Alzheimer's Disease (AD) is a significant neurological disorder that afflicts more than 4.5 million Americans and more than 10 million people worldwide. The lack of a cure for AD will result in a demand for better and safer AD drugs. All of the drugs on the market today have serious side effects. Recently, researchers at The Blanchette Rockefeller Neurosciences Institute, Rockville, MD have hypothesized and shown that protein kinase C (PKC) and its activation are important means of ameliorating AD pathophysiology and cognitive impairment. They have shown that sub-nanomolar concentrations of bryostatin 1, a potent PKC activator, dramatically enhance the generation of non-amyloidogenic soluble amyloid precursor protein (sAPP) in fibroblasts from AD patients. Bryostatin 1 was effective in reducing brain amyloid plaques (A240 and A242 in AD) in double-transgenic mice while improving behavioral outcomes and the rate of premature death. These researchers have also shown that bryostatin 1 not only produces a neuroprotective effect but also enhances cognitive memory in AD animal models. Bryostatin 1 is a complex cyclic macrolide molecule that occurs in very small concentrations (~ 5 to 25 ppm) in a bryozoan, sometimes referred to as a "sea moss" found off the coast in Southern California. Bryostatin 1 is also more hydrophobic than paclitaxel, the potent anticancer drug with well-known formulation difficulties. Aphios has developed and patented improved methodologies and manufacturing processes for cost-effectively isolating pharmaceutical-grade bryostatin 1 from Bugula neritina. Our scientists and engineers have also developed methods for formulating hydrophobic molecules such as bryostatin 1 in stable, readily bioavailable oil-based formulations, and novel nanotechnology formulations of bryostatin 1 that will further improve oral bioavailability. Aphios'Zindol(R) product, which contains oil soluble gingerols and shogaols, recently completed a successful Phase II/III clinical trial for nausea and emesis in cancer patients undergoing chemotherapy. Our Phase I Specific Aims are to: (1) Develop conventional and nanotechnology oral formulations of bryostatin 1;and (2) Test stability of selected formulations under accelerated conditions of temperature and humidity, and evaluate in vitro characteristics and in vivo efficacy. We have set three milestones to be achieved before moving on to Phase II. Our Phase I milestones are as follows: stable lyophilized and/or oil-based nanoparticles formulation of bryostatin-1 in the size range of 100 to 200 nm range containing 1 to 10 5g/mL bryostatin 1 with a drug:polymer ratios of 1:10 to 1:100;brief (5-15 minutes), low dosages (0.04-0.2 nM) and application frequencies 1-2 x /week will provide maximal PKC activation and minimal downregulation;and 30% to 50% enhancement of learning and memory in the wild type of mice and even greater enhancement in the transgenic mice due to neuroprotection. Our Phase II Specific Aims are as follows: (1) Specific Aim 1: For selected formulations, radioactive bryostatin 1 will be assayed to determine the pharmacokinetics and tissue distribution. Pharmacologic efficacy will also be measured, particularly in the brain and plasma compartments by total PKC activity, membrane/cytosolic PKC activity ratios, and phosphorylation of ERK 1/2 MAP Kinase;and (2) Specific Aim 2: Establish cGMP manufacturing of the bryostatin 1 API (active pharmaceutical ingredient) and FDP (final or formulated drug product) at the pilot-scale level. Establish a Drug Master File, design IND-enabling preclinical studies and Phase I/II clinical trials, and draft IND package: In a Phase III commercialization effort, we will conduct IND-enabling preclinical in vivo studies, including toxicology, efficacy, pharmacology and stability testing of selected formulation of bryostatin 1 drug product under Good Laboratory Practices (GLP) conditions. These studies will be conducted by a CRO such as Southern Research Institute or Covance Laboratories. As part of our commercialization effort, Aphios Corporation will also establish a wholly owned subsidiary Amylon Pharmaceuticals to focus on the discovery and development of novel therapeutics for Alzheimer's Disease and Cognitive Disorders with bryostatin-1 as its lead compound. Amylon Pharmaceuticals will raise a Series A round of $20 million USD in equity capital to accelerate the development of bryostatin 1 for Alzheimer's Disease and Cognitive Disorders. This capital will be utilized to: (i) establish a management and product development team;(ii) conduct Phase I human clinical trials;(iii) research and development of second- generation products;and (iv) manufacture cGMP products over a two-year period. Within 12 months of the Series A raise, Amylon plans to initiate the establishment of a $25 million USD Series B round to conduct Phase II clinical trials in year 3. Later, Amylon plans to do an IPO to raise $100 million to conduct Phase III clinical trials and commercialize bryostatin 1 for Alzheimer's Disease and Cognitive Disorders. Alternatively, at this stage, Amylon will merge with a mid-tier public company or be acquired by a multinational pharmaceutical company.

Public Health Relevance

Alzheimer's Disease (AD) is the third largest cause of death in America and among the highest in the industrial world. AD is a significant neurological disorder that affects more than 4.5 million Americans and more than 10 million people worldwide. This problem will increase with the demographics of aging populations in United States, Europe and Japan. Experts estimate that 22 million people around the world and more than 8 million Americans would be affected with AD by 2025. The total market of AD drugs in 2005 was over $2.7 billion. Due to the changing demographics, the market is expected to grow quickly. Because of the growing number of new cases each year, the market is expected to grow at a rate of 17.5%. To meet this unmet medical need and market demand, we propose to develop a novel therapeutic that has the potential to significantly reduce the personal quality of life and national financial impact of this debilitating disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZRG1-ETTN-C (11))
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Refolo, Lorenzo
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Aphios Corporation
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