Alzheimer’ disease

In 2008, Allon will complete patient assessment, analyze data and release results from a Phase II clinical trial evaluating the safety, tolerability and effect of AL-108 on patients with amnestic mild cognitive impairment (aMCI), a precursor of AD.

The Phase II trial of AL-108 in aMCI will provide key information for progression into a larger but more focused Phase II trial in Alzheimer’s diease.

Trial design and objectives

The Phase II trial is a double-blind, randomized, placebo-controlled, multiple-dose study to evaluate the safety, tolerability and effect on cognitive function of AL-108 after 12 weeks of intranasal administration in patients with aMCI.

The trial is being conducted at 15 sites in the United States in patients aged 55 to 85 years diagnosed with aMCI. The trial was designed to achieve statistical significance with 120 patients, but enrolled over 140. Three groups of patients received either placebo, low dose of AL-108 (5 mg once a day) or high dose (15 mg twice a day) intranasally for 12 weeks. Completion of patient enrolment was announced October 2, 2007.

The objective of the primary endpoint of the trial is to demonstrate an overall improvement on memory performance after 12 weeks of treatment with AL-108. This overall memory performance will be determined from a composite score of different tests that together measure short-term memory, recognition, working memory, strategic use of memory, episodic memory and associative learning.

The secondary endpoints represent signals of efficacy that correlate to the specific cognitive changes impacted by AL-108 treatment. These secondary endpoint objectives will demonstrate an impact of AL-108 on a number of individual cognitive performance tests over the 16 weeks of the trial, including improvements in memory, learning, problem solving and motor control. These individual measures are in addition to further analysis of overall memory performance in the composite score both during and after the treatment period.

Allon’s aMCI clinical strategy

A gradual decline in cognition is a characteristic of normal aging, however, there is increasing evidence that some forms of cognitive impairment are recognizable as an early reflection of Alzheimer’s disease. Approximately 15% of the elderly population suffers from mild cognitive impairment (MCI) — and 85% of these people will develop Alzheimer’s disease, according to the Alzheimer’s Society.

Until recently, it has been difficult to use this population as a surrogate for AD because of the wide variation in the severity and pathology of MCI. New research has determined that there are distinct segments of the MCI population and one of them, the amnestic MCI group, is the precursor state of AD. These patients display some of the hallmarks of AD and progress to AD at a defined rate.

Because aMCI patients have greater cognitive functioning capacity than AD patients, much more can be measured in a clinical setting — and these patients present an excellent opportunity to test new drugs at an early stage of disease progression. Allon’s aMCI Phase II trial uses standardized, validated and objective tests to measure the impact of AL-108 on the memory performance of these patients.

All of Allon’s tests have been validated and are widely used in MCI and early-stage AD clinical trials. Several of Allon’s tests are based on the CANTAB computerized platform devised by Cambridge Cognition of Cambridge, MA and Cambridge, England. The Cantab platform is currently being used by eight large pharmaceutical companies in MCI and AD trials.

Schizophrenia-related cognitive impairment

In 2008, Allon will release results of a Phase II clinical trial evaluating the safety, tolerability and effect of AL-108 on cognitive impairment associated with schizophrenia (CIAS).

The trial is a multicenter ascending dose, double blind, placebo-controlled study of AL-108 in chronic schizophrenia funded and managed by TURNS (Treatment Units for Research on Neurocognition and Schizophrenia). TURNS was created by the U.S. National Institute of Mental Health to identify drugs that improve cognition and that can be combined with anti-psychotic drugs that control the psychotic episodes that characterize schizophrenia.

Most schizophrenics suffer from cognitive impairment, an indication known as schizophrenia-related cognitive impairment, although cognitive impairment is independent of the psychotic symptoms of the illness.

Cognitive impairments are common at the onset of schizophrenia and can frequently be identified before psychotic symptoms emerge. In contrast to psychotic symptoms which are typically episodic, impairments in cognition appear to be a chronic feature of the illness.

Cognitive impairments are important as a treatment target because they have a substantial impact on the outcome of schizophrenia. Apart from psychotic symptoms, cognitive deficits in schizophrenia patients impact how they function, including social outcome, vocational outcome, and success in rehabilitation programs.

To date, first and second generation anti-psychotic drugs have shown little impact on cognition impairment suffered by schizophrenia patients.

As many as 60 million people worldwide have schizophrenia, according to various surveys. In North America, Datamonitor estimates more than two million people have schizophrenia. In Europe, the European Federation of Associations of Families of People with Mental Illness estimates that 6.6 million people suffer from schizophrenia.

Left image: Assembled microtubules
Right image: Disassembled microtubules

AL-108 and AL-208 protect astrocytes, large supportive cells found in brain tissue, against cell damage by binding to tubulin and promoting microtubule assembly.