Davunetide intranasal

Allon’s lead product davunetide is being evaluated in human clinical trials as a treatment for Alzheimer’s disease, for schizophrenia cognitive impairment, and frontotemporal dementia (FTD). The Company has robust Phase IIa human efficacy data for davunetide in patients with aMCI and will commence a Phase IIb trial in Alzheimer’s patients with a partner.

In addition, the Company will initiate a Phase II study to examine the effect of davunetide on human brain metabolism, which declines with progression of AD. Positron emission tomography (PET) scans will be used to image glucose metabolism in the brains of patients with AD, providing a method for evaluating the short-term treatment effects of davunetide.

In Q3 2009, positive top-line results from a Phase IIa clinical trial showed that davunetide has a positive impact on the ability of schizophrenia patients to carry out important activities in their daily lives. The trial was funded largely by TURNS (Treatment Units for Research on Neurocognition and Schizophrenia), which is supported by the U.S. National Institute of Mental Health.

Phase II aMCI Trial Design

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

The trial was conducted at 15 sites in the United States in 144 patients aged 55 to 85 years and evenly divided between genders. Three groups of patients received either placebo, low dose of davunetide (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 mean age was 69.4 years for the entire population and roughly consistent through the three arms (placebo: 70; low: 69.4; high: 68.9). The drop-out rate for the study was 13%, with higher rates in the placebo and low dose and a lower rate in the high dose.

Cognitive function was measured in the trial by tests that are widely-used and validated in clinical trials evaluating patients with mild cognitive impairment and Alzheimer’s disease. Four of the six tests are from the Cambridge Neuropsychological Test Automated Battery (CANTAB). CANTAB is currently being used by eight large pharmaceutical companies in mild cognitive impairment and Alzheimer’s disease trials. CANTAB has been shown in more than 500 peer-reviewed publications to be a sensitive and reliable tool for the measurement of drug and disease effects on cognition and psychological function.

The four CANTAB tests used and the cognitive domains measured in the trial are:

•   Delayed match-to-sample (recognition, short-term and working memory);
•    Spatial working memory (working memory);
•    Paired associated learning (episodic memory and learning); and
•    Stockings of Cambridge (executive function and problem solving).
The other cognitive tests used in the trial are:
•    Digit span (short term and working memory and language and speech processing).
•    Spielberger State-Trait Anxiety Inventory (a measure of anxiety and included to rule out false positives caused by anxiety)

Prior to receiving drug or placebo, the cognitive function of each patient was measured with these tests. These results became the baseline for each patient’s performance during the trial. Patients were treated for 12 weeks and retested at weeks four, eight, 12 and 16. Each patient’s test results were compared with his or her baseline performance and the performance of the entire trial group.

The safety results of this study in 144 patients substantiates that davunetide is safe and well tolerated. The rate of adverse events was equally distributed between the placebo and treated groups and reflected events typical in this type of study.

Trial Results

Results

Delayed-Match-to-Sample (DMTS)
The delayed-match-to-sample (DMTS) task is a test of simultaneous and delayed sample matching. This test assesses both visual matching ability and delayed visual recognition memory. A complex pattern is presented to the patient and the patient is required to choose the correct pattern from four choices. A time delay from display of the pattern and the four choices places a demand on the individual’s memory.

High dose davunetide resulted in a statistically significant improvement in DMTS, 12 second delay. Improvement increased with the duration of treatment. After four weeks, a trend in improvement was observed with a 34.2% change from baseline (p=0.067 , versus placebo). After eight weeks of treatment, the change from baseline increased to 46.8% (p=0.039, versus placebo), and by Week 16, a 62.4% change from baseline was observed (p=0.038, versus placebo). The effects of davunetide on DMTS performance were selective and dose-dependent. As expected, davunetide did not affect performance under the simultaneous, zero or four second delay conditions in which the memory challenge of the task was minimal.

Previous work published by Swainson et. al (2001) demonstrated that performance on DMTS, 12 second delay, was able to significantly differentiate AD patients from MCI patients (p<0.001) and that
performance on this test correlated with a global decline on the mini-mental state examination (MMSE) (rs=0.29, p=0.03). The ability of davunetide to improve performance on DMTS, 12 second delay, therefore has the potential for a clinically meaningful impact. The absence of an effect under simultaneous display or the shorter delays (zero or four seconds) provides internal consistency in the interpretation of the results and suggests that davunetide is having an effect on the memory component of the DMTS test. Many lesion studies have indicated that DMTS is primarily sensitive to damage in the medial temporal lobes, particularly the hippocampus, especially at the encoding stage, with more anterior lesions disrupting retrieval processes.

Digit Span

Digit span is a test of working memory in which a subject is read a list of numbers and then asked to repeat it both forward and backward. Digit span requires functional processing of language, speech and sub-vocal domains as well as the ability to store, transform and manipulate information.

An improvement on digit span forward of the high dose group was observed as early as Week 4 with performance trending toward significance compared to placebo (p=0.059, versus placebo) with a 10.3% change from baseline. The degree of improvement was relatively stable throughout the course of the study and by Week 8, an 11.2% change from baseline was statistically significant (p=0.032, versus placebo), and remained significant at Week 16 with an 11.7% change from baseline (p=0.052, versus placebo). The low dose davunetide was no different from placebo.

For the age-adjusted digit span combined, the high dose group performed consistently better than both placebo and the low dose group throughout the study. At both Week 4 and 16, the high dose resulted in a 11.7% and 17.2% change from baseline which was statistical significance compared to placebo (p=0.037 and 0.028, respectively versus placebo). The mean improvement of the low dose was better than placebo at all assessments, but not statistically significant.

Digit span is a sensitive test of working memory, which is necessary for holding and manipulating information. Progressive deterioration of performance on digit span has been reported in AD and it appears that processing of working memory involves the dorsolateral and ventrolateral frontal cortex. The significant improvement by davunetide on the digit span test is consistent with a clinically meaningful impact in AD.

Schizophrenia-related cognitive impairment

Allon said statistically significant efficacy (p=0.015) was achieved on the UCSD (University of California at San Diego) Performance-based Skills Assessment (UPSA). The UPSA scale assesses the functional capacity of skills for daily living. In total, six domains were tested in staged tasks: medication management, comprehension/planning, financial, communication, transportation, and household skills.

The UPSA scale has been recognized by drug regulators as an important co-primary endpoint in patients suffering from schizophrenia-related cognitive impairment. While there are drug sales of $4-billion to treat the psychosis associated with schizophrenia, there are no approved drugs treating schizophrenia-related cognitive impairment.

In addition to evaluating davunetide with the UPSA scale, the drug was also evaluated with the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) composite battery of tests, the primary outcome. Davunetide did not show significance on this measure.

The trial was managed by TURNS (Treatment Units for Research on Neurocognition and Schizophrenia), with substantial financial support from the National Institute of Mental Health (NIMH), part of the U.S. National Institutes of Health.

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.

Frontotemporal dementia

Frontotemporal dementia (FTD) is a collection of neurodegenerative syndromes characterized clinically by behavioural disturbance, impaired fluency of speech, difficulty in finding words and involuntary movements in some cases. In contrast to AD, FTD generally affects younger patients aged 45-65 years.

FTD is a devastating disease with a median survival of approximately six years from symptom onset and three years after diagnosis in some types. The median time from symptom onset to institutionalization is approximately five years but only one year from formal diagnosis. According to Orphanet, the European portal for rare diseases and orphan drugs, the prevalence for FTD is approximately 3.6-15 per 100,000. Age at onset for FTD is generally earlier than AD and it is referred to as a pre-senile disorder.

FTD is most closely associated with atrophy of the brain involving the frontal lobes, temporal lobes or both, often asymmetrically. Neurochemical evaluations have demonstrated that the cholinergic system is largely intact while dopaminergic and serotoninergic systems are compromised. A variety of neuropathologic changes can be seen including neuronal loss, astrogliosis and loss of synapses but there is no single signature of changes.

Tau abnormalities are seen in several variants of FTD and make up approximately 50% of the FTD population. Neurofibrillary tangles that stain positive for tau are particularly associated with coritcobasal degeneration and progressive supranuclear palsy.