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REVIEW OF MERCK'S NEW DRUG APPLICATION (NDA) OF INDINAVIR
Data from interim analysis of protocol 028 was presented publicly for the first time. Protocol 028 is a clinical endpoint study of comparing indinavir alone (800 mg three times daily) versus AZT alone (200 mg three times daily) versus indinavir plus AZT in untreated HIV+ individuals with CD4 counts of between 50 and 250 cells/mm3. The study is being conducted in Brazil.
A total of 750 patients were enrolled in the study. A subset of these patients (244 patients) was included in the interim surrogate marker analysis. At baseline, the median CD4 count was 139 cells/mm3 and the median serum viral RNA was 29,000 copies/ml (or 4.46 log). Seventy-five percent of these participants were male and 25% were female.
At week 24, 59 patients receiving indinavir for whom data is available had a median viral load decline of 0.8 log as compared to median reductions of 1.3 log and 0.3 log in 58 patients receiving indinavir plus AZT and 62 patients receiving AZT alone, respectively. Interim data at week 24 also revealed that 40% of those receiving indinavir alone (59 patients) or indinavir plus AZT (58 patients) had viral load fell below the limit of assay detection or less than 500 HIV RNA copies/ml as compared to about 8% of those (62 patients) receiving AZT alone.
CD4 counts increased by about 100 cells/mm3 above baseline at week 24 in both indinavir-containing arms. CD4 counts remain unchanged in the AZT alone arm at week 24.
Results from another study (protocol 033) were also presented publicly for the first time. Protocol 033 is designed to assess the immunologic and virologic effects of indinavir alone (800 mg three times daily) versus AZT alone (200 mg three times daily) versus indinavir plus AZT in untreated HIV+ individuals with CD4 counts of between 50 and 500 cells/mm3.
Of the total 742 patients enrolled, 266 patients were included in the surrogate marker analysis. At baseline, the median CD4 count was 258 cells/mm3 and the median serum viral RNA was 22,000 copies/ml. Ninety-one percent of the study participants were male and 9% were female.
At week 24, patients receiving indinavir alone (34 patients) or indinavir plus AZT (37 patients) for whom data is available had achieved viral load reduction of 1.3 log at week 24. By contrast, those (38 patients) receiving AZT alone had a 0.3 log drop in viral load at week 24. Based on a separate analytical method, 50% of those patients receiving indinavir alone had viral load fell below the limit of assay detection or less than 500 HIV RNA copies/ml at week 24 as compared to 40% and 0% of those receiving indinavir plus AZT and AZT alone, respectively.
At week 24, CD4 counts increased by 110 cells/mm3 and 80 cells/mm3 above baseline in the indinavir alone group (75 patients) and in the indinavir plus AZT group (73 patients), respectively. CD4 counts remain unchanged in the AZT alone group (72 patients) over the same period.
Interim results were presented at the hearing, based on analyses of additional patients enrolled in a recent study (protocol 035) examining indinavir in combination with AZT/3TC; the patients were previously treated with AZT, but were 3TC-naive. These findings have added more weight to the preliminary data based on analyses of a fewer number of patients from this study, which was presented publicly for the first time at the Third Conference on Retroviruses and Opportunistic Infections held in Washington, D.C.
At 24 weeks, 22 patients receiving the triple combination of indinavir plus AZT and 3TC had mean reductions in viral load of 1.77 logs (98%) as compared to 0.95 log (89%) in 20 patients receiving indinavir alone and 0.67 log (78%) in 19 patients receiving AZT and 3TC. A higher proportion of patients (20 of 22) on the triple drug regimen (91%) had viral load levels declined to below assay detection limit, which was less than 500 copies/mL. By contrast, 35% of those (7 of 20 patients) receiving indinavir alone and none (0 of 19 patients) receiving AZT and 3TC had viral load levels below the limit of assay detection. Patients taking indinavir alone or in combination with AZT and 3TC had mean CD4 count increases of 100 cells/mm3, compared to mean CD4 increases of 33 cells/mm3 in those taking AZT and 3TC at week 24.
Based on data contained in the NDA, indinavir was recommended by the FDA advisory committee for accelerated approval of monotherapy and combination therapy with approved nucleoside analogues for individuals with HIV infection when treatment is warranted. This approval is based on surrogate marker improvements. Clinical endpoint data is not yet available.
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