Market
Neurodegenerative disease results from the gradual loss of brain and spinal cord cells, which are composed of neurons that regulate movements, process sensory information and control decision making. There are currently more than 600 neurologic disorders identified, with approximately 50 million Americans affected each year.
Major neurodegenerative conditions include Alzheimer’s disease (AD), Parkinson’s disease (PD), cognitive impairment associated with schizophrenia (CIAS) and frontotemporal dementias (FTD). Many of these illnesses are age related and will have an increased impact on society as the elderly population continues to grow. There is a desperate need for new and improved treatments for these diseases, which can have a devastating impact on people’s quality of life.
To date, therapeutic intervention in these diseases has focused on symptomatic treatment. However, neuroprotection is emerging as the preferred strategy for combating these diseases because of its ability to limit neurological tissue damage and disease progression.
Progressive Supranuclear Palsy
Progressive supranuclear palsy (PSP) is a particularly devastating type of frontotemporal dementia (FTD), a collection of progressive neurodegenerative diseases. PSP is often characterized by progressive difficulty with balance and walking, eye movement abnormalities, and cognitive and personality changes. Patients are typically diagnosed when they are between 45 and 75 years of age and have a median survival of approximately six to seven years from symptom onset.
Approximately 25,000 in the United States and 50,000 people in the European Union have PSP. The disease is slightly more common in men than women, but there are no known geographical, occupational or racial patterns.
PSP is caused by changes in the accumulation of abnormal tau, a protein that normally supports the internal structure of the nerve cell and serves as a transport mechanism for nutrients and other molecules. In disease states, the abnormal tau aggregates into tangles and disrupts normal nerve cell processes, ultimately leading to the death of the cells.
There are no treatments approved by the U.S. Food and Drug Administration for FTD or PSP. Allon is currently enroling a pivotal Phase 2/3 trial of davunetide in patients with PSP.
Alzheimer’s Disease
Alzheimer’s disease (AD), the most common cause of dementia among people aged 65 and older, is an age-related, irreversible brain disorder that develops over a period of years and generally leads to death in eight years.
It is estimated that there are currently 18 million people worldwide with AD. In the United States, as many as 5.3 million people are living with AD but this is expected to increase to between 11 million and 16 million by 2050. In the United States alone, direct and indirect annual costs of caring for individuals with AD are at least $100 billion. Pharmaceutical sales were $7.4 billion in 2009.
As AD progresses, neurofibrillary tangles (abnormal collections of the protein tau) and amyloid plaques (fragments of a protein called beta-amyloid peptide) form throughout the brain, causing healthy neurons to work less efficiently. After losing the ability to function and communicate, the neurons eventually die.
Current therapies for AD have only been shown to help the symptoms the disease. A therapy that could slow the progression of the disease itself would represent a breakthrough for the millions of patients living with AD.
Parkinson’s Disease
Parkinson’s Disease (PD) is a progressive neurological condition affecting approximately one person in every 500, principally those aged 50 or over. This means that there are an estimated 1.5 million people in North America suffering from PD and its incidence is expected to increase significantly over the next 25 years. The worldwide pharmaceutical market in PD was $4.2 billion in 2009.
The loss of dopaminergic neurons in the substantia nigra leads to the emergence of typical PD symptoms such as tremor, rigidity and slowness of movement. PD is considered a synucleinopathy due to the deposition of alpha-synuclein aggregates in the brain. In PD, these are referred to as Lewy bodies and differ from the neurofibrillary tangles seen in PSP and AD.
The symptoms of PD can be controlled using a combination of drugs, therapies and occasionally surgery in an attempt to normalize the levels dopamine in the brain. None of the approved therapies are able to step the degeneration of the brain or to slow the progression of symptoms.
Drugs that modulate the microtubule system may have applications in PD since there appears to be an interplay between tau, microtubules and alpha-synuclein. For instance, overexpression of alpha synuclein has been shown to impair microtubule-dependent trafficking. It is thought that alpha-synuclein interaction with microtubules may start a cascade of events that lead to cellular dysfunction and ultimately cell loss.
Cognitive Impairment Associated with Schizophrenia (CIAS)
As many as 60 million people worldwide have schizophrenia, a disease that interferes with a person’s ability to think clearly, distinguish reality from fantasy, manage emotions, make decisions and relate to others. Most people with schizophrenia also suffer from CIAS, although it is independent of the psychotic symptoms of the illness.
More than two million people in North America have schizophrenia and it is estimated that 6.6 million Europeans suffer from the disease.
For the vast majority of schizophrenics with cognitive impairment, short-term memory is consistently impaired and long-term memory involving the acquisition and recall of new information may be impaired at relatively severe levels. Patients with schizophrenia show reduced mental speed and reaction time. These symptoms suggest damage to frontal-temporal regions and related hindrance of connectivity or interactions. CIAS affects how patients function socially, on the job and in rehabilitation programs.
There are currently no FDA-approved drugs to treat CIAS. First and second-generation anti-psychotic drugs have shown little impact on cognitive impairment suffered by schizophrenia patients. The treatment of cognitive impairment can have a substantial impact on the outcome of schizophrenia, underscoring the importance of finding new therapies for these conditions.
It has been observed that schizophrenic patients have fewer 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 by promoting this cytoskeletal structure, davunetide might promote better cognitive outcomes in these patients.
Neuropathies
Neuropathies result from peripheral nerve damage, which leads to a loss of nerve function. The symptom manifestations of neuropathies depend on the type of nerve affected, but often includes pain and discomfort, numbness and muscle weakness. Neuropathy can be the result of other diseases such as diabetes, autoimmune diseases, including lupus and rheumatoid arthritis, and exposure to toxic substances such as chemotherapeutics used in cancer treatment.
In cancer treatment, the development of painful neuropathy is often dose-limiting meaning that patients are unable to tolerate the recommended dose of chemotherapy. This includes treatment with some of the most widely used anti-cancer drugs including oxaliplatin, carboplatin, cisplatin, paclitaxel, docetaxel, bortezomib, lenalidomide, thalidomide, epothilone, and the vinca alkaloids. The rate of neuropathy can reach as high as 75% with some of these agents. Peripheral neuropathy can result from a number of causes with the largest percentage attributed to diabetes. More than eight million Americans experience some type of neuropathy.
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 might reduce or inhibit progression of the neuropathic injury.