LY2140023: Progress in Schizophrenia Treatment?

In the 1950's, a new class of antipsychotic drugs was
discovered: the
antipsychotics.   href="" rel="tag">Chlorpromazine
(Thorazine®) was the first.

By the 1970's, several related compounds had been discovered.
1976, it was learned that there is a direct linear relationship between
the strength with with the compounds bind at the dopamine D2 receptor,
and the clinical potency of the drug.


face="Times New Roman, Times, serif">[Figure from Seeman,
Molecular Psychiatry (1998)3, 123-124]

The discovery of this direct relationship was taken as
strong evidence
for the relationship between dopamine receptor blockade and therapeutic
effect.  Some even went so far as to say that this proved that
dopamine excess was the cause of schizophrenia, but that was a bit of a
stretch.  In any event, therapeutic research focused primarily
the D2 receptor for decades.

Researchers and astute clinicians knew, however, that there was more to
the story.


Some people would respond well to one drug, but not another,
though the two drugs both blocked the same D2 receptors.
 There had to be
more to the story.  There were too many things like that,
that tickled the intuition, for well-informed persons to feel confident
that dopamine was the whole story.

One of the unsettling observations was the unparalleled efficacy of rel="tag" href="">clozapine.
Clozapine was first developed in 1961, and was found to be remarkably
more efficacious than any other antipsychotic
drug.  Something else was going on, something other
than blockade of the D2 receptor.

We know now that this is partly due to the effect that clozapine has on
blocking 5HT2 receptors (a subtype of serotonin receptor).
line of study led to the expansion of what is now an entire family of
so-called href="">atypical
antipsychotic drugs

Now, is, somewhat uncharacteristically, gushing over a
recent phase-II trial of a different kind of antipsychotic medication.

hopes for new schizophrenia drugs

Drug trial hailed as first major breakthrough for 50 years.

Published online: 2 September 2007; doi:10.1038/news070827-9

Alison Abbott

Psychiatrists have welcomed the unveiling by a US drug
company of the first new class of schizophrenia drugs since the 1950s.

According to early clinical-trial data, the prototype drug —
codenamed LY2140023 and produced by Eli Lilly researchers in
Indianapolis, Indiana — seems to be as effective as
olanzapine, the best currently available drug. The drug's developers
hope that it will offer psychiatrists a new alternative for treating
their patients, and one that may offer greater benefits in relation to
the side effects...

LY404039 is a selective agonist for href="">metabotropic
glutamate 2/3 (mGlu2/3) receptors.  It turns on the
receptors, which lowers the activity of glutamate in the synapse.
 (LY2140023, the drug in the study, is a prodrug that is
metabolically changed into LY404039.)

The study that the news article is based upon is this one: rev="review"
of mGlu2/3 receptors as a new approach to treat schizophrenia: a
randomized Phase 2 clinical trial.  The authors
studied mice.  They also studied 196 humans, which admittedly
does add to the clinical validity of the study.  

Patients were randomized to receive olanzapine (an atypical
antipsychotic), placebo, or LY2140023:

After 4 weeks of treatment, both the
LY2140023 group (32.0%, P less than 0.001) and the olanzapine group
(41.2%, P less than 0.001) showed significantly greater response rates
than the placebo group (3.2%).

That is a good result.  The reason I am sounding
skeptical is that it is hard to think of this as "a major
breakthrough."  Many phase-II drugs never make it to market;
we have seen many disappointing fizzled products.  

Even if it is a major breakthrough, it would not count as the "first
major breakthrough" unless you disregard the introduction of clozapine,
not to mention rel="tag">risperidone and possibly depot href="">fluphenazine.

If this does work out as is hoped, it will be a welcome advance.
 That is for two reasons.  One, hardly anyone gets a
fully satisfactory response from the current medications.
 Therefore, any new approach is likely to help some people who
could not be helped before.  Or it might bring a greater
degree of improvement in people who have unsatisfactory responses to
existing medications.  

Two, the new drug appears to have a much lower adverse effect burden
than existing antipsychotic medications.  Drugs are useful
only if they cause more benefit than harm, and they are useful only if
people actually are willing to take them.  Having a lower
adverse effect burden would make both outcomes more likely.
 However, given the very small number of humans who have been
exposed to LY2140023, and the short time scale of the study, it would
be wise to withhold judgment on this point.

If this does work out, Lilly will make a lot of money from it, and they
will deserve it.  I just hope they start working on a depot
formulation right away, rather than making us wait forever.  I
also hope they start work on the possible efficacy for bipolar
disorder, rather than conducting those studies as an afterthought.
 (Or playing patent-life games by getting a second indication
years after the first.)

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It is refreshing to see something like this.  Both drugs are available as generics, so the financial motivation for a study like this is not great.  But the clinical benefit could e substantial, albeit for a small subset of patients. Clozapine is considered to be the most efficacious antipsychotic…

If the new drug turns out to have fewer adverse effects, maybe they won't need a depot formulation. On a somewhat related note: I haven't seen anything yet about the drug's other receptor affinities -- that is, apart from its activity at mGlu2/3. Does anybody have any information on that?

Pharmacological and pharmacokinetic properties of a structurally novel, potent, and selective metabotropic glutamate 2/3 receptor agonist: in vitro characterization of agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid (LY404039).
Rorick-Kehn LM, Johnson BG, Burkey JL, Wright RA, Calligaro DO, Marek GJ, Nisenbaum ES, Catlow JT, Kingston AE, Giera DD, Herin MF, Monn JA, McKinzie DL, Schoepp DD.

Neuroscience Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, DC0510, Indianapolis, IN 46285, USA.

Group II metabotropic glutamate (mGlu) receptor agonists, including (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740) and (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), have demonstrated efficacy in animal models of anxiety and schizophrenia, and LY354740 decreased anxiety in human subjects. Herein, we report the in vitro pharmacological profile and pharmacokinetic properties of another potent, selective, and structurally novel mGlu2/3 receptor agonist, (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039) and provide comparisons with LY354740. Similar to LY354740, LY404039 is a nanomolar potent agonist at recombinant human mGlu2 and mGlu3 receptors (K(i) = 149 and 92, respectively) and in rat neurons expressing native mGlu2/3 receptors (Ki = 88). LY404039 is highly selective for mGlu2/3 receptors, showing more than 100-fold selectivity for these receptors, versus ionotropic glutamate receptors, glutamate transporters, and other receptors targeted by known anxiolytic and antipsychotic medications. Functionally, LY404039 potently inhibited forskolin-stimulated cAMP formation in cells expressing human mGlu2 and mGlu3 receptors. Electrophysiological studies indicated that LY404039 suppressed electrically evoked excitatory activity in the striatum, and serotonin-induced l-glutamate release in the prefrontal cortex; effects reversed by LY341495. These characteristics suggest LY404039 modulates glutamatergic activity in limbic and forebrain areas relevant to psychiatric disorders; and that, similar to LY354740, it works through a mechanism that may be devoid of negative side effects associated with current antipsychotics and anxiolytics. Interestingly, despite the slightly lower potency (approximately 2-5-fold) of LY404039 versus LY354740 in binding, functional, and electrophysiological assays, LY404039 demonstrated higher plasma exposure and better oral bioavailability in pharmacokinetic experiments. Collectively, the current data indicate that LY404039 may be valuable in the treatment of neuropsychiatric disorders, including anxiety and psychosis.

In vivo pharmacological characterization of the structurally novel, potent, selective mGlu2/3 receptor agonist LY404039 in animal models of psychiatric disorders.
Rorick-Kehn LM, Johnson BG, Knitowski KM, Salhoff CR, Witkin JM, Perry KW, Griffey KI, Tizzano JP, Monn JA, McKinzie DL, Schoepp DD.

Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, DC0510, Indianapolis, IN 46285, USA.

RATIONALE: Data from both preclinical and clinical studies have provided proof of concept that modulation of limbic and forebrain glutamate, via mGlu2/3 receptor agonists, might provide therapeutic benefits in many psychiatric disorders including schizophrenia and anxiety. OBJECTIVE: The aim of this study was to assess the efficacy of a structurally novel, potent, selective mGlu2/3 receptor agonist with improved bioavailability (LY404039) in animal models predictive of antipsychotic and anxiolytic efficacy. MATERIALS AND METHODS: LY404039 was assessed in amphetamine- and phencyclidine-induced hyperlocomotion, conditioned avoidance responding, fear-potentiated startle, marble burying, and rotarod behavioral tests. Monoamine release and turnover were assessed using microdialysis and ex vivo tissue levels. RESULTS: LY404039 attenuated amphetamine- and phencyclidine-induced hyperlocomotion (3-30 and 10 mg/kg, respectively). LY404039 (3-10 mg/kg) inhibited conditioned avoidance responding. LY404039 also reduced fear-potentiated startle in rats (3-30 microg/kg) and marble burying in mice (3-10 mg/kg), indicating anxiolytic-like effects. Importantly, LY404039 did not produce sedative effects or motor impairment as measured by rotarod performance and lack of escape failures in the conditioned avoidance task (at doses up to 30 and 10 mg/kg, respectively). LY404039 (10 mg/kg) also increased dopamine and serotonin release/turnover in the prefrontal cortex. CONCLUSIONS: These results demonstrate the broad preclinical efficacy of LY404039 across multiple animal models of antipsychotic and anxiolytic efficacy. Additionally, this compound modulates mesocortical neurotransmission and provides a novel mechanism for the treatment of psychiatric disorders that may be associated with improved efficacy and reduced incidence of undesirable side effects. As glutamatergic dysfunction has been linked to the etiology of schizophrenia, clinical studies with more potent mGlu2/3 agonists, such as LY404039, may be useful to explore the validity of this hypothesis.

I appreciate this information, but what I'd like to know is, what are the dissociation constants of this new molecule at different receptor types and subtypes? Not to be ungrateful -- this is interesting, as far as it goes.

I think I know what you are getting at: most molecules interact with more than one receptor type, and before we give this to people, we would like to be fully informed about what transmitter systems are going to be affected, not to mention which cytochrome enzymes are going to be affected. I don't see anything more specific in the public literature.

If Mark Demitrack is still with Lilly in Indianapolis, he might be willing to open up a little about the specifics. I have to believe they have done a lot of work to characterize their new molecular entity, but they are not openly sharing much of it.

Last I knew, Mark's email was madmd (ha ha, Mark A Demitrack, Mad MD) at lilly dot com. But I haven't been in touch with him since he left the Eating Disorder program. That was what, 12 years ago?

It was a long time. Atul Pande went to Lilly too I think. Thanks again for the info.

Nice post, Joseph. Your measured assessment is appreciated, re: the cautiously optimistic outlook on Phase II results. You alluded to depot delivery so I assume you refer to the rapid clearance and relatively short half-life of 404039. There's no published values for CYP or liver metabolism that I can find, but LY354740 (poorer bioavailability, but longer half-life) looks like it's cleared unmetabolized through the kidneys. Whether this applies to LY404039, well, I expect the folks at Lilly know.

stumpy, I'm not sure which "different receptors" you're referring to, and you may have already found the table from the article Joseph cited, but what the hey, I'll post it 'cause I can.

From Rorick-Kehn et al. Pharmacology and Exp. Thearpeutics 2007:

TABLE 4 Effects of mGlu2/3 receptor agonists at ionotropic glutamate receptors, glutamate transporter subtypes, and monoamine and other receptors

The Ki was determined for each neurotransmitter receptor or transporter. Data are presented as the mean ? S.E.M. of two to three separate experiments. Where affinities are reported as greater than 1 uM concentration, this was the highest concentration tested that inhibited <50% specific bound radiolabel in the assay.

Ki or IC50 values are expressed in micromolar; first column is LY354740 & the second is LY404039. - Doc Bushwell

iGluR ligand (Ki)
[3H]CGP 39653 (NMDA) >100 >100
[3H]AMPA >100 >100
[3H]Kainate >100 >100
Transporter subtype (IC50)
Rat EAAT1 >5 >5
Rat EAAT2 >5 >5
Rat EAAT3 >5 >5
Monoamine ligand (Ki)
Dopamine, D1 >100 >10
Dopamine, D2 >100 >10
Serotonin, 5-HT2 >100 >10
Adrenergic (Ki)
1-Adrenergic >100 >10
2-Adrenergic >100 >10
-Adrenergic >100 >10
Miscellaneous (Ki)
Histamine, H1 >100 >10
Benzodiazepine >100 >10
GABAA >100 >10
Muscarinic >100 >10

But is this drug out on the market and if so-how much does it cost?

The drug is not yet available. I realize now that I did not mention that fact, thinking it was obvious. But the reasons it is obvious are not obvious. For one, the name LY404039 is an indication that the drug is still under investigation. Once it is available to the general public, it will have a flashy name, rather than a number. The other clue is that these were phase II studies. There are three phases that have to be done before a drug is submitted for approval.

So, it is "obvious" only if you happy to know those things, which most people will not know.

I will try to remember to be more clear next time.

Does anyone know when the phase III will be completed? My daughter is schizophrenic. We are still trying to find a medication to stabilize her. thanks

By Jim Stewart (not verified) on 31 Aug 2009 #permalink

Lilly's site lists it as still being in Phase II as of 1 July, 2009. There is no way of knowing when or if it will progress to phase III.