September 7, 2007

Will Lilly's New Glutamate Agonist Antipsychotic Be A Blockbuster?

It really depends on what you're asking. But the answer is yes.  But don't by LLY yet.

LY404039 is a highly selective glutamate receptor agonist (mGlu2/3). This receptor controls the release of presynaptic glutamate, so this drug actually decreases the release of glutamate.

LY404039 isn't well absorbed, so a prodrug form of it, called LY2140023 was used.  After ingestion, it is hydrolyzed to the active LY404039.

In the main study, 40mg BID was tested against 15mg Zyprexa and placebo.  Zyprexa 15mg was only slightly more efficacious than LY2140023.  This doesn't mean the new drug is inferior-- it could simply mean equivalent efficacy requires more than 80mg. 

The selling point of the drug will be the absence of weight gain-- in fact, there was an average of .5kg lost vs. Zyprexa's .5kg gain.  Prolactin, akathisia and other EPS were no different than placebo. 

There's the background.  Now here's some things you need to know to really assess the drug's potential.

First, this is a glutamate agonist.  The logic is that its opposite, PCP-- a glutamate antagonist-- produced psychotic like symptoms: "positive" symptoms of psychosis: hallucinations, thought disorder, delusions, agitation, and some "negative"  symptoms: flat affect, anhedonia, emotional withdrawal, etc.  All antipsychotics treat postive symptoms (acutely, at least-- tolerance develops quickly.)  Negative symptoms are much harder to treat-- atypicals are considered to be better for them (whether they are or not is not the point here.)

In order for this drug to be a meaningful advance, it has to be better for negative symptoms than what exists.   In the Nature study, LY2140023 was as good as Zyprexa 15mg in reducing negative symptoms, so this is optimistic, but I want for more than 97 people to get it.

Second: one side effect the authors did not discuss is the 4% rate of increased CPK.  CPK increases from antipsychotics indicate that excess muscle rigidity is causing muscle breakdown; muscle proteins then clog up your kidneys, leading to death, a disorder called, neuroleptic malignant syndrome (NMS).  In this study, placebo and Zyprexa did not cause increased CPK.   In this era of diabetes and weight gain paranoia, we forget that ten years ago doctors were insanely obsessed with NMS and TD.  Forensic lectures to psychiatrists dealt nearly exclusively with suicide and TD/NMS.  If this isn't fresh in the minds of residents, it certainly will be in the FDA's.  I'd need to see more details about this to see if the FDA would even approve the drug at all, let alone get used by doctors.

But Will It Sell?

Oh, yes.

No one who is not a doctor will believe me, but I swear this is true: whether the drug works or not is irrelevant.  What matters is that academics tell us to use them. (And I'm an academic, which is uncomfortable to talk about.)

This is a novel agent, with a novel mechanism of action, and no weight gain.  Look back in history at another such drug: Abilify.

It was launched in Nov. 2002.  By March 2003, it had 4% market share-- $80M in sales in 2003.  By 2004, it made $191M with 10% market share.   In the second quarter of 2007 it made $324M.  And most psychiatrists do not have high opinions of Abilify, but they use it because "it doesn't cause diabetes."  Zyprexa made $4.4B in 2006, and psychiatry hates it, for God's sake.  Think about that.

In terms of the existing atypicals, LY would likely gain at the expense of Abilify-- the other weight neutral drug-- and Zyprexa, which will be generic soon anyway.  But docs will use it anyway for the novelty factor and concoct every whacked out pseudo-pharmacological/semiotic reason to use it everywhere.

In Furious Seasons there was some skepticism about antipsychotics being a $12B domestic market.  I think $12B may be too low.  Remember, antipsychotics aren't going to be just for schizophrenics; they will also be used in "bipolars"-- however we decide to expand that diagnosis-- and as antidepressants.  SSRIs are going generic, which means that they will not be used.  Each SSRI ran about $4B a year-- that entire market gets catabolized by antipsychotics.  And don't forget mood stabilizers (read: Depakote).  In the old days (like, Thursday) it was "antidepressant + mood stabilizer+ antipsychotic."  Next year it will be "antipsychotic + antipsychotic of different mechanism."  I've already spoken of Abiliquel.  LY-Quel, anyone?  Abilif-LY?  Zy-LY?

As an investment, Lilly is no good yet.  I don't know how this drug will get past the FDA unless the NMS issue is satisfactorily quashed.  Meanwhile, Zyprexa sales won't fall, but there's no growth. 51-56 is the range, enjoy it. 


If bifeprunox didn't make w... (Below threshold)

September 8, 2007 3:52 PM | Posted by Stephany: | Reply

If bifeprunox didn't make with FDA approval, then why will this one from Lilly?

Alone's response: I'm not suer it will, especially with the CPK thing. I'm just saying if it gets approved, it will be huge, regardless of whether it works.

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As always I appreciate your... (Below threshold)

September 9, 2007 8:41 PM | Posted by rubyvoyager: | Reply

As always I appreciate your knowledge, scraping beneath the first 4 layers, wit and cynicism. I feel incongruous to laugh at a pharmacokinetics article. Thanks.
On this drug I think the research interesting and meaningful, though I agree that that has little to do with presscribing patterns.

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For any readers unfa... (Below threshold)

August 24, 2008 3:21 PM | Posted by Jerod Poore: | Reply

For any readers unfamiliar with new drug naming protocols, the LY prefix just means that it's an Eli Lilly drug that's undergoing clinical trials. No generic name has yet to be derived, or at least released to the unwashed masses. They may have a brand name in the works, but LY isn't a factor.

As for antipsychotics being a US$12 billion market, the latest numbers I had handy were from 2005. Give or take a billion that was about right. With all the pharm reps pushing atypical antipsychotics as monotherapy for bipolar disorder I agree that US$12 billion is now probably a bit low. Back in the good old days (i.e. before everyone knew that Zyprexa, Seroquel and Risperdal put people at risk for type 2 diabetes) Zyprexa was responsible for around 40% of Eli Lilly's total sales revenue.

Let us hope the FDA pays attention to the NMS issue. They would have actual numbers in front of them should this drug get past phase three trials. It's not like it would be a surprise should people start dying nasty deaths, tearful families demanding action in front of congressional committees, and the entire class of antipsychotics be tarred with the stigma of killer drugs.

Better yet, a selective glutamate agonist could be developed that has a much lower chance of causing NMS.

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Does anyone know when this ... (Below threshold)

January 24, 2009 9:14 PM | Posted by Phillies: | Reply

Does anyone know when this drug if approved will get on the market?

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I was waiting to find out w... (Below threshold)

April 15, 2009 9:47 PM | Posted by Cathy: | Reply

I was waiting to find out what the down side of this med would be, it seems there is always at least one. But I am grateful to know about the CPK problem before getting my hopes up! Thanks for letting us know.

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March 12, 2012 9:14 AM | Posted by Nitram: | Reply

Hello and thank you for your interesting article. This might be quite the same but a different approach. Prof Stahl has an article at CNSspectrum which poses the hypoactive NMDA theory. Above that there's a study made in Iran, teheran where the nootropic Piracetam has been used in conjuction with haldol with good results. Piracetam is said to increase the NMDAreceptors.

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