August 17, 2006 (AIDSmeds)—Forty-eight week results from a phase II clinical trial of TNX-355, an HIV-entry inhibitor,
were reported today at the XVI International AIDS Conference in
Toronto. While the study found that the two doses of TNX-355 explored
in the study were associated with greater reductions in viral load
compared to placebo, the U.S. Food and Drug Administration has
requested additional dosing studies before the drug is moved into
late-stage development.
TNX-355 contains genetically
engineered antibodies, known as monoclonal antibodies. These antibodies
bind to the CD4 receptor on T-cells
(CD4 cells). Once TNX-355 binds to these receptors, HIV cannot
successfully connect with the surface of CD4 cells, thus preventing the
virus from infecting healthy cells. The drug is unlike any other
experimental HIV therapy in phase II or phase III development in that
it is administered intravenously once every two weeks. It also works
differently from other entry inhibitors in late-stage development, such
as vicriviroc and maraviroc.
The
clinical trial, conducted by Tanox and reported at IAC by Stanley
Lewis, MD, Medical Director of the company, involved 82 HIV-positive
patients who had tried and failed drugs in all three major classes
(PIs, NNRTIs, and NRTIs) and had viral loads of at least 10,000 upon
entering the study.
The study was designed to compare
two doses of TNX-355 – 10 mg per kilogram of body weight (mg/kg) and 15
mg/kg – to that of placebo. Patients were randomized to receive 10
mg/kg every week for eight weeks followed by every two weeks
thereafter, 15 mg/kg every two weeks, or placebo every two weeks. All
of the patients enrolled in the study received optimized background
therapy (OBT) – a combination of approved HIV drugs that patients'
viruses were believed to be at least partially sensitive to based on
the results of drug-resistance testing.
After
48 weeks, treatment with the 10 mg/kg dose of TNX-355 resulted in an
average viral load reduction of 0.96 log, compared with a 0.14 log
reduction in the placebo group. Patients who received the 15 mg/kg dose
of TNX-355 had an average viral load reduction of 0.71 log, compared
with a 0.14 log reduction in the placebo group. The differences in
viral load reductions between the two TNX-355 groups and the placebo
group were statistically significant, meaning that the results were not
due to chance.
Unfortunately, the percentages of
patients with undetectable viral loads after 48 weeks of treatment were
low, with no statistically significant differences between the three
groups. In the 15 mg/kg TNX-355 group, 7% had viral loads below 400 and
4% had viral loads below 50. In the 10 mg/kg TNX-355 group, 4% had
viral loads below 400 and no patients had viral loads below 50. In the
placebo group, no patients had viral loads below 400 or 50.
Patients
in both TNX-355 groups experienced greater CD4 cell increases compared
to those in the placebo group. There was an average increase of 48
cells in the 10 mg/kg group, an average increase of 51 cells in the 15
mg/kg group, and an average increase of one cell in the placebo group.
The differences between the TNX-355 groups and the placebo group were
statistically significant.
Dr. Lewis reported that both
doses of TNX-355 were well tolerated, with no severe adverse events
related to the drug. No infusion-site reactions were reported.
Development
of TNX-355 has been slowed due to U.S. Food and Drug Administration
questions related to this study. Before the drug can move into
late-stage phase II and phase III clinical trials – which Tanox was
hoping to move forward with this year – the FDA has requested that the
company first conduct additional early-stage phase II studies to
determine the correct dose of the drug.
As was reviewed by
Dr. Lewis, the drop in viral load was actually higher in the 10 mg/kg
TNX-355 group than in the 15 mg/kg group. Normally, a higher dose would
be expected to reduce viral load even more than a lower dose. It is
likely that questions surrounding the more limited viral load response
in the higher dose group, compounded by the fact that only two doses
have been tested in clinical trials, sparked the FDA to require
additional study data involving different doses.
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