Caprospinol, Therapy for Alzheimer's Disease (AD)Samaritan Pharmaceuticals’ caprospinol (SP-233) is an investigational agent under development for the treatment of Alzheimer’s disease (AD). Towards the end of 2006, Samaritan submitted an investigational new drug (IND) application to the US FDA to seek approval to begin clinical testing of its new drug. Caprospinol is the company’s lead compound in a series of investigational agents being developed for AD and other neurodegenerative disorders. It is designed to target the toxic beta-amyloid plaques that develop in the brains of AD patients. After drugs that target cholinergic neurotransmission, anti-amyloid therapies represent the next largest group of compounds in development for AD. TOWARDS DRUGS WITH DISEASE-MODIFYING EFFECTS AD is a degenerative disease of the brain characterised by the progressive loss of cortical neurones and synapses leading to a loss of memory and cognition and accompanying functional impairment. "Caprospinol is the company’s lead compound in a series of investigational agents being developed for AD and other neurodegenerative disorders."
At post-mortem, the neocortex and hippocampus regions of the brains of AD patients show evidence of amyloid plaques, sometimes termed neuritic or senile plaques, as well as neurofibrillary tangles due to hyperphosphorylation of Tau protein. The discovery that senile plaques in the brains of AD patients contained an accumulation of insoluble toxic beta-amyloid (β-amyloid42, derived from amyloid precursor protein (APP), led to the search for compounds that could either prevent the deposition of toxic beta-amyloid in the brain or eliminate existing plaques. It is hoped that by targeting what is believed to be a key step in the pathogenesis of AD, such compounds will have disease-modifying effects. CAPROSPINOL MAY PROTECT AGAINST β-AMYLOID-INDUCED TOXICITY Caprospinol (SP-233) is a spirostenol (steroid derivative) that has shown evidence of protecting neuronal mitochondria from beta-amyloid-induced cytotoxicity and cell death in preclinical studies. Mitochondria, cytoplasmic organelles that are critical to aerobic respiration, and needed to maintain neuronal cell energy levels. Impaired mitochondrial functioning is seen in several CNS diseases including AD. Caprospinol (SP-233) is believed to act by binding to beta-amyloid peptide and preventing its oligomerisation and entry into neurones. Oligomerisation of beta-amyloid is an early step in the formation of senile plaques considered the primary pathological feature of AD. In addition to caprospinol (SP-233), Samaritan Pharmaceutical’s pipeline also contains two other drugs in development for AD, SP-004 and SP-008, and two stem cell neuron differentiation therapies SP-sc4 and SP-sc7. The latter are designed to induce dormant brain cells to differentiate rapidly into adult neurones. COMBATING THE RISING PREVALENCE OF AD Estimates suggest that some 12–15 million people in the world have AD, 4.5 million in the US alone. Prevalence of AD is strongly age-related; in those aged 60 years and older prevalence doubles every five years. With the growing proportion of elderly and very elderly (>85 years) in the world’s population, prevalence will continue rising. By 2025 it is estimated that there will be more than twice as many people with AD than there are today, unless more effective treatments can be developed. "New drugs with genuine disease-modifying effects are urgently required to stop the rising prevalence of AD."
Today the treatment of AD is dominated by the use of acetylcholinesterase inhibitors, which are designed to raise the concentration of acetycholine at sites of neurotransmission in the cerebral cortex and forebrain. These drugs, three of which are clinically approved, provide modest symptomatic improvement to AD patients in the mild to moderate stage of the disease. However, they do not address the underlying pathology of AD. Moreover, their effects on cognition, executive functioning and behaviour are only temporary. Of currently approved anti-dementia drugs, none have disease-modifying effects that can halt the progression of the disease and stop cognitive decline. New drugs with genuine disease-modifying effects are urgently required to stop the rising prevalence of AD, the most common form of dementia to afflict the elderly. Drugs targeted at central cholinergic dysfunction and toxic beta-amyloid peptide represent two major therapeutic approaches for AD, others include:
MARKETING COMMENTARY Still in its infancy, the current market for anti-dementia therapies has amongst the highest growth dynamics in the CNS market, driven by a growing elderly population and unmet clinical need. Samaritan Pharmaceuticals’ caprospinol (SP-233) is about to enter a phase I maximum dose and safety study and is thus in the earliest stage of clinical development. It remains to be seen whether it will progress into phase II and then pivotal phase III trials but the preclinical data look encouraging.
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  Loss of acetylcholine, an important neurotransmitter, is a key pathological feature of Alzheimer's disease (AD) and contributes to the cognitive decline that characterises this disease. | |
 In most patients, Alzheimer's disease (AD) is a slowly progressive disease in which loss of short-term memory is often one of the earliest symptoms. | ||
 Potential sites of action of anti-amyloid agents. | ||
 Prevalence of Alzheimer's disease (AD) rises steeply in the very elderly. |
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