In January 2007, MDA and the nonprofit biotech ALS Therapy Development Institute (ALS TDI) of Cambridge, Mass., launched a three-year, $36 million drug discovery partnership. In January 2010, MDA extended that partnership with a $2.5 million grant.
ALS TDI’s first research update webcast of 2010, hosted on Jan. 14, included a rundown on the status of the Institute’s drug development pipeline and its leading therapeutic, ALS TDI 00846; recent grant and collaboration news; an innovative addition to its online message board (ALS Forum); and an introduction to the “Dashboard,” the face of the Institute’s information management system.
ALS TDI Chief Scientific Officer Steve Perrin provided an update on ALS TDI’s leading therapeutic candidate, a protein biologic known as ALS TDI 00846.
The compound is an antibody (immune system protein) designed to modulate the immune response through a pathway called CD40L. ALS TDI scientists have determined that in mice with an ALS-like disease, CD40L pathway activity is increased (“upregulated”) in the spinal cord, skeletal muscle and sciatic nerve.
ALS TDI 00846 hits the CD40L target, a particular cell-surface receptor that is present on a number of different types of cells associated with the immune system, Perrin reported.
Multiple ALS TDI mouse studies of the compound have shown a small but significant increase in survival, muscle function and survival of motor neurons (which normally die in ALS); and a decrease in the harmful activation of normally supportive cells called astrocytes.
Perrin noted that once scientists were confident the drug was working, they then began trying to figure out how it worked. Pinpointing that mechanism may help in the identification of related drugs with better safety profiles, greater specificity, or the ability to hit similar pathways that produce an even greater effect.
“It’s a very important question,” said Perrin. “Once we find a drug that has an effect similar to the size of the effect we’re seeing with this drug, we could treat them as a combo therapy and try to amplify the effect with a combination of the two drugs at various doses.”
Study results in mice have shown that the drug knocks down almost every one of the approximately 20 genes in the CD40L pathway. But it remains to be seen whether the CD40L pathway data from mice with ALS is relevant to humans with the disease.
Over the last three years, Perrin noted, ALS TDI has partnered with several MDA clinics nationwide that have been collecting samples of blood, muscle, skin and fat from people with ALS. The collection currently contains approximately 400 blood samples, which scientists at the Institute have profiled, along with an equal number of non-ALS samples, in order to measure patterns of gene activity (gene “expression”). They found a subset of patients — approximately half — have highly upregulated genes in the CD40L pathway.
Perrin affirmed that a great deal of work has been done on 00846, including testing in hundreds of mice. He said the Institute hopes to move the compound into clinical trials by the end of 2010, and that it’s working to find a pharmaceuticals partner to help move the compound through testing and into the clinic as quickly as possible.
In addition to 00846, Perrin noted, ALS TDI has many drugs in its pipeline and ALS TDI researchers are working on 30-plus different potential therapeutics.
New funding, partnerships
ALS TDI Communications Director Rob Goldstein reported on a number of developments on the Institute’s funding front, including a renewal of “critical funding” from MDA.
Goldstein thanked MDA for providing “a renewal of their partnership and investment in ALS research,” with the new $2.5 million grant aimed at continuing the search for therapeutic targets in ALS. The funds were awarded through MDA’s Augie’s Quest, a fast-track ALS research initiative spearheaded by ALS Co-Chairs Augie and Lynne Nieto. Four times a year, representatives from MDA and ALS TDI, along with a number of expert ALS researchers, will review the goals and progress associated with the milestone-driven grant.
Another key funding partnership, announced Jan. 12, has come in the form of a multiyear grant awarded through the 2010 Defense Appropriations Act, signed by President Obama on Dec. 22, 2009, and provided to ALS TDI through the Department of Defense. The money will fund development and advancement of new therapeutics.
Goldstein also reported on the Applied Proteomics partnership announced Dec. 12, 2009, that will use animal and human samples to identify and validate protein markers for ALS. Protein markers — changes in protein levels that correlate with disease progression — are useful for diagnosis and analyzing response to treatment.
The work “will help us to further understand and prioritize what’s going on,” both in the ALS model and with human samples collected from clinics, “to identify key points that we can attack with new therapeutics,” Goldstein explained. This in turn may help speed clinical trials by allowing phase 1 trials to be bypassed.
Goldstein said the proof-of-concept work is complete and data will be presented at the next ALS TDI research update webcast in April.
New Web site feature
The ALS Forum — ALS TDI’s lively and comprehensive message board for people with ALS and their caregivers — has welcomed the newly formed ALS Forum Response Committee. The committee meets once a week to discuss some of the topics raised on the Forum, and posts responses designed to inform participants and help steer discussions.
“These posts are not meant to be an ‘answer’ or to replace any specific advice you are given by your personal medical team,” said Perrin in announcing the new feature.
The hope, said Goldstein, is that the experts’ responses will contain “both information from the preclinical, and experience from the clinical side of research,” and that these responses “will enable readers to become better informed and therefore better armed to make treatment decisions in consultation with their personal medical team.”
Forum moderators at ALS TDI will identify topics from among those that come up on the message boards and submit them to the committee for review and response. There are no plans to allow direct questions from readers as, Goldstein said, “the idea is to add value to the conversation taking place between ALS patients, caregivers and others on the ALS Forum — not replace that system altogether.”
Response Committee members include three ALS experts with close ties with MDA: Merit Cudkowicz, Jonathan Katz and Stanley H. Appel. Other members are ALS TDI preclinical experts John Lincecum and Fernando Vieira, and medical/science writer Carey Goldberg.
MDA research grantee Cudkowicz at Massachusetts General Hospital in Boston also is director of the MDA/ALS center at that institution and serves as an adviser to MDA’s translational research program. Jonathan Katz serves as co-director of the MDA/ALS Center at California Pacific Medical Center in San Francisco.
A longtime MDA adviser and research grantee, Appel is director of the MDA/ALS Clinical Research Center at the Methodist Neurological Institute in Houston. An MDA clinic director since the 1970s, Appel is a member of MDA’s Board of Directors, has served as chairman of the MDA Scientific Advisory Committee and currently serves as an adviser on matters concerning MDA’s translational research efforts.
Forum readers may access the experts’ responses at www.als.net/aboutus/committee.aspx.
‘Dashboard’ points the way
Perrin also briefed viewers on “The Dashboard,” the face of the ALS TDI information management system that is an effort to bring together all information on ALS, including thoughts and comments on journal papers and related literature, lab processes and any relevant “information in the scientist’s brain.”
The Dashboard electronically captures data and puts it into a database, and tracks scientist input. It’s hoped it will inspire ideas that lead to projects and then serve as a project management tool by helping researchers gauge where the project stands, what’s holding it up and how to proceed.
The idea, Perrin said, is to “capture live and archive forever.”
The next quarterly ALS TDI research update will take place April 22 at 6 p.m. EST. To participate in the webcast, go to www.als.net. Registration (free) is required.
The first-quarter 2010 webcast has been archived on the Institute’s Web site.