chunk of change…

Posted on Wednesday 29 April 2015

Pharmalot: WSJ
By Ed Silverman

Otsuka Pharmaceuticals was dealt a setback yesterday when the FDA approved four generic versions of its best-selling Abilify® antipsychotic pill, following an unusual and protracted legal battle. Shortly thereafter, Teva Pharmaceuticals announced that it was launching a copycat medicine. The move comes after Otsuka cited complex regulatory law to thwart generics, but the agency rejected the argument and decided that generic versions meet the standard for approval… And Otsuka also has a great deal at stake – Abilify® generated $4.9 billion in U.S. sales last year.

As we wrote previously, the FDA late last year approved Abilify® for treating children with Tourette syndrome, a neurological disorder that causes tics. Since Abilify® had a so-called orphan designation, which refers to a drug used to treat a rare malady like Tourette’s, Otsuka won another seven years of exclusive marketing rights – through late 2021 – before low-cost generics could appear.

But in February, the FDA surprised Otsuka by approving Abilify® to treat adults with Tourette syndrome. This widened the market, but Otsuka contends FDA law would trigger a labeling change that could usher in generics. Otsuka filed a lawsuit claiming the FDA isn’t allowed to approve an indication for which a drug maker didn’t apply and charged the agency was actually attempting to usher in generic copies.

For its part, the FDA backpedaled and earlier this month told Otsuka that Abilify® was now approved to treat Tourette syndrome, but only for children. However, the agency also indicated it may use a so-called carve-out approach to approve generics for treating psychiatric disorders, but not Tourette syndrome. And that is what the FDA did Tuesday…
Well, speaking of Abilify®, just as I was starting to look up how much it brought in per year, Ed Silverman to the rescue – $4.9 B! which explains why there’s so much noise. No small chunk of change by anybody’s standard. Thus, there’s the rush to anchor Abilify®Maintena and Brexpiprazole to hold onto some of that cash, and the move to hold onto Abilify® itself, if possible [apparently not]. I’ve never prescribed Abilify® and know nothing about it from experience. Here’s what Johanna Ryan on Rxisk had to say about it:
Personally, I wonder the same thing I thought about with Seroquel®. When it was in-patent, people asked for it. Out of patent, and I don’t hear about it anymore or run into anyone taking it. Are they all taking Abilify® now? Will Abilify® go out of style too? I don’t get it…
    Sandra Steingard
    April 29, 2015 | 10:48 PM

    My own clinical experience with aripiprazole:
    When it came out, they suggested starting at 15 mg and increasing to 30 if there was no response. I was slow to prescribe this drug but I had people come to me on it. When I finally tried it (initially for people who had poor responses to other drugs), I had two back to back patients develop severe akathisia on the higher doses. The other interesting thing is that it is now considered weight neutral. This has not been my experience (and my clinic colleagues agree). We have all had numerous patients who gain considerable amounts of weight on this drug.
    Re: the hype around the LAIs: Dr. Kane and colleagues are publishing many papers on the benefits of LAIs. I think the data is mixed but I also think that haloperidol or fluphenazine used in low doses are as effective and have overall a comparable side effect profile – and they are much cheaper. In recent years, we have had problems obtaining these drugs. I have come to wonder if there is some funny business that causes production problems for these less expensive generics.
    As for efficacy, it is hard to say but at lower doses, aripiprazole can be a well tolerated drug.
    (And I am using it to target psychotic symptoms.)
    But this drug was promoted as a “dopamine system stabilizer: because of its mixed agonism/antagonism effects. This is what made it different and there was hope it might help with negative symptoms but this has not panned out. They were not able to demonstrate any effects on reducing negative symptoms in the premarketing studies and I think this is another hypothesis that just fell away. With the larger market for mood symptoms, that is what ended up getting promoted.

    April 29, 2015 | 11:11 PM


    ” With the larger market for mood symptoms, that is what ended up getting promoted.”


    I noticed that same emphasis on BrexpiprazoleMDD : Schizophrenia :: 2 : 1. Since the vast majority of people I see in a Charity Clinic who are depressed have plenty of reasons for their symptoms, I rarely see patients with what I would call “mood disorders,” so I have no experience with what seems to be the ubiquitous “adjunctive therapy” with Atypical Antipsychotics. But I see a lot of patients medicated elsewhere with Abilify, and I can’t correlate their diagnosis with anything specific. I think Abilify is being used as a “nerve pill” much like Seroquel was in the past. And I agree with you about weight gain. I’ve also done slow tapers because withdrawal symptoms are reasonably common.

    When Cymbalta went generic, I had lots of patients who asked about it [from TV I think]. I’m anticipating something similar with Abilify. In my late career, I’ve learned a lot about getting people off of medications. I used to see starting medications as a therapeutic trial. Now I see discontinuing medications as a therapeutic trial – “Let’s see if it’s still helping.” Patients have more sense than we give them credit for and many are willing to try D/C-ing meds. I think that the most important thing is to not mess with “meds” until you get to know the patient and what the “meds” mean to them.

    With psychotic patients, the only Atypical I’ve had success with is Risperdal, and the side effects are always just around the corner. One of the advantages to being in a small rural place is that I know all the pharmacists and I can get them to hunt around and stock fluphenazine. They call it my old medicine and ask me if I’m going to be ordering up any leeches…

    April 30, 2015 | 5:06 PM

    This is great news! Glad to see they’re not going to bilking the system for another 7 years, that’s 35 billion dollars. Sometimes I have concerns over how abilify got such a bad reputation and fear that we’re sacrificing a somewhat unique agent because of anger about its parent company’s marketing and shady dealings. I use abilify significantly more than other psychiatrists, mainly because I’ve found that my pts consider it relatively less “inhibitory” than other antipsychotics. My guess is this is due to it being the only one with partial agonism as opposed to being a full antagonist (obviously this only applies when dosed judiciously). I find that most instances of akisthisia can be averted by a slower titration, and if there isn’t time to slowly titrate then an alternative option should likely be used. Of importance, there’s the paper below which shows a lack of dopaminergic supersensitivity in a murine model. I’m definitely not saying that abilify revolutionized antipsychotics but I consistently hear from my schizophrenic patients that they feel less “inhibited” by abilify. I’d also like to note that I usually don’t have to go up to the full 30mg for schizophrenia, I usually use 15 or 20 (but 10 doesn’t really work). There was also a strange case where cogentin (benztropine) fixed the akisthisia. Even after titrating propranolol to 120mg TID, he still had it, once he took his old cogentin 1/1 (on his own) his akisthisia stopped completely….. even after the propranolol was dc’d. Very strange, didn’t know what to make of this as I’d never seen akisthisia respond in this manner. It makes me wonder if this “akisthisia” we cite in abilify is really a slightly different entity bc of the partial agonist pharmacology of abilify.

    April 30, 2015 | 8:11 PM

    I quite frequently get people who have been dosed with Abilify as an adjunct to an antidepressant who developed akathisia from one or the other drug, and are subsequently prescribed a benzo to mask the adverse effects.

    There is no defensible therapeutic effect for a drug cocktail that causes unrelenting adverse effects.

    They have a very difficult time going off any of the 3 drugs. It’s a disgrace that the adverse effects are not recognized as an indication that the drug cocktail should be minimized, not elaborated upon.

    And that’s the story of Abilify as a marketing triumph and cash cow for Otsuka.

    Joseph Arpaia
    May 1, 2015 | 12:44 AM

    Since dopamine is involved in the reward system, I continue to be confused as to why dopamine-blockers are used so often as adjunctive antidepressants.

    Steve Lucas
    May 1, 2015 | 8:21 AM

    From a business perspective we need to remember that all of the cost of a drug is in the first pill produced. The research and production cost are all part of that pill and all of the follow on pills are marginally cost with only the ingredients and production cost relating to equipment maintenance.

    Marketing then becomes our biggest cost with TV ads, print, and those doctor’s office visits. This is a very large number and if you look marketing is a larger expense than R&D in a drug company’s financial reports.

    We now find, as reported in the April, 27, 2015 WSJ that Firms Buy Rival Drugs, Then Raise Their Prices. So now we have reached the worse of both worlds of high prices and high volume.

    With our sunk cost behind us and marketing our next big play we want to maximize that impact so as to produce the greatest revenue stream possible. The worse day in pharma is better than the best day in any other industry, not my quote. Drug stocks were considered for decades a widows and orphans stock due to the cash flow and dividends paid.

    We do not have to look far to find a whole series of “silent killers” just waiting to stop our lives. LDL, eggs, butter, colds, flu, weight, and there was a pill to counter act these terrible man killers.

    I became involved in medial blogs many years ago after having doctors repeatedly tell me of all of my myriad health issues while repeating verbatim the TV ads I had seen the night before. No test needed, you have to watch these “silent killers.” Pharma knows and I have a “special” relationship with the drug companies.

    I know this was marketing and was insulted that someone though I was that dumb. I was more concerned that the doctors involved were that dumb that they bought into all this junk science.

    Drugs have their place for the right patient, at the right dose, with the right monitoring. The problem is pharma wants us all on some drug and the financial incentives for doctors who are paid per office visit are to prescribe. Add the drug reps free lunch, paid speaker fees, and other incentives and only a few doctors will say you are good enough, go live your life.

    With medical practices being owned by people other than the doctors involved, and as pointed out in another WSJ article, now venture capitalist, there is no incentive to treat patients, merely generate revenue.

    Steve Lucas

    Gad Mayer
    May 1, 2015 | 8:28 AM

    In some countries other than the US some neuroleptics have been used for decades as antidepressants or adjuncts to antidepressants. Usually this is done with low dosages of neuroleptics that are clinically seen as “activating”, such as flupenthixol and sulpiride (similar to claims about aripiprazole). The relationship between dopamine and depression is probably not so simple. See for example:

    James O'Brien, M.D.
    May 1, 2015 | 1:34 PM

    I don’t get the success of this drug especially given the costs. I can think of about twelve things I would do before going to Abilify as an adjunctive treatment.

    James O'Brien, M.D.
    May 1, 2015 | 1:37 PM
    May 2, 2015 | 5:00 AM

    I have nothing against aripiprazole specifically, it seems to works about as well (or poorly) as the others. But from the start I’ve been dismayed by consumer advertising to sell Abilify as an antidepressant. Not that it can’t help in selected cases, but the risks and drawbacks far outweigh the benefits most of the time. I agree with James O’Brien above: there are about a dozen things I’d try before using Abilify as an adjunctive treatment for non-psychotic depression.

    It’s this dubious use — and other dubious uses, like using it as a non-addictive sleeping pill — that makes Abilify America’s top selling prescription drug. It really says something about a culture when its most profitable medicine is an antipsychotic.

    May 2, 2015 | 6:07 AM

    With psychotic patients, the only Atypical I’ve had success with is Risperdal, and the side effects are always just around the corner.

    Mickey, you don’t/didn’t find Clozapine useful?

    May 2, 2015 | 2:40 PM

    Why not ask Noah Phillip, M.D. on the psychiatry faculty at Brown why he thinks aripiprazole has “significant efficacy as augmenting agents for unipolar, nonpsychotic major depressive disorder (MDD)”? (By the way, the patient had developed akathisia from the drug when it was added to her massive cocktail.)

    R I Med J (2013). 2013 Feb;96(2):13-4.
    An aripiprazole discontinuation syndrome.
    Philip NS.


    Major depression is a common and debilitating illness. Over recent years, new pharmacologic treatments have been approved for this disorder, including the atypical antipsychotics. One of the benefits of these medications is their significant efficacy as augmenting agents for unipolar, nonpsychotic major depressive disorder (MDD).Aripiprazole (marketed as Abilify, Bristol-Myers Squibb/ Otsuka Pharmaceuticals) was the first medication of this class approved for adjunctive treatment of MDD, and is the 5th most commonly prescribed medication in the United States in 2010. However, despite the frequency of its use, little has been described regarding events surrounding aripiprazole discontinuation. Here I describe what is, to my knowledge, the first reported case of an aripiprazole discontinuation syndrome. While directly relevant to psychiatrists and behavioral specialists, the symptoms described here are pertinent for internists and neurologists who may encounter this medication in their clinical practice.

    From full text at :
    Noah S. Philip, MD
    Assistant Professor of Psychiatry and Human Behavior (clinical),
    Alpert Medical School of Brown University, Butler Hospital

    James O'Brien, M.D.
    May 2, 2015 | 5:22 PM

    What is meant by the phrase “I frequently get people”? This sounds like the practice of medicine.

    May 2, 2015 | 5:45 PM

    I’d also like to note that Dr. Philip, above, and Sansone, et al 2013 Aripiprazole withdrawal: a case report. both referred to Internet forums like mine for anecdotal reports supporting their published case reports of aripiprazole withdrawal syndrome, so I guess collecting those patient accounts has some value to some clinicians.

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