A Multicenter Study of NAP (AL-108) in Schizophrenia

Summary

The TURNS is a NIMH-funded contract for the evaluation of new compounds for the treatment of cognitive impairments in schizophrenia (HHSN 27820044 1003C; P.I.: Steve Marder, M.D.). Despite advances in the safety, tolerability, and effectiveness of antipsychotic medications for the treatment of schizophrenia, many patients continue to be plagued by impairments in social and work functioning. Persons with schizophrenia commonly show deficits in a number of areas of cognition that include impairments in attention, memory, and executive functioning (the ability and organize one's behavior). Importantly, a large body of literature now shows a link between cognition and community functioning in schizophrenia. It is believed that treatments that improve cognitive deficits may lead to improvements in work and social functioning. One approach to improve the community functioning of patients with schizophrenia is to develop new agents that treat the cognitive deficits of the illness. A promising agent is called AL-108. This drug is administered as a nasal spray. Studies in animals suggest that this drug may protect neurons and may improve cognition in schizophrenia. The current study is a twelve-week multicenter, double-blind, randomized clinical trial of two doses of AL-108 (5 and 30 mg/day intranasally) versus placebo in the treatment of persistent cognitive dysfunction in schizophrenia. The study medication will be added to patients' current atypical antipsychotic medication or to their current injectable first-generation antipsychotic medication. The primary outcome measure will consist of the composite score of the MATRICS neuropsychological battery. Secondary outcome measures will include scores on symptoms, functional outcome, and safety measures. Sixty clinically stable patients with schizophrenia, drawn from eight sites, will participate in the study. Twenty-five patients will be enrolled at UCLA.

Timeline

Start

2007-07

Primary completion

2009-04

Completion

2009-04

Outcome

Missed primary endpoint

registry analysis (superiority or other test); AL-108, 5 mg/Day vs Placebo; p = 0.21; Mean Difference (Final Values) 1.9; ANCOVA NCT00505765 ↗

registry analysis (superiority or other test); AL-108, 30 mg/Day vs Placebo; p = 0.44; Mean Difference (Final Values) 1.2; ANCOVA NCT00505765 ↗

Publications

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• Background Jackman AH, Doty RL. Utility of a three-item smell identification test in detecting olfactory dysfunction. Laryngoscope. 2005 Dec;115(12):2209-12. doi: 10.1097/01.mlg.0000183194.17484.bb.
• Background Gozes I, Divinski I. The femtomolar-acting NAP interacts with microtubules: Novel aspects of astrocyte protection. J Alzheimers Dis. 2004 Dec;6(6 Suppl):S37-41. doi: 10.3233/jad-2004-6s605.
• Background Rothermundt M, Arolt V, Bayer TA. Review of immunological and immunopathological findings in schizophrenia. Brain Behav Immun. 2001 Dec;15(4):319-39. doi: 10.1006/brbi.2001.0648.
• Background Rapaport MH, Delrahim KK. An abbreviated review of immune abnormalities in schizophrenia. CNS Spectr. 2001 May;6(5):392-7. doi: 10.1017/s1092852900021763.
• Background Kelly DL, Conley RR. A randomized double-blind 12-week study of quetiapine, risperidone or fluphenazine on sexual functioning in people with schizophrenia. Psychoneuroendocrinology. 2006 Apr;31(3):340-6. doi: 10.1016/j.psyneuen.2005.08.010. Epub 2005 Sep 28.
• Background Gozes I, Meltzer E, Rubinrout S, Brenneman DE, Fridkin M. Vasoactive intestinal peptide potentiates sexual behavior: inhibition by novel antagonist. Endocrinology. 1989 Dec;125(6):2945-9. doi: 10.1210/endo-125-6-2945.
• Background Rotstein M, Bassan H, Kariv N, Speiser Z, Harel S, Gozes I. NAP enhances neurodevelopment of newborn apolipoprotein E-deficient mice subjected to hypoxia. J Pharmacol Exp Ther. 2006 Oct;319(1):332-9. doi: 10.1124/jpet.106.106898. Epub 2006 Jul 5.
• Background Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003 Jul 31;39(3):409-21. doi: 10.1016/s0896-6273(03)00434-3.
• Background Braga RJ, Mendlowicz MV, Marrocos RP, Figueira IL. Anxiety disorders in outpatients with schizophrenia: prevalence and impact on the subjective quality of life. J Psychiatr Res. 2005 Jul;39(4):409-14. doi: 10.1016/j.jpsychires.2004.09.003. Epub 2004 Nov 13.
• Background Alcalay RN, Giladi E, Pick CG, Gozes I. Intranasal administration of NAP, a neuroprotective peptide, decreases anxiety-like behavior in aging mice in the elevated plus maze. Neurosci Lett. 2004 May 6;361(1-3):128-31. doi: 10.1016/j.neulet.2003.12.005.
• Background Gozes I, Alcalay R, Giladi E, Pinhasov A, Furman S, Brenneman DE. NAP accelerates the performance of normal rats in the water maze. J Mol Neurosci. 2002 Aug-Oct;19(1-2):167-70. doi: 10.1007/s12031-002-0028-0.
• Background Gozes I, Giladi E, Pinhasov A, Bardea A, Brenneman DE. Activity-dependent neurotrophic factor: intranasal administration of femtomolar-acting peptides improve performance in a water maze. J Pharmacol Exp Ther. 2000 Jun;293(3):1091-8.
• Background Ito M, Depaz I, Wilce P, Suzuki T, Niwa S, Matsumoto I. Expression of human neuronal protein 22, a novel cytoskeleton-associated protein, was decreased in the anterior cingulate cortex of schizophrenia. Neurosci Lett. 2005 Apr 22;378(3):125-30. doi: 10.1016/j.neulet.2004.12.079.
• Background Benitez-King G, Ramirez-Rodriguez G, Ortiz L, Meza I. The neuronal cytoskeleton as a potential therapeutical target in neurodegenerative diseases and schizophrenia. Curr Drug Targets CNS Neurol Disord. 2004 Dec;3(6):515-33. doi: 10.2174/1568007043336761.
• Background Kolluri N, Sun Z, Sampson AR, Lewis DA. Lamina-specific reductions in dendritic spine density in the prefrontal cortex of subjects with schizophrenia. Am J Psychiatry. 2005 Jun;162(6):1200-2. doi: 10.1176/appi.ajp.162.6.1200.
• Background Hill JJ, Hashimoto T, Lewis DA. Molecular mechanisms contributing to dendritic spine alterations in the prefrontal cortex of subjects with schizophrenia. Mol Psychiatry. 2006 Jun;11(6):557-66. doi: 10.1038/sj.mp.4001792.
• Background Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain. 1999 Apr;122 ( Pt 4):593-624. doi: 10.1093/brain/122.4.593.
• Background Smith-Swintosky VL, Gozes I, Brenneman DE, D'Andrea MR, Plata-Salaman CR. Activity-dependent neurotrophic factor-9 and NAP promote neurite outgrowth in rat hippocampal and cortical cultures. J Mol Neurosci. 2005;25(3):225-38. doi: 10.1385/JMN:25:3:225.
• Background Fradley RL, O'Meara GF, Newman RJ, Andrieux A, Job D, Reynolds DS. STOP knockout and NMDA NR1 hypomorphic mice exhibit deficits in sensorimotor gating. Behav Brain Res. 2005 Sep 8;163(2):257-64. doi: 10.1016/j.bbr.2005.05.012.
• Background Brun P, Begou M, Andrieux A, Mouly-Badina L, Clerget M, Schweitzer A, Scarna H, Renaud B, Job D, Suaud-Chagny MF. Dopaminergic transmission in STOP null mice. J Neurochem. 2005 Jul;94(1):63-73. doi: 10.1111/j.1471-4159.2005.03166.x.
• Background Shimizu H, Iwayama Y, Yamada K, Toyota T, Minabe Y, Nakamura K, Nakajima M, Hattori E, Mori N, Osumi N, Yoshikawa T. Genetic and expression analyses of the STOP (MAP6) gene in schizophrenia. Schizophr Res. 2006 Jun;84(2-3):244-52. doi: 10.1016/j.schres.2006.03.017. Epub 2006 Apr 19.
• Background Bosc C, Andrieux A, Job D. STOP proteins. Biochemistry. 2003 Oct 28;42(42):12125-32. doi: 10.1021/bi0352163.
• Background Harrison PJ. The neuropathological effects of antipsychotic drugs. Schizophr Res. 1999 Nov 30;40(2):87-99. doi: 10.1016/s0920-9964(99)00065-1.
• Georgiades A, Davis VG, Atkins AS, Khan A, Walker TW, Loebel A, Haig G, Hilt DC, Dunayevich E, Umbricht D, Sand M, Keefe RSE. Psychometric characteristics of the MATRICS Consensus Cognitive Battery in a large pooled cohort of stable schizophrenia patients. Schizophr Res. 2017 Dec;190:172-179. doi: 10.1016/j.schres.2017.03.040. Epub 2017 Apr 20.

Drugs

Evaluation	Drug	Modality	Dose	Route
Subject	NAP	Peptide	5 mg	Intranasal
Subject	NAP	Peptide	30 mg	Intranasal

Indications