TNX-355, new entry inhibitor, effective in highly treatment-experienced patients

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A randomised phase II trial has found that the experimental entry inhibitor TNX-355 can reduce viral loads and allow CD4 cell counts to rise, when combined with an optimised background regimen. The study’s 48-week results were presented on Thursday at the Sixteenth International AIDS Conference in Toronto.

TNX-355 is an artificial antibody that attaches to the CD4 receptor on the surface of CD4 T-cells. By blocking the binding of HIV to this receptor, it prevents the virus from entering the cell and disrupts the viral life-cycle. It acts prior to either chemokine inhibitors or fusion inhibitors in the process of HIV engagement with receptors on the surface of target cells.

In the study presented in Toronto, 82 HIV-positive patients with experience of all three major classes of anti-HIV drugs were randomised to receive one of two doses of TNX-355 or placebo, along with an optimised background regimen. TNX-355 was given by infusion into a vein.

Glossary

placebo

A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.

log

Short for logarithm, a scale of measurement often used when describing viral load. A one log change is a ten-fold change, such as from 100 to 10. A two-log change is a one hundred-fold change, such as from 1,000 to 10.

receptor

In cell biology, a structure on the surface of a cell (or inside a cell) that selectively receives and binds to a specific substance. There are many receptors. CD4 T cells are called that way because they have a protein called CD4 on their surface. Before entering (infecting) a CD4 T cell (that will become a “host” cell), HIV binds to the CD4 receptor and its coreceptor. 

p-value

The result of a statistical test which tells us whether the results of a study are likely to be due to chance and would not be confirmed if the study was repeated. All p-values are between 0 and 1; the most reliable studies have p-values very close to 0. A p-value of 0.001 means that there is a 1 in 1000 probability that the results are due to chance and do not reflect a real difference. A p-value of 0.05 means there is a 1 in 20 probability that the results are due to chance. When a p-value is 0.05 or below, the result is considered to be ‘statistically significant’. Confidence intervals give similar information to p-values but are easier to interpret. 

phase II

The second stage in the clinical evaluation of a new drug or intervention, in which preliminary data on effectiveness and additional information about safety is collected among a few hundred people with the disease or condition.

Twenty-eight patients received 10mg TNX-355 per kilogram of body weight once a week for the first eight weeks, followed by infusions every other week, whereas 27 patients received 15mg/kg every week. Patients in any arm who did not have a viral load fall of 0.5 log10 or more after 16 weeks could switch to taking 15mg/kg TNX-355 every two weeks, with a new optimised background combination.

The primary endpoint of the study was the mean viral load reduction at week 24. Secondary endpoints were the percentage of participants who acheived a viral load reduction of at least 0.5 log by week 24, the proportion who acheived a 1 log reduction by week 24 and the change in absolute and percentage CD4 cell count by week 24.

At week 24, participants who received 15mg/kg weekly throughout the study had a mean viral load reduction of -0.95 log at week 24, compared to -0.20 log in the placebo group (p=0.003). Participants who received the 10mg/kg dosing schedule had a mean viral load reduction of -1.16 log at week 24, compared to -0.20 log in the placebo group (p=0.001).

After 48 weeks, intent-to-treat analysis found that patients receiving either dose of TNX-355 had greater reductions in viral load than those randomised to the placebo arm. The 10mg/kg group had a mean viral load fall of 0.96 log10, and the 15mg/kg group had a mean viral load fall of 0.71 log10. In contrast, the placebo group’s mean viral load reduction was 0.14 log10 (p

It took the patients taking TNX-355 longer to experience virological failure: 230 and 253 days, respectively, compared to zero days in the placebo arm (p = 0.003). CD4 cell counts also rose more in the TNX-355 arms (48 and 51 cells/mm3) than in the placebo arm (0 cells/mm3, p

No serious adverse events could be attributed to the study drug, and in particular, no infusion site reactions were noted. Injection site reactions have been a frequent side-effect of enfuvirtide, the fusion inhibitor which is injected subcutaneously twice a day.

“Treatment with TNX-355 is associated with durable viral load reductions and clinically meaningful increases in CD4 counts in treatment-experienced patients,” conclude the investigators.

Earlier this month the drug's manufacturer Tanox announced that the US Food and Drug Administration had asked the company to carry out an additional phase II dose finding study to define the dose that will be taken forward in development.

References

Norris D et al. TNX-355, in combination with optimized background regimen (OBR), achieves statistically significant viral load reduction and CD4 cell count increase when compared with OBR alone in phase 2 study at 48 weeks. Sixteenth International AIDS Conference, Toronto, abstract THLB0218, 2006.