LOS ANGELES — An agent that was designed to be neuroprotective while not increasing bleeding risk is safe at the highest dose tested and does not increase the rate of hemorrhage in stroke patients, new research suggests.
Previous studies of other neuroprotective agents in the setting of stroke have failed, but this new one might be different: It’s the first to assess such an agent in the context of thrombectomy, so at-risk tissue is actually being targeted.
Although the findings related to hemorrhage didn’t reach significance, they’re “interesting, intriguing, and are consistent with our prediction,” study author Patrick Lyden, MD, chair, Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, told Medscape Medical News. “They support the hypothesis that the drug is not dangerous as an anticoagulant.”
Results of the RHAPSODY study were presented here at the International Stroke Conference (ISC) 2018.
The molecule being tested is a protease activator receptor (PAR) recombinant variant of activated protein C (APC). It was created to retain the ability to protect brain cells — for example, neurons, epithelial cells, glia — but also to stabilize the blood-brain barrier and have less of an anticoagulation effect.
Unique Qualities
Lyden explained that this agent has several unique qualities, one of which is that it appears to work even when given relatively late following a stroke.
“Most of our failed compounds only worked when they were given immediately; with this one, there is actually some evidence in mice that it works out to 24 hours.”
As well, most previously tested neuroprotective agents work through a single mechanism, said Lyden. “It was one magic bullet trying to hit one step in a very complicated ischemic cascade of events.”
With the molecule now being tested, he said, once it binds to PAR, it activates several pro-survival pathways in the cell aimed at saving that cell from the ischemic insult.
The new multicenter, placebo-controlled, double-blind study was designed to find a safe dose of the drug — called 3K3A-APC — that could be used in stroke patients in whom risk for bleeding is a serious concern.
The study randomly assigned 44 patients with acute ischemic stroke to receive placebo and 66 to get 3K3A-APC. The demographic characteristics were typical of a stroke population. For example, the National Institutes of Health Stroke Scale score was 14 in both the treatment and placebo groups, and both groups had “reasonably good” premorbid modified Rankin Scale (mRS) scores, said Lyden.
In addition to placebo or treatment drug, patients also received intravenous tissue plasminogen activator (tPA) alone (about half of each group), mechanical thrombectomy alone (5%), or both interventions (just over 40%).
The thrombectomy procedure was shown in clinical trials to be valid about a third of the way through this current study. “So we adapted it, and opened it up to the patients in our study,” he said.
The protocol included four doses of the drug — 120 μg/kg, 240 μg/kg, 360 μg/kg, and 540 μg/kg — given in five boluses spaced over 5 hours.
Safety Concern
In almost every patient getting thrombectomy, 3K3A-APC was administered beforehand. In those receiving tPA, treating physicians were asked to wait 30 minutes before starting the first dose of 3K3A-APC.
“The reason for that is there is a residual concern for safety,” as the drug is an anticoagulant, Lyden explained.
The primary purpose of the study was to find the highest safe dose without a dose-limiting toxicity (DLT) in excess of 10%.
There were seven DLTs (four in the placebo group and three in the treatment group). The researchers determined that 540 μg/kg was the maximum tolerated dose, with an estimated DLT rate of about 7%.
When the researchers looked at the hemorrhage rate at day 30, 67.4% of patients taking 3K3A-APC had some evidence of hemorrhage compared with 86.5% taking placebo (P = .05).
The total volume of blood in the brain was 0.8 mL in the treatment group and 2.1 mL in the placebo group (P = .07).
That the drug did not worsen bleeding is an important finding. “Giving an anticoagulant with tPA is considered dangerous,” Lyden said. “We had to prove that we weren’t making things worse, and we found that there is no doubt about that.”
In addition to safety, investigators collected data on pharmacokinetics, but these results have not yet been presented. Although researchers also collected 90-day mRS scores, that exploratory analysis is “still ongoing,” he noted.
Going forward, future studies of 3K3A-APC will require that all patients get thrombectomy. A phase 2b trial is being planned to confirm the current findings, he said.
Still Skeptical
Commenting on the study for Medscape Medical News, Larry B. Goldstein, MD, Ruth L Works Professor and Chairman, Department of Neurology, and co-director, Kentucky Neuroscience Institute, University of Kentucky, Lexington, said that while the molecule appeared to provide some benefit, he remains cautious.
“We have been down this road before, so we’re all skeptical,” he said.
However, this new study represents a significant advance in that at least some of the patients had their clots removed with thrombectomy. “That alone is important and may change this entire field,” he said.
A problem with many of the previous neuroprotection trials was that “we weren’t even sure the drug we were giving, which we thought was neuroprotective, was actually reaching the tissue” of concern, said Goldstein.
“Those drugs that we abandoned before may actually have worked had we been able to get them to the tissue that was at risk.”
Goldstein cautioned that in the current trial, “the number in any one group was relatively small.”
He also noted that the data on hemorrhage rates appeared to suggest that there was an increase from the lowest to the intermediate dose that then went down again at a higher dose.
Lyden received a National Institutes of Health Research Program Grant ( R01) that funded this study. Goldstein has disclosed no relevant financial relationships.
International Stroke Conference (ISC) 2018. Late breaking abstract 18. Presented January 26, 2018.
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