DAPD- preliminary antiviral activity, tolerability, and resistance

At the Retrovirus Conference, Doug Richman reported initial results on the tolerability and antiviral activity from a 14-day dose ranging monotherapy study. DAPD turns into DXG in the human body so I may refer to either interchangeably. This link will take you to a report from the '99 Resistance Workshop last Summer in San Diego --

The report describes DAPD turning into DXG, and has additional information on the resistance profile for DAPD. Richman described the antiviral activity of DXG against AZT and 3TC resistant recombinant HIV. Richman showed 3 recombinant HIV viruses with resistance to both AZT and 3TC, and DXG displayed no resistance to them. A fourth virus had resistance only to 3TC (>100-fold), but no resistance to AZT, and again DXG displayed no resistance to this virus. Based on the sum of the preliminary resistance data, it appears as though DAPD may be effective in suppressing HIV for a number of people with NRTI resistance. The data also suggests that some people who have some of the multi-drug NRTI resistant mutants may not respond well. But its early in the development process.

Richman reported the viral load reductions and CD4 increases for 4 twice daily dosing regimens: 25 mg, 100 mg, 200 mg, 300 mg. There were 7-8 people in each dose group. One group is receiving 600 mg once daily but the data was not yet available. 21 men and 8 women. The baseline viral load in the highest dosing group was 53,000 copies/ml, and the median CD4s were 431. At day 15, the viral load reduction was the highest in the 300 mg group-- 1.5 log. After stopping drug viral load went back to baseline. The 200 mg group had about a 1.2 log reduction in viral load. The reductions were dose dependent. Richman reported 80% of patients receiving 300 mg DXG had a 1.5 log reduction. Plasma half-life of DXG is 7-8 hours and a Triangle Pharma official said the blood levels "have a with nice long tail meaning it hangs around longer and hopefully gets into PBMCs". So, hopefully once-a-day dosing will work. Upon examining 21 patients pre- and post-treatment samples, no genotypic changes were seen. During the 14-day study DXG appeared to be well tolerated.

Fold Change in IC50 from Wild-Type

Richman went on to describe the antiviral activity of DXG against drug resistant virus. One triple-mutant virus containing the mutli-drug resistant mutant 151M and 65R had high level resistance to DAPD. Two other triple-mutant viruses without the 65R but with the 151M were about 5-fold resistant to DXG. Two triple mutant viruses containing the 69 (SS) were fully  sensitive to DXG.

IC50 Fold Change