PR Newswire - 21 December 1995

Protease inhibitors are a new class of drug with a mechanism of action that is different from the previously available antiretroviral treatments for AIDS. Nucleoside analogues, such as AZT and ddC, work by inhibiting the action of reverse transcriptase, an enzyme involved in the replication of the virus's genetic material. Protease inhibitors, such as ritonavir, block the action of an enzyme involved in the final processing of viral proteins. By blocking protease activity, protease inhibitors prevent production of infectious viral particles.

"Ritonavir offers physicians and patients a powerful protease inhibitor for the fight against HIV infection and AIDS," says Andre Pernet, Ph.D., vice president of pharmaceutical products research and development at Abbott. "Based on what we now understand about viral dynamics, it appears that early intervention with a combination of antiretroviral agents may be the best treatment strategy for HIV infected patients. Ritonavir is being developed in both capsule and liquid form and will be administered in a twice-daily dosing regimen."

Data from two double-blind, multicenter, multicountry, randomized trials demonstrated the effectiveness of ritonavir for the treatment of HIV infection. The first trial (M94-247) studied the safety and efficacy of ritonavir plus current therapy vs. placebo plus current therapy. In this trial, 1,090 patients were randomized to receive daily either 1,200 mg of ritonavir or placebo concomitant with existing nucleoside therapy (if any). Patients with CD4 counts of 100 or less are considered the most seriously ill AIDS patients. At entry, all patients had CD4 lymphocyte counts of 100 cells/microliter.

In the first 159 patients enrolled with high baseline HIV RNA levels, ritonavir produced statistically significant decreases in mean viral RNA levels compared to placebo over the first 16 weeks of the study. In the ritonavir group, patients showed a maximal mean decrease in HIV RNA levels of 90 percent after two weeks of treatment. The magnitude of the decrease attenuated over time. This compares with negligible mean changes at all time points in the placebo group. Measurement of viral RNA levels are indicative of the amount of the HIV virus in a patient's blood.

CD4 counts were analyzed from the first 211 patients randomized. Statistically significant increases in average change of CD4 count from baseline were observed with ritonavir as compared to placebo over the first 16 weeks.

The second trial (M94-245) compared the efficacy of ritonavir alone, zidovudine (AZT) alone, or the combination of ritonavir and AZT in HIV-infected patients without prior antiretroviral therapy. In this trial, 356 patients were randomized to one of the three treatment groups. All patients had at least one screening CD4 lymphocyte count of at least 200 cells/microliter and at least one screening of HIV RNA level 15,000 particles/mL. Over the first 16 weeks of the study, ritonavir produced statistically significant decreases in mean average viral RNA levels compared to the combination and AZT groups. In the ritonavir group, a mean decrease in HIV RNA of greater than 90 percent from baseline was observed after two weeks of treatment. The magnitude of decrease persisted with the ritonavir group over the 16 week observation period. In addition, statistically significant mean average increases in CD4 count were observed with both arms compared to AZT. In the ritonavir alone group, mean increases exceeding 62 cells/microliter were observed by the second week of treatment, and were maintained or exceeded at all later visits.

In addition, data from a supportive study (M94-208) showed that the use of ritonavir in combination with the nucleoside analogues AZT and ddC demonstrated more potent antiviral activity than any single agent or combination of agents previously tested with ritonavir in therapy-naive patients.

An open-label, multicenter, six-month evaluation (M94-208) of the safety and antiviral activity of ritonavir in combination with AZT and ddC studied 32 HIV-positive patients enrolled in the trial. After two weeks of treatment, the mean viral RNA levels decreased 95 percent 1.26 logs) from baseline in ritonavir-treated patients. In addition, the median increase in CD4 cell count ranged from 80 cells/microliter after eight weeks of treatment to 106 cells/microliter at week 12. After 20 weeks of treatment, the mean viral RNA levels decreased 98% (1.76 logs) from baseline in ritonavir-treated patients and the median CD4 cell count was 171 among ritonavir-treated patients. Improvement in immunological status was apparent after two weeks of treatment and continued throughout the 20-week observation period.

Ritonavir generally was well tolerated in clinical trials. In all three trials, the most common adverse events observed were diarrhea, nausea, vomiting, asthenia, and circumoral paresthesia. It was noted that, in trial M94-247, the incidence of each of these adverse events was highest in the first two weeks after commencing use of ritonavir.

Abbott Laboratories is the second manufacturer to file an NDA for a protease inhibitor.

Abbott Laboratories is a worldwide manufacturer of health care products, employing 50,000 people. In 1994, the company's sales and net earnings were $9.2 billion and $1.5 billion, respectively, with earnings per share of $1.87.

CONTACT: Douglas Petkus, 708-938-3531 or Laureen Cassidy, 708-938-7743, both of Abbott Laboratories

Copyright (c) 1995/PR NewsWire. Reproduced with permission. Reproduction of this article (other than one copy for personal reference) must be cleared through the Permissions Desk, PR Newswire, 810 Seventh Avenue, New York, NY 10019.
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