.7
9.0
Somnolence
2.2
3.2
4.4
3.2
10.1
Vertigo
1.1
2.1
0
1.1
10.1
Abnormal
Dreams
1.1
4.2
0
1.8
5.6
Rash
0
0
1.1
0.4
5.6
In
conclusion, the study authors write, "All doses of TMC278 demonstrated significant
and sustained efficacy similar to that of EFV over 48 weeks in ART-naïve
patients."
"TMC278
was generally well tolerated with lower nervous system, rash, and lipid effects
than EFV."
Commentary
In
this Phase 2b study TMC278 demonstrates potent and sustained viral suppression
over 48 weeks similar to that of efavirenz. In addition, the drug shows a lower
incidence of rash and lipid effects (cholesterol/triglycerides). Finally, compared
with efavirenz, TMC278 in this Phase 2 study has a substantially lower incidence
of central nervous system (CNS) disorders, affecting 33% of those receiving TMC278
compared with 53% of those receiving efavirenz, according to Dr. Pozniak.
This
novel NNRTI is being developed by Tibotec as a component of once-daily dosing
in combination therapy with other antiretroviral drugs. Results of this Phase
2b study are promising and suggest that this new experimental compound could be
a safe and effective component of therapy for HIV infection. Trials of longer
treatment duration with TMC278 in treatment-naïve and treatment experienced
HIV patients are already underway or being planned.
Chelsea
and Westminster Hosp, London, UK; Clinical Res, San Juan, Puerto Rico; Univ of
the Witwatersrand, Johannesburg, South Africa; Hosp Gabriel Mancera IMSS, Mexico
City, Mexico; Srinagarind Hosp, Khon Kaen, Thailand; Tibotec BVBA, Mechelen, Belgium;
and Tibotec Inc, Yardley, PA, US.
Reference
A Pozniak, J Morales-Ramirez, L Mohapi, and others. 48-Week Primary
Analysis of Trial TMC278-C204: TMC278 Demonstrates Potent and Sustained Efficacy
in ART-naïve Patients. 14th CROI. February 25-28, 2007. Los Angeles, CA.
Abstract 144LB.
