Bristol-Myers Squibb Company (NYSE: BMY) presented resistance data today 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.
Resistance DataData 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.
Virologic Suppression and Lipid DataData 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(r) (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 percent 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.
Patients may be enrolled in the EAP through physicians only. Physicians may call 1-877-7BMSEAP (1-877-726-7327) or visit www.ATVEAP.com for more information about the program.
Bristol-Myers Squibb is a global pharmaceutical and related health care products company whose mission is to extend and enhance human life.
This press release contains certain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that may be identified by terminology such as "expects" and other words or terms of similar expression or meaning. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. These factors include, among other things, uncertainties relating to product development, unexpected regulatory delays and government regulation generally. For further details and a discussion of these and other risks and uncertainties, see the Company's Securities Exchange and Commission filings, including the Company's 2001 Annual Report on Form 10-K. We undertake no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise.
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