NXY-059

NXY-059 is the disulfonyl derivative of the neuroprotective spintrap phenylbutynitrone or "PBN". It was under development at the drug company AstraZeneca. A 2005 phase-3 clinical trial^{[1] [2]} called "SAINT-1" reported some efficacy in the acute treatment of ischemia injury due to stroke. However, a 2006 attempt to repeat this trial indicated no significant activity. After ruling out other causes, the authors tentatively attributed the positive results in the first trial to "chance"^[3]. This was even though the probability of the SAINT-1 results happening by chance was roughly one in 25 for the main part of the SAINT-1 study, involving the Modified Rankin scale. It was also one chance in 200 for a parallel study looking at inhibition of hemorrhagic stroke from use of the "clot-buster" alteplase or "tPA".

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AstraZeneca then terminated the development programme^[4]. Interestingly, PBN and its derivatives hydrolyze and oxidize in vitro to form respectively MNP-OH ( AKA, NtBHA ) and its parent spin-trap MNP. Such pharmacologically-active "contaminants" are known to be responsible for some of the actions of PBN itself.^[5]. Though AstraZeneca denies this, a similar process may account for the positive results in the first trial[1].

Putative mechanism of action

Beginning in the late 1970's Harry Demopoulos and his coworkers at New York University reported^[6] that Free radicals, especially Reactive oxygen species, play a key role in the progression of brain injury due to ischemia from stroke. They likewise reported that much of this process occurs outside the brain at the level of the blood vessel lining or endothelium. They and subsequent researchers enlarged upon and extended these two key discoveries and the general role of free radicals in the ischemic cascade.

NXY-059 was expected to be a practical application of this work. First, both NXY-059, its parent PBN and their hydrolysis/oxidation product MNT are very powerful scavengers of free radicals. Unlike most antioxidants, this does not involve the further production of a reactive free radical. So they are particularly effective in terminating radical chain reactions. Likewise, unlike PBN and its derivatives, most reducing antioxidants can act as pro-oxidants. Finally, the negatively-charged sulfate groups of NXY-059 limits penetration of the drug into the brain, resulting in a low volume of distribution and a primary site of action at the level of the vascular endothelium.

This rationale appeared to be confirmed in small trials with both animals and humans. However, in large-scale Phase III clinical trials the first (Saint-1) clinical trial worked, while, inexplicably, the second (Saint-2) trial failed. AstraZeneca then terminated development of the drug.

The failure of the Saint-2 trial in the face of the success of the Saint-1 trial raises numerous questions. Something similar had previously been seen with the parent drug, PBN. "Aged" PBN would show pharmacological activity in one study and not in another done with newly-prepared PBN. This was later traced to hydrolysis and oxidation during storage of PBN to t-Butylhydroxylamine (NtBHA) and its parent spintrap, 2-methyl-2-nitrosopropane (MNP) [2], which proved to be the active agents.

One interpretation is that the Saint-1 trial reflected the presence of such a neuroprotectant, while the failure of the Saint-2 trial merely established that this neuroprotectant is not NXY-059. The difference could have arisen by subtle, perhaps even deliberate, changes in the storage and administration of the agent between the two trials.

References

1. ^ http://content.nejm.org/cgi/content/short/354/6/588
2. ^ http://www.drproctor.com/nxy-059/outcomes.htm
3. ^ http://content.nejm.org/cgi/content/short/357/6/562
4. ^ http://investors.renovis.com/phoenix.zhtml?c=148297&p=irol-newsArticle&t=Regular&id=921678&
5. ^ http://www.centpharm.com
6. ^ http://stroke.ahajournals.org/cgi/content/abstract/9/5/445

Review Articles

Oxidants, antioxidants and the ischemic brain [3]

NXY-059: Review of Neuroprotective Potential for Acute Stroke [4]

Neuroprotection website