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What's in the pipeline

December 1, 2007
by William M. Glazer, MD
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A look at antipsychotic agents in development

The most compelling finding from the recent National Institute of Mental Health-sponsored Clinical Antipsychotic Trials of Intervention Effectiveness or “CATIE” study was that only one in four subjects stayed on their medication. This randomized study compared the effectiveness of several second-generation antipsychotics (SGAs) to one of the first-generation antipsychotics (FGAs). The subjects could have remained on the medication that they received for up to 18 months. Instead 74% switched their antipsychotic either because they or their doctor felt that it wasn't working or side effects were intolerable.

If nothing else, this ambitious project told us that better antipsychotics are needed to treat schizophrenia and bipolar illness. Help is on the way. This article describes what is new in the development of antipsychotic medications. While an impressive number of compounds are under investigation, I focus only on the ones that are either in later stages of development or have been described in peer-reviewed publications.

Bifeprunox—Back to the Drawing Boards

Earlier this year, the field was disappointed to learn that bifeprunox, a compound that has a “partial dopamine agonist/antagonist” mechanism of action like Bristol Myers Squibb's Abilify (aripiprazole), was rejected by the FDA because of lack of evidence for efficacy. It was hoped that this medication would have offered efficacy and safety advantages over the available antipsychotics. Hopefully the co-developers, Wyeth and Solvay, will go back to the drawing boards and find an application for this agent. But don't expect to see bifeprunox on the market anytime soon.

Asenapine and Iloperidone—Next at Bat?

Asenapine. Asenapine is the next new agent expected to be considered by the FDA as an antipsychotic medication. Asenapine is a serotonin and dopamine (5HT/D2) antagonist like other available agents in the SGA class, such as clozapine, risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), and paliperidone (Invega). Asenapine is being developed by Organon (which has been acquired by Schering-Plough) and is in phase III of development. The FDA has accepted Schering-Plough's new drug application for asenapine.

Asenapine's efficacy and safety are under investigation in several studies together called the Olympia Clinical Trial Program. Up to now around 2,500 patients have been included in this program. The company's FDA filing most probably will include studies for asenapine in both schizophrenia and bipolar disorder. The design of these studies includes comparisons to placebo. The FGA haloperidol and SGAs risperidone and olanzapine are used to assay sensitivity. Thus far, there does not appear to be any signals of clinically significant problems with weight gain, blood sugar, lipids, or QT interval prolongation—issues that have plagued numerous SGAs.

Asenapine's pharmacologic profile appears to differ from all of the other SGAs in its highly potent binding profile for several of the brain's serotonergic receptors thought to be responsible for problems in feeling state (depression, anxiety, etc.) and cognition. Two ongoing studies are examining asenapine's efficacy for the negative symptoms of schizophrenia (i.e., dull affect, lack of motivation). If asenapine turns out to be more effective for negative symptoms than its SGA predecessors, it could fill a significant gap in clinical practice.

Iloperidone. After being dropped by Novartis due to existing market conditions in 2001 and concerns that iloperidone may have an effect on electrical impulses of the heartbeat, Vanda Pharmaceuticals is studying iloperidone in late phase IIIb studies. When Novartis was studying iloperidone, peer-reviewed publications indicated that its mechanism of action is probably similar to the SGAs with serotonin and dopamine (5HT/D2) antagonist. Iloperidone also has high affinity for α2C-adrenergic receptors, which may provide antidepressant and anxiolytic activity and improve cognitive function.

While there are no published peer-reviewed papers from the company to date, Vanda has reported on the National Institute of Health's “ClinicalTrials.gov” Web site that it is evaluating the compound's safety and efficacy in patients with specific genetic profiles that would identify them as a subgroup of patients that would benefit most from the drug. If the findings turn out to be clinically significant, iloperidone would be the first agent in psychiatry to be prescribed via genetic profiling. These genetic tests, however, will not be a requirement for treatment, but would be available as tools to aid clinicians in the decision-making process of what drug and dose to give patients in need of antipsychotic treatment.

Vanda reported, via a poster presentation at the 2007 American Society of Human Genetics annual meeting, on a study comparing the genetics of iloperidone and ziprasidone, which also has been found to prolong electrical impulses of the heartbeat. To date, ziprasidone's effect on the heart has not been shown to be particularly clinically significant. It is reassuring that iloperidone does not differ much from ziprasidone's profile in this area.

The FDA has accepted Vanda's new drug application for iloperidone. In addition, investigators at Yale have been studying iloperidone for “glycine transport inhibitor” effects. Deepak Cyril D'Souza, MD, associate professor of psychiatry at Yale School of Medicine, is testing iloperidone in healthy subjects to see if it increases glycine at the synapse, a mechanism thought to be efficacious for treating schizophrenia.

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