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New Protease Inhibitor GW640385/RTV
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Report by Jules Levin
This new PI for patients with resistance appears safe, tolerable & potent in this interim analysis at week 24 in treatment-experienced & pi resistant patients.
I'm at ICAAC & this afternoon D Ward reported in an oral talk 24 week interim study results for this new PI in highly resistant patients. 55 patient blood samples (isolates from PI experienced patients) showed extensive resistance to other PIs but sensitivity to this new PI. This study is a 48 week trial open-label single arm where patients received brecanavir (BCV) 300mg/rtv 100mg bid with 2 nukes. Patients were naive or experienced. Median viral load was 4.71 log & CD4 was 311 cells. The 6 PI resistant patients had median of 7 protease mutations, 2 primary PI mutations, 5 NRTI mutations, average CD4 count of 389 & viral load of 3.98 log (10,000 copies/ml). The median phenotypic fold resistance was 1.03 to BCV, but 8.3-fold to Lopinavir, 4-fold to Reyataz, 2-fold to amprenavir, 10-fold to nelfinavir, 3.6 fold to SQV, & 6.5 fold to indinavir. There were 4 discontinuations of study drug: 2 due to adverse events (1 nausea & vomiting, 1 grade 3 increasing LFTs), 2 patients withdrew consent. ANTIVIRAL ACTIVITY (ITT, MD=F): 81% (25/31) <400 copies/ml; 77% (24/31) <50 copies/ml; median CD4 increase of 84 cells. Median viral load reduction was -2.2 log for PI resistant & -3.3 log for PI sensitive patients. The presenter outlined 1 patient, subject D, who had extensive resistance (K103N [NNRTI], 5 NRTI mutations, & 9 PI mutations [82A, 63, 53L, 48V, L10, L24, L33; in addition the patient had 70 fold lopinavir resistance, 35-fold NFV resistance, 56 fold Reyataz resistance, but was only 1.16 BCV resistant]. Of note this patient had >3 log viral load reduction at week 24. The new PI appeared safe & tolerable; grade 2-4 drug related adverse events by week 24: fatigue 13%, dyspepsia 10%, nausea 10%, abdominal pain upper 3%. Lab abnormalities (grade 3-4): CPK 10%, hypertriglyceridmea 6%, AST 3%, GGT 3%, hypoglycemia 3%, total bilirubin 3%, neutropenia 3%. LIPID Increases (median) -- total cholesterol: 30.9 mg/dL (n=25); HDL: 3.9 mg/dL (n=25); LDL: 0.0 mg/dL (n=21; triglycerides: 62.3 mg/dL (n=25). No serious adverse events.
The following release was issued today by GSK & Vertex:
GSK and Vertex Pharmaceuticals Announce Presentation of Data Supporting Development of Investigational HIV Protease Inhibitor Brecanavir
-- Positive Data Presented at 45th Annual ICAAC --
CAMBRIDGE, Mass., Dec. 16 /PRNewswire-FirstCall/ -- GlaxoSmithKline (GSK) and Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) presented positive results today from a study evaluating the safety, tolerability and antiviral activity of the investigational HIV-1 protease inhibitor (PI), brecanavir* (formerly known as GW640385 or VX-385)(1). These data were presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) held in Washington DC. Interim findings following 24 weeks of dosing demonstrated potent antiviral activity for brecanavir in both PI-sensitive and PI-resistant HIV-infected adults.
"These results support the ongoing development program for brecanavir, which is anticipated to enter Phase III development in 2006," said Lynn Marks, MD, Senior Vice President of the Infectious Disease Medicines Development Centre at GSK. "If approved, brecanavir may be useful in treating patients infected with strains of HIV that have become resistant to multiple protease inhibitors, and its clinical advancement underscores GSK's commitment to developing new anti-HIV drugs."
Clinical Data on Brecanavir
Brecanavir is an HIV protease inhibitor in Phase IIb clinical development. Brecanavir has received fast track designation from the U.S. Food and Drug Administration and is being developed by GSK as part of a collaboration with Vertex Pharmaceuticals.
Data presented were from a planned, 24-week analysis of an open-label study (HPR10006) of 48 weeks' duration evaluating the safety, tolerability, antiviral activity and pharmacokinetics of ritonavir-boosted brecanavir. Thirty-one HIV-1 infected adults received 300mg of brecanavir twice-daily boosted with 100mg of ritonavir in combination with two nucleoside reverse transcriptase inhibitors based on patient medical history and viral genotype.
Out of 31 patients, 81 percent had plasma HIV-1 RNA below the level of detection of standard assays (<400 copies/mL of blood) at Week 24 (based on an intent-to-treat, missing or discontinuation equals failure analysis), and 77 percent had viral load below the level of detection of ultrasensitive assays (<50 copies/mL). Patients with PI-sensitive and highly PI-resistant virus had similar response rates (Note from Jules Levin: in the presentation today at ICAAC, PI resistant patients had -2.2 log viral load reduction & PI sensitive had -3.3 log reduction). Improvements in immunologic status were observed, with a median increase in CD4+ cell count of 84 cells/mm3.
"These early data are encouraging and support the further development of brecanavir in clinical trials in both antiretroviral treatment-naive and experienced patients," commented lead investigator Douglas Ward, MD, FACP of the Dupont Circle Physicians Group. "Because many HIV-infected patients undergoing treatment develop viral resistance to those medicines already available, a critical need for new antiretrovirals remains."
A safety assessment showed that brecanavir was well-tolerated with few Grade 2-4 drug-related adverse events and no serious adverse events. Most adverse events were reported as mild and did not require treatment modification or discontinuation. Clinically relevant changes in laboratory assessments were also infrequent.
About HIV Protease
Once inside a human immune cell, HIV uses enzymes within that cell to make copies of itself. Protease is one such enzyme involved in HIV replication. HIV protease inhibitors block the HIV protease enzyme, yielding copies of HIV that cannot infect new cells.
About Vertex
Vertex Pharmaceuticals Incorporated is a global biotechnology company committed to the discovery and development of breakthrough small molecule drugs for serious diseases. The Company's strategy is to commercialize its products both independently and in collaboration with major pharmaceutical companies. Vertex's product pipeline is principally focused on viral diseases, inflammation, autoimmune diseases and cancer.
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