Neuroprotection in stroke: worth another crack?
This article was originally published in Scrip
Hopes that a neuroprotective agent can be developed to reduce the damage caused by ischaemic stroke have received a boost, with data from a Phase II trial in the The Lancet Neurology showing promise for a protein acting on a post-synaptic brain protein. Together with some promising early data for two other potential neuroprotective agents, experts say the data seem to support renewed efforts in developing such drugs despite their chequered developmental history.
The latest product, NA-1, is in development by two private companies, Arbor Vita in the US and NoNO of Canada, and NoNO says late-stage trials are planned in multiple acute neurological disorders. The drug targets the post-synaptic density-95 protein (PSD-95), which links NMDA glutamate receptors to neurotoxic signalling pathways; by disrupting these links, NA-1 is thought to inhibit stroke damage.
Small strokes, or transient ischaemic attacks, are a common complication of brain surgery, with up to 90% of patients undergoing endovascular repair for aneurysms showing small, embolic and procedurally induced ischaemic strokes on MRI, making them an ideal population for research. In the ENACT study, 185 patients who had an intracranial aneurysm amenable to endovascular repair were randomised to receive an IV infusion of either NA-1 or saline at the end of their endovascular procedure. While the primary outcome was safety, primary clinical outcomes were the number and volume of new ischaemic strokes as defined by MRI between 12 and 95 hours after infusion.
The researchers found that patients in the placebo group experienced fewer infarcts than those given placebo, although there was no difference between the groups in the size of the lesions found (around two thirds of the study population experienced infarcts). There were two minor, but no serious, adverse events judged to be associated with NA-1. "Our findings suggest that neuroprotection in human ischaemic stroke is possible and that it should be investigated in larger trials," they concluded.
Lead author Professor Michael Hill, at the University of Calgary's Hotchkiss Brain Institute in Canada, added, "Safe drugs to provide tissue neuroprotection – defined as salvage of brain tissue by enhancing its resilience to the restricted blood flow that patients experience during these procedures – is a major unmet need in stroke treatment, and translation from animal studies to humans has been markedly unsuccessful so far."
Past failures include Ono's astrocyte modulator Arocyte (Proglia, ONO-2506), AstraZeneca's free-radical trapping neuroprotective NXY-059 (licensed from Renovis), and Cenes/Boehringer Ingelheim's NMDA antagonist Cerestat (aptiganel).
But writing in an accompanying commentary, Dr Markku Kaste of the Helsinki University Central Hospital, said the results with NA-1 lend support to those of two other potential neuroprotective drugs, edaravone and ginsenoside-Rd. Mitsubishi Tanabe Pharma's free-radical scavenger edaravone has already received approval in Japan but not elsewhere, while the receptor-operated calcium channel antagonist ginsenoside-Rd has shown efficacy in a Chinese trial in ischaemic stroke. Another candidate is D-Pharm's neuroprotective agent DP-b99 – a metal ion chelator – which is in Phase III in South Korea.
Dr Kaste believes that these products could be particularly useful in areas of limited resources, where alteplase, the current thrombolytic therapy for stroke, is less feasible. "Such drugs should first be assessed in large, well-designed and well-executed randomised placebo-controlled double-blind clinical trials. Only after such trials will we know whether NA-1 – or one of the other drugs which have shown comparable effects – is the long-awaited Holy Grail for the treatment of patients with ischaemic stroke. The door is now reopening for new neuroprotection trials in stroke."