Aphios amylon ncs_presentation_110113

Partnering for the future of human health™

a wholly owned subsidiary of Aphios Corporation

Developing a Novel Therapeutic, APH-1104

for

Alzheimer’s Disease and Cognitive Disorders

Dr. Trevor P. Castor President & CEO

3-E Gill Street, Woburn, MA 01801, USA

November, 2013


Alzheimer’s Disease (AD)

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

Significant neurological disorder that affects more than 4.5 million Americans and more than 10 million people worldwide

Total market of AD drugs in 2005 was over $2.7 billion; the market is expected to grow at a rate of 17.5% per year

The 4 FDA-approved drugs (e.g. Aricept, a cholin-esterase inhibitor) only treat the symptoms, not the underlying disease; currently, there is no cure for AD


Amyloid Plaque and Neurofibri l lary Tangle Formation in Alzheimer’s Disease


Novel Alzheimer’s Disease Therapeutics

Proteolytic processing of APP leading to extracellular A deposits involves the action of - and γ-secretases

Inhibitors of both - and γ-secretases have been evaluated as Aplaque-suppressing therapeutics in AD; while they are active in vitro, clinical trials have been largely unsuccessful

A recent Phase III clinical trial with Semagacestat, a γ-secretase inhibitor, by Eli Lilly was halted because of accelerated dementia

A recent Phase II clinical trial with a β-secretase inhibitor, LY2886721, also by Eli Lilly, was halted because of liver toxicity

There have been several Phase II and III clinical trial failures by Pfizer, AstraZeneca, Johnson & Johnson and Baxter


APH-1104 for Alzheimer’s Disease• A potent α-secretase modulator for

ameliorating Alzheimer's Disease patho-physiology and cognitive impairment with neuroprotection

• Exploratory Phase I/IIa clinical trial in the Bahamas (IV administration)

• Preclinical development of oral formulation (capsule and PNS nanotechnology)

• Next Steps – IND followed by Phase I/II clinical trials in the US


APH-1104 - Novel AD Therapeutic

APH-1104, an analog of APH-0703, up-regulates the production of -secretase which cleaves the amyloid precursor protein APP into a harmless soluble form sAPP- , which is non-neurotoxic and limits the formation of amyloid plaques

Both β-secretase and γ-secretase cleave APP to form an insoluble amyloid plaque (A ) that leads to tau entanglement

Thus, unlike current strategies which suppress β-secretase and γ-secretase to minimize A plaque formation, our strategy involves the activation of α-secretase leading to beneficial amyloid precursor processing and prevention of A buildup


Nanoencapsulated APH-0703 Effectively Activates -Secretase in Neuroblastoma Cells

α–secretase activity induced by APH-0703, Nano A, Nano B, Nano C and Nano D at 10-8M, 10-9M , 10-10M in SH-SY5Y neuroblastoma cells for 3h

APH-0703


Morris Maze TrialsA B

Latency to escape(Seconds to reach hidden platform)

Morris Maze trials (A) were conducted to measure the latency in seconds (B) of wild type and AD transgenic mice treated with vehicle alone and 5g APH-0703 to escape from mice swimming pool


APH-0703


Phase I / I Ia Exploratory Clinical Study of APH-0703, Nassau, Bahamas (n= 1)

• Patient - a 95 year old male with severe Alzheimer’s Disease

• Over 6-month period, MMSE score dropped from 20 to 15

• ADAS-Cog score increased from 29 to 38

• Patient also on several medications including Donepezil (Aricept 10 mg) and Memantine (10 mg) for memory loss

• After 2 i.v. cycles of APH-0703, patient very alert, remembers date, mind active, engaged in watching TV, aware of need to relieve himself, sleeping through the night


Summary

APH-0703, intravenously administered, shows preliminary efficacy in an Alzheimer’s Disease patient (n=1 study)

APH-0703 is a potent activator of -secretase which cleaves APP to form the soluble s-APP which is harmless, supports the formation of synapses, and can be removed in neuronal fluids

Nanoencapsulated APH-0703 significantly increases that activity of native APH-0703 in -secretase and PKC in vitro assays

APH-0703 continues to stimulate -secretase for at least 24h after it is removed from the cellular environment


Summary ( cont inued)

Oral APH-0703 in oil and nanoparticle formulations significantly improve learning and memory retention in the transgenic mouse model, APP/PS1, of Alzheimer’s disease

These effects are seen within 2 weeks of administration, earlier than in any previous study

Retention studies indicate that memory improvements persist for at least 3 weeks following drug washout

APH-1104, a more potent analog of APH-0703, formulations represent a highly effective modality for treating Alzheimer’s Disease


Next Steps

Establish cGMP for API and FDP at the pilot-scale level (ongoing)

Establish a Drug Master File, design IND enabling preclinical studies and Phase I/IIa clinical trials, and draft IND package (ongoing)

Conduct FDA-necessary IND-enabling preclinical in vivo studies, including toxicology, efficacy and pharmacology, under GLP

Perform stability testing of API and FDP under GLP

File IND for conducting Phase I/IIa clinical trial of oral APH-1104

Conduct Phase IIb clinical trials


Contact Information

• Office Phone: 001 (781) 932-6933

• Cell Phone: 001 (781) 858-7520

• Office Fax: 001 (781) 932-6865

• E-mail: [email protected]

• Website: www.aphios.com

• Mailing Address: 3-E Gill St. Woburn,

MA 01801 USADr. Trevor P. Castor, CEO

mailto:[email protected]

http://www.aphios.com/

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Aphios amylon ncs_presentation_110113

Health & Medicine