Monday September 27, 8:42 am Eastern Time
Company Press Release
SOURCE: Vertex Pharmaceuticals
Cross-Resistance to Agenerase(TM) and Other
Protease Inhibitors Assessed in Patients with Previous PI Experience
SAN FRANCISCO, Sept. 27 /PRNewswire/ -- In vitro data from a study analyzing rates of antiviral resistance to the five
currently approved protease inhibitors, including Agenerase (amprenavir), among heavily pre- treated patients with HIV were
presented here today at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Agenerase is
an HIV protease inhibitor discovered at Vertex Pharmaceuticals (Nasdaq: VRTX - news) and licensed for development to
Glaxo Wellcome.
Among virus samples isolated and cultured from 92 patients, 89 of whom had been previously treated with at least one
protease inhibitor, the frequency of resistance (using the Virco Antivirogram(TM) assay) to amprenavir differed from the rates
found with four other PIs: indinavir (Crixivan®; Merck), ritonavir (Norvir®; Abbott Labs), nelfinavir (Viracept®; Agouron)
and saquinavir (Fortovase®; Roche), according to phenotypic analysis. Twenty- four percent (22 of 92) of isolates showed
eight-fold resistance to amprenavir. By contrast, 43 percent (39 of 90) of patients showed a similar level of resistance to
indinavir, with 63 percent (57 of 91) of isolates resistant to ritonavir, 61 percent (55 of 90) to nelfinavir and 53 percent (48 of
90) to saquinavir.
In addition, data on cross-resistance between protease inhibitors were presented. The median number of protease inhibitors
each patient had taken was three. Three percent (n=3) had no prior PI use, 17 percent (n=16) had used one PI, 28 percent
(n=26) had received two, 32 percent (n=29) had received three, and 20 percent (n=18) had experience with four PIs.
''Cross- resistance data are becoming an important consideration in the treatment of patients failing their current antiretroviral
regimen,'' said Vincent Calvez, M.D. from the Laboratoire de Virologie of l'Hopital Pitie-Salpetriere in Paris, and principal
virologist of the study. ''Although cross-resistance data from viral isolates has not yet been fully evaluated, studies such as this
are important steps to better understanding the implications for HIV treatment.'' ''This study of Agenerase is another part of our
continuing efforts to understand the mechanism of HIV resistance and its clinical relevance,'' said Lynn Smiley, M.D., vice
president, HIV and Opportunistic Infections Clinical Development at Glaxo Wellcome.
In vitro and genotypic analysis of isolates from Agenerase-treated patients showed mutations at 46I/L, 47V, 50V, 54L/V and
84V. A single mutation does not result in significant reduction in susceptibility; multiple mutations are needed to cause significant
loss of susceptibility. The 50V mutation has not been seen in patients treated with other protease inhibitors or as a natural
variant; however resistance to Agenerase has been observed in patients without the 50V mutation. The clinical relevance of the
genotypic and phenotypic changes associated with Agenerase therapy has not been established. Varying degrees of
cross-resistance among protease inhibitors have been observed. The potential for protease inhibitor cross-resistance in HIV-1
isolates from amprenavir-treated patients has not been fully evaluated.
Agenerase in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection. This indication is
based on analyses of plasma HIV RNA levels and CD4 cell counts in controlled studies up to 24 weeks in duration. At
present, no results from controlled trials evaluating long- term suppression of HIV RNA or disease progression with Agenerase
have been presented to the FDA for evaluation.
The safety of Agenerase was studied in over 1,400 adult patients. In patients receiving protease inhibitors, diabetes mellitus,
hyperglycemia, acute hemolytic anemia and redistribution/accumulation of fat have been reported. Severe and life-threatening
drug interactions could be associated with therapy with Agenerase (see full prescribing information for specific drug
interactions). Severe or life-threatening skin reactions, including Stevens-Johnson syndrome, have rarely occurred in patients
treated with Agenerase. There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with
protease inhibitors.
The majority of adverse events were of mild to moderate intensity, early to onset and transient in nature. The most frequently
reported adverse events were nausea, diarrhea, vomiting, rash and perioral paresthesia.
Agenerase was discovered by scientists at Vertex Pharmaceuticals of Cambridge, MA. Glaxo Wellcome has been responsible
for product formulation and manufacture of Agenerase, design and implementation of clinical trials, and regulatory submissions
to the FDA. Glaxo Wellcome also leads the commercialization efforts for Agenerase with co-promotion assistance from Vertex
Pharmaceuticals.
Glaxo Wellcome is the pharmaceutical industry leader in HIV research and therapies. Glaxo Wellcome also manufactures and
markets the widely prescribed anti-HIV drugs Combivir® (lamivudine/zidovudine), Epivir® (lamivudine), Retrovir®
(zidovudine) and Ziagen(TM) (abacavir sulfate). The company is engaged in basic research programs designed to investigate
new targets to treat HIV, and is continuing to lead the way in pioneering efforts to study the viability of increasing access to
HIV therapies in the developing world.
Vertex Pharmaceuticals Incorporated is engaged in the discovery, development and commercialization of novel, small molecule
pharmaceuticals for the treatment of diseases for which there are currently limited or no effective treatments. The Company is a
leader in the use of structure-based drug design, an approach to drug discovery that integrates advanced biology, biophysics,
chemistry and information technologies. The Company is concentrating on the discovery and development of drugs for the
treatment of viral diseases, cancer, autoimmune and inflammatory diseases, and neurodegenerative diseases.
There can be no assurance that clinical trials will continue, that initial clinical trial results will be predictive of any future results,
that drugs under development by the Company or its partners will receive marketing approval from the U.S. Food and Drug
Administration or other regulatory authorities, or that drugs, if any, which receive such approval will be marketed successfully.
Investors are also directed to consider other risks and uncertainties discussed in Vertex documents filed with the Securities and
Exchange Commission.
Press, Investor Contact on Site at ICAAC:
Michael Partridge, Manager, Product Communications
Pager (800) 265-9265, Cell Phone (617) 571-6108
Additional Contact:
Michele Karpf, Manager, Product Communications (617) 577-6259
Vertex's press releases are also available by fax-on-demand at (800) 758-5804,
code 938395.
For complete prescribing information on Agenerase please go to
www.agenerase.com
SOURCE: Vertex Pharmaceuticals |
