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Press Release from Vertex Pharmaceuticals
  FOS-AMPRENAVIR Update: Vertex Reports Preliminary 48-Week Data from Phase III Study of 433908, an Investigational HIV Protease Inhibitor
This update reports 48-week results while at Retrovirus 24-week results were reported. And the updated data is different. At Retrovirus researchers reported that the proportion of patients who were virological successes by a 400 copy cut-off were 58% in the Fos-Amprenavir once daily group, 60 % in the BD Fos-amprenavir arm and 69 % in the Kaletra arm. In this press release 50% in the FosAmprenavir QD arm had <400 copies/ml, and the proportion of patients with viral load below 400 copies/mL was 908/r BID (58%) and LPV/r BID (61%). The prior drug exposure for the patients and differences in prior drug exposure was not reported in the press release but at Retrovirus researchers reported a difference. Fewer patients in the Kaletra arm had taken 2 prior protease inhibitors (28 %) compared with the QD (40 %) and BD (34 %) Fos amprenavir arms. Similarly, Kaletra patients had received less prior nucleoside analogue therapy, with 35 % of Kaletra patients only having received 1 or 2 NRTI's, compared with 29 % of the QD and 14 % of the BD Fos-amprenavir groups.
Cambridge, MA, July 24, 2003 -- Vertex Pharmaceuticals Incorporated today reported preliminary 48-week data from the CONTEXT study conducted by GlaxoSmithKline of the investigational HIV protease inhibitor (PI) 433908 (908).
The CONTEXT study, an open-label Phase III clinical trial, enrolled 320 treatment-experienced patients with prior virologic failure. The study was designed to assess the safety and efficacy of once daily (QD) or twice daily (BID) dosing of 908 boosted with ritonavir compared to a third treatment arm with the PI lopinavir/ritonavir (LPV/r) BID, all in combination with two nucleoside reverse transcriptase inhibitors, in patients with prior HIV PI treatment experience. The primary objectives of the CONTEXT study were to assess antiviral efficacy and safety of the three study regimens at 24 and 48 weeks.
Top-line results of the study indicate that 908 exhibited antiviral activity in treatment-experienced patients. In an evaluation of time-averaged change in viral load (AAUCMB), which was the primary endpoint of the study, non-inferiority of 908/r BID and 908/r QD compared to LPV/r BID could not be established at 48 weeks. However, in an analysis of the proportion of patients with viral load below 400 copies/mL, 908/r BID (58%) and LPV/r BID (61%) demonstrated comparable levels of antiviral activity. The proportion of patients who achieved vRNA below 50 copies/mL at 48 weeks was also similar in the 908/r BID (46%) and LPV/r BID (50%) arms.
"908 is an investigational HIV protease inhibitor with the potential to offer potency and convenience for patients taking PI-based regimens," said John Alam, M.D., Senior Vice President of Drug Evaluation and Approval at Vertex. "The CONTEXT data in treatment-experienced patients complement the results from the Phase III NEAT and SOLO trials, which supported the antiviral activity and tolerability of 908 in unboosted and boosted regimens in treatment-naive patients."
Vertex anticipates that 908 can be approved and launched in the United States in the fourth quarter of 2003 and in European countries beginning in 2004.
Study Design
Patients enrolled in the CONTEXT study were randomized to receive either 1400 mg of 908 combined with 200 mg ritonavir QD (n=105), 700 mg of 908 combined with 100 mg ritonavir BID (n=107), or 400 mg lopinavir/100 mg ritonavir BID (n=103). All three groups took the medications in combination with two active nuceloside reverse transcriptase inhibitors (NRTIs). Antiretroviral response was assessed by measuring the time-averaged change in viral load (vRNA) from baseline (AAUCMB) at 24 and 48 weeks as well as by measuring proportions of patients with vRNA < 400 copies/mL and < 50 copies/mL at 24 and 48 weeks.
Efficacy of 908 in Treatment-Experienced Patients
The results of the CONTEXT study support the antiviral activity of 908 in treatment-experienced patients and are consistent with results seen in other clinical trials of 908. At 48 weeks, the mean AAUCMB (log10 c/mL) was -1.49 for patients on 908/r QD, -1.53 for those on 908/r BID and -1.76 for those taking LPV/r BID. Non-inferiority at 48 weeks using the primary AAUCMB endpoint could not be established because the upper limits of the 97.5% confidence intervals for the differences in mean AAUCMB between each of the 908/r treatment arms to LPV/r comparisons were above 0.5.
The proportion of patients who achieved HIV viral RNA (vRNA) below 400 copies/mL at 48 weeks was similar in the LPV/r BID and 908/r BID arms (61% and 58%, respectively). Evaluating the proportion of patients with vRNA below 400 copies/mL is a standard measure of efficacy in HIV clinical trials and was used as a secondary endpoint in the CONTEXT study. Fifty percent of patients in the 908/r QD arm achieved vRNA below 400 copies/mL. The proportion of patients who achieved vRNA below 50 copies/mL at 48 weeks was also similar in the LPV/r BID and 908/r BID arms (50% and 46%, respectively).
Prior Treatment Experience
Patients enrolled in CONTEXT had significant prior treatment experience. The median prior duration of exposure to PIs, NRTIs and NNRTIs was longer in both 908/r groups compared to the LPV/r group. In addition, a larger proportion of subjects randomized to the 908/r BID group appeared to be more heavily pre-treated with a greater number of prior NRTIs and NNRTIs than either the 908/r QD or LPV/r BID groups.
The overall incidence of drug-related adverse events of at least moderate severity was comparable between the 908/r BID and LPV/r BID treatment groups and there were no statistical differences in any individual adverse events.
GlaxoSmithKline and Vertex anticipate presenting the final comprehensive analysis of the 48-week results from the CONTEXT trial at a future medical meeting.
In 2002, Vertex and GlaxoSmithKline reported that the NEAT and SOLO studies met their endpoints at 48 weeks, and that the CONTEXT study met its endpoints at 24 weeks. NEAT (n=249 patients) and SOLO (n=660 patients) compared 908 to nelfinavir in treatment-naive patients.
About 908
In clinical trials, 908 has been dosed as two tablets, twice a day. In combination with low-dose ritonavir, 908 has been dosed as two tablets once a day or one tablet twice a day. Once approved, 908 will be the first protease inhibitor with no food or water requirements. The 908 compound was co-discovered by GlaxoSmithKline (GSK) and Vertex Pharmaceuticals.
About Vertex
Vertex Pharmaceuticals Incorporated is a global biotechnology company focused on the discovery, development and commercialization of breakthrough drugs for a range of serious diseases. Both independently and with partners, Vertex is developing 15 small molecule drug candidates to treat viral diseases, inflammation, cancer, autoimmune diseases, neurological disorders and genetic disorders. Vertex's first approved product is an HIV protease inhibitor that Vertex co-promotes with GlaxoSmithKline. Vertex is headquartered in Cambridge, Massachusetts and has major research sites in San Diego, California and Oxford, U.K. For more information, please visit: www.vrtx.com.
Vertex Safe Harbor Statement
This press release may contain forward-looking statements, including statements that we anticipate that 908 can be approved and launched in the United States in the fourth quarter of 2003, and in Europe beginning in 2004, and that once approved, it will be the first PI with no food or water requirements. While management makes its best efforts to be accurate in making forward-looking statements, such statements are subject to risks and uncertainties that could cause Vertex's actual results to vary materially. These risks and uncertainties include, among other things, the risk that 908 may not obtain regulatory approval or that approval may be delayed, and other risks listed under Risk Factors in Vertex's form 10-K filed with the Securities and Exchange Commission on March 31, 2003.
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