News Release

48-wk resistance data comparing GW433908 boosted & unboosted with nelfinavir

Peer-Reviewed Publication

Public Communications Inc.

Boston (Feb. 11, 2003) – Forty-eight-week data were presented here today from two Phase III studies (NEAT and SOLO) of treatment-naïve patients with HIV infection, evaluating the resistance profile of the investigational protease inhibitor (PI) GW433908 (908) dosed twice a day (BID) or 908 boosted with the PI ritonavir (908/r) dosed once a day (QD) compared to the PI nelfinavir (NFV) BID. The medications in both studies were administered as part of combination therapy that also included 300 mg abacavir (ABC) BID and 150 mg lamivudine (3TC) BID. ABC and 3TC are nucleoside reverse transcriptase inhibitors (NRTIs).

908 is the calcium phosphate ester pro-drug of amprenavir (APV) and was co-discovered by GlaxoSmithKline (GSK) and Vertex Pharmaceuticals (Nasdaq: VRTX). In the SOLO study, no patients (0 percent) in the 908/r arm, out of 32 subjects experiencing virologic failure or with ongoing viral replication, had detectable primary or secondary PI mutations. In contrast, 27 of 54 patients (50 percent) in the NFV arm developed primary or secondary PI mutations. The clinical relevance of the resistance data is currently under evaluation.

In the NEAT study, 5 of 29 patients (17 percent) who experienced treatment failure in the unboosted 908 arm had mutations characteristic of APV resistance. NFV-selected mutations were observed in 7 of 26 patients (27 percent) who experienced virologic failure in the nelfinavir arm.

In the NEAT study, mutations selected by 908 were consistent with the spectrum of mutations selected by APV. Mutations detected in patients taking unboosted 908 included I54L/M, M46I and V32I+I47V. Mutations observed with other PIs (D30N, I54V, V82A/T/S, L90M) were not detected among patients taking unboosted 908.

In the SOLO study, there was a statistically significant difference between 908/r QD and NFV BID in the incidence of treatment emergent mutations selected by either the study PI (P<0.001) or the NRTIs ABC and 3TC (P<0.001). There were no primary nor secondary protease mutations in the 908/r QD arm, including those associated with the development of resistance to APV or ritonavir. Likewise, there was no development of reduced phenotypic susceptibility. Emergence of resistance in NFV-treated subjects was significantly greater with D30N and/or L90M detected in 21 of 54 patients (39 percent) who experienced virologic failure.

The incidence of resistance to 3TC was significantly lower (13 percent) in patients treated with 908/r who experienced treatment failure or had ongoing viral replication (4 of 32 subjects) than those treated with NFV (57 percent; 31 of 54). Resistance to ABC was rare (<1 percent) across both the NEAT and SOLO studies, affecting only 5 of 900 patients exposed to ABC. Two isolates with a K65R mutation and three isolates with the L74V substitution were observed.

Emergence and incidence of resistance was determined using genotypic and phenotypic analyses of viral protease, reverse transcriptase and gag cleavage sites at baseline and during therapy for patients who were experiencing virologic failure or who had ongoing viral replication.

“The potential development of virological resistance is an important consideration for patients receiving combination therapy,” said Doug Manion, M.D., vice president of Clinical Development, GSK. “The absence of PI-resistance selection at 48 weeks by 908 boosted with ritonavir is encouraging.”

These data add to 48-week safety and efficacy results of the NEAT trial and 24-week safety and efficacy data from the CONTEXT trial, also presented this week, and 48-week data from the SOLO trial, presented in November 2002 at the 6th International Congress on Drug Therapy in HIV Infection in Glasgow, United Kingdom.

Summary of Clinical Trials with 908

More than 1,200 people have participated in three Phase III trials to test the safety and efficacy of 908: NEAT, SOLO and CONTEXT. NEAT was a Phase III, randomized, open-label, parallel-group, 48-week study that compared 908 BID and nelfinavir BID, both in combination with ABC and 3TC in 249 antiretroviral therapy-naïve patients. The primary endpoint was the proportion of subjects with vRNA <400 c/mL at 24 and 48 weeks. Forty-eight-week data from the NEAT study will also be presented this week.

The SOLO study was an open-label trial with 649 HIV+, treatment-naïve patients. Participants were randomized to receive either 1400 mg of 908 plus 200 mg ritonavir (908/r) QD or 1250 mg of nelfinavir BID. All also received the two NRTIs ABC and 3TC. The trial, conducted at more than 100 research centers worldwide, was designed to assess the safety and efficacy of each regimen over a period of 48 weeks.

The CONTEXT study is an open-label trial in PI-experienced subjects with prior virologic failure assessing 908 dosed at 700 mg BID in combination with 100 mg ritonavir, or 908 at 1400 mg QD in combination with 200 mg ritonavir, compared to a third treatment arm of 400 mg lopinavir/100 mg ritonavir BID. Participants also receive two NRTIs. The trial is fully enrolled with more than 300 patients and is being conducted at more than 100 research centers worldwide. The study is assessing the safety and efficacy of each regimen at 24 and 48 weeks. Results at 24 weeks from the CONTEXT trial will also be presented here.

Once approved, GSK will market 908 and GSK and Vertex will co-promote it in the United States and key markets in Europe.

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GlaxoSmithKline is one of the world’s leading research-based pharmaceutical and healthcare companies and an industry leader in HIV research and therapies. The company is engaged in basic research programs designed to investigate new targets to treat HIV.

This press release may contain forward-looking statements, including that 48-week interim analysis of the NEAT and SOLO studies in GlaxoSmithKline’s pivotal program for 908 is indicative of a promising clinical and commercial outlook for 908, once approved. 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 approval will be delayed or will not be obtained, that 908 will not be commercially successful, and those other risks listed under Risk Factors in Vertex’s form 10-K filed with the Securities and Exchange Commission on April 1, 2002.

AT A GLANCE

After 48 weeks, no mutations characteristic of amprenavir (APV) resistance were observed in patients taking the investigational protease inhibitor (PI) 908 boosted with ritonavir.

Mutations selected by unboosted 908 were consistent with those selected by APV.

Mutations observed with other PIs were not detected among patients taking boosted or unboosted Media contacts:
Mary Faye Dark, GlaxoSmithKline
Cell phone: (919) 946-0190 – 2/10 through 2/14
Office: (919) 483-2839

Beth Schlesinger, Public Communications Inc.
Pager: (800) 759-8888, PIN 1050707 – 2/10 through 2/14
Office: (312) 558-1770


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