Report by Jules Levin, Executive Director, NATAP (April 17, 1998)
Dr. Steven Deeks reported data from a 28 day phase I/II study of monotherapy PMPA. During the Summer of 1997 a 28 day study of intravenous PMPA showed antiviral activity. Based upon these results an oral prodrug was developed (bis-poc PMPA). The highest dose used in the study being currently reported was 300 mg once daily. This dose was 3 or 4 times less equivalent to the highest dose used in the IV study. The dose used in the IV study showed more antiviral activity. If safety is established with the 300 mg dose higher doses will be explored. (See the PMPA report and July Issue of NATAP Reports on the NATAP website.)
Deeks said PMPA had potent activity in HIV-infected macaques, has a prolonged intracellular half-life of 15-30 hours, has a favorable resistance profile. The NATAP Reports July 1997 issue has a detailed PMPA report which includes more details about the IV study.
The current trial was a randomized, double blinded, placebo controlled, dose escalation of study PMPA monotherapy. At baseline participants had HIV RNA >10,000 copies/ml. and CD4> 200, Three dose levels were explored (75 mg, 150 mg, 300 mg); 10 Patients per dose level (8 active, 2 placebo). 5 extra patients were enrolled at the 75 mg dose to confirm safety. A single dose was given on day 1 followed by a 7 day washout and then by once a day dosing on days 8-35 (28 days).
At baseline: the median CD4 in the group receiving PMPA was 375 cells (n=28); the median viral load was 4.5 log (31,600 copies/ml); 68% had prior therapy; 32% had prior PI therapy ; in the placebo group median baseline viral load was 4.5 log; 354 CD4, 25% had prior therapy; 13% had prior PI therapy.
Bioavailability was 27% without food, 41% with food; AUC and Cmax were dose proportional; Serum half-life was 17 hours.
Table. Changes in HIV RNA from Day 0 to Day 35
Investigators conducted a resistance mutation analysis at baseline and day 35 for the individuals taking 150 and 300 mg/day. They reported no patient developed a mutation. 5 patients had at baseline the 3TC M184V mutation. The virologic response was similar to those without M184V.
Table. Grade 3 or 4 Adverse Events; possibly or probably drug related
|Active Drug Group||Placebo|
|Increased CK||5 (18%)||1 (13%)|
|Increased AST/ALT||3 (11%)||0 (0%)|
|Peripheral Neuropathy||1 (4%)||1 (13%)|
No additional grade 2 to 4 clinical adverse events reported.
Gilead Sciences, the developer of PMPA, is now in the process of designing and starting a variety of studies. As I stated above the 300 mg dosing used in this study was not equivalent with the highest dosing used in the IV study where better antiviral activity was shown. Gilead expects to explore higher dosing when the 300 mg dose shows safety.