Friday, July 24, 2009

Asenapine Study Fails? Just Mix In Some New Measures -- Then Run it Longer

Back in April, asenapine missed a primary endpoint. Schering-Plough's solution? Run it longer, and add some longer term measures, all to prepare for the FDA Advisory Committee session on July 30, 2009.

Take a look:

. . . . These results follow those of a previously reported clinical trial in this patient population using the same study design and protocol in which both asenapine and olanzapine reduced negative symptoms after one year of treatment, but the difference between the two was not statistically significant. . . .

This study was a 26-week extension of a randomized, double-blind, multicentered, multinational 26-week clinical trial evaluating the efficacy and safety of SAPHRIS compared to olanzapine in the treatment of patients with stable predominant, persistent negative symptoms of schizophrenia. Patients were initially randomized in the core study to SAPHRIS 5 to 10 mg twice daily or olanzapine 5 to 20 mg once daily for 26 weeks. In the core study, both SAPHRIS and olanzapine reduced negative symptoms over the 26-week treatment period, but the difference between the two was not statistically significant. Patients who continued after six months were maintained on the same double-blind treatment regimen for the 26-week extension study. In the extension study, SAPHRIS demonstrated statistically significantly greater change in NSA-16 total score from the core study baseline after one year of treatment, the primary prespecified endpoint of the extension study. A total of 468 patients were randomized in the core study, 195 of whom entered the extension study, with 146 completing a total of one year of treatment. . . .


Kerri Cooks said...

Nobody cares about you or your silly blog!

Condor said...

Thanks, Carrie -- erh, "Kerrie" -- Cox, erh "Cooks"!

Feel free to scroll on by; but I think you'll look fabulous in that orange jumpsuit!


Anonymous said...

Yeah, but was olanazpine any different than placebo. If not then it wasn't adequate or well controlled as a drug that works should have worked. Since there was not placebo this is a worthless study from an efficacy point of view.

Note I don't believe that any antipsychotic is approved for treating negative symptoms. The efficacy is based on change in both positive and negative symptoms with the driver being the change in positive symptoms. In fact resistance to improvement in negative symptoms is something all companies working on (there may be a minor change). in discussing this study indicated antipsychotics like Haldol may worsen negative symptoms. It that's true then that means the greater degree of improvement typically seen with Haldol in drug studies compared to the atypical antipsychotics means that the atypicals in general are worse in controlling the hallucinations, delusions, and thought disorders which are really the core symptoms of psychosis.

Note this is a six month study and was not an extension from earlier exposure. Yet with Vioxx the increase in deaths weren't seen even with post marketing data originally until after a year. As more data was obtained this got shorter. Also Phen-Fen showed 30% of patients having changes on 2D echo after 3 months. So major symptoms and deaths probably wouldn't be apparent until much later too (i.e. > 1-2 years).

Typically when a drug isn't approved on time and additional information like this for longer term (snicker) data is available to consider it means a signal was seen in the review and FDA senior managers and the company are colluding to dilute out the signal.

Maybe a difference in the risk of toxicities between asenapine and olanzapine wouldn't be apparent until after 18 months or 24 months and only with much larger numbers of subjects.

The timing of the completion of Dec 2008 1 month before the approvable letter and submission 3 weeks later of additional safety information plus FDA's sudden policy change on June 23rd, 2008 allowing FDA to extend the PDUFA due date unilaterally (See and Fred's rant on the June 30th makes me suspicious.


Anonymous said...

Sorry it was the extension for 1 year total. indicates the earlier study was completed in Dec 2008 and this was Completed in Jan 2009.

Strange the comparison in end dates indicates that the extension study may have been terminated early to include safety data for review for the approvable letter which would be anticipated by SP. If so this may be evidence of collusion between FDA officials and SP.


Anonymous said...


146 subjects completed 1 year of exposure for one of 2 drugs at a total of 2 possible dosages for asenapine and 4 possible dosages for olanzapine.

Assuming a single dosage for each and an equal number of drop outs for each drug. To even detect 1 death the lethality rate has to be at least 1 in 24 people (> 4%).

Of course this was schizophrenia where the typical lethality rate for drugs during a year is ~1%. So what about bipolar disorder where the typical dosage is doubled. Not to mention higher exposures in kids or greater risk in the elderly.

To me this is not very reassuring safety data.


Anonymous said...

Sorry got which study it was an extension for mixed up.

This study 25544 (completed Jan 2009) was an extension for study 25543 which was completed in June 2007.

The 6 month study completed in Dec 2008 was study A7501013 it's extension A7501014 was completed in May 2009.

The timing relative to the approvable letter is still strange and the other comments about death rates still hold.

For some incredibly interesting reading take a look at regarding ACRE.


Slob O. Fettucini said...

Salmon you fool! 4 posts to get your point across??? Snap out of it!

Anonymous said...

Take a look at the following thread

Anonymous said...

Found a little bit of info on this study at

"In the study, SAPHRIS was significantly more effective than olanzapine in the reduction of negative symptoms as measured by change from baseline to Day 365 in the NSA-16 total score, the primary endpoint of the study. By using a mixed model for repeated measures (MMRM), least square mean changes in the NSA-16 total score were -15.8 for SAPHRIS vs. -11.0 for olanzapine (P=0.015). Full results of the trial, including efficacy, safety and tolerability data, will be submitted for presentation at a medical meeting at a later date."

Another report for up to 6 months shows no difference in effect but a higher incidence of EPS with asenapine but less weight gain (possibly a wash side effect wise.)

"There was no difference in effect between olanzapine and asenapine on negative symptoms at 6 months. This study continued things for another 6 months and found a statistically significant difference at 12 months. There was also a lot more weight gain reported with olanzapine."

Some of the caveats is that these studies used a new rating scale called NSA-16. I'm not familiar with it but since changes in the negative symptoms on the PANSS is much less and never reaches statistical significance by itself without the additive changes in the positive symptoms (which are the biggies). Makes you wonder if this new scale is just cutting things finer to be able to detect differences that aren't really clinically significant in terms of the degree of difference.

The other big caveat is this study uses MMRM (mixed modeling of repeated measures) as a statistical technique. My experience with this is that you need to know what is making people drop out of the study and account for each different reason. In practice even when attempted you can't get reliable data for this and so you have to impute the reasons and that's not a very good assumption because what is true for one drug is not necessarily true for another.

When I see MMRM I immediately know the statistical analysis is likely based on a bunch of fudge factors that are likely wrong.

Plus without a placebo and knowing the scale it's hard to interpret whether this is of any real benefit.

Lastly, even if it is real it may imply that there's poorer efficacy on the positive symptoms and may be why 3 of 4 pivotal trials in support of the acute treatment of an acute psychotic episode in schizophrenia were negative.

FDA needs to be more transparent in the future and release all reports and data.