Alzheimer’s disease

Scientists agree that the brains of Alzheimer’s patients are characterized by plaque accumulation outside neurons and by neurofibrillary tangles inside neurons. No drug on the market today has any impact on these plaques and tangles. Drugs on the market today treat only the symptoms of Alzheimer’s — that is, they slow memory loss or modify emotional volatility or treat other behavioural symptoms.

In 2008, Allon will 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 disease.

Allon’s preclinical studies have shown that AL-108 improves both plaques and neurofibrillary tangles. AL-108 also protects healthy neurons from the formation of plaques and tangles.

Although the neurobiological mechanisms underlying MCI and AD are not completely understood, recent studies have found neurofibrillary tangles in the brains of aMCI and AD patients.

Neurofibrillary tangles are the result of a break down of the networks inside brain cells that are necessary for the transport of nutrients and the relay of information. These networks are comprised of proteins in tubular structures called microtubules. A key constituent of microtubules is tau protein, which is necessary for microtubules to remain stable and functioning. If the tau protein becomes hyperphosphorylated (a structural change that occurs with disease or injury in which phosphate groups are added to the protein), it detaches from the microtubule, forms neurofibrillary tangles and can no longer stabilize the microtubule network. The transport of chemicals inside brain cells is thereby compromised and a “death signal” is initiated which begins a process that results in the degeneration or death of the cell.

Allon has shown in preclinical animal studies that its drug AL-108 interacts with microtubules 1) preventing the formation of neurofibrillary tanges and protecting the network from a “death signal” or 2) repairing the network if the brain cell death process has already begun. The restoration of the microtubule network explains the results Allon observed in animal models, in which treated animals have improved cognitive performance compared to untreated groups.

It is well established that tangles correlate well to the severity and type of cognitive impairment that patients report. For example, tangles in the hippocampus and medial temporal lobe correlate to short-term and episodic memory deficiencies. Animals treated with AL-108 have demonstrated specific memory function improvements that correlate to reduction of tangles in the specific corresponding regions of the brain.

Currently, it is estimated that 4.5 million Americans have AD. In the seven major pharmaceutical markets (United States, France, Germany, Italy, Spain, the United Kingdom, and Japan) there are 16 million AD patients, a number that is expected to grow to 21 million by 2010. It is also the 8th leading cause of death in the United States and once diagnosed, the average life span of an Alzheimer's patient is eight years.

In the United States alone, direct and indirect annual costs of caring for individuals with AD are at least $100 billion, according to estimates used by the Alzheimer's Association and the National Institute on Aging. Sales for Alzheimer's therapies are estimated to increase to more than $7.8 billion by 2010 in the seven major markets.

Schizophrenia –related cognitive impairment

Most patients suffering from schizophrenia show cognitive impairment, although it 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 and certainly the patient’s quality of life. 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, according to 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.

In 2008, in collaboration with TURNS, Allon will complete dosing, analyze data and release results of a Phase II clinical trial evaluating the safety, tolerability and effect of AL-108 (intranasal administration) on cognitive impairment associated with schizophrenia (CIAS). This trial is being funded and managed by TURNS.

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.

It has been observed that schizophrenia patients have decreased volume of cortical and hippocampal neurons, areas of the brain most responsible for cognition. In addition to the transport function, microtubules provide cellular structure. Consequently, it is hypothesized that AL-108, by promoting this cytoskeletal structure will, in turn, promote better cognitive outcomes in the patients.

Mild cognitive impairment from bypass surgery

Mild cognitive impairment (MCI) is a common result after coronary artery bypass graft surgery (CABG – commonly known as "bypass surgery").

In 2008, Allon will release results of a Phase II clinical trial evaluating the safety, tolerability and effect of AL-208 in the prevention of mild cognitive impairment (MCI) resulting from ischemic damage during coronary bypass graft surgery (CABG).

Trial results will also indicate AL-208’s potential as a treatment for the ischemic damage resulting from stroke.

Some studies estimate that cognitive impairment after CABG surgery can occur in up to 90% of the cases in the first week post-surgery, that more than 50% of patients show impairment when discharged from the hospital, and that 24% continue to show impairment after six months. The studies also showed that after five years, 42% of patients were significantly cognitively impaired compared to their pre-surgery performance.

Approximately 500,000 patients in the United States and 800,000 patients worldwide undergo coronary artery bypass graft surgery every year. The post-CABG MCI market is estimated to be US$500 million annually. Currently there is no therapy available that ameliorates or treats the cognitive damage associated with artery bypass surgery.

Stroke

Every 45 seconds in the United States, someone experiences a stroke. This fact translates into approximately 700,000 new or recurrent strokes in the Unites States each year. It is the second leading cause of mortality in the world after cardiovascular disease, the third leading cause of death in the United States, and is the leading cause of long-term disability. The annual cost of stroke related care in the U.S. will exceed $58 billion in 2006.

There are two types of stroke - ischemic and hemorrhagic. Ischemic strokes (83%) are caused by blood clots that block blood flow to the brain when build-up of fatty deposits blocks an artery. Hemorrhagic strokes (17%) are caused by the rupture of a blood vessel resulting in blood spilling into the brain, damaging the surrounding tissue.

There are currently no treatments available for hemorrhagic stroke patients and only 2 - 5% of ischemic stroke victims receive the single available drug Activase®, which exceeded sales of $184 million in 2003. The current drugs available for stroke decrease the ability of blood to form clots, requiring the type of stroke to be diagnosed prior to their administration due to the possibility of killing a patient with a hemorrhagic stroke by increasing the blood loss and brain damage.

In spite of this failure to provide effective treatments, there remains a significant opportunity and the market is projected to grow significantly with the introduction of new therapies.

In 2008, Allon will release results of a Phase II clinical trial evaluating the safety, tolerability and effect of AL-208 as a prevention for the mild cognitive impairment (MCI) resulting from ischemic damage during coronary artery bypass graft surgery (CABG).

Trial results will also indicate AL-208’s potential as a treatment for the ischemic damage resulting from stroke.

Allon believes that treatment with AL-208 would not require the patient’s stroke type to be diagnosed prior to its administration, saving valuable therapeutic intervention time and allowing more patients to receive the drug.

In animal studies, AL-208 has demonstrated efficacy following a long period between the induction of the stroke and administration of the drug: A single intravenous injection of AL-208 given up to four hours following the middle cerebral artery occlusion, resulted in a significant reduction in infarct size, and suggested a broad human therapeutic window.

Other Potential Indications

Neuropathies

Neuropathies are a result of peripheral nerve damage, which leads to a loss of nerve function. The symptom manifestations of neuropathies depend on the type of nerve affected, but may include pain and discomfort, numbness and muscle weakness. Neuropathy can be the result of other diseases such as diabetes, autoimmune diseases including lupus rheumatoid arthritis, and exposure to toxic substances such as chemotherapeutics.

Most treatments for neuropathies aim to manage the cause of the neuropathy and to provide symptom relief.

Allon’s neuroprotective compounds are intended to prevent neuronal death and thereby reduce or inhibit progression of the neuropathic injury. The mechanism of action of AL-108 involves strengthening and reorganizing the microtubular network, which is essential for the maintenance of neuronal cell integrity.

More than eight million Americans experience some type of neuropathy, with a large percentage attributed to diabetes. The market for the top three neuropathic medications was approximately $2 billion in 2005.

Traumatic brain injury

Traumatic brain injury is an injury to the head caused by an external force that kills neurons, leads to inflammation and disruption to the normal function of the brain.

There are approximately 5.5 million Americans with TBI and there is an incidence of over 1.5 million cases per year. TBI is the major cause of morbidity in the young adult population in the U.S. The estimates of the economic cost of TBI are over $48 billion, with almost $32 billion coming directly from hospital costs.

There are no treatments for the actual injury; rather medications used in TBI treat symptoms. The main therapies used were developed for other neurological disorders, such as anti-epileptics used to treat seizures often observed in TBI patients.

Allon’s compounds have demonstrated neuroprotective effects in a TBI animal model at considerably lower concentrations than other therapeutics in development for TBI.

Glaucoma and diseases of the eye

Several diseases of the optic nerve and retina, including glaucoma, involve the degeneration of retinal ganglion cells, a group of specialized neurons of the visual system responsible for transmitting information to the brain.

Glaucoma, or glaucomatous optic neuropathy, is defined by characteristic visual field defects and structural changes in the optic nerve head as a result of death of the retinal ganglion cells. The
optic nerve damage usually occurs due to high intraocular pressure caused by a backup of fluid in the eye. Glaucoma is now treated with medication (usually eye drops), surgery, or, in some cases, both. Both eye drops and surgery work by helping the fluid to drain from the eye and/or decreasing the amount of fluid that is produced in the eye. The whole purpose of treatment is to prevent further loss of vision by keeping the intraocular pressure under control.

Results of an Allon-sponsored preclinical study, published in the March 2005 issue of Investigative Ophthalmology & Visual Science, determined that two Allon compounds, AL-108 and AL-209 have the potential to become new treatments for these diseases. The study demonstrated that administration of AL-108 and AL-209 enhanced the survival of retinal ganglion cells by 167% and 177% respectively,
compared with the control and enhanced neurite growth by 117% and 126% respectively, compared with the control.