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Opinions Mixed on Future for Lilly’s mGluR2/3 Agonist for Schizophrenia

6 August 2012. In a July 11 press release, Eli Lilly and Company announced that its metabotropic glutamate receptor agonist pomaglumetad methionil (also called LY2140023) has failed a Phase 2 clinical trial designed to evaluate its efficacy at improving positive and negative symptoms of patients with schizophrenia. Although the full data from this study—the third Phase 2 trial of monotherapy with this drug—are yet to be released, we do know enough to be disappointed: in contrast to the antipsychotic risperidone, the Lilly drug was no better than placebo at reducing symptoms.

The question of what this means for further research with mGluR2/3 drugs draws mixed responses from the schizophrenia research community. Some researchers wonder if the drug could still have positive effects in a subset of patients, or on a subset of symptoms. "Even if the primary endpoint didn’t meet criteria, you then go back and see if there are other symptoms that seem to have responded," said Daniel Javitt, of the Nathan Kline Institute.

In contrast, Bita Moghaddam of the University of Pittsburgh, whose animal experiments provided the initial rationale for the development of the drugs (Moghaddam and Adams, 1998), does not advocate for following up on direct mGluR2/3 receptor agonists as monotherapy, noting, “Once there are clinical data out there, you cannot argue with that.” She does, however, suggest there may be other ways to effect beneficial changes in glutamate neurotransmission in schizophrenia.

In this article, SRF looks back on the effort to develop a truly novel medication for schizophrenia, and asks some experts their opinions on the future of this enterprise.

The Great Glutamate Hope
Agonists of metabotropic glutamate receptor subtypes 2 and 3 have been on the schizophrenia stage for nearly 15 years, ever since Moghaddam’s 1998 study demonstrated that this class of drugs could reverse the cognitive deficits and psychosis induced by phencyclidine (PCP) exposure in an animal model. However, previous Phase 2 trials of the current drug have been mixed. The first extremely promising study reported a large reduction in symptoms after four weeks’ treatment with LY2140023 (a prodrug that is metabolized into the bioactive compound LY404039), assessed via Positive and Negative Symptom Scale (PANSS) change from baseline, an effect comparable to the antipsychotic olanzapine (see SRF related news story). However, in a second four-week trial, treatment with neither the mGluR2/3 agonist nor olanzapine was more effective than placebo at improving PANSS score. A greater-than-average placebo response was blamed for the lack of effect of both drugs, and thus, the second study was considered a wash (see SRF related news story; Kinon et al., 2011).

The current study, which began in early 2010 and concluded in May 2012, was similar to the design of the previous two, except that the drug was administered for seven weeks. Approximately 1,000 patients with an acute exacerbation of schizophrenia were given placebo, risperidone (2 mg twice daily), or LY2140023 (either 40 or 80 mg twice daily). Unfortunately, neither dose of the mGluR2/3 prodrug met the primary endpoint of the trial—a significant improvement in PANSS score over placebo—although risperidone did. The same was true regardless of whether all schizophrenia subjects were considered, or whether only a genetic subgroup (based on previous studies) was examined. LY2140023 was well tolerated and, importantly, no new safety information was reported.

The first two studies were consistent in terms of response to the Lilly drug. What differed was the response to placebo, providing hope that the previous failed study had been driven by the elevated placebo response. The expectation was that this third trial would replicate the original, bringing us one step closer to a rationally designed treatment for schizophrenia. But the current findings—that risperidone separated from placebo but LY2140023 did not—call into question the efficacy of the mGluR2/3 agonism mechanism, and may have put the problematic placebo hypothesis to rest.

The reaction of the community has been one of great disappointment. “This is obviously a discouraging finding,” said Yale University’s John Krystal. “And we all know that we have a tremendous need for the development of new medications for schizophrenia that target novel brain mechanisms.”

For Jeffrey Lieberman, of Columbia University, New York, the results were very surprising. “In many cases drugs fail … because of mistakes that are made on the part of the pharmaceutical industry or because of some kind of flaw in the development strategy. But this result comes about through no fault of Lilly,” he told SRF. “The theoretical rationale on which this compound was developed is very sound, and there were very strong preclinical data … indicating that it should be effective."

With one positive study, one inconclusive study, and now one failed study, the question is, Which one reflects reality? said Krystal. Of note, in the first study, patients on placebo actually got slightly worse across the trial, making the comparison to the mGluR2/3 drug look more favorable and raising concerns that the positive finding may have been “unrepresentative,” he added. In addition, Krystal said, the current data indicate that there’s a lot we still need to learn about the mechanism of the mGluR2/3 drug, and about the mGlu2 and mGlu3 receptors at which it acts. The two receptor subtypes have different functions, and thus, further basic science studies are needed to better understand the conflicting clinical data.

Hope springs pharmaceutical
In an e-mail, Lilly spokeswoman Keri McGrath told SRF, “We are disappointed by the results. However, Lilly's innovation strategy, which is based on advancing a pipeline of approximately 60 molecules currently in clinical development, does not rest on the success or failure of any single compound.” For now, Lilly says that they are pressing forward with the development of the mGluR2/3 agonist. A Phase 3 trial of the drug is ongoing, with results anticipated following its completion in February of 2013.

Although the current data on mGluR2/3 agonism as a monotherapy are not encouraging, it is possible the drug may work as an adjunct therapy to currently approved antipsychotics. In fact, preclinical data have suggested a synergism between these two classes of drugs (see SRF related news story). Lilly is currently awaiting results from a recently finished, long-term study (16 weeks) examining the efficacy of LY2140023 in addition to atypical antipsychotics in schizophrenia patients with prominent negative symptoms. Another possibility, says Krystal, is that the mGluR2/3 agonist may only be effective in a subgroup of patients, perhaps those who are early in their illness course, consistent with a clinical trial of another glutamate-enhancing drug, sarcosine (see SRF related news story).

Lilly is currently in the process of using a pharmacogenetics approach to identify subgroups of patients who may benefit from LY2140023. Thus far, 23 single nucleotide polymorphisms (SNPs), the majority of them located in the serotonin receptor 2a gene, have been significantly associated with mGluR2/3 agonist response to the PANSS (Liu et al., 2012). Presumably, it is these same SNPs that were used to define the genetic subgroup in the current study. However, the lack of mGluR2/3 agonist efficacy in this subpopulation of patients noted in the press release argues against this approach.

Javitt suggests that Lilly may need to keep searching to find the right indication for this compound. “There’s a lot invested in just demonstrating the safety of the compound, and it sounds like there were no safety issues. So then, often, what you try to do is look through the study to see where a signal is.” For example, one possibility is that LY2140023 may be more effective at improving cognitive deficits as opposed to positive and negative symptoms, consistent with early clinical data in healthy subjects demonstrating that mGluR2/3 agonists can improve working memory deficits induced by ketamine exposure (Krystal et al., 2005). However, it does not appear that the Phase 2 studies have made any cognitive measures, and thus, it will not be possible to address this issue with the current data.

Since efficacy with LY2140023 treatment was achieved in the acute study but not in the most recent one of longer duration, perhaps an allosteric site away from the main ligand binding site would be a better target. Moghaddam was not surprised at all by the current results, saying, "The initial data were from short-term exposure, and this being a direct agonist, it would be expected that this particular ligand … may not work for chronic exposure. Once the actual raw data are made available, if there’s something there early on that disappears, then we may still say that this particular receptor is a good target, but we need to go with allosteric modulation of it.”

Javitt also wonders if mGluR2/3 agonism may be better suited as a treatment for bipolar disorder, since increasing glutamate release through blockade of NMDA receptors produces hyperactivity in rats (Toth and Lajtha, 1986), perhaps for agitation or anxiety rather than psychosis.

The implications of this failed trial reach beyond schizophrenia, says Lieberman, and “reflect a difficulty in developing not just psychotropic drugs for mental disorders … but mechanistically novel drugs that may be trying to become first-in-class and forge a whole new therapeutic strategy.” Clearly, the animal models that we have for screening these compounds for efficacy have limitations, and once the data are released, says Javitt, it will be time to go back to basic science to see if we can use the present results to refine the models.—Allison A. Curley.

Comments on News and Primary Papers
Comment by:  Philip Seeman (Disclosure)
Submitted 15 August 2012
Posted 22 August 2012

The Lilly results of 11 July 2012 are not surprising, considering that the main ingredient of LY2140023 is LY404039, which is both a glutamate agonist and a weak partial dopamine agonist with only one-hundredth the potency of aripiprazole (Seeman and Guan, 2009; Seeman, 2012a), and considering that closer inspection of the clinical data (Kinon et al., 2011) showed that olanzapine was effective in schizophrenia, while LY2140023 was not (Seeman, 2012b).

References:

Kinon BJ, Zhang L, Millen BA, Osuntokun OO, Williams JE, Kollack-Walker S, Jackson K, Kryzhanovskaya L, Jarkova N, . A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia. J Clin Psychopharmacol . 2011 Jun ; 31(3):349-55. Abstract

Seeman P, Guan HC. Glutamate agonist LY404,039 for treating schizophrenia has affinity for the dopamine D2(High) receptor. Synapse. 2009 Oct ; 63(10):935-9. Abstract

Seeman P. An agonist at glutamate and dopamine D2 receptors, LY404039. Neuropharmacology. 2012a Jul 4. Abstract

Seeman P. Comment on "A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia" by Kinon et al. J Clin Psychopharmacol. 2012b Apr ; 32(2):291-2; author reply 292-293. Abstract

View all comments by Philip SeemanComment by:  Hugo Geerts
Submitted 15 August 2012
Posted 22 August 2012

This is indeed another setback for the schizophrenia patient community, and it underscores the difficulty of translating animal model outcomes to the clinical situation. We have to think about introducing a new technology in schizophrenia drug discovery and development that would combine the best of preclinical animal information, but transplanted into a humanized environment to reverse this string of clinical failures.

One such approach is Quantitative Systems or Network Pharmacology, a computer-based mechanistic disease model of biophysically realistic neuronal networks that combines preclinical neurophysiology with human pathology, and clinical and imaging data (the topic of a recent NIH White Paper). Such an approach can be calibrated with retrospective clinical data, and then used to predict and examine future clinical trials. Applying this quantitative paradigm to the (also much publicized) failure of Dimebon in AD, researchers found that there was a fundamental off-target effect that precluded Dimebon from having cognitive benefits. Further analyses suggested that an imbalance in a common dopaminergic phenotype could increase part of the clinical signal difference as observed in the first (successful) Phase 2 trial.

In the case of schizophrenia, we find that affecting glutamatergic (such as with the mGluR2/R3 agonist) or GABA neurotransmission almost always leads to an inverse U-shaped dose response, because of the intrinsic balance between excitation and inhibition in cortical networks. Using such an approach forces discovery scientists to look beyond the single target and think about the impact on networks and circuits that ultimately drive human behavior and pathology in CNS disorders.

Unlike the traditional, currently used "cartoon"-based qualitative drawings, this approach allows for a quantitative outcome that, in principle, can help define the optimal "sweet spot" of the dose response by looking at the outcome of endophenotypes such as BOLD fMRI.

References:

Athan Spiros, Hugo Geerts. 2012. A quantitative way to estimate clinical off-target effects for human membrane brain targets in CNS Research and Development. Exp Pharmacology, 4; 53-61.

Athan Spiros, Patrick Roberts, Hugo Geerts. (2012) A Quantitative Systems Pharmacology Computer Model for Schizophrenia Efficacy and Extrapyramidal Side Effects, Drug Dev. Res, 73(4): 1098-1109.

View all comments by Hugo Geerts

Comments on Related News


Related News: Studies Explore Glutamate Receptors as Target for Schizophrenia Monotherapy

Comment by:  Dan Javitt, SRF Advisor
Submitted 3 September 2007
Posted 3 September 2007

A toast to success, or new wine in an old skin?
Patil et al. present a landmark study. It is the kind of study that represents the best of how science should work. It pulls together the numerous strands of schizophrenia research from the last 50 years, from the development of PCP psychosis as a model for schizophrenia in the late 1950s, through the links to glutamate, the discovery of metabotropic receptors, and the seminal discovery in 1998 by Moghaddam and Adams that metabotropic glutamate 2/3 receptor (mGluR2/3) agonists reverse the neurochemical and behavioral effects of PCP in rodents (Moghaddam and Adams, 1998. The story would not be possible without the elegant medicinal chemistry of Eli Lilly, which provided the compounds needed to test the theories; the research support of NIMH and NIDA, who have been consistent supporters of the “PCP theory”; or the hard work of academic investigators, who provided the theories and the platforms for testing. The study is large and the effects robust. Assuming they replicate (and there is no reason to suspect that they will not), this compound, and others like it, will represent the first rationally developed drugs for schizophrenia. Patients will benefit, drug companies will benefit, and academic investigators and NIH can feel that they have played their role in new treatment development.

Nevertheless, it is always the prerogative of the academic investigator to ask for more. In this case, we do not yet know if this will be a revolution in the treatment of schizophrenia, or merely a platform shift. What is striking about the study, aside from the effectiveness of LY2140023, is the extremely close parallel in both cross-sectional and temporal pattern of response between it and olanzapine. Both drugs change positive and negative symptoms in roughly equal proportions, despite their different pharmacological targets. Both drugs show approximately equal slopes over a 4-week period. There is no intrinsic reason why symptoms should require 4 or more weeks to resolve, or why negative and positive symptoms should change in roughly the same proportion with two medications from two such different categories, except that evidently they do.

There are many things about mGluR2/3 agonists that we do not yet know. The medication used here was administered at a single, fixed dose. It is possible that a higher dose might have been better, and that optimal results have not yet been achieved. The medications were used in parallel. It is possible that combined medication might be more effective than treatment with either class alone. The study was stopped at 4 weeks, with the trend lines still going down. It is possible that longer treatment duration in future studies might lead to even more marked improvement and that the LY and olanzapine lines might separate. No cognitive data are reported. It is possible that marked cognitive improvement will be observed with these compounds when cognition is finally tested, in which case a breakthrough in pharmacotherapy will clearly have been achieved.

If one were to look at the glass as half empty, then the question is why the metabotropic agonist did not beat olanzapine, and why the profiles of response were so similar. If these compounds work, as suggested in the article by modulating mesolimbic dopamine, then it is possible that metabotropic agonists will share the same therapeutic limitations as current antipsychotics—good drugs certainly and without the metabolic side effects of olanzapine, but not “cures.” The recent study with the glycine transport inhibitor sarcosine by Lane and colleagues showed roughly similar overall change in PANSS total (-17.1 pts) to that reported in this study, but larger change in negative symptoms (-5.5 pts), and less change in positive symptoms (-2.3 pts) in a similar type of patient population. Onset of effect in the sarcosine study also appeared somewhat faster. The sarcosine study was smaller (n = 20) and did not include a true placebo group. As with the Lilly study, it was only 4 weeks in duration, and did not include cognitive measures. It also included only two, possibly non-optimized doses. As medications become increasingly available to test a variety of mechanisms, side-by-side comparisons will become increasingly important.

There are also causes for concern and effects to be watched. For example, a side effect signal was observed for affect lability in the LY group, at about the same prevalence rate as weight increase in the olanzapine group. What this means for the mechanism and how this will effect treatment remains to be determined. Since these medications are agonists, there is concern that metabotropic receptors may downregulate over time. Thus, whether treatment effects increase, decrease, or remain constant over the course of long-term treatment will need to be determined. Nevertheless, 50 years since the near-contemporaneous discovery of both PCP and chlorpromazine, it appears that glutamatergic drugs for schizophrenia may finally be on the horizon.

References:

Moghaddam B, Adams BW. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science. 1998 Aug 28;281(5381):1349-52. Abstract

View all comments by Dan Javitt

Related News: Studies Explore Glutamate Receptors as Target for Schizophrenia Monotherapy

Comment by:  Gulraj Grewal
Submitted 4 September 2007
Posted 4 September 2007
  I recommend the Primary Papers

Related News: Studies Explore Glutamate Receptors as Target for Schizophrenia Monotherapy

Comment by:  Shoreh Ershadi
Submitted 8 June 2008
Posted 9 June 2008
  I recommend the Primary Papers

Related News: ICOSR 2009—Unpleasing Placebos Cloud Antipsychotic Drug Trials

Comment by:  Paul Shepard
Submitted 23 April 2009
Posted 26 April 2009

When the 17 sites with high placebo responders were removed from the analysis, were only participants randomized to placebo removed or were all subjects who were recruited at these sites removed?

View all comments by Paul Shepard

Related News: ICOSR 2009—Unpleasing Placebos Cloud Antipsychotic Drug Trials

Comment by:  C. Anthony Altar
Submitted 28 April 2009
Posted 2 May 2009

Reply to P. Shepard
At ICOSR, Dr. Kinon presented the effects on PANSS positive values over 4 weeks for the placebo group, the groups receiving various LY2140023 doses, and those receiving olanzepine, but "without the 17 sites." I am reasonably sure, but not 100% positive, that this excluded all data from those sites, not just the placebo responders. Anything less would have introduced an unacceptable bias, even for a post-hoc analysis.

View all comments by C. Anthony Altar

Related News: ICOSR 2009—Unpleasing Placebos Cloud Antipsychotic Drug Trials

Comment by:  Ralph Hoffman
Submitted 19 May 2009
Posted 20 May 2009

These placebo results are certainly irksome, but may be important in positive ways. I am thinking of two hypotheses to account for these results. First, perhaps second-generation antipsychotic drugs (that are now more widely in use than ever) have more sustained therapeutic effects after discontinuation, so when patients are taken off their prescribed drugs to participate in these trials, their vulnerability to symptomatic worsening is less.

Of course, this would not explain the greater improvements in placebo groups. But perhaps with growing expectations regarding patient safety and support during randomized clinical trials overall, participants are getting more contact with research staff, which may have non-specific positive effects. We have, for instance, solid data indicating that significant social isolation is a trigger for psychotic symptoms independent of neuropsychological impairment in vulnerable individuals (unpublished data). The combination of reduced social isolation, increased staff support, plus (perhaps) sustained protective effects of second-generation drugs might account for emergence of greater positive placebo response.

View all comments by Ralph Hoffman

Related News: ICOSR 2011—Some Hope for Alleviating Negative Symptoms

Comment by:  Kimberly E. Vanover
Submitted 20 June 2011
Posted 20 June 2011

Thank you for your summary of the presentations from the New Drug Session at ICOSR 2011 on the Schizophrenia Research Forum. The Forum is a helpful and important resource.

I just wanted to clarify your description of ITI-007’s properties at the D2 site. As a dopamine phosphorylation modulator, ITI-007 acts as a pre-synaptic partial agonist and a post-synaptic antagonist with mesolimbic/mesocortical selectivity (Wennogle et al., 2008). In addition to its antagonism of 5-HT2A receptors and unique interaction with D2 receptors, it has affinity for D1 receptors, consistent with partial agonism linked to downstream increases in NMDA NR2B receptor phosphorylation (Zhu et al., 2008), and it is a serotonin reuptake inhibitor (Wennogle et al., 2008). Unfortunately, the short, 10-minute talk during the ICOSR session wasn’t sufficient time to go into the details of the mechanism and supporting preclinical data.

I did notice that a brief description for the mode of action for ITI-007 is listed as “5-HT2A antagonist + dopamine phosphoprotein modulator” with a role in schizophrenia listed as “DA stabilizer + 5hT-T inhibitor” in the Forum’s Drugs in Clinical Trials section. This is a nice, brief way to describe a rather complex mechanism.

References:

Wennogle LP, Snyder GL, Hendrick JP, Vanover KE, Tomesch JT, Li P, O’Callaghan JP, Miller DB, Fienberg AA, Davis RE, Mates S (2008) Unique antipsychotic profile of a novel 5-HT2A receptor antagonist and dopamine receptor protein phosphorylation modulator. Schizophrenia Research 98:Suppl1:15.

Zhu H, Snyder GL, Vanover KE, Rana M, Tsui T, Hendrick JP, Li P, Tomesch J, O’Brien JJ, Guo H, Davis RE, Fienberg AA, Wennogle LP, Mates S (2008) ITI-007: A novel 5-HT2A antagonist and dopamine protein phosphorylation modulator (DPPM) induces a distinct NR2B expression pattern in mouse brain. Program No. 155.14 2008 Neuroscience Meeting Planner. Washington, DC Society for Neuroscience, 2008. Online.

View all comments by Kimberly E. Vanover