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A New Possible Class of Drugs for the Treatment of Schizophrenia

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A New Possible Class of Drugs for the Treatment of Schizophrenia Clinical News Robert R. Conley, MD Editor-in-Chief A New Possible Class of Drugs for the as a treatment for schizophrenia. However, understanding Treatment of Schizophrenia how to affect the many different kinds of glutamate receptors A clinical trial in the September issue of Nature in medically beneficial ways has proved complicated and has Medicine describes a drug, LY2140023, which may be ef- not lead to any beneficial therapies. So, instead of focusing fective in people with schizophrenia psychosis. This drug on the receptors blocked by PCP and ketamine, Dr. Schoepp is thought to work by targeting glutamate-mediated neuro- and colleagues concentrated on modulating the action of transmission. Previously, glutamate neurotransmission has glutamate receptors in the brain’s prefrontal cortex, an area been touted as an important factor in schizophrenia, but responsible for personality and learning. Dr. Schoepp left clinical evidence of efficacy has been lacking. All current an- Lilly in March to become the head of neuroscience research tipsychotic drugs target dopamine receptors. It is this mode for Merck. However, it has been reported that Dr. Schoepp of action that is thought to be responsible for extrapyrami- and Dr. Steven Paul, the president of Lilly Research Labora- dal side effects, including tardive dyskinesia and dysphoria, tories, have both said that his departure would not hurt the which cause many patients to frequently discontinue their development of LY2140023. medication. LY2140023 is a selective agonist of a specific Because this was a “proof-of-concept” study designed to subtype of glutamate receptor, known as mGlu2/3. It is re- test the efficacy of LY2140023 in the treatment of schizophre- ported that Lilly Research Laboratories will begin a larger nia, no rigorous comparison was made against olanzapine in clinical trial for the drug immediately. If that trial confirms terms of efficacy. However, in the reported study, the effects the results seen so far, the new drug could mark a break- of the drugs were similar. Optimal dosing of LY2140023 has through in the treatment of schizophrenia. not yet been determined. The research team tested LY2140023 in a double-blind, Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, et placebo-controlled trial of 196 patients with schizophrenia al. Nat Med 2007;13(9):1102-1107. and compared how well it worked versus olanzapine, which, as we know, targets dopamine receptors. The trial was con- Allon Therapeutics and TURNS Begin ducted in Russia from August 2005 to June 2006. People who Collaborations for Phase II were treated with LY2140023 showed improvements in both Schizophrenia Cognition Trial the positive symptoms (hallucinations, delusions and thought Schizophrenia is associated with a range of impairments disorder) and the negative symptoms (social withdrawal, in cognition. These impairments are a core clinical feature of apathy and emotional blunting) of schizophrenia compared schizophrenia. They are largely untouched by current phar- to placebo after four weeks of treatment. Treatment with macotherapy. Antipsychotic medications may lead to some LY2140023 was safe and well tolerated. People treated with improvement in cognition in schizophrenia, although the LY2140023 did not differ from placebo-treated patients with overall effects are relatively weak. This gap in the effective- respect to prolactin elevation, extrapyramidal symptoms or ness of antipsychotic drugs for neurocognition has inspired weight gain. Adverse events linked to LY2140023, including a search for co-treatments that can be added to an antipsy- insomnia, nausea, headache and somnolence, were mild to chotic to improve cognition. moderate in severity and were not treatment-limiting. The There is a new set of academic and industry collabora- drug must still be evaluated on many more patients to test tions called the Treatment Units for Research on Neurocog- for the possibility of side effects that have not yet emerged, nition and Schizophrenia (TURNS). The TURNS program and thus is still years from completing regulatory review. is a National Institute of Mental Health (NIMH) supported Lilly’s new drug emerged from almost two decades of network providing an infrastructure for clinical studies of research by Dr. Darryle D. Schoepp. The work is based on pharmacological agents for enhancing neurocognition in consistent observations that interference with the action of people with schizophrenia. Goals of the TURNS project the n-methyl-d-aspartate (NMDA) ionophoric receptor in include: neurons caused by drugs like phencyclidine (PCP) and ket- • Establishing a clinical research network where amine can lead to symptoms similar to those of people with clinical studies on the safety, efficacy, schizophrenia. PCP and ketamine action at NMDA receptors pharmacokinetics and pharmacodymanics of new is linked to the presence of glutamate. This led Dr. Schoepp agents for the treatment of cognitive deficits of and others to study ways to stimulate glutamate receptors schizophrenia can be investigated. 218 • Clinical Schizophrenia & Related Psychoses October 2007 Clinical News Oct.indd 1 9/28/07 1:58:38 PM Robert R. Conley • Characterize and define key aspects of cognition in Further Work on Schizophrenia schizophrenia as potential treatment targets. Cognition Drugs Using Nicotine • Identify and select promising compounds for Receptors as a Target studies. Another cognition-related clinical trial is set to begin. • Define optimal experimental designs to evaluate the Targacept reported that its collaborator, AstraZeneca, has efficacy of primary and augmentation strategies to initiated a Phase IIb clinical trial of AZD3480 in cognitive enhance cognition in schizophrenia. deficits in schizophrenia (CDS). AZD3480 is a selective • Identify and develop opportunities for industry/ agonist at the neuronal nicotinic receptor of the alpha4beta2 academia/government collaboration in testing subtype. The CDS trial is a double-blind, placebo-controlled compounds of potential utility in alleviating study being conducted at sites in the U.S. and Canada. The cognitive deficits in schizophrenia. trial design provides for approximately four hundred patients • Promote broad adoption and utilization by currently taking medication from the class known as atypi- academia and the pharmaceutical industry of cal antipsychotics to be randomly assigned to one of three standardized methods and measures to accelerate dose groups of AZD3480 or to placebo, and to be dosed over testing and regulatory approval of new compounds a twelve-week period, Targacept and AstraZeneca said. The targeting cognitive deficits in schizophrenia. primary outcome measure of the trial is a test battery that in- • Broadly and equitably disseminate state-of-the- cludes assessments of cognitive functions across nine differ- art measurement tools and methodological ent domains. Secondary measures include measures of life strategies to evaluate the efficacy of treatments for functioning, such as performance in day-to-day tasks and cognitive deficits in schizophrenia. social skills, the companies added. The companies said they Allon Therapeutics announced that in collaboration expect the trial to be complete by the end of 2008. AZD3480 with TURNS, and with support from the National Associa- has been evaluated to date in twelve clinical trials in tion for Research in Schizophrenia and Affective Disorders, approximately 540 subjects. In a previous Phase IIb clinical it will add an imaging-biomarker component to the current trial conducted by Targacept in age-associated memory im- Phase II efficacy trial evaluating AL-108 as a treatment for pairment, AZD3480 achieved statistically significant results schizophrenia-related cognitive impairment. This drug is on all of the primary endpoints, reflecting improved cogni- administered as a nasal spray. Studies in animals suggest that tive performance by memory-impaired older adults. It has this drug may protect neurons and may improve cognition been shown that administration of AZD3480 over ten days in schizophrenia. The current studies include a twelve-week, produced statistically significant enhancement of several double-blind, randomized clinical trial of two doses of AL- cognitive measures in healthy adults, attention and episodic 108 (5 and 30 mg/day intranasally) versus placebo in the memory, compared to placebo. The EEG pattern shown for treatment of persistent cognitive dysfunction in schizophre- AZD3480 was consistent with that previously described nia. The study medication will be added to patients’ current with other drugs known to improve attention and vigilance, atypical antipsychotic medication or to their current inject- including nicotine. In addition, subjects given AZD3480 able first-generation antipsychotic medication. The primary showed improvements of preattentional cognition mecha- outcome measure will consist of the composite score on a nisms. It has long been known that many people with neuropsychological battery. Secondary outcome measures schizophrenia smoke tobacco, and recently it has been ob- will include scores on symptoms, functional outcome, and served that smoking may reduce the likelihood of a person safety measures. Sixty clinically stable patients with schizo- developing Alzheimer’s disease. Possibly, medications such phrenia, drawn from eight sites, will participate in the study. as AZD3480 will bring some of the cognitive benefits of Three different imaging techniques will be used
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