Davunetide

Davunetide, Allon’s lead neuroprotective drug candidate, is in a fully enrolled Phase 2/3 study for progressive supranuclear palsy (PSP), a form of frontotemporal demential (FTD). Allon has completed two Phase 2a human efficacy studies for davunetide in patients with amnesic mild cognitive impairment (aMCI), a precursor to Alzheimer’s disease, and in patients with cognitive Impairment associated with schizophrenia (CIAS).

Phase 2/3 PSP Trial Design

Allon is conducting a fully enrolled pivotal Phase 2/3 double-blinded, placebo controlled trial in PSP. This study will enrol approximately 300 patients randomized 1:1 to receive either placebo or 30 mg of davunetide intranasally twice a day for 12 months. This multi-national study is being conducted at premier medical institutions in the United States, Australia, Germany, France, Canada and the United Kingdom. The study Principal Investigator is Adam Boxer, MD, PhD, Associate Professor of Neurology at the University of California San Francisco (UCSF) and Director of the Alzheimer’s disease and frontotemporal dementia clinical trials program at the UCSF Memory and Aging Center. Enrolment began in the fourth quarter of 2010.

The primary outcome measures will be the Progressive Supranuclear Palsy Rating Scale (PSPRS) and the Schwab and England Activities of Daily Living (SEADL) scale. Secondary measures will include Clinical Global Impression (CGI) and brain imaging by magnetic resonance tomography (MRI). Additional exploratory endpoints include cognitive and executive function as well as cerebrospinal fluid (CSF) biomarkers.

This study is being conducted under a Special Protocol Assessment (SPA), granted by the United States Food and Drug Administration (FDA).

A list of the clinical trial sites can be found at www.clinicaltrials.gov, NCT 01110720.

Phase 2 aMCI Trial Design

The Phase 2 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 old 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 enrollment was announced on October 2, 2007.

In the trial, patients’ cognitive functions were measured by tests that are widely used and validated in evaluating patients with mild cognitive impairment (MCI) and AD. Four of the six tests are from the Cambridge Neuropsychological Test Automated Battery (CANTAB), which has been shown in to be a sensitive and reliable tool for the measurement of drug and disease effects on cognition and psychological function. The safety results of this study indicate that davunetide was generally well tolerated. The rate of adverse events was equally distributed between the placebo and treated groups.

Trial Results

Cognitive Measures

Delayed-Match-to-Sample (DMTS) The delayed-match-to-sample (DMTS) task is a test of simultaneous and delayed sample matching assessing both visual matching ability and delayed visual recognition memory. A complex pattern is presented to the patient who is asked to select the correct pattern from four choices. Instead of having the sample pattern displayed simultaneously, the time delayed evaluation examines an individual’s memory. High dose davunetide resulted in a statistically significant improvement in DMTS, 12 second delay, which also increased over the duration of treatment. After four weeks, a trend in improvement was observed with a 34.2 percent change from baseline (p=0.067, versus placebo). After eight weeks of treatment, the change from baseline increased to 46.8 percent (p=0.039, versus placebo), and by week 16, a 62.4 percent 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.

Digit Span

Digit span is a sensitive test of working memory, which is necessary for holding and manipulating information. To asses an individual’s functional processing of language, speech and sub-vocal domains as well as the ability to store, transform and manipulate information, patients are read a list of numbers and then asked to repeat it both forward and backward. 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. An improvement on digit span forward of the high-dose group was observed as early as week four with performance trending toward significance compared to placebo (p=0.059, versus placebo) with a 10.3 percent change from baseline. The degree of improvement was relatively stable throughout the course of the study and by week eight, an 11.2 percent change from baseline was statistically significant (p=0.032, versus placebo), and remained significant at week 16 with an 11.7 percent change from baseline (p=0.052, versus placebo). The low dose davunetide was no different from placebo. For the age-adjusted digit span, the high-dose group performed consistently better than both the low-dose and placebo groups throughout the study. At both week four and 16, the high dose resulted in a 11.7 percent and 17.2 percent change from baseline which was statistically significant 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.

Cognitive -impairment associated with schizophrenia (CIAS)

Top-line results were announced in 2009 from a Phase 2 clinical trial evaluating the safety and efficacy of Allon’s lead neuroprotective drug candidate davunetide in patients with CIAS. Cognitive impairments are important as a treatment target because they have a substantial impact on the outcome of schizophrenia. Allon reported statistically significant efficacy results (p=0.015) on the University of California at San Diego’s (UCSD) 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. Results and analysis presented during a U.S. neuropsychopharmacology scientific conference indicate the following:

• The trial did not achieve statistical significance on the primary endpoint, which was the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) composite battery of tests. However, numerically positive treatment effects were seen in specific tests that measured visual learning and working memory.
• The trial achieved a statistically significant positive treatment effect on a secondary endpoint, which was the UCSD (University of California at San Diego) Performance-based Skills Assessment (UPSA) test. The UPSA scale assesses the functional capacity of skills for daily living and has been recognized by drug regulators as an appropriate co-primary endpoint in patients suffering from schizophrenia-related cognitive impairment.

While there are $4 billion in worldwide drug sales to treat the psychosis associated with schizophrenia, there are no approved drugs treating CIAS. This trial was funded largely by Treatment Units for Research on Neurocognition and Schizophrenia (TURNS), which is supported by the United States National Institute of Mental Health.

Davunetide subcutaneous Davunetide second generation is being developed as a subcutaneous product. Allon has previously reported that a Phase 2a clinical trial in patients who had undergone coronary artery bypass surgery demonstrated that davunetide intravenous was generally well tolerated by patients at a dose 20 times greater than the dose in the davunetide intranasal aMCI trial, with similar side effects to placebo. Allon is using this as the basis for the development of an extended release drug product injected subcutaneously. This product is currently in preclinical research and development.