Aphios Corporation is developing a novel Alzheimer's disease therapeutic called APH-1104. Preliminary studies show APH-0703, an analog of APH-1104, improved cognition in an Alzheimer's patient and transgenic mouse models. APH-1104 works by increasing alpha-secretase activity to produce a harmless form of amyloid precursor protein, preventing amyloid plaque buildup. Aphios plans to establish manufacturing and submit an investigational new drug application to the FDA to begin clinical trials of an oral formulation of APH-1104.

1. 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

2. Partnering for the future
of human health™
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 cholinesterase inhibitor) only treat the symptoms, not the
underlying disease; currently, there is no cure for AD

3. Partnering for the future
of human health™
Amyloid Plaque and Neurofibrillary Tangle
Formation in Alzheimer’s Disease

4. Partnering for the future
of human health™
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 A
plaque-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

5. Partnering for the future
of human health™
APH-1104 for Alzheimer’s Disease
• A potent α-secretase modulator for
ameliorating Alzheimer's Disease pathophysiology 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

6. Partnering for the future
of human health™
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 γsecretase to minimize A plaque formation, our strategy involves the
activation of α-secretase leading to beneficial amyloid precursor
processing and prevention of A buildup

7. Partnering for the future
of human health™
Nanoencapsulated APH-0703 Effectively Activates
-Secretase in Neuroblastoma Cells
APH-0703
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

8. Partnering for the future
of human health™
Morris Maze Trials
A
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 5
g APH-0703 to escape from mice swimming pool

9. Partnering for the future
of human health™
APH-0703

10. Partnering for the future
of human health™
Phase I/IIa 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

11. Partnering for the future
of human health™
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

12. Partnering for the future
of human health™
Summary
(continued)
 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

13. Partnering for the future
of human health™
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

14. Partnering for the future
of human health™
Contact Information
• Office Phone: 001 (781) 932-6933
• Cell Phone: 001 (781) 858-7520
• Office Fax: 001 (781) 932-6865
• E-mail: tcastor@aphios.com
• Website: www.aphios.com
• Mailing Address: 3-E Gill St. Woburn,
Dr. Trevor P. Castor, MA 01801 USA
CEO