Wednesday, May 25, 2005

CNS Pipeline Update;
Was Dr. Angell Right After All?

Sub-subtitle: A study of the intersection between pharmaceutical science, marketing, and reimbursement

Dapoxetine  is under review by the US FDA for treatment of premature ejaculation, having completed phase III trials.  The company announced that makes it plans to market 30mg and 60mg doses.  Dapoxetine is a serotonin reuptake inhibitor.  Presumably, it acts by stimulating the 5HT-2 receptors, thereby diminishing the strength of perception of sexual stimulation.  This effect occurs in some, but not all people; the reasons for the variation in response are not at all clear.

dapoxetine structure from http://chem.sis.nlm.nih.gov/chemidplus/
dapoxetine chemical structure
Benzenemethanamine, N,N-dimethyl-alpha-(2-(1-naphthalenyloxy)ethyl)-, (+)-

The drug has an interesting history.  It was developed by Eli Lilly, the makers of fluoxetine, atomoxetine, and duloxetine, as a putative antidepressant.  In was licensed to a different company, PPD, for development.  PPD subsequently obtained patent rights, then licensed it to ALZA, which partnered with Ortho-McNeil Pharmaceutical, Inc. (a subsidiary of Johnson & Johnson), to bring it to market.  You'll have to ask someone else to explain all the financial wheeling and dealing.  I did learn that Forbes anticipates sales of dapoxetine to be about $500 million in the first year.  Perhaps that is too small a sum for Lilly to bother themselves with.

The curious reader will ask, no doubt: why in the world we need another serotonin reuptake inhibitor?  In the USA, we already have the selective serotonin reuptake inhibitors fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, and escitalopram (Prozac, Zoloft, Paxil, Luvox, Celexa, and Lexapro, respectively).  (Did I leave any out?)  If you include nonselective agents, add venlafaxine, duloxetine, and soon norvenlafaxine (Effexor, Cymbalta, and brand name pending, respectively).  Not to mention almost all of the tricyclics (almost all of the tricyclics, respectively).

Last year, Marcia Angell wrote a book (The Truth About the Drug Companies) criticizing the pharmaceutical industry for developing "me too" drugs, saying that research dollars would be better spent developing novel drugs.  I actually wrote a post criticizing that notion, saying that these drugs are not really interchangeable in clinical practice.  The development of dapoxetine might change my opinion on that.  How many of these things do we really need?

The devil is in the details.  In this particular situation, the devil is in the details of pharmacokineticsAccording to PPD (170 KB PDF file) dapoxetine has "favorable" pharmacokinetics.  I wasn't able to find the details; Medline gives only five hits for dapoxetine and none of them is very informative.  I assume, with a high degree of confidence, that the drug is absorbed quickly, metabolized (via N-dealkylation) quickly, and looses effect quickly.  14C-labeled dapoxetine is undetectable in rats within 72 hours, which implies a half-life (in rats) of about 7-14 hours.  (See how hard bloggers sometimes have to scrounge for tidbits of information.)

As an aside, pharmaceutical companies don't publish most of their basic science studies, which makes sense from a fiduciary standpoint, but is irritating anyway.  Even so, publicly available information can be pretty informative, perhaps more so than they realize. 

The PPD document that I linked to above indicates that the pharmacokinetic profile is suitable for PRN dosing.  PRN means "as needed."  You can take the drug whenever you feel like taking it.  Will there be adverse effects?  They don't say, but most likely nausea, headache, and insomnia will occur in 10-20% of people.  Some might get sleepy instead of having insomnia. 

Do I have any concerns about the drug?  Not really.  I wonder, though, if they really will get a half billion dollars a year out of it.  Assuming they get the FDA approval, and they probably will, it will be the only FDA-approved drug for premature ejaculation.  But all those other drugs (except maybe duloxetine) I mentioned probably will work just as well.  What this means is that dapoxetine will come to market with FDA approval, which is a marketing advantage, but probably will not have any significant medical advantage. 

I could be wrong about that, since Lilly/PPD/ALZA/Ortho-McNeil/J&J haven't release all the specifics yet, but I am fairly sure their scientists won't be able to come up with anything that makes the drug clearly preferable over the others.  It will be interesting to see what their marketing people will try to come up with.  I'm sure they'll have to use a turnip press to squeeze science out of a vegetable.  (I know that's a metsed mixaphore, but you know what I mean.)

Science and marketing always have an interesting relationship in the pharmaceutical industry.  The dapoxetine story is different, though, in the way that science, marketing, and reimbursement will converge once the product is on the market.

In order for a pharmaceutical product to be profitable, it is (or ought to be) safe and effective, AND be accepted by patients, AND be reimbursed for by insurance companies.  That latter point may be diminished somewhat in the case of dapoxetine, since people are more willing to pay out of pocket for something that improves their sex life, as compared to, say, something that treats cancer.  Still, the insurance reimbursement is a significant factor in the profitability of a drug.  If Forbes is correct, and dapoxetine results in $500 million in sales in the first year, that potentially means that the insurance industry will have to come up with an extra $500 million dollars next year, that they did not have to pay this year.  Actually, 500,000,000 minus unspecified discounts, minus copays and deductibles, minus what people pay out of pocket.  Even with all those offsets, it would be a significant expense. 

It is safe to assume that the insurance companies aren't going to want to part with that half-billion dollars, but do they have a choice? Perhaps: generic paroxetine has a half life of 16 hours (on average, in humans).  The retail price (the insurance company will pay much less) of generic paroxetine is $72 for 30 pills online at Walgreens.  The price is going to decline rapidly over the next year. Probably a half of one of those pills would do the job.  Therefore, even before the price drops, paroxetine can be gotten for $36 dollars for thirty doses, and probably the average person would use at most 15 doses in a month.  Let's say the retail cost for 15 doses is going to be $18/month, and the copay is $5, and the insurance company actually pays less than $10 per month.

We do not know what Ortho-McNeil is going to charge for dapoxetine.  However, nobody is going to go through the trouble of bringing a new pharmaceutical to market if the retial price is only going to be $18/patient-month.  I'll venture a guess that they are going to shoot for about $75/patient-month, with the insurance company paying ~$50/month.  Those are very rough estimates, but it illustrates the point. 

Given the enormous price differential, it would make sense for insurance companies to urge physicians to prescribe generic paroxetine instead of brand-name dapoxetine.  Will they do that? Probably?  Will they try to do it with an honest countenance?  Surely.  If they do this, will it expose them as damn liars?  Yes.

You see, insurance company often try to deny payment for perfectly legitimate prescriptions by arguing that the drug is "not approved" for the patient's diagnosis.  That's already an untruth, since the fact that the doctor wrote the Rx is prima facie evidence that the doctor approved it.  So what does the phrase "not approved" mean in this context?  What it might mean is that it was not FDA approved, although they never actually specify it that way.  If that is their intended meaning, then the reason they don't specify "FDA approved" is that there is not a shred of evidence that FDA approval is a sensible or justifiable way to make reimbursement decisions.  The artful use of the passive voice ("it is not approved" vs. "The FDA has not approved it") obscures the fact that the agency that not approving it has no legitimate jurisdiction over the approval process.  The other possible rationale for the use of the passive voice is that they do not want to come right out and say "we do not approve it."  If that is the case, then they are dodging their responsibility.  This may not seem obvious to the uninitiated, but take my word for it, it is true.

Now, the introduction of dapoxetine will put them in a difficult position.  Do they try to maintain the charade of insisting that FDA approval should be a precondition for reimbursement (if that is the meaning of the vague phrase "not approved"), or do they admit that it is the insurance company who is taking responsibility for not approving it; or, do they suggest that the doctor prescribe (inexpensive) generic paroxetine instead of (expensive) branded dapoxetine?  Do they stick to their principles, as misguided as they may be; or, do they try to save a few hundred million dollars?

This might turn out to be an interesting study in medical economics.  I wouldn't know about that.  However, I do think it is an interesting study of human behavior. 

Addendum: It occurs to me that there might be a rason to be concerned about unexpected adverse effects from dapoxetine.  Although the predicatable adverse effects will be minor, there will be a group of patients that could be susceptible to psychiatric disturbance.  Specifically, patients with bipolar disorder could be prone to have a manic episode if exposed to a serotonin reuptake inhibitor.  Admittedly, the probability of that is small for any given person, but if millions of people take it, it would be reasonable to expect several cases per year.  If the FDA is doing their job, they will require postmarketing survelliance for this potential problem.

(Note: The Rest of the Story/Corpus Callosum has moved. Visit the new site here.)
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The side effects observed in phase III were Nausea for 30 mg 8.7%, Headche 6% with 4% discontinuation due to adverse effects. For 60mg nausea was 20%, Headache 7%, Diarrhea and dizzines. Efficacy measured by IELT (Intravaginal Ejaculation Latency time) was increased a minute or two, and other secondary endpoints, like Control over ejaculation were still less impressive. With this efficacy one has to wonder why would FDA even approve this drug and run the risk of finding out unexpected side effects once it hits the market.
The Drug was considered Non-approvable by the FDA at the end of Oct 05. But it was not for lack of efficacy or other endpoint data which was clinically significant in the phase III trial publications which you can read and are readily available on-line.

Your posting of the actual IELT is far from the whole picture. Remember, you are talking about men who are going from a period of mere seconds up to several minutes. This is significant for those individuals not to mention the increased partner satisfaction data that was published as part of the study parameters.

As with ED drugs, this becomes a real life style issue and indeed using an SSRI could be called into question even though Dr.s are currently using other SSRI's for this very issue. However, with Dapoxetine having a much shorter half-life then all of the others, as well as this drug being taken as a PRN (as needed) compound, the risks really would be minimized in terms of any unwanted serious CNS side effects for the vast majority of people who would take it.

I think the question then arrises what happens when a person who is taking another SSRI already or who has previously been treated with an SSRI for Bi-Polar depression takes dapoxetine?? I think that if you are already taking an SSRI you would not be a candidate for the use of dapoxetine no matter what the half-life is since really the mechanism of action for the SSRI's as a whole is a side effect of the drug. It may have been for resons such as this that dapoxetine came back as non-approvable at this time. This is different from NOT Approvable so additional study data will have to be submitted if the drug is going to be further pursued.

Ortho McNeil has since eliminated it's Urology division which it had created back in Oct of 2004 for the eventual launch of Dapoxetine so I am not sure they are going to pursue the drug any futher or not.

Let's stay tuned I guess for further developments.
My name is Judith Haven and i would like to show you my personal experience with Effexor.

I am 37 years old. Have been on Effexor for at least 1 years now. As soon as I was on the beginning dose I could feel releave from my anxiety. My family life is so much better. My kids notice it. They applaud my for taking the side affects for a better live with them. No explosive episode any more.

I have experienced some of these side effects-
Nightsweats, I have twitches if I forget a dose.

I hope this information will be useful to others,
Judith Haven
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