Green's Review

Green's review gives us the opportunity to consider some issues in detail. I solicit and will post comments, for and against.

Dr. Green states: "...Proctor and Tamborello (2007) have proposed that the positive SAINT I result was due to an impurity in the drug substance not present in the SAINT II investigation."

Dr P: Clearly, our issue is only whether these were in pharmacologically-effective amounts in SAINT-I. According to AstraZeneca's "'527 patent" NXY-059 always contains significant hydrolysis products, even when stabilized.

Dr Green: "This hypothesis is based on the fact that a hydroxylamine derivative has been shown to be present in samples of another nitrone (phenylbutyl nitrone)and is a potent radical scavenger (Atamna et al., 2000)...

Dr P: Rather, we cite AstraZeneca's '527 patent showing that NXY-059 contains significant NtBHA, Green's "hydroxylamine derivative". In fact, the '527 patent implies NXY-059 hydrolyzes much more readily than phenybutylnitrone (PBN). Similarly, PBN is not just "another nitrone", but is the parent compound of NXY-059, its disulfonyl derivative.

Dr Green: "...However, this proposal has been rapidly refuted by the investigators (Lees et al., 2007),"

Dr. P: "The investigators", Lees et al, only "rapidly refuted" our proffered examples concerning the source of differences between SAINT-I and SAINT-II, not the proposal itself. ( In fact, I would dearly love to see a detailed refutation to which I can properly respond. ). Similarly, we had a good basis for these conjectures in the form of SEC filings from Centaur Pharmaceuticals and Renovis-- e.g.,CENTAUR PHARMACEUTICALS INC, Form:10-K405, 4/2/2001.

Dr Green: “... and even cursory examination of the original in vitro study on the hydroxylamine (Atamna et al., 2000) indicates that the amount of impurity that has to be present in the drug substance is likely to be quite enormous to produce a pharmacological effect, which renders this suggestion untenable.”

Dr P: The same workers (Atamna and Ames, US pat#6,455,586) indicate a “ 10 mg kg-1 i.v. bolus dose” of NtBHA given three-hours post ischaemic-insult significantly reduces brain infarct size in rats. Similarly, 5 mg kg-1 NtBHA produces significant radioprotection in mice (Lee et al, 2004). These in vivo studies are more directly-relevant to the SAINT trials than the in vitro cellular-aging study cited by Green.

For example, human equivalent doses ( HEDs ) are used to set human doses in phase-1 clinical trials. The body surface area FDA-standard HED (2005) for the rat is 6.2. For mice, the HED is 12.3. These translate respectively to a human dose of 1.6 mg/kg of NtBHA for neuroprotection in ischemic injury and 0.4 mg/kg for radioprotection.

The SAINT trials typically-infused roughly 13-24 grams per day of NXY-059. The '527 patent indicates up to 1% hydrolysis of NXY-059, even when well-stabilized*. Thus, patients in the SAINT trials received as much as 2-3 mg/kg/day of NtBHA and co-products. This is well-within the range of potential efficacy calculated above. This also ignores synthesis co-product NtBHA and MNP. Minimizing this was the subject of AstraZeneca patents 6,479,697, 6,512,143 and 6,689,911. "Contamination" happened at all stages and was clearly an on-going problem.

___________________________________________________

* Unfortunately, AstraZeneca has only stated the degree of hydrolysis in the SAINT trials was “low”. However, in regulatory terms 1% is a “low” degree of contamination.

Back