HONG KONG – Early oral administration of an immune modulator that is normally used for treatment of relapsing multiple sclerosis (MS) significantly reduced brain inflammation and improved the clinical outcomes of acute ischemic stroke (AIS) patients enrolled in a small, early phase pilot study conducted in China.

Characterized by a loss of brain function due to an inadequate cerebral blood supply that can lead to permanent neurological and physical disabilities, stroke is associated with a significant global burden of morbidity and mortality.

According to World Health Organization data, acute ischemic stroke (AIS) was the second leading cause of mortality worldwide in 2011, accounting for around 11 percent of all deaths. Stroke is also the leading cause of death in China, where it kills more than 1.5 million people each year.

Treatment of AIS patients involves physical therapy to regain lost function, while prevention of recurrence may involve administration of antiplatelet agents such as aspirin or a thienopyridine, for example Plavix (clopidogrel, Sanofi SA and Bristol-Myers Squibb Co.). Some patients may also benefit from thrombolysis with a tissue plasminogen activator (t-PA) such as Activase (alteplase, Roche AG unit Genentech).

The only treatment for AIS that has been approved by the FDA, tPA works by dissolving clots and improving blood flow to the brain. If given within three hours, tPA may improve the chances of recovering from a stroke, but the benefit of tPA is highly time dependent, with loss of benefit beyond 4.5 hours from the onset of symptoms having been documented by pooled analysis.

However, AIS patients also suffer from deleterious cerebral inflammation, on which the currently available conventional stroke treatments have little or no effect.

"Post-stroke cerebral inflammation contributes significantly to stroke severity and disability, especially in the acute period," said the leader of the pilot study, Fu-Dong Shi, a professor in the Department of Neurology at Tianjin Medical University General Hospital, Tianjin, and director of the Neuroimmunology Laboratory at the Barrow Neurological Institute, St. Joseph's Hospital and Medical Center in Phoenix.

Immediately following AIS, cessation of cerebral blood and oxygen supply activates the innate and adaptive immune systems, compromising the blood-brain barrier and leading to a massive migration of peripheral leukocytes into the ischemic brain regions. This influx then orchestrates localized inflammatory responses, catalyzes cerebral tissue death and exacerbates clinical outcomes.

Shi pointed out, however, that the different conventional stroke treatments have little or no anti-inflammatory activity. "Aspirin and clopidogrel have only a little anti-inflammatory activity in high doses, while tPA can activate matrix metalloproteinases and thereby have pro-inflammatory activity," he said.

"We reduced lymphocyte migration to the brain during the first 72 hours of acute ischemic stroke via the oral administration of three doses of Gilenya (fingolimod, Novartis AG)," said Shi.

A sphingosine-1-phosphate (S1P) receptor modulator that appears to work by influencing immune cell trafficking, in 2010 Gilenya became the first S1P receptor modulator to receive U.S. FDA approval for the treatment of relapsing MS and was recently reported to have central nervous system activity. (See BioWorld Today, May 27, 2014.)

The results of the Chinese pilot study, which was conducted by Shi and colleagues from the departments of Neurology and Radiology at the Tianjin Neurological Institute, Tianjin Medical University General Hospital, were published in the Dec. 8, 2014, early online issue of Proceedings of the National Academy of Sciences.

In the open-label, evaluator-blinded, parallel-group pilot trial, the investigators recruited 22 patients who were matched for clinical and magnetic resonance imaging (MRI) characteristics at study baseline and who had had anterior cerebral circulatory occlusion and an onset of stroke exceeding 4.5 hours.

Eleven patients in a control group then received standard management alone, while 11 others in a comparator group were treated with the standard management protocol plus oral Gilenya 0.5 mg/day for three consecutive days.

"Standard management in both the control and fingolimod-treated groups essentially included supportive therapies, as well as aspirin and physical therapy," Shi told BioWorld Today, adding "we only used low-dose aspirin (100 mg/day), with an equal distribution in the groups with or without fingolimod."

Compared with the controls, the Gilenya recipients were shown to have lower circulating lymphocyte counts, milder neurological deficits, and significantly better recovery of neurological functions, with this difference being shown to be the most profound during the first week, when the respective reductions in the U.S. National Institutes of Health Stroke Scale were 4 vs. -1 (p = 0.0001).

Neurological rehabilitation was also shown to be more rapid in the Gilenya-treated group vs. controls. "We used a modified Barthel index and modified Rankin score . . . as surrogates for neurological rehabilitation," Shi explained.

Using MRI, the researchers were also able to demonstrate that the enlargement of lesion size was significantly more restrained between baseline and day seven in the Gilenya-treated group than among the controls, at 9 vs. 27 mL, respectively (p = 0.0494).

In addition, they established that at seven days, rT1 percent, which is an indicator of microvascular permeability, was significantly lower in the Gilenya-treated group at 20.5 vs. 11.0 (p = 0.005), while no drug-related serious adverse events were observed in the Gilenya-treated group.

"We conclude that in patients with acute and anterior cerebral circulation occlusion stroke, oral fingolimod within 72 hours of disease onset was safe, limited secondary tissue injury from baseline to seven days, decreased microvascular permeability, attenuated neurological deficits and promoted recovery," said Shi.

In addition, "the administration of Gilenya led to a significant reduction of secondary lesion enlargement, microvascular permeability, and better clinical outcomes during the acute phase and at the three-month follow-up visit," he added.

"This study will provoke new investigations on the efficacy of modulation of brain inflammation in acute ischemic stroke," said Shi, noting that in the future "other combinations with Gilenya might be worth investigating, for example, endovascular therapy."