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Update on Agouron's Nelfinavir
EARLY RESULTS OF NELFINAVIR PLUS d4T STUDY
Agouron's late breaker abstract on its preliminary results from a study of nelfinavir plus d4T (protocol #510) was not accepted by the Scientific Program Committee of the Conference. The company did, however, convened a community meeting where the combination data along with the status of pivotal Phase II/III nelfinavir studies were discussed.
Preliminary data from an ongoing pilot study of nelfinavir given in combination with d4T in HIV-infected individuals have shown that nelfinavir may produce profound acute antiviral effects when combined with other anti-HIV drugs. Patients had CD4 counts of greater than 200 cells/mm3 and viral RNA titer of greater than 15,000 copies/ml with no prior d4T and protease inhibitor experience. In addition, patients were either AZT-naive or AZT-experienced. Chiron's bDNA test with a lower detection limit of 500 copies/ml of viral RNA was employed (i.e. viral load level below 500 copies/ml is considered undetectable).
Patients were randomized to one of the 4 treatment groups: 500, 750, or 1,000 mg of nelfinavir three times per day plus d4T, or d4T alone. Mean CD4 counts at baseline were slightly above 300 cells/mm3. There were CD4 increases in the nelfinavir plus d4T groups which ranged from about 100 to 200 cells/mm3 in 24 evaluable patients over 28 days. CD4 increases were observed in all three nelfinavir/d4T dose groups.
Baseline viral load titers were between 50,000 and 70,000 copies/ml. Mean reductions of plasma viral RNA were 99% or greater in patients receiving nelfinavir (500, 750 or 1,000 mg three times per day) plus d4T, as compared to a mean reduction of 75% in those treated with d4T alone after 4 weeks. Viral load reductions were maintained by about 2.5 logs in patients receiving nelfinavir in combination with d4T after 45 days in some cases.
Agouron also displayed a graph depicting the percentage of antiviral responders at 4 weeks (see table 3A ).
Table 3A--% of responders at 4 weeks Nelfinavir + d4T (<20 patients) % of patients HIV RNA reduction 100% > 1.0 log 100% > 1.5 log 75% < 500 copies*
*below assay limit of detection. In another pilot 4-week study, mean maximum reductions of plasma viral RNA of 96%, 98% and 98% in patients receiving nelfinavir monotherapy at doses of 500, 750 and 1,000 mg three times daily, respectively. HIV fell below detection limit of the assay in 20%, 60% and 50% of those receiving nelfinavir at doses of 500, 750, and 1,000 mg three times daily, respectively.
Nelfinavir was generally well tolerated with loose stool/diarrhea as the most commonly reported side effect.
Based on the findings from this combination study and other pilot phase II studies of several doses of nelfinavir involving more than 100 HIV-infected patients, Agouron announced the initiation of its pivotal phase II/III studies of nelfinavir. These studies will assess the safety and efficacy of nelfinavir (500 or 750 mg three times daily) administered in combination with other anti-HIV drugs such as AZT, 3TC and/or d4T in about 1,000 patients.
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