Allon’s Phase II clinical trial shows statistically significant efficacy on human cognition and memory
VANCOUVER, February 26, 2008 — Allon Therapeutics Inc. (TSX: NPC), The Neuro Protection CompanyTM, today released top-line results of a Phase IIa clinical trial showing that its drug AL-108 has a positive impact on memory function in patients with amnestic mild cognitive impairment (aMCI), a precursor to Alzheimer’s disease (AD).
Allon said statistically significant efficacy was achieved on key endpoints that measured short-term, working and recognition memory, three types of memory that are clinically relevant in AD. The trial also demonstrated that AL-108 was safe and well tolerated by patients.
A significant, dose-dependent and durable improvement was seen in two key cognitive tests, delayed-match-to-sample and digit span, tests that are widely recognized and validated as effective measures of memory function. The high dose (15 mg twice daily) group showed a 62.4% improvement from baseline (p=0.038, versus placebo) in the delayed-match- to- sample test by the end of the trial. Similarly, the high dose group showed a 17.2% increase from baseline (p=0.028, versus placebo) in the digit span test.
Gordon McCauley, Allon’s President and CEO, said these trial results validate the potential of AL-108 to treat the symptoms and halt the progression of Alzheimer’s disease. “As a business we had two objectives with this trial: show that the drug works in humans and works well enough to justify the next trial in Alzheimer’s. We have met these objectives — the drug works and the results are clear. The Company will proceed into Phase IIb in Alzheimer’s and continue to explore other Phase IIb studies supported by this data set.”
Dr. Donald E. Schmechel, the principal investigator of the trial, said these results are compelling and potentially important for the treatment of Alzheimer’s disease and millions of Alzheimer’s patients and their families.
“Short-term memory, recognition, and working memory deteriorate rapidly in the early stages of Alzheimer’s disease,” said Dr. Schmechel.
“Improving these memory functions with 12-weeks of treatment is certainly relevant to clinical practice in Alzheimer’s disease.”
“Successfully impacting these specific memory domains indicates AL-108 is active in the regions of the brain responsible for their function — primarily the medial temporal lobe, hippocampus and prefrontal cortex, said Dr. Schmechel.
“The combination of the symptomatic impact shown in this clinical trial and Allon’s pre-clinical data showing an impact on plaques and tangles, the classic hallmarks of Alzheimer’s disease, highlights the potential of AL-108 as a disease-modifying therapy,” Schmechel added.
Dr. Schmechel is an adjunct Professor of Medicine (Geriatics), at Duke University Medical Center in Durham, North Carolina, and the Medical Director of The Falls Neurological and Memory Center at the Caldwell Memorial Hospital.
Allon Therapeutics will hold a conference call and webcast to discuss the Phase IIa results of AL-108 today, February 26, 2008 at 5:00 p.m. Eastern Time. The call will be hosted by Matthew Carlyle, CFO of Allon, and include Mr. Gordon McCauley, President and CEO of Allon, Dr. Bruce Morimoto, Vice-President, Drug Development of Allon, and Dr. Donald E. Schmechel, the principal investigator of the trial. The conference call will be followed by a question and answer session.
To access the conference call by telephone, dial 416-644-3416 or 1-800-732-9303. Please connect approximately 15 minutes prior to the beginning of the call to ensure participation.
The conference call will be archived for replay until March 5, 2008 at midnight. To access the archived conference call, dial 416-640-1917 or 1-877-289-8525 and enter the reservation number 21264561 followed by the number sign.
A live audio webcast of the conference call will be available at: http://www.allontherapeutics.com/ir_calendar.htm. Please connect at least 15 minutes prior to the conference call to ensure adequate time for any software download that may be required to join the webcast. The webcast will be archived on the Company’s website for 30 days.
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 AL-108 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 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 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 AL-108 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.
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 AL-108 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 AL-108 on DMTS performance were selective and dose-dependent. As expected, AL-108 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
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 AL-108 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 AL-108 on the digit span test is consistent with a clinically meaningful impact in AD.
Dr. Bruce Morimoto, Vice President of Drug Development at Allon, said the data set released today is the result of a top-line analysis of the data from this trial. The Company intends to complete analysis of the full data set in the near future.
“We are very encouraged by the statistical significance seen in key cognitive tests relevant to Alzheimer’s disease. Allon and our panel of external physicians and scientists believe that a full analysis of the data may provide additional insight about the effect of AL-108 on other cognitive domains. This additional analysis will provide important guidance in the design of future clinical trials, and potentially the mode of action of AL-108” said Dr. Morimoto.
AL-108 is derived from a naturally occurring neuroprotective brain protein known as activity dependent neuroprotective protein (ADNP). Allon’s laboratory and animal studies have shown that AL-108 restores the function of structures in the brain — known as microtubules — which are critical to communication between brain cells and the structure of individual cells.
About aMCI and Alzheimer’s Hallmarks
There is increasing evidence that some forms of cognitive impairment are precursors to Alzheimer’s disease. Amnestic mild cognitive impairment (aMCI) is a subset of MCI in which only the memory components of an individual’s function are affected. The Alzheimer’s Society estimates that 85% of persons with MCI will develop Alzheimer’s disease and so it is generally recognized as a precursor to Alzheimer’s.
Scientists agree that the brains of Alzheimer’s patients are characterized by two classic hallmarks of the disease: amyloid beta plaque accumulation outside neurons and neurofibrillary tangles inside neurons. No drug on the market today has any impact on these plaques and tangles.
Scientific studies have shown that the pathology of aMCI and Alzheimer’s is similar. For example, amyloid beta plaques and neurofibrillary tangles occur in both. Allon’s extensive animal data show that AL-108 dramatically reduces neurofibrillary tangles, reduces plaques, and that treated animals have significantly improved cognition. AL-108 is the first drug in development to have shown reduction of both neurofibrillary tangles and amyloid beta plaques in animal studies.
“The human clinical trial data we have released today shows AL-108 has a direct impact on memory performance,” McCauley said. “These results mean that our drug is the first to validate in humans the so-called ‘tangle’ pathway. With the most advanced tangle program, human efficacy data, and a completely unique mechanism, this is a meaningful advantage for Allon.”
“It is important to note that the efficacy results we announced today also validate one of Allon’s technology platforms, ADNP, from which AL-108 was developed. Our pipeline has various other products developed from ADNP and these results define ADNP as a human validated drug target, meaning that our pipeline has clear relevance to numerous other central nervous system diseases,” added Professor Illana Gozes, Allon’s Founder and Chief Scientific Officer.
Additional Efficacy Trials
Allon has two additional on-going Phase II human efficacy trials from which data will be released in 2008.
A Phase II study in schizophrenia cognitive impairment is evaluating the potential of AL-108 to be used as a treatment for the debilitating cognitive impairment suffered by most schizophrenia patients. The efficacy shown by the aMCI trial supports the hypothesis of an effect in schizophrenia related cognitive impairment because the aMCI results show an effect in the same regions of the brain that are implicated in schizophrenia.
A Phase II study in mild cognitive impairment post-coronary artery ypass graft (MCI-CABG) is evaluating the potential for AL-208 to be used as a treatment for the ischemic damage that results from heart bypass surgery as well as other indications, such as stroke. AL-208 is administered intravenously.
Each of these studies has the potential to lead to a significant treatment opportunity and is evaluating Allon’s drugs in different patients, medical conditions and clinical endpoints using two different routes of administration.
Allon Therapeutics Inc. is a clinical-stage biotechnology company developing treatments for major neurodegenerative conditions. In Q1 ’08 Allon’s drug AL-108 demonstrated robust human efficacy in amnestic Mild Cognitive Impairment, a precursor to Alzheimer’s disease. Allon has two other Phase II human efficacy trials underway pursuing three large underserved markets: Alzheimer’s disease, stroke and cognitive impairment associated with schizophrenia. The Company is listed on the Toronto Stock Exchange under the trading symbol “NPC” (Neuroprotection CompanyTM) and based in Vancouver. For additional information please visit the Company’s website: www.allontherapeutics.com.
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