SAN DIEGO—GSK 249320, an investigational drug intended to help repair brain injury, appears to be safe for patients with stroke, according to a phase I/II study presented at the 65th Annual Meeting of the American Academy of Neurology. The drug is a monoclonal antibody that blocks myelin-associated glycoprotein to promote neurite outgrowth and protect oligodendrocytes.
Serious adverse events were reported in 10 of 42 subjects and were distributed evenly among three treatment groups, said Steven C. Cramer, MD, Professor of Neurology and Vice Chair of Research at the University of California, Irvine. Local investigators considered three of the serious adverse events to be potentially drug-related. No adverse event was fatal. One patient in the high-dose group had acute renal failure 18 days after stroke onset and a second stroke 38 days after stroke onset. One patient in the moderate-dose group had dysgeusia.
Assessing Three Doses of the Antibody
Dr. Cramer and colleagues enrolled 42 patients at 24 to 72 hours after the onset of a new stroke to evaluate the safety and tolerability of GSK 249320. Eligible patients had a wide range of NIH Stroke Scale scores and weakness in the arm, leg, or both. The trial was conducted at 15 sites in the United States, Germany, and Canada.
Subjects were randomized to two IV doses of the monoclonal antibody or placebo. The first infusion was administered 24 to 72 hours after stroke onset, and the second one was given approximately nine days later. Patients in the active group received 1-, 5-, or 15-mg/kg doses. Seventeen participants received placebo.
Subjects completed seven study visits during a four-month follow-up period. The researchers performed end-point exams, ECG, adverse event reporting, nerve conduction testing, MRI, transcranial magnetic stimulation, modality-specific measures of function (eg, gait velocity), and global measures of outcome (eg, NIH Stroke Scale score and modified Rankin Scale score) for all patients.
Gait Velocity Improved for Two Dose Groups
Patients’ average age was 59 to 67 across the four groups. Average infarct volumes were approximately 30 cm3, which indicated moderate strokes. The average infarct volume in the high-dose group, however, was 15 cm3. The average time from stroke onset to treatment was 46 to 55 hours. Patients’ baseline NIH Stroke Scale scores were approximately 7.
“The pharmacokinetic profile was as expected for an IgG antibody,” said Dr. Cramer. Of the 25 patients who received the monoclonal antibody, one had pre-existing antibodies to the antibody, and two developed transient antidrug antibodies. None of the immunogenicity-positive responses were associated with alterations in pharmacokinetics or in adverse events.
The investigators observed a trend toward improvement in gait velocity among patients who received the monoclonal antibody, compared with controls. “There were greater gains for the antibody, when you combined all three doses, compared to placebo at day 30, day 90, and day 112,” said Dr. Cramer. At five days after stroke onset, the average gait velocity of ambulatory patients was approximately 0.5 m/s. At four months after stroke onset, the average gait velocity was about 0.8 m/s. Patients who received 1- or 5-mg/kg doses showed improvement, but gait velocity was similar among patients who received 15-mg/kg doses and patients who received placebo, keeping in mind that the patients receiving the 15-mg/kg doses tended to have milder strokes.
“The main point here is that, across three escalating doses, this antibody was well tolerated in human subjects with moderate stroke,” concluded Dr. Cramer.
—Erik Greb
Senior Associate Editor
Suggested Reading
Cramer SC, Abila B, Scott NE, et al. Safety, pharmacokinetics, and pharmacodynamics of escalating repeat doses of GSK249320 in patients with stroke. Stroke. 2013 Mar 12 [Epub ahead of print].
Krupinski J, Slevin M. Emerging molecular targets for brain repair after stroke. Stroke Res Treat. 2013;2013:473416.