Bristol-Myers Squibb Company, a global pharmaceutical and related health care products company, presented resistance data at a medical meeting in Boston from several Phase II and Phase III studies of atazanavir, an investigational protease inhibitor (PI) under development for the treatment of HIV/AIDS.

The data suggest that the I50L is the signature amino acid change following atazanavir treatment that results in atazanavir-specific resistance and increased susceptibility to all other PIs. In addition, the company presented data suggesting that long-term therapy with atazanavir resulted in sustained virologic suppression and that patients switching to atazanavir from nelfinavir (another protease inhibitor) exhibited improved virologic suppression and a significant decrease in serum lipid levels.

Data presented suggested that early use of atazanavir may lead to increased viral susceptibility to other marketed protease inhibitors and may help preserve other treatment options due to the unique I50L amino acid change that leads to atazanavir-specific resistance.

The retrospective study of more than 1,500 patients treated in two Phase II and three Phase III clinical trials showed that overall, the emergence of atazanavir resistance was infrequent. Of the 26 atazanavir resistant isolates recovered from patients susceptible to atazanavir (used as the sole PI) at the time of treatment initiation, all contained the unique I50L amino acid change.

"The distinct resistance profile of atazanavir may help preserve future treatment options with other marketed protease inhibitors," said Richard Colonno, vice president, Infectious Diseases Drug Discovery, Bristol-Myers Squibb. "If approved, atazanavir could provide physicians with additional flexibility in treating their patients should resistance to atazanavir occur."

Studies on recombinant viruses also showed that the I50L substitution was indeed responsible for this unique resistance phenotype. In contrast, isolates resistant to atazanavir at study entry failed to induce an I50L change and, subsequently, displayed higher resistance levels to both atazanavir and other protease inhibitors.

Data from a long-term, open-label observational switch study showed that patients who switched from nelfinavir to atazanavir for 24 weeks of treatment experienced improved virologic suppression and a clinically significant reduction of total cholesterol (TC), LDL (bad cholesterol) and triglycerides (TG).

Three hundred sixty-nine patients completing a Phase II dosing trial (BMS study AI424-008) were eligible for the open-label switch trial (BMS study AI424-044), which looked at the safety and efficacy of atazanavir. After 72 weeks, patients were eligible to switch from a nelfinavir-based regimen to one containing atazanavir (400 mg once-daily), Zerit (stavudine) (40 mg twice-daily) and 3TC (150 mg twice-daily). Sixty-three subjects were switched from nelfinavir to atazanavir, and patients who were previously on atazanavir in the Phase II study remained on treatment.

Twenty-four weeks following a switch from nelfinavir to atazanavir, 86 percent of the 63 subjects had HIV-RNA less than 400 copies/mL, compared to 71 percent prior to the switch at study entry (ITT analysis). In addition, 59 percent of patients in the nelfinavir/atazanavir switch arm had HIV-RNA less than 50 copies/mL, compared to 50 per cent of patients at study entry (ITT analysis).

Patients in the nelfinavir/atazanavir switch arm also experienced significant decreases in total cholesterol, LDL-C and triglyceride levels toward pre-antiretroviral treatment levels. Patients switched from nelfinavir to atazanavir experienced median reductions in TC from 202 mg/dL to 169 mg/dL; reduction in fasting LDL from 132 mg/dL to 99 mg/dL and reduction in fasting TG from 127 mg/dL to 102 mg/dL.

Discontinuations due to adverse events were infrequent and comparable across cohorts. Asymptomatic elevation in indirect bilirubin (without hepatic transaminase elevation) was the most frequent laboratory abnormality.

On December 20, 2002, Bristol-Myers Squibb submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for atazanavir, an azapeptide viral protease inhibitor of HIV-1. It is the first NDA for a protease inhibitor to be submitted with pharmacokinetic data supporting the potential for once-daily administration. In May 2002, Bristol-Myers Squibb filed for the registration of atazanavir with the European Medicines Evaluation Agency (EMEA).

In the United States, Bristol-Myers Squibb is currently enrolling patients in an Early Access Program (EAP) to provide atazanavir to eligible patients infected with HIV. An EAP provides medicines to patients in need of alternative therapy prior to the medicine's approval.

HIV-infected patients who have experienced treatment failure with other available antiretroviral agents and who require an alternative antiretroviral agent in order to construct a new treatment regimen may be eligible to participate in the EAP. Reasons for treatment failure include a sufficient degree of antiretroviral resistance, intolerance or adherence problems. Physicians must use atazanavir in combination with two or more new or recycled antiretroviral agents. In addition, patients must meet other protocol-specified eligibility criteria.