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

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.

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.

• Drug: AL-108
  AL-108, 5 mg/day- one spray in each nostril once per day
• Drug: AL-108
  AL-108, 30 mg/day- 3 sprays in each nostril, twice per day
• Drug: Placebo
  Placebo- 3 sprays in each nostril, twice per day
• Drug: Placebo
  Placebo- one spray in each nostril, once per day

• Experimental: AL-108, 30 mg/day
  AL-108, 30 mg/day- 3 sprays in each nostril, twice per day
  Intervention: Drug: AL-108
• Experimental: AL-108, 5 mg/day
  AL-108, 5 mg/day- one spray in each nostril once per day
  Intervention: Drug: AL-108
• Placebo Comparator: Placebo, 3 sprays BID
  Placebo- 3 sprays in each nostril, twice per day
  Intervention: Drug: Placebo
• Placebo Comparator: Placebo, 1 Spray Daily
  Placebo- one spray in each nostril, once per day
  Intervention: Drug: Placebo

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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.

• University of Maryland
• Washington University School of Medicine
• Massachusetts General Hospital
• Nathan Kline Institute for Psychiatric Research
• Columbia University
• Duke University
• Beth Israel Deaconess Medical Center