In the final analysis of this 48-week trial data, 68 percent of HIV+ patients achieved undetectable viral load with 908/r compared to 65 percent of patients taking NFV BID in this open label study. The 908 compound was co-discovered by GlaxoSmithKline (GSK) and Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX).
At a Glance
- 68% of HIV+ patients achieved undetectable viral load (VL) with the investigational protease inhibitor 908/r compared to 65% of patients taking nelfinavir (NFV) BID in this open label study.
- 71% of patients in the 908/r arm with high VL (>500,000 copies/mL) at baseline achieved undetectable VL compared to 53% of patients with high VL at baseline in NFV arm.
- Virologic failure at 48 weeks was seen in 4% of patients in the 908/r QD arm and 15% of patients in the NFV BID arm.
- The SOLO study population was treatment-naive, ethnically and gender diverse, with a high proportion of patients with advanced disease.
- The most significant adverse event was diarrhea, which occurred in 16% in the NFV BID arm and 9% in the 908/r QD arm.
Efficacy Results from SOLO
In the SOLO study, 660 patients (649 treated) were randomized to receive either 1400 mg of 908 QD combined with low dose ritonavir (200 mg QD), or 1250 mg of NFV BID. Both groups took the medications in combination with 300 mg BID of ABC and 150 mg BID of 3TC. ABC and 3TC are nucleoside analogue reverse transcriptase inhibitors (NRTIs).
In the 908/r QD arm, 68 percent of 322 patients achieved viral suppression (vRNA less than 400 copies/ml), compared to 65 percent of 327 patients in the NFV arm. Virologic failure at 48 weeks was seen in 4 percent of patients taking 908/r QD, compared to 15 percent of those taking NFV BID. Further, a viral load below 50 copies/ml was achieved in 56 percent of patients taking 908/r QD compared to 52 percent of patients taking NFV BID.
Seventy-one percent of patients in the 908/r arm with high viral load (>500,000 copies/ml) at baseline (n=51) achieved undetectable viral load, compared to 53 percent of patients with high viral load at baseline (n=47) in the NFV arm. Likewise, 73 percent of patients in the 908/r arm with low CD4 count (<50) at baseline (n=62) achieved undetectable viral load compared to 51 percent of patients with low CD4 counts at baseline (n=69) in the nelfinavir arm. Quantitative plasma HIV-1 RNA measures in the SOLO study were made using the Amplicor HIV-1 MONITOR Test, Version 1.5, with the UltraSensitive sample preparation method (limit of detection=50 copies/ml).
"These results give significant insight into the potency, durability and tolerability of 908/r dosed once a day with four pills in therapy naïve patients. Currently approved protease inhibitors require at least six pills a day," said Joseph Gathe, M.D., medical director, Therapeutic Concepts, Houston, and SOLO study investigator.
SOLO, the second of three pivotal trials to support regulatory submission of 908, adds to the results of the NEAT trial presented earlier this year at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). The primary endpoint of the NEAT trial is the proportion of subjects with vRNA <400 c/ml at 24 and 48 weeks. The SOLO study's primary endpoint is the proportion of subjects with vRNA <400 c/ml at 48 weeks.
Safety Results from SOLO
In the SOLO trial, the incidence of dose limiting adverse events (AEs) and severe laboratory abnormalities was low in both groups. The only drug related AE that was significantly different between the two groups was diarrhea, which was significantly (p=0.008) more prevalent in patients on NFV (16 percent) than patients on 908/r (9 percent). Most common other AEs with 908/r were allergy (7 percent), nausea (7 percent), and vomiting (6 percent).
The incidence of Grade 3-4 lipid abnormalities was <1 percent with the exception of triglycerides, which were 6 percent in patients taking 908/r QD versus 2 percent in the NFV BID arm. All mean fasting cholesterol levels remained below the recommended National Cholesterol Education Program (NCEP) intervention guidelines. In addition, normalization of HDL-C was achieved in a substantial proportion of subjects.
"While the overall rates of discontinuation were similar in both study groups, more subjects withdrew due to insufficient viral response in the NFV BID group – 8 percent, or 27 patients – compared to only 1 patient in the 908/r QD group. At the same time, 9 percent, or 28 subjects, withdrew due to AEs in the 908/r QD group, compared to 5 percent, or 16 subjects, in the NFV BID group," said Dr. Gathe.
Study Demographics
The study population comprised patients enrolled in 19 countries worldwide, who were considered to be highly representative of the current treatment-naïve HIV patient population. The study included:
- A large proportion of patients with advanced HIV disease. The patients enrolled in the SOLO trial generally had advanced HIV disease at baseline (median vRNA 4.8 log10 c/ml), with 43 percent having a viral load greater than 100,000 copies/ml. In addition, 20 percent had CD4 counts <50 cells/mm3 at baseline. Although patients with active or acute Class C events were excluded, 22 percent of subjects in the SOLO trial had a history of Class C events, designated by the U.S. Centers for Disease Control and Prevention as signs of advanced infection.
- Gender diversity. Females represented 30 percent of the patients in the 908/r QD arm and 24 percent in the NFV BID arm.
- Ethnic Diversity. In the 908/r QD arm, 38 percent of patients were of African descent and 7 percent were Hispanic. In the NFV BID arm, 33 percent were African and 8 percent Hispanic.
- Age range of patients was 18-69 (median 36) years.
- Sexual orientation. 48 percent of 908/r QD recipients were heterosexuals, versus 44 percent in the NFV BID arm.
Summary of Ongoing Clinical Trials with 908
The investigational PI 908 is the calcium phosphate ester pro-drug of amprenavir. 908 is being studied in several dosing regimens: QD in combination with ritonavir in SOLO, BID in the NEAT trial, and BID and QD with ritonavir in the CONTEXT trial. 908 is being studied in regimens with or without food.
More than 1,100 people are participating in Phase III trials to evaluate the safety and efficacy of 908. SOLO is a phase III, randomized, open-label, 48-week study comparing 908/r QD and nelfinavir BID in combination therapy in 649 anti-retroviral therapy naïve patients. The primary endpoint is the proportion of subjects with vRNA <400 c/ml at 48 weeks. NEAT is a phase III, randomized, open-label, 48-week study comparing 908 BID and NFV BID both in combination with the NRTIs ABC and 3TC in 249 anti-retroviral therapy naïve patients. The primary endpoint of the NEAT study is the proportion of subjects with vRNA <400 c/ml at 24 and 48 weeks.
The CONTEXT study is an open-label trial in PI-experienced subjects assessing 908 dosed at 700 mg BID in combination with 100 mg ritonavir (RTV), or 908 at 1400 mg QD in combination with 200 mg RTV, compared to a third treatment arm of 400 mg lopinavir/100 mg RTV BID. Participants also receive two active reverse transcriptase inhibitors. The trial is fully enrolled with more than 300 patients and is being conducted at more than 80 research centers worldwide. The study is assessing the safety and efficacy of each regimen at 24 and 48 weeks. Results from the CONTEXT trial are expected to be presented in 2003.
Once approved, GSK will market 908 and Vertex will co-promote it in the United States and key markets in Europe.
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 statements (i) that GlaxoSmithKline plans to file for market approval of 908 in the United States and the European Union, and (ii) that the 48-week interim analysis of the SOLO study in GlaxoSmithKline's pivotal program for 908 is indicative of a promising clinical and commercial outlook for 908. 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, those listed under Risk Factors in Vertex's form 10-K filed with the Securities and Exchange Commission on April 1, 2002.