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.