May 5, 2005

A Report on the 2005 ALSA Drug Company Working Group Meeting

The 2005 meeting of The ALS Association (ALSA) Drug Company Working Group highlighted innovative techniques by biotech industries for finding new treatments for amyotrophic lateral sclerosis. The participants also learned details on the collaborative approach to prioritizing promising treatments for ALS.  

Some 40 leading ALS clinicians, academicians and representatives from industry, and the National Institutes of Health, and the Food and Drug Administration, came together on April 12 at this affiliate gathering at the American Academy of Neurology annual meeting in Miami. Participants from ALSA included Stevan Gibson, Vice President, Government Relations & Public Affairs, Ellyn Phillips, ALSA National Trustee and Chair of ALSA’s Advocacy Committee and President of ALSA’s Greater Philadelphia Chapter, and Dara Alexander, ALSA National Trustee and President of ALSA’s Florida Chapter.

ALSA initiated the annual gathering in 1995 to stimulate and accelerate advances in treatment. The Working Group provides a forum for ongoing dialogue on the opportunities and challenges in translating laboratory findings on the disease process of ALS into clinical advances. Goals for this Spring 2005 meeting were to update industry representatives, scientists and clinicians about progress in prioritizing existing candidates for testing, and inform on industry approaches to finding new candidate therapies.

ALSA Vice President and Science Director Lucie Bruijn, Ph.D., opened the meeting by noting "This is a time when true partnerships with industry are possible. Already progress is evident in the cooperative effort with the National Institutes of Neurological Diseases and Stroke, and other ALS organizations, as well as industry," Bruijn said.

Selection and Prioritization of Therapeutic Candidates for ALS

Bryan Traynor, M.D., of Massachusetts General Hospital in Boston, explained how promising therapeutics for ALS are being prioritized. For 112 proposed therapeutics, experts have tried to determine what additional information is needed to enter an agent into definitive clinical testing, that is, a Phase III trial.

The group working on this project has purposefully sought a broad variety of molecular mechanisms of action in selecting candidates. They also sought compounds with the best evidence for safety and lack of toxicity. Experts in ALS, pharmacologists, clinicians, and researchers from NINDS, have reviewed the merits and drawbacks to all available drugs or compounds that have been suggested to protect nerve cells. Input has also come from the ALS community internationally to inform the decision process.

The goal is to produce a document that will guide the community where to invest the appreciable time and money required for clinical trials. The manuscript of prioritized candidate treatments will be submitted for peer review shortly. ALSA’s Research Department will be issuing a request for proposals in the upcoming months to fund a pilot study or studies based on this effort.

Biotech Approaches to ALS

Representative biotech companies presented their approaches towards ALS therapies. Bruijn noted, “It is encouraging that so many biotech companies are paying attention to the disease.”

Ann Sluder, Ph.D., with Cambria Biosciences, Mass., described the millimeter long worm, C. elegans, as a powerful tool that biotech companies use to model many neurodegenerative diseases. The transparent worm has 959 cells, and the wiring diagram is explicitly understood. Genetics are easily manipulated, and the turn around to make a transgenic worm is days rather than months for a mouse.

Cambria Biosciences is now going to take the worm into the ALS arena, to try to learn more about Riluzole. The sole drug approved for use in ALS, Riluzole is only a small step towards effective therapy in the disease. Using well described techniques and genetic approaches in the worm, investigators hope to identify additional targets that Riluzole may be acting on to change the disease course. This knowledge may potentially lead to improved therapeutics.

Frank Bennett, Ph.D. of Isis Pharmaceuticals in San Diego, discussed the company’s flagship antisense approach to treating diseases. The strategy, to stop production of proteins by promoting degradation of specific RNAs (as RNA translates the genes into proteins), allows scientists to rapidly turn a gene discovery into a therapeutic. Isis has used this approach in other diseases: one antisense agent is already in clinical use in an eye disease, and several more are in clinical trials.
 
In an ongoing collaboration with leading ALS researchers, Isis is providing antisense agents for tests in animal models of ALS. Discussions are under way on how to bring this approach into the clinic. Working with ALSA funded researcher Don Cleveland, at the University of California, San Diego, Isis aims to get an RNA based therapeutic into clinical testing. Although this approach is currently designed to dampen the production of mutant SOD1 and is therefore effective for only a small percentage of ALS patients, it may have application for other forms of the disease as we learn more about the proteins involved. Secondly these studies provide an important proof of concept for the use of antisense in neurological disorders, Bennett emphasized.

Raymond Bartus, Ph.D., spoke about the prospects for a gene therapy for ALS, with the contribution toward that goal from his San Diego based company, Ceregene Inc.. Three decades of research show that the nerve maintaining factors such as nerve growth factor, and insulin-like growth factor (IGF-1), have potential for neurodegenerative diseases such as ALS. An appropriate trophic factor can attack the root cause of these diseases, even if we don’t know what that is, Bartus said. Gene therapy can get these trophic factors into the target tissue without producing side effects from misplaced actions in the rest of the body.

A collaborative effort to put a gene therapy delivering IGF-1 into clinical testing is a new direction for the company (see http://www.alsa.org/news/article.cfm?id=477 ). Bartus and Ceregene were focused on Parkinson’s disease and Alzheimer’s, when they were captivated by the exciting work published in 2003 in the journal Science, on the potential for bringing a trophic factor directly to the ailing nerve cells in ALS. A collaborative research team involving Fred Gage, Ph.D., and colleagues at The Salk Institute for Biological Studies in San Diego, and Jeffrey Rothstein, M.D., Ph.D., of Johns Hopkins University in Baltimore, reported that IGF-1 can be efficiently transported from muscle to motor neurons using a viral transport mechanism. This treatment increased survival of transgenic mice modeling the disease.

The biotech industry knows now that ALS is a promising target for innovative effort, according to Bruijn. “When results come from the academic labs and the companies see a way to move it forward,” Bruijn said, “we at ALSA can help facilitate these partnerships.”