Peter Loftus, over at the the Wall Street Journal, wrote an article about the limited Merck and Schering-Plough new hiring disclosures on May 12, 2009 -- with almost all the content of the first three paragraphs following the trail I had laid down on May 9, 2009. He next collected a company quote about the need for some pre-launch Saphris new-hires -- something I'd never do -- but his focus clearly was on the limited new hiring I was the first to cover. He then went on to explain why Wall Street largely yawned at this news, thus:
. . . .[Regarding Saphris (asenapine),] some analysts have had low expectations, citing unimpressive clinical data and the perception that a cautious FDA had raised the bar for approval of mental-health drugs. Even if the drug gets approved, it would enter a crowded antipsychotic market dominated by AstraZeneca PLC's (AZN) Seroquel and relatively cheap generic versions of Johnson & Johnson's( JNJ) Risperdal.
Doubts about asenapine's prospects were reinforced last year when the FDA rejected another experimental antipsychotic, iloperidone from Vanda Pharmaceuticals Inc. (VNDA), signaling the FDA was taking a tough stance toward new antipsychotics.
But last week the FDA reversed course and approved Vanda's drug, which will be sold under the brand Fanapt. The Fanapt approval doesn't guarantee the FDA will do the same for Schering's asenapine, but it does show that the FDA's bar for new antipsychotics isn't insurmountable. . . .
As we all now know, our very own frequent commenter "Salmon" has been providing these latter sorts of insights on asenapine, right here [s/he has also followed Schering-Plough's Bridion (sugammadex)], in a series I've come to call "Salmon's Asenapine Chronicles" -- over the last eleven months. Well-done, Salmon -- we both made the Journal, at least in a manner of speaking. Much more of Salmon's keen analysis of the tortured path asenapine has followed -- from discovery to its latest FDA filings -- appeared in three posts in October of 2008 here, here and here. Worthy reads, if you'd like a deeper dive than Loftus provides.
3 comments:
There were a couple of interesting psychopharmacologic drug advisory committee meetings a few weeks ago. The first one was for sertindole which was recommended by the committe to not be approved.
4930 patients received sertindole and 4928 patients received risperidole for up to 1 year.
Sertindole caused 1 sudden cardiac death in each 379 patients and risperdal 1 scd per 1642 patients.
For other types of cardiac deaths sertindole caused caused 1 death per 159 patients and risperdal 1 death per 410 patients.
For death from any cause sertindole caused 1 death per 79 patients and risperdal 1 death per 80 patients.
Now this is only for treatment for up to 1 year so many patients probably were treated for much shorter durations. Yet for Vioxx the death rate really began to climb AFTER 1 year, and is likely due to intimal wall thickening and pulmonary hypertension. Plus for every cardiac death you have heart attacks, congestive heart failure, arrhythmias etc. that don't result in death.
Now if you look at the response rate to antipsychotics for mania it's only about 20 people in 100, and it's much less than that who are helped for a year in fact it's only one or 2 out ot 100 that are still taking drug that long. Finagling with the numbers the risk of death vs. the benefit begins to not look so great. Especially in populations like children where you have forced compliance for years at a time. Now imagine if will that you have a drug that in head to head trials with another drug known to have a lot of cardiac and especially long term cardiac tox looks to be 6 to 8 times worse. Add on top of that you know the studies are designed to minimize the chance of it occurring by keeptng drugs out of the adjuvant treatment studies that you know will really increase toxicity but that the indication that will be approved will imply that it's OK to use with.
Add on top of this that the you can show that for half the population the approval is being sought for that it won't work at all and you can predict this even before putting anyone on the drug but for marketing purposes you mixed this population into the efficacy study because you know they have to label the entire population it was studied in not just the half who is driving the statistical significance.
Now if you came across a situation like that what would you recommend?
Salmon
PS remember that 2 days before the asenapine approvable letter went out FDA gave the green light to off label promotion. Plus next month there's and AC meeting on pediatric use of antipsychotics for bipolar. Now I'm not saying that the studies won't say they don't work in the population that's studies. But that doesn't mean that you can't find subgroups within the study that it won't or that the similar populations as the adult studies were studied. Plus what's to stop someone from then prescribing another antipsychotic off label or any of them off label for say 'bipolar spectrum disease' or emerging bipolar disorder (i.e. ADHD and the kid gets irritable occassionally, which is really every kid with ADHD).
Salmon
Condor,
Remember that Pfizer dropped asenapine after Phase III (and $300 million). Now Ziprasidone (Geodon) is marketed by Pfizer inspite of the following bolded labeling. Makes you wonder how much of a dog must asenapine be.
QT Prolongation and Risk of Sudden Death
Ziprasidone use should be avoided in combination with other drugs that are known to prolong
the QTc interval (see CONTRAINDICATIONS, and see Drug Interactions under
PRECAUTIONS). Additionally, clinicians should be alert to the identification of other drugs
that have been consistently observed to prolong the QTc interval. Such drugs should not be
prescribed with ziprasidone. Ziprasidone should also be avoided in patients with congenital long
QT syndrome and in patients with a history of cardiac arrhythmias (see
CONTRAINDICATIONS).
A study directly comparing the QT/QTc prolonging effect of oral ziprasidone with several other
drugs effective in the treatment of schizophrenia was conducted in patient volunteers. In the first
phase of the trial, ECGs were obtained at the time of maximum plasma concentration when the
drug was administered alone. In the second phase of the trial, ECGs were obtained at the time of
maximum plasma concentration while the drug was co-administered with an inhibitor of the
CYP4503A4 metabolism of the drug.
In the first phase of the study, the mean change in QTc from baseline was calculated for each
drug, using a sample-based correction that removes the effect of heart rate on the QT interval.
The mean increase in QTc from baseline for ziprasidone ranged from approximately 9 to 14
msec greater than for four of the comparator drugs (risperidone, olanzapine, quetiapine, and
haloperidol), but was approximately 14 msec less than the prolongation observed for
thioridazine.
In the second phase of the study, the effect of ziprasidone on QTc length was not augmented by
the presence of a metabolic inhibitor (ketoconazole 200 mg BID).
In placebo-controlled trials, oral ziprasidone increased the QTc interval compared to placebo by
approximately 10 msec at the highest recommended daily dose of 160 mg. In clinical trials with
oral ziprasidone, the electrocardiograms of 2/2988 (0.06%) patients who received GEODON and
1/440 (0.23%) patients who received placebo revealed QTc intervals exceeding the potentially
clinically relevant threshold of 500 msec. In the ziprasidone-treated patients, neither case
suggested a role of ziprasidone. One patient had a history of prolonged QTc and a screening
measurement of 489 msec; QTc was 503 msec during ziprasidone treatment. The other patient
had a QTc of 391 msec at the end of treatment with ziprasidone and upon switching to
thioridazine experienced QTc measurements of 518 and 593 msec.
Some drugs that prolong the QT/QTc interval have been associated with the occurrence of
torsade de pointes and with sudden unexplained death. The relationship of QT prolongation to
torsade de pointes is clearest for larger increases (20 msec and greater) but it is possible that
smaller QT/QTc prolongations may also increase risk, or increase it in susceptible individuals,
such as those with hypokalemia, hypomagnesemia, or genetic predisposition. Although torsade
de pointes has not been observed in association with the use of ziprasidone at recommended
doses in premarketing studies and experience is too limited to rule out an increased risk, there
have been rare post-marketing reports (in the presence of multiple confounding factors) (see
ADVERSE REACTIONS; Other Events Observed During Post-marketing Use).
A study evaluating the QT/QTc prolonging effect of intramuscular ziprasidone, with
intramuscular haloperidol as a control, was conducted in patient volunteers. In the trial, ECGs
were obtained at the time of maximum plasma concentration following two injections of
ziprasidone (20 mg then 30 mg) or haloperidol (7.5 mg then 10 mg) given four hours apart. Note
that a 30 mg dose of intramuscular ziprasidone is 50% higher than the recommended
10
therapeutic dose. The mean change in QTc from baseline was calculated for each drug, using a
sample-based correction that removes the effect of heart rate on the QT interval. The mean
increase in QTc from baseline for ziprasidone was 4.6 msec following the first injection and 12.8
msec following the second injection. The mean increase in QTc from baseline for haloperidol was
6.0 msec following the first injection and 14.7 msec following the second injection. In this study,
no patients had a QTc interval exceeding 500 msec.
As with other antipsychotic drugs and placebo, sudden unexplained deaths have been reported
in patients taking ziprasidone at recommended doses. The premarketing experience for
ziprasidone did not reveal an excess risk of mortality for ziprasidone compared to other
antipsychotic drugs or placebo, but the extent of exposure was limited, especially for the drugs
used as active controls and placebo. Nevertheless, ziprasidone’s larger prolongation of QTc
length compared to several other antipsychotic drugs raises the possibility that the risk of sudden
death may be greater for ziprasidone than for other available drugs for treating schizophrenia.
This possibility needs to be considered in deciding among alternative drug products (see
INDICATIONS AND USAGE).
Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or
sudden death in association with the use of drugs that prolong the QTc interval, including (1)
bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that
prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.
It is recommended that patients being considered for ziprasidone treatment who are at risk for
significant electrolyte disturbances, hypokalemia in particular, have baseline serum potassium
and magnesium measurements. Hypokalemia (and/or hypomagnesemia) may increase the risk of
QT prolongation and arrhythmia. Hypokalemia may result from diuretic therapy, diarrhea, and
other causes. Patients with low serum potassium and/or magnesium should be repleted with
those electrolytes before proceeding with treatment. It is essential to periodically monitor serum
electrolytes in patients for whom diuretic therapy is introduced during ziprasidone treatment.
Persistently prolonged QTc intervals may also increase the risk of further prolongation and
arrhythmia, but it is not clear that routine screening ECG measures are effective in detecting
such patients. Rather, ziprasidone should be avoided in patients with histories of significant
cardiovascular illness, e.g., QT prolongation, recent acute myocardial infarction, uncompensated
heart failure, or cardiac arrhythmia. Ziprasidone should be discontinued in patients who are
found to have persistent QTc measurements >500 msec.
For patients taking ziprasidone who experience symptoms that could indicate the occurrence of
torsade de pointes, e.g., dizziness, palpitations, or syncope, the prescriber should initiate further
evaluation, e.g., Holter monitoring may be useful.
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