Objective: To compare the efficacy, durability, and tolerability of GW433908 (908), 1400 mg twice-daily (BID), with nelfinavir (NFV), 1250 mg BID.
Methods: This was an international, multicenter, randomized, open-label study (NEAT) in antiretroviral therapy (ART)-naive HIV-infected adults with plasma HIV-1 RNA (vRNA) at screening ≥5000 copies/mL (c/mL). Patients were randomly assigned to 908 or NFV (2:1) for a minimum of 48 weeks, with a background of abacavir (ABC) and lamivudine (3TC).
Results: A total of 166 patients received randomized treatment with 908 BID and 83 received NFV BID. The population was diverse with regard to race and gender (76% Hispanics and blacks, 31% female) and had advanced HIV disease at screening (45% had vRNA >100,000 c/mL, 48% had CD4 cell counts <200 cells/mm3, 20% had a history of Centers for Disease Control class C events). After 48 weeks of study by an intention-to-treat rebound or discontinuation = failure analysis, a greater proportion of patients in the 908 BID group (66%) than the NFV BID group (51%) achieved vRNA <400 c/mL. Furthermore, more patients with screening vRNA >100,000 c/mL (67 vs. 35%) or CD4 <50 cells/mm3 (48 vs. 24%) achieved undetectable viral loads taking 908 BID compared with NFV BID, respectively. Favorable immunologic responses were observed for both groups. Diarrhea, which was more common in the NFV BID group (18 vs. 5%), was the only drug-related grade 2-4 adverse event with a significant difference (P = 0.002) in incidence between groups.
Conclusion: Administration of 908 BID resulted in a potent and sustained antiretroviral response, notably in ART-naive patients with advanced HIV disease. GW433908 was generally well tolerated and provides a convenient dosing option without food or fluid restrictions.
GW433908 (908, fosamprenavir) is an HIV protease inhibitor (PI) currently in late-stage clinical development for the treatment of HIV infection in adults and children. 1,2 GW433908, formulated as 700-mg film-coated tablets, can be taken without food or water restrictions, may be administered with ritonavir in either a twice-daily (BID) or once-daily (QD) dosing regimen, or alone as part of a BID regimen. 3,4 Upon absorption, 908 is rapidly hydrolyzed to amprenavir plus inorganic phosphate, thus retaining the distinct resistance profile of the active moiety, amprenavir. 5,6
GW433908 has been studied in a phase 2 development program including a dose-ranging study in which 1395 mg (3 × 465-mg tablets) and 1860 mg (4 × 465-mg tablets) BID doses of 908 were shown to be comparable to the standard dose of amprenavir (when administered as Agenerase, 1200 mg BID; GlaxoSmithKline, Ware, UK). Agenerase is formulated as soft-gel capsules containing 150 mg of amprenavir requiring 8 capsules BID. GW433908 achieved a reduction in plasma HIV-1 RNA (vRNA) of approximately 2 log10 copies/mL (c/mL) over 4 weeks while maintaining a favorable tolerability profile. 2 Based on the similarity in plasma amprenavir pharmacokinetics, short-term virologic and immunologic efficacy, and safety profile between the 2 dosage regimens, the 1395-mg BID regimen was selected for further study. Study APV10006 demonstrated bioequivalence between the 465-mg and 700-mg tablet presentations. 7 Newly formulated 700-mg film-coated tablets were used without ritonavir in the NEAT study to achieve a dosing regimen requiring just 2 tablets BID.
In the NEAT study, we compared the efficacy, safety, and tolerability of 908 1400 mg BID, with that of nelfinavir (NFV) 1250 mg BID, over 48 weeks of dosing. Both PIs were given in combination with an abacavir (ABC)/lamivudine (3TC) background. The primary objective was to compare the efficacy and durability of the antiviral response to 908 and NFV when each drug was administered to antiretroviral therapy (ART)-naive subjects in combination with ABC and 3TC. Secondary objectives were to compare the safety and tolerability of 908 and NFV, to compare virologic and immunologic responses, to compare the occurrence of events related to metabolic abnormalities, and to assess the development of viral resistance to the two treatment regimens.