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Myeloma Institute for Research and Therapy, Arkansas University for Medical Sciences. http://myeloma.uams.edu (Accessed May 2014).
Athersys
Athersys
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Athersys
The promise of stem cell research is being realized by biotechnology companies bringing the discoveries of great scientists out of the academic world, into therapeutic development, and to the market where they can be delivered to patients in need. Athersys Incorporated (Athersys), based in Cleveland, Ohio, is one of these biotechnology companies. Considered a clinical-stage biotechnology company, Athersys is developing therapies created using adult stem cells isolated from bone marrow and other tissue sources. They refer to these stem cells as multipotent adult progenitor cells (MAPC), which can be expanded on a large scale following isolation from a donor. Athersys’s current programs are based in part on the proprietary product under the registered trademark name MultiStem but also involve the use of their RAGE (Random Activation of Gene Expression) and other proprietary technologies used to identify various drug targets. These are described below.
History and Collaborations
Athersys was founded in October 1995 by Gil Van Bokkelen, PhD, and John Harrington, PhD, both who, as of 2014, continue to lead the company as chief executive officer and as chief scientific officer, respectively. Both also serve as directors. Dr. Harrington was a leader in the development of the proprietary RAGE technology. Described further below, RAGE is a novel gene activation approach that has applications in gene discovery, drug discovery, and commercial protein production, and has been in the demand of several other companies for use since its development. In 1997, Harrington helped Athersys create the first synthetic human chromosome. He now oversees process development, manufacturing, and clinical development.
In 2000, Athersys filed for initial public offering (IPO) with the goal of raising $115 million, as a functional genomics company. However, the proposed IPO was withdrawn six months later and instead went public in 2007 via a reverse-merger (or reverse IPO), with $65 million of funding coming from private companies Radius Venture, OrbiMed Advisors, RA Capital Management, Accipiter Capital Management, Hambrecht & Quist Capital Management, MPM BioEquities, and Pappas Ventures. The company now trades on the NASDAQ exchange under the ticker symbol ATHX.
In 2002, the two founders were the recipients of Ernst & Young LLP’s Entrepreneur of the Year Award in Biotech. The self-described “supersonic” projection of Athersys in 2002 continued through 2007, when the company advanced commercial collaborations with Bristol-Myers Squibb Company and Angiotech Pharmaceuticals Incorporated, representing success in applications of its technologies to pharmaceutical/drug applications. Athersys continues today as a biotechnology and regenerative medicine company whose primary activities are the discovery and development of therapeutic product candidates. As such, the company forms collaborations with other larger companies to take promising product candidates further to commercialization. Bristol-Myers Squibb primarily benefited from its multiyear collaboration with Athersys with RAGE technology, providing multiple successful drug targets in a variety of therapeutic areas, which have become active drug development programs at Bristol-Myers Squibb. On the other hand, the collaboration between Athersys and Angiotech is more narrowly focused per the interests of Angiotech, with Athersys providing multiple animal studies that demonstrate the safe delivery of MultiStem via cardiac catheter and the provision with such delivery, of functional benefit in models of acute myocardial infarction. Further details of RAGE and MultiStem follow.
Athersys was a founding partner of the National Center for Regenerative Medicine at Case Western Reserve University (CWRU) in 2003, along with CWRU, Cleveland Clinic, University Hospitals Case Medical Center, and The Ohio State University. The center focuses efforts on nonembryonic stem cell research with applications in heart disease, cancer, genetic disorders, and neurodegenerative diseases. In 2011, researchers collaborating from CWRU and Athersys published a study that demonstrated the regenerative potential of MultiStem in treating spinal cord injury. Several FDA investigational new drug (IND)–approved clinical trials have taken place at the center, along with an annual mesenchymal stem cell conference that began in 2007. In August 2014, the center presented an inaugural cancer stem cell conference and continues to provide an annual “Cell-Based Therapy and Tissue Engineering” short course that began in 2000. More information can be found at the center’s website: www.ncrm.us.
Random Activation of Gene Expression (RAGE)
The creation and process of RAGE was described in the 2001 Nature Biotechnology publication entitled “Creation of Genome-Wide Protein Expression Libraries Using Random Activation of Gene Expression,” led by John Harrington. RAGE is essentially a method or procedure of creating genome-wide libraries of cDNAs. In this seminal publication, the creation of RAGE libraries containing only 5 million individual clones was described as expressing all genes of interest tested, including those genes normally silent in the parent cell line, and with endogenous genes being expressed at similar frequencies and levels in libraries created from multiple different human cell lines. Various insertion vectors are utilized containing a promoter sequence, and an unpaired splice site allows the vector to be inserted via nonhomologous recombination, randomly into a eukaryotic cell’s (host) genome. The promoter sequence helps to activate expression of a gene transcript where the insertion point is upstream of a host gene, resulting in a chimeric protein made up in part of the vector-encoded sequence and a portion of the host cell protein.
One candidate protein isolated using the RAGE method that had become a lead product candidate for Athersys is a selective serotonin receptor 5HT2c agonist, called ATHX-105. The serotonin receptor 5HT2c is located in the area of the brain controlling appetite and food intake. Thus, the utility of the ATHX-105 agonist of this receptor is to reduce appetite and encourage weight loss. However, despite the completion of several phase I clinical trials for ATHX-105 demonstrating good safety tolerability, exposure levels, and regional absorption, toxicology findings in rodents and related expected risk, time, and costs of tests to resolve concerns resulted in the decision for Athersys to withdraw application for FDA IND and phase II clinical trials in 2008. The company is instead pursuing next-generation compounds with improved characteristics. Other product candidates identified using RAGE and other Athersys proprietary technologies that are in the Athersys pipeline include those for treating metabolic disorders and central nervous system disorders.
MultiStem
MultiStem is a patented stem cell product being developed by Athersys from multipotent adult progenitor cells (MAPCs) to be used in several different therapeutic areas, such as inflammatory, immune, neurological, and certain cardiovascular disorders. Examples include stroke, bone marrow transplantation, and oncology support, as well as other disease indications. As a stem cell–based product, it is considered a biologic product and as such falls under certain FDA and International Conference on Harmonization (ICH) guidelines. To meet these, Athersys is working with independent and clinical research institutions in the United States and in Europe, including Case Western Reserve University, as described above, and larger pharmaceutical companies such as Pfizer, Inc. In 2014, Athersys announced interim results from a phase II clinical trial, conducted by Pfizer, using MultiStem as a cell therapy in the treatment
