Correspondence

NXY-059 for the Treatment of Stroke

N Engl J Med 2007; 357:2198-2199November 22, 2007

Article

To the Editor:

Shuaib et al. (Aug. 9 issue)1 report that in the Stroke–Acute Ischemic NXY Treatment II (SAINT II) trial, NXY-059 did not improve the outcome for patients with acute stroke. The authors state that NXY-059 met all the Stroke Therapy Academic Industry Roundtable (STAIR) preclinical recommendations2 and thus question the relevance of animal models to the development of therapies for acute stroke. Analysis of the NXY-059 preclinical data reveals many deficiencies and nonadherence to the STAIR guidelines.3 Most of these studies failed to confirm adequate vascular occlusion, as exemplified by one study in which many animals had no infarcts.4 Many investigations were not conducted in a blinded or randomized manner, reducing confidence in the validity of the data. The only reproducibility in the suture model was reduced damage when the drug was given 3 hours after occlusion. More worrisome is the finding in another study that the drug was protective when given 5 minutes after occlusion but not when given 3 hours after occlusion.5 Reproducibility of robust treatment effects in extended time windows is an important part of the STAIR criteria. The NXY-059 problems should galvanize investigators to increase the rigor of animal testing on the basis of which new therapies are evaluated and advanced to clinical trials.

Sean I. Savitz, M.D.
University of Texas Houston Medical School, Houston, TX 77030
sean.i.savitz@uth.tmc.edu

Marc Fisher, M.D.
University of Massachusetts Medical School, Worcester, MA 01605

5 References

1. 1

   Shuaib A, Lees KR, Lyden P, et al. NXY-059 for the treatment of acute ischemic stroke. N Engl J Med 2007;357:562-571
   Full Text | Web of Science | Medline

2. 2

   Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 1999;30:2752-2758
   CrossRef | Web of Science | Medline

3. 3

   Savitz SI. A critical appraisal of the NXY-059 neuroprotection studies for acute stroke: a need for more rigorous testing of neuroprotective agents in animal models of stroke. Exp Neurol 2007;205:20-25
   CrossRef | Web of Science | Medline

4. 4

   Kuroda S, Tsuchidate R, Smith ML, Maples KR, Siesjo BK. Neuroprotective effects of a novel nitrone, NXY-059, after transient focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 1999;19:778-787
   CrossRef | Web of Science | Medline

5. 5

   Lapchak PA, Araujo DM, Song D, Wei J, Zivin JA. Neuroprotective effects of the spin trap agent disodium-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (generic NXY-059) in a rabbit small clot embolic stroke model: combination studies with the thrombolytic tissue plasminogen activator. Stroke 2002;33:1411-1415
   CrossRef | Web of Science | Medline

Author/Editor Response

Savitz and Fisher allege that there were deficiencies in the preclinical development of NXY-059. First, according to the sponsor, evaluations were blinded in the studies in animals that were conducted at the University of Cambridge and the sponsor's laboratories.1,2 Second, although we agree that SAINT II does not invalidate all preclinical modeling for stroke therapy, a nonbiased survey, conducted before SAINT II, concluded that hypothermia and NXY-059 each satisfies the STAIR criteria; thus, the failure of SAINT II suggests that the STAIR criteria are not sufficient for predicting clinical efficacy.3 We still do not know what time window for initiation of neuroprotection in animals reflects the time window in humans, the latest time after stroke onset at which neuroprotection may be effective in humans, which animal behaviors predict human functional recovery, and whether morphometric outcomes in rodents contribute useful data.

Rigorous validation of preclinical stroke modeling will require the advent of effective neuroprotection in humans and then back-validation of predictive models. In the meantime, we must examine empirical predictions of other end points to infer which results in animals seem to predict certain outcomes in humans. The STAIR process initiated rigor in preclinical experimentation, but further “Delphi panel” exercises — arguing from first principles — will not drive the field forward in the absence of experimental results.

Patrick Lyden, M.D.
University of California San Diego Stroke Center, San Diego, CA 92103

Kennedy R. Lees, M.D.
University of Glasgow Stroke Division, Glasgow G11 6NT, United Kingdom
k.r.lees@clinmed.gla.ac.uk

Ashfaq Shuaib, M.D.
University of Alberta, Edmonton, AB T6G 2B7, Canada

3 References

1. 1

   Marshall JWB, Cummings RM, Bowes LJ, Ridley RM, Green AR. Functional and histological evidence for the protective effect of NXY-059 in a primate model of stroke when given 4 hours after occlusion. Stroke 2003;34:2228-2233
   CrossRef | Web of Science | Medline

2. 2

   Sydserff SG, Borelli AR, Green AR, Cross AJ. Effect of NXY-059 on infarct volume after transient or permanent middle cerebral artery occlusion in the rat: studies on dose, plasma concentration and therapeutic window. Br J Pharmacol 2002;135:103-112
   CrossRef | Web of Science | Medline

3. 3

   O'Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 Experimental treatments in acute stroke. Ann Neurol 2006;59:467-477
   CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   K Jeyaseelan, KY Lim, A Armugam. (2008) Neuroprotectants in stroke therapy. Expert Opinion on Pharmacotherapy 9:6, 887-900
   CrossRef