An alpha (α)-secretase modulator for ameliorating Alzheimer's Disease pathophysiology and cognitive impairment with neuroprotection

Alzheimer's Disease

APH-0703 AD-Susceptible-PersonThe symptoms of Alzheimer's Disease (AD) are associated with progressive brain tissue shrinkage and death. In the early stages of AD, degeneration of cells in the hippocampus leads to short-term memory loss and reduced ability to perform routine tasks (cognitive disorders). As AD spreads through the cerebral cortex, judgment declines, emotional outbursts often occur and language skills become impaired.

AD progression leads to the death of additional nerve cells and loss of synapses and gradually worsening behavior changes, such as wandering and agitation. In the final stages, patients lose the ability to recognize faces, communicate and control bladder and bowel movements. The average time from diagnosis to death is 4 to 8 years, although it may take 20 years or more for the disease to run its course.

While there is some understanding of this disorder, there is still a lack of preventive and therapeutic remedies. AD is the third major cause of death in America and among the highest in the industrial world. AD is a widespread and significant neurological disorder that affects more than 4.5 million Americans and more than 10 million people worldwide. Epidemiologically, AD is anticipated to increase with the demographics of the aging populations in United States, Europe and Japan. Experts estimate that 22 million people around the world and more than 8 million Americans will be afflicted with AD by 2025.

Current AD Treatments

Five prescription drugs are currently approved by the US Food and Drug Administration (FDA) to treat people who have been diagnosed with Alzheimer's. While these drugs may treat the symptoms of AD, none of these medications is a cure for the disease.

Four of these medications, including Aricept®, are called cholinesterase inhibitors and are prescribed for the treatment of mild to moderate AD. They may help delay or prevent symptoms from becoming worse for a limited time and may help control some behavioral symptoms. The fifth approved medication, known as Namenda®, is believed to work by regulating glutamate, another important brain chemical that, when produced in excessive amounts, can cause excitotoxicity that leads to brain cell death. All of the drugs on the market today have serious side effects.

Alpha (α)-secretase, a Novel Approach for Treating AD

Current research in AD prophylaxis and therapy is centered on identification of methods to decrease Beta amyloids (Aβ) and tau entanglement. Beta (β)-secretase inhibitors have been extensively investigated, but have been difficult to translate into effective clinical treatments for AD. A recent Phase II clinical trial with a β -secretase inhibitor, LY2886721, was halted because of liver toxicity. Gamma (γ)-secretase inhibitors may also reduce Aβ accumulation. A recent Phase III clinical trial with the γ-secretase inhibitor, 'semagacestat' (LY-450139), was halted because of evidence for accelerated dementia. Most of the recent clinical AD trial failures have been with β-secretase and γ-secretase inhibitors.

Alpha (α)-secretase is another enzyme in the neuronal pathway that influences amyloid precursor protein, APP. Both β-secretase and γ-secretase cleave APP to form an insoluble amyloid plaque (Aβ) that leads to tau entanglement. α-secretase, on the other hand, cleaves APP into a harmless soluble form, 's-APPα', that support new synapse formation and is readily cleared from the brain. Thus, unlike current strategies which suppress β-secretase and γ-secretase to minimize Aβ plaque formation, our strategy involves the activation of α-secretase leading to beneficial amyloid precursor processing and prevention of Aβ buildup.

APH-0703 is neuroprotective via activation of PKC isoforms, down-regulation of pro-inflammatory factors and angiogenic processes and the conversion of beta amyloid into its soluble form, s-APPα. Aphios has successfully developed and patented efficient methods for manufacturing and formulating APH-0703. Aphios and its collaborators at Louisiana State University have demonstrated by both in vitro mechanistic studies (data not shown) and in vivo efficacy studies that APH-0703 has a high clinical translation potential.

In Vivo Studies of Orally Administered APH-0703 in Triple Transgenic AD Mice

Recently, we evaluated the ability of an oral formulation of APH-0703 to restore learning and memory in a triple transgenic AD mouse model. This model incorporates the human 'Swedish' (swe) amyloid precursor protein and presenilin mutations, which are found in progressive human AD.

A proprietary oil formulation of APH-0703 (US Patent Pending) was administered by oral gavage 3 times in the week prior to testing and then daily during 5 consecutive days of Morris Water Maze testing (4 trials per day). Treated mice were compared to untreated transgenic controls and wild-type mice.

Tg AD mice treated with APH-0703 showed significantly improved performance in the water maze compared to untreated AD Tg mice. The APH-0703 treated mice exhibited significantly shorter latencies and swimming distances to find the hidden platform, with no difference in their swimming speeds. The most profound effect was found in the early days of testing with APH-0703 treated mice exhibiting maze performance nearly identical to the wild-type controls.

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Nanotechnology Formulation

Aphios has also developed improved methods for APH-0703 in oil and nanotechnology formulations for improving oral delivery and bioavailability (US Patent Pending).

APH-0703 Analogs

Aphios has discovered several novel analogs of APH-0703 that are equipotent or more potent than APH-0703 (US Patent Pending).

Partnering Opportunity

We are seeking a strategic corporate partner for the development and commercialization of APH-0703 and its analogs for Alzheimer's Disease and Cognitive Disorders.

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