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ALION’S COMPUTATIONAL CHEMISTRY

A measure of success of any novel approach in the development of new therapeutics is the speed and cost effectiveness of the methods. By these measures Alion’s proprietary computational approach has passed the test. Within one year, the approach identified molecules that have proven (in independent assays) active against our therapeutic targets, for Central Nervous System diseases.

Ion channel modulation offers an entirely new approach to the development of therapeutics. Unfortunately, as a consequence of a lack of structural information, ion channel modulators have only been identified by screening hundreds of thousands to millions of compounds, often with less than acceptable outcomes. Alion’s unique technology allows us to screen fewer than 500 compounds to identify potent ion channel modulators. Alion’s technology dramatically reduces the time and cost of early stage drug development.

The technology is applicable to designing small molecule leads for specific ion channels, namely:

  1. voltage sensitive Ca channels, including Ca V2.2
  2. N-type Ca channel blockers
  3. L-type Ca channel blockers
  4. P/Q Ca Channels
  5. a-Adenergic receptor
  6. NMDA and AMPA
  7. neuronal sodium channels
  8. nAchR, including non-competitive agonists and gated ion channel agonists 

Small-molecule inhibition of the direct protein–protein interactions that mediate many important biological processes is an emerging and challenging area in drug design. Conventional drug design has mainly focused on the inhibition of a single protein, usually an enzyme or receptor, since these proteins often contain a clearly defined ligand-binding site with which a small-molecule drug can be designed to interact. Designing a small molecule to bind to a protein–protein interface and subsequently inhibit the interaction poses several challenges, including the initial identification of suitable protein–protein interactions, the surface area of the interface (it is often large) and the location of small regions suitable for drug binding (from White et al. Expert Reviews in Mol Med., 10, March 2008).

Alion’s computational approach lends itself to the efficient discovery of compounds to modulate protein-protein interactions as demonstrated by numerous independent assays conducted for our Alzheimer’s disease and other Central Nervous System therapeutics projects. The methods are also capable of the efficient design of small molecule mimics of antibodies.

  1. With our computational algorithms we need only physically screen 200-700 Molecules to find highly active lead therapeutics. Often our lead molecules demonstrate nM affinity for their  target.
  2. Typically we have a 1-7% success in discovering very active leads from the first models. We have very stringent requirements for a molecule to be considered as “active”. Compounds with IC50 values greater than 2 µM are generally considered “inactive” by our selection criteria. Contrast this assessment with typical lead compounds that are developed in industry,  having mM IC50 values which means Alion’s approach is a significant improvement.
  3. Computational Chemistry and Biophysics. Physics and Chemistry are important antecedents to Biology.
  4. Proprietary computational algorithms.
  5. Confirm lead interaction with the target before biological studies.
  6. Multiple assays

ALZHEIMER’S DISEASE AND CEREBRAL AMYLOID ANGIOPATHY

Alzheimer’s Disease International have provided the following sobering figures,

(a) there were 36 million people living with dementia worldwide in 2010, increasing to 66 million by 2030 and 115 million by 2050,

(b) by 2010 the global cost of dementia was estimated at $604 billion,

(c) unless there is a cure or a treatment that delays the onset or progression of the disease, 682 million people will live with dementia in the next 40 years.

It is estimated that in 2015, more than 5 million people in the United States have Alzheimer’s disease. The number of Americans with Alzheimer's disease and other dementias will grow each year as the size and proportion of the U.S. population age 65 and older continue to increase. By 2025, the number of people age 65 and older with Alzheimer's disease is estimated to reach 7.1 million — a 40 percent increase from the 5.1 million aged 65 and older affected in 2015. By 2050, the number of people age 65 and older with Alzheimer's disease may nearly triple, from 5.1 million to a projected 13.8 million, barring the development of medical breakthroughs to prevent or cure the disease (from the U.S. Alzheimer’s Association).

Alion’s approach to the development of new AD therapeutics is twofold. Our computational approach identified New Chemical Entities (NCE’s) and existing therapeutics, developed for diseases other than AD. We have confirmed the activities of the NCE’s and existing therapeutics in a number of assays conducted both internally and independently of Alion. A repurposed therapeutic approach offers rapid entry into the clinic with anticipated therapeutic benefits to current AD patients. A second stage of therapeutic benefit is anticipated to follow as the NCE’s are evaluated in a clinical setting. Combination therapeutics may result from both the NCE’s and repurposed therapeutics.

Another aspect of Alion’s AD program is an anticipated effect of our molecules on the deposition of amyloidogenic proteins within the cerebral vessel wall. Cerebral amyloid angiopathy (CAA) is a frequent cause of intracerebral hemorrhage (ICH), a deadly and common type of stroke. Manifestations of CAA include dementia, ICH and small vessel ischemic strokes. CAA is very common in Alzheimer’s disease, with approximately 80% of AD patients having evidence of CAA. Up to 50% of patients with CAA will have clinical or pathologic evidence of AD. However, it is often an ICH that leads to the clinical presentation of patients with CAA. Besides AD, age is the most significant risk factor for CAA. There are no known methods to prevent the development of CAA or to prevent the development of ICHs in patients with CAA.

It is postulated that an age dependent and chronic deposition of amyloid protein(s) in CAA weakens the vessel wall and leads to microaneurysm formation and subsequent ICH. Another important aspect of amyloid deposition is the process of fibril formation. Soluble amyloid monomers are thought to aggregate and form larger amyloid fibrils, which are less soluble. As a consequence of the several MOA’s exhibited by Alion’s NCE’s and repurposed therapeutics, we anticipate that a treatment for CAA falls within the potential of our molecules.

FUTURE PROGRAMS

As our principal programs to develop therapeutics to treat Alzheimer’s disease has advanced, many new opportunities have emerged as a consequence of the central role the disease targets may play in the treatment of other indications. This follows from the central premise of the company, namely, that one molecule directed against a given target will have applications in the treatment of more than one disease. In 2016, Alion identified molecules the modulate α-synuclein and other proteins implicated in the development of Parkinson’s disease. In early 2017, Alion’s Parkinson’s therapeutics development program will begin.

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