In contrast to traditional drug discovery approaches, which heavily focus initial drug development efforts primarily on compound potency and selectivity, Athersys has employed a rigorous compound assessment approach that broadens selection criteria to include extensive toxicity, PK, and bio-distribution testing early in the lead development process. We believe this approach has enabled the company to eliminate less promising compounds earlier in development. Athersys has advanced programs only where it has developed multiple, patentable compound series and where its compounds meet stringent performance requirements.
An early step in the drug discovery process involves screening a large number of compounds to identify molecules that affect the activity of specific drug targets of interest. To facilitate large-scale compound screening, Athersys has made use of a strong high-throughput screening (HTS) capability that allows for the rapid analysis of the company’s small molecule library. Utilizing its semi-automated screening platform, Athersys has demonstrated the ability to undertake multiple screening formats on a wide-range of drug target classes.
During HTS, Athersys has utilized its core compound screening deck of approximately 100,000 molecules. This proprietary set of compounds has been extensively optimized for drug-like physical and chemical properties, as well as for a high degree of chemical diversity. The company has an additional 300,000 compounds within its library, primarily consisting of analogs related to compounds found within the screening deck. This has provided Athersys with the ability to quickly access and test compounds that are closely related to active compounds identified during HTS, leading to the rapid improvement of drug characteristics. The Athersys library has proven to be a rich source of novel, patentable compounds directed to several CNS and peripheral drug targets.
Following HTS, compounds initially identified as “hits” have been further optimized using traditional medicinal chemistry through the development of structure-activity-relationships (SAR). The company has focused on rapid structural confirmation of new compounds, allowing molecules to move rapidly from synthesis to pharmacological testing. Moreover, its analytical chemistry approach has enabled the company the ability to analyze compound concentrations in biological tissues and quickly understand ADME (absorption, distribution, metabolism and excretion) properties.
As part of its drug discovery strategy, Athersys has focused on multiple, distinct chemical series in each of its target programs. This strategy ensures that the success of the program is not dependent on a single class of compounds, and thus increases the likelihood that a compound will emerge that meets the company’s high standards of efficacy and safety.
Historically, Athersys’ medicinal chemistry approach has emphasized rapid iterative cycles of synthesis, and in conjunction with the application of pharmacology early in the development cycle (see below). This approach has resulted in exceptional productivity. While Athersys does not currently have extensive internal medicinal chemistry capabilities, the company utilizes outside contract service organizations to advance active discovery stage projects in a selective and focused manner.
As part of the company’s rigorous and disciplined approach to drug discovery, all compounds have been taken through a three-tier evaluation system in which compounds must pass increasingly stringent standards for further development. Important safety analyses have been performed in the first and second tiers so that compounds that might have side effect liabilities have been quickly identified and eliminated from further consideration. This has allowed the company to focus its efforts on those compounds that have the greatest chance of future clinical success.
As compounds progress through the Athersys tier system, we have obtained information related to compound specificity, selectivity, half-life and disposition in animals, toxicological properties, and efficacy in disease models. Athersys has applied a rigorous pharmacological testing, including testing for effects on liver enzymes, specific cardiac channels, and a large number of unrelated targets where interactions might be problematic. In addition, the company has evaluated the effects of compounds on animal behavioral endpoints, organ pathology and cardiovascular function to further increase confidence that a compound will be safe and efficacious.