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

Background

AL-108 is an intranasal drug product containing NAP, an 8 amino-acid peptide (Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln; NAPVSIPQ, MW=824.9) fragment of the much larger (approx. 124KD) Activity-Dependent Neuroprotective Protein (ADNP), which participates in neurodevelopment and neuroprotection. In mice, ADNP knockouts are lethal exhibiting CNS dysgenesis. ADNP mediates its effects in part through interaction with microtubules. Because of its large size, ADNP is assumed to not penetrate the BBB and thus cannot be used pharmacologically. NAP was chosen because it represents the epitope most associated with microtubule interaction and neuroprotection. NAP is absorbed following IV or intranasal administration, and has been shown to cross the BBB.

Rationale for NAP treatment: tubulin function in brain function

The cytoskeleton plays a key role in maintaining the highly asymmetrical shape and structural polarity of neurons that are essential for neuronal physiology. The cytoskeleton is made up of microfilaments, intermediate filaments and microtubules. Microfilaments (4-9 nm diameter) are made up of actin monomers and they function mainly to provide mechanical support and locomotion to the cell. Intermediate filaments are cytoplasmic fibers of ~10nm diameter. They provide supporting framework within the cell. Microtubules (~24nm diameter) consist of tubulin and microtubule associate proteins. They function to transport nutrients and chemical messengers along the cell. Neurofibrillary tangles are twisted bundles of neurofibrils formed when the microtubule-associated protein, tau, dissociates from microtubules and clusters to form an insoluble mass. Under normal conditions tau binds to microtubules, stabilizing neuronal structure and integrity.

Hyperphosphorylation of tau is assumed to be the cause for the formation of neurofibrillary tangles. Although neurofibrillary tangles are most associated with cognitive dysfunction in Alzheimers disease, some increase in neurofibrillary pathology has also been reported in schizophrenia, potentially as consequence of antipsychotic medication (1). Thus, mechanisms underlying microtubular function may be relevant to schizophrenia as well. In association with tubulin polymerization into microtubules, NAP influences tau dynamics by increasing the ratio of non-phosphorylated tau to phosphorylated tau, implying a dynamic process of cellular maintenance of the microtubular network, which is essential for the survival of the cell.

In brain, tubulin frameworks are stabilized by recently described STOP proteins (2) (aka MAP6). Linkages to allelic variation in STOP genes has been reported in schizophrenia, along with altered STOP protein expression in some brain regions (3). STOP knockdown mice show disturbances in dopaminergic neurotransmission (4) along with deficits in PPI and hypermotility that were partially reversed with clozapine (5). Thus, neuropathological features of schizophrenia may be due, in part, to abnormal STOP-related stabilization of microtubular structure, and NAP may stabilize STOP-related abnormal neurophysiological processes in schizophrenia.

Inclusion criteria

• DSM IV/DSM IV TR diagnosis of schizophrenia
• Capable of providing informed consent
• Males and Females
• Age: 18 and 60
• Caucasian or Non Caucasian
• Subjects will be treated with one of the following second generation antipsychotics: risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole for the previous two months, with no change in dose in the last month, and/or with injectable depot antipsychotics (fluphenazine or haloperidol decanoate) with no change in last 3 months.
• Subjects will meet the following symptom criteria:

• Average Brief Psychiatric Rating Scale (BPRS) item score >3 (mild)
• Simpson-Angus Scale total score less than or equal to 6
• Calgary Depression Scale total score less than or equal to 10
• Subjects will meet the following cognitive performance criteria:

• Performance less than the maximum cutoff (in parentheses) for ONE of the following MCCB tests:

• Letter-number span (20);
• HVLT total (31); and
• CPT d-prime (3.47)
• Able to complete the baseline MCCB validly as assessed by Chief Neuropsychologist or NP tester
• Raw score of 6 or greater on the WTAR

Exclusion criteria

• Current treatment with oral conventional antipsychotics (e.g. fluphenazine, haloperidol) or clozapine.
• Subjects with a DSM-IV diagnosis of alcohol or substance abuse (other than nicotine) within the last month or a DSM-IV diagnosis of alcohol or substance dependence (other than nicotine) within the last 6 months
• Subjects with a history of significant head injury/trauma, as defined by one or more of the following:

• Loss of consciousness (LOC) for more than 1 hour
• Recurring seizures resulting from the head injury
• Clear cognitive sequellae of the injury
• Cognitive rehabilitation following the injury
• Subjects with a clinically significant neurological, metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, and/or urological disorder (e.g. unstable angina, decompensated congestive heart failure, CNS infection or history of HIV seropositivity), which would pose a risk to the patient if they were to participate in the study or that might confound the results of the study.
• Clinically significant abnormalities in physical examination, ECG, or laboratory assessments.
• Clinically significant renal disease.
• Women who are pregnant or of child-bearing potential, either not surgically-sterile nor using appropriate methods of birth control
• Women who are breast-feeding
• Prior participation in a clinical trial of investigational medication within 60 days.