First, go read the post here, relating to MacGuffin's asenapine ponderings -- then, here are more of Salmon's elaborations, post FDA-approval of Saphris® (asenapine) -- on the arguably deceptive marketing themes outlined by MacGuffin:
. . . .I do believe MacGuffin has led me to strike gold once again and I will address this in a second post (in Part 2, coming soon), but first let me address MacGuffin's questions.
Yes, the lack of published human studies is a signal, but minor compared to what we’ve already discussed.
The rat and receptor studies are as MacGuffin suggests selective publication of data to highlight the marketing angles that SP wants to emphasize in fact the FDA clinical pharmacologist’s review points this out for cognitive effects and worries that they may be used for pushing asenapine off-label in the dementia in the elderly. In addition to this and the push for marketing for negative symptoms they also appear to be direct hits at the clinical pharmacologist’s concerns about the potential for 5HT2B inverse agonism by metabolites and his concerns about phen-fen like effects as SP has published showing antagonism of asenapine at the suspect receptor while providing no data on metabolites that are present in much much higher amounts that would likely be more than enough to counteract any effect of asenapine itself. (In fact someone even put the asenapine info sans comments on metabolite receptor binding in Wikipedia.)
The FDA reviews provide sufficient detail to show the problems in these human studies but by not publishing them they are much harder to find and thus likely won’t be critiqued in the medical literature. Plus as the FDA reviews won’t show up in pubmed no one will think to look for them other than in the labeling (which is misleading) as basically academics don’t know to look for FDA reviews at Drugs@FDA. However even if the human studies are published, many times the data, and the spin, and the take home message of published studies are much different than the FDA analysis of them.
As for the peer reviewed asenapine study. This is the phase II study (study 41004) and the 174 patients are spread over 3 treatments, so less than 60 subjects per arm with the drop out rate so high that only 21 – 28 subjects remained at the end so that the statisticians felt it wasn’t adequately controlled. Plus if you notice the abstract from MacGuffin’s footnote 7 it doesn’t report PANSS score change for risperidone because it wasn’t significant and thus as the clinical pharmacologist points out this was a failed study. [Yet Saphris won approval(!) -- Ed.] As for significance for positive symptoms alone this is a post-hoc analysis and typically no one ever does this a priori.
September 6, 2009 @ 11:07 PM
Part Two, shortly.