August 17, 2006

IAC: Encouraging TNX-355 Data

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.