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SIRS 2012—Schizophrenia Drug Development: Does the Pipeline Have A Pulse?

The final day of the Schizophrenia International Research Society meeting in Florence began with a session on new drug development, chaired by Wolfgang Fleischhacker of the Medical University of Innsbruck, in Austria.

Donald Goff of Harvard University, Cambridge, Massachusetts, USA, opened with an overview of some of the factors that have led to stagnation in the development of new drugs for schizophrenia, including some that are well known: animal models that fail to predict effects in humans, the heterogeneity of the disorder, and poor assay sensitivity in clinical trials. He suggested that current animal models may suffer largely from the fact that they do not recapitulate any parts of what appears to be a neurodevelopmental disorder or vulnerability. Thus, the pairing of neurodevelopmental animal models with a better understanding of the prodrome and the brain antecedents of the first episode may prove more fertile ground for finding new drug targets. He also suggested that in the short term, pharmacogenomics may advance to the point that it will allow researchers to look for stronger signals in subpopulations of the very heterogeneous subject pools that populate clinical trials.

John Kane, of the North Shore-Long Island Jewish Healthcare System, New York, USA, followed with a look at the problems that face drugs able to make it through the discovery phase to clinical trials. He presented this in the framework of a series of open questions that the community needs to address, the first being whether researchers are really studying homogeneous samples of patients experiencing acute exacerbation of symptoms, as opposed to mixed samples that also include patients who are chronically symptomatic. These patients may experience improvement over baseline, but that does not really count as remission, he argued, and researchers must find a way to reliably identify patients having an acute exacerbation.

Assessing relapse prevention also presents problems: only a third of patients who relapse in trials are hospitalized, he said, and we don't have a good way to know how informative hospitalization is as a measure of relapse. Few relapse prevention trials monitor real recovery, or adherence, Kane said.

Kane also mentioned the recent rise in failed trials (note: a failed trial is one in which a proven marketed drug does not separate from placebo, as opposed to a negative trial, where the test drug does not separate from placebo). The issue is not specific to trials of antipsychotic medications; indeed, it is even more of a problem for antidepressants. But when combined with a dearth of new molecular targets, the end result is that several major drug companies have dropped out of psychiatric drug development. There does not appear to be any one reason for this—among the candidates are excessive delays before treatment, too many inappropriate subjects, lack of inter-rater reliability and reliable informants, (see also Kinon et al., 2011)—and thus any single solution is unlikely to resolve the problem.

The basic list of questions that Kane left the audience with was: How do we establish true drug efficacy? Can we confirm the presence of an acute exacerbation? How can we establish a stable baseline and minimize placebo response in studies involving negative or residual positive symptoms? Are there better ways to assess long acting antipsychotics? In the Q:A session, the difficulties posed by heterogeneous and sometimes inappropriate subject populations were echoed. One drug company researcher in the audience mentioned that the industry, which spends about $2.5 billion to bring a drug to market, gives a counterproductive incentive to contract research organizations: get us many patients quickly.

News from the front

The overview talks were followed by updates from drug companies on their development efforts, and here we summarize some of these. Presenting on behalf of Forest Laboratories and Gedeon Richter, Anjana Bose of Forest, New York, USA, discussed cariprazine, a dopamine D3/D2 partial agonist, which has high selectivity for D3 compared to other antipsychotic drugs (APDs) and very low potency at other neurotransmitter receptors. In a Phase 3 trial, cariprazine was significantly more effective than placebo and aripiprazole, a standard APD. Although weight gain appears to be low with this drug, there was evidence for increased extrapyramidal symptoms. The drug also has been shown to separate from placebo in bipolar mania trials.

Robert Conley of Eli Lilly, Indianapolis, Indiana, USA, provided new data on one of Lilly's metabotropic glumate 2/3 receptor agonists. The data he showed indicated comparable efficacy to standard APDs, but without the weigh gain. It also appears that the drug can be used safely with some of these standard APDs. Lilly has also looked at weight gain separately, and find that it may be mediated by c-Fos in orexin (hypocretin)-containing cells. The high weight-gain drugs appear to have highest c-Fos in these cells.

The next speaker was Gerhard Gross of Abbot Laboratories in Ludwigshafen, Germany, which does not currently have a compound in clinical trials. Though their selective D3 antagonist failed to show therapeutic effects in a recent trial, Gross discussed preclinical data that keep the drug in active development. For example, there is some evidence that the drug ameliorates the behavioral effects of NMDA receptor antagonists in animals, and this parallels some positive results seen on cognitive tests in the human clinical trial.

David Hosford of Targacept, Inc., Winston-Salem, North Carolina, USA, provided an update on the α7 nicotinic cholinergic receptor partial agonist TC-5619. Looking to make sense of conflicting earlier data regarding differential effects on tobacco users versus non-users (see SRF report from the 2011 International Congress on Schizophrenia Research), Targacept has conducted new studies that indicates their positive results on cognition and negative symptoms were driven by the smokers in the study.

In a post hoc analysis of their work showing negative symptom improvement with a glycine reuptake inhibitor, F. Hoffmann-La Roche, Ltd., in Basel, Switzerland did a factor analysis to determine which aspects of negative symptomatology drove the signal. Daniel Umbricht reported that factors mapping onto the domain of avolition, as opposed to those considered to contribute to blunted affect/expressive deficits, were mainly improved. This is encouraging if indeed, as has recently been argued, avolition is the core problem in negative symptom schizophrenia (see, e.g., Foussias and Remington, 2008). — Hakon Heimer.

Comments on Related News


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