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REVIEW OF ABBOTT'S NEW DRUG APPLICATION (NDA) OF RITONAVIR
The ritonavir NDA included data from two pivotal studies (M94-245 and M94-247).
Protocol M94-245 was designed to assess virological effect of ritonavir alone (600 mg twice daily) versus AZT alone (200 mg three times daily) versus ritonavir in combination with AZT in previously untreated patients with CD4 counts of greater than 200 cells/mm3 and HIV RNA of >15,000 copies/ml. At baseline, the mean CD4 count was about 360 cells/mm3 and the mean viral load was 4.84 logs.
There was a decline of 1.2 logs or >90% in viral load at both week 2 and week 16 in the ritonavir alone group. CD4 counts increased by 70 and 80 cells/mm3 above baseline at week 8 and week 16, respectively. By contrast, there was a decline of 1.1 log or >90% in viral load at both week 2 and week 16 in the ritonavir plus AZT group. CD4 counts increased by 40 and 30 cells/mm3 above baseline at week 8 and week 16, respectively.
Both immunologic and virologic responses were more robust in the ritonavir monotherapy group as compared to the ritonavir plus AZT group. The combination of ritonavir and AZT, as administered in the study, led to poorer and higher premature discontinuation rate (39%) than either monotherapy arms. Study participants may not be taking quite the full dose of study medications each time. Indeed, Abbott tested for ritonavir levels in study participants and found that the levels in the ritonavir plus AZT arm to be significantly lower than those in the monotherapy arms.
The other pivotal study, protocol M94-247, was performed in patients with advanced HIV disease with CD4 counts of less than 100 cells/mm3. Participants must have at least 9 months of prior treatment with up to but no more than 2 approved antiretroviral drugs such as AZT, ddI, ddC or d4T. 3TC was considered as an experimental agent at that time (prior to its approval) and was not permitted as a concurrent therapy. The study objective was to determine the antiviral activity and clinical efficacy of ritonavir in this advanced, heavily pre-treated population.
A total of 1,090 study participants were randomized to receive ritonavir (600 mg twice daily) or placebo in combination with concurrent antiretroviral therapy. About 18% of patients had no other concurrent antiretroviral therapy during the course of the study (i.e. they received either ritonavir alone or placebo alone).
Abbott presented encouraging virological data from a subset of patients in the ritonavir plus concurrent antiretroviral therapy group. Seventy-five patients had a maximum mean decrease of 0.8 log in viral load at 16 weeks which was sustained out to 32 weeks.
Finally, Abbott's ongoing pediatric study was presented. This is a phase I/II multi-dose trial being conducted at the National Cancer Institute and in Florida. Two age groups are being examined: 6 months to 2 years old and 2 to 18 years old. For safety considerations, ritonavir monotherapy is initiated for 12 weeks, after which AZT/ddI or 1 of the 2 drugs can be added. Both treatment-naive and -experienced individuals are eligible. To date, 15 to 20 patients have been enrolled. One patient has discontinued the study due to elevated liver enzymes. Lymph node biopsies may be performed as a part of a substudy.
Based on the data contained in the NDA, ritonavir was approved by the FDA for monotherapy and combination therapy with approved nucleoside analogues for individuals with advanced disease. For less advanced individuals, approval of ritonavir was based on improvements in surrogate markers (viral load and CD4 counts). Clinical endpoint data for the less advanced population is currently not yet available.
COMMENTS: Unfortunately, the study design dictated individuals remain on the same antiretroviral therapy for 4 months, until those in the ritonavir placebo group were crossed over to receive ritonavir. Dr. John Leonard of Abbott pointed out that this is not the optimal way to use a protease inhibitor. Optimally, you want each drug in your combination regimen to have as much efficacy as possible. That means, when initiating therapy with a protease inhibitor the other drugs used in the combination should also be newly initiated. The maximum RNA reduction was 1.3 log at 2 weeks, and by 16 weeks it had returned to 0.8 log. This could have been due to the study design that a participant must remain on the same therapies (you could say, in effect, study participants were taking ritonavir monotherapy), and also because the study population was a very advanced disease group; the average CD4 count was 28 cells/mm3 and 25% had CD4 counts of 10 cells/mm3 or below.
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