Neuroprotection: the end of an era?

Abstract

Stroke research suffered a setback last week when AstraZeneca announced that its experimental compound NXY-059 had been dropped from clinical development because the results of the pivotal phase III trial, SAINT II, were negative for all endpoints. SAINT I, which was published in The New England Journal of Medicine earlier this year, suggested that NXY-059 might be efficacious, although some critics said it was underpowered.NXY-059 joins a long list of neuroprotective compounds that have failed to be proven clinically useful in the treatment of ischaemic stroke. A recent review estimated that over 1000 compounds have been tested in animal models of ischaemic stroke; none of the 114 compounds that have entered clinical trials have been successful.After so many years of failure, it is appropriate to ask whether researchers should continue to pursue neuroprotective strategies for stroke. Translation of positive results obtained in the laboratory into the clinic has been exceptionally elusive, and the stroke community needs to think long and hard about whether these animal models are financially and ethically viable. At the moment it looks unlikely that a pharmaceutical neuroprotectant will be available anytime soon. But other approaches—such as inducing hypothermia or controlling blood glucose—should be investigated further.The one clear message that is already apparent from the SAINT trials is that pharmaceutical companies must do at least two adequately powered phase III trials that show consistent results, especially in subgroup analyses, before regulatory authorities grant approval to the new compound. Replication is a key tenet of the scientific endeavour and the many examples of trial programmes that have fallen at the last hurdle show just how important reproducibility is. Stroke research suffered a setback last week when AstraZeneca announced that its experimental compound NXY-059 had been dropped from clinical development because the results of the pivotal phase III trial, SAINT II, were negative for all endpoints. SAINT I, which was published in The New England Journal of Medicine earlier this year, suggested that NXY-059 might be efficacious, although some critics said it was underpowered. NXY-059 joins a long list of neuroprotective compounds that have failed to be proven clinically useful in the treatment of ischaemic stroke. A recent review estimated that over 1000 compounds have been tested in animal models of ischaemic stroke; none of the 114 compounds that have entered clinical trials have been successful. After so many years of failure, it is appropriate to ask whether researchers should continue to pursue neuroprotective strategies for stroke. Translation of positive results obtained in the laboratory into the clinic has been exceptionally elusive, and the stroke community needs to think long and hard about whether these animal models are financially and ethically viable. At the moment it looks unlikely that a pharmaceutical neuroprotectant will be available anytime soon. But other approaches—such as inducing hypothermia or controlling blood glucose—should be investigated further. The one clear message that is already apparent from the SAINT trials is that pharmaceutical companies must do at least two adequately powered phase III trials that show consistent results, especially in subgroup analyses, before regulatory authorities grant approval to the new compound. Replication is a key tenet of the scientific endeavour and the many examples of trial programmes that have fallen at the last hurdle show just how important reproducibility is.