- ALS TDI has added a valuable new tool to its preclinical drug development program — the recently developed TDP43 research mouse model of ALS, which has a mutation in the TDP43 gene.
- The Institute has increased its emphasis on the development and use of biological indicators called "biomarkers" that can be used to show the presence and progression of a disease, the potential for a patient to respond to a specific drug therapy, or an indication of whether a therapy is working in an individual.
- ALS TDI's experimental drug ALSTDI-00846 may provide an example of how a nonprofit can reduce the time and cost associated with developing a drug and moving it to the clinic.
In continuing efforts to refine its preclinical drug development program, the ALS Therapy Development Institute (ALS TDI) of Cambridge, Mass., has added a new research mouse model to its operations, along with two new projects aimed at helping researchers test and develop therapies in the new mouse.
The Institute also has increased its emphasis on the study and use of biological indicators called “biomarkers,” and is working on practices designed to hasten ALS drug development industry-wide.
ALS TDI reported these new developments in an hourlong webinar (online seminar) produced May 18.
A new ALS mouse model
|ALS TDI researchers are working to fully characterize a new ALS research mouse, which has a mutation in the TDP43 gene.
ALS TDI Chief Scientific Officer Steve Perrin reported that the Institute will soon begin studying the recently developed TDP43 research mouse model of ALS, which has a mutation in the TDP43 gene.
Until now, most nonhuman ALS research has been conducted in the SOD1 research mouse, a strain engineered to have mutations in the superoxide dismutase 1 gene. However, familial (inherited) SOD1-related ALS accounts for only 1 percent to 3 percent of all human cases of the disease. Applicability of the SOD1 model to ALS that results from other causes has long been a matter of debate.
The TDP43 mouse is a valuable addition to the ALS toolkit, providing researchers with another model in which to study disease onset and progression, and to test experimental treatments.
Two new projects
Perrin described two TDP43 mouse model projects that ALS TDI intends to tackle as quickly as possible.
In the first, ALS TDI researchers will study and characterize the TDP43 mouse in an effort to best understand how to use it efficiently and rigorously in testing. Data will be collected on measurements such as the onset of paralysis and the rate of progression of the disease in these new research mice.
“ALS TDI’s [work] on the SOD1 mouse has really helped the community think about how to test and develop therapies in the SOD1 model,” Perrin said. “And we want to do this in the TDP43 model as quickly as we can.”
In the second project, the Institute will compare measurements in the TDP43 mouse with those in the SOD1 ALS mouse model and in mice without the disease — a critical next step, since it’s vital to know how various forms of ALS do and don’t overlap. Such testing also will help researchers determine whether an experimental treatment has an effect on any relevant biological pathways or processes, even if it doesn’t stop or slow the progression of ALS.
ALS TDI has increased its emphasis on the development and use of biomarkers — biological indicators (such as a mutation in a gene, or the presence of a protein in spinal fluid) that can be used to show the presence of a disease, the progression of a disease, the potential for a patient to respond to a specific drug therapy, or an indication of whether a therapy is working in an individual.
As an example, Perrin referenced some of the work TDI has done on its leading drug candidate, ALSTDI-00846.
Testing in the SOD1 mouse has shown that the immune system appears to attack the myelin sheaths insulating nerve fibers that send signals to skeletal muscles, he said. In animals treated with ALSTDI-00846 there are significantly fewer immune system cells associated with this attack.
“That’s an important biomarker,” Perrin noted, “just to be able to demonstrate that the drug is affecting a particular process or pathway.”
Out of approximately 600 blood samples taken from individuals with ALS, ALS TDI researchers have found that approximately half have biomarkers indicating increased activity in the pathway that ALSTDI-00846 is designed to target.
“That’s the type of information you want to present to a pharmaceutical company when you go to partner your molecule,” Perrin said.
Speeding drug development by reducing cost, time, risk
The way to get drugs to the clinic more quickly, Perrin said, is to “de-risk” the investment for pharmaceutical companies. This means taking on the risk and expense associated with the early stages of drug development, so pharmaceutical companies interested in taking the drug to market face less of a financial gamble.
Perrin reported that in 2007, it took an average of eight years to bring a drug to commercialization, at a cost of approximately $800 million. A discouraging study published in Nature Biotechnology in March 2010 showed the industry is now taking an average of 13 years to commercialize a drug at a cost of $1.8 billion.
ALS TDI’s experimental drug ALSTDI-00846 provides an example of how a nonprofit can dramatically increase the efficiency of this process, Perrin said.
The 00846 program has moved from the discovery of the relevant pathway in multiple tissues in ALS mice, to analyzing and building the drug, to understanding the way it works in the model and how to properly dose it, to survival efficacy studies demonstrating which doses work best in males and females, to identifying biomarkers of drug response. The entire process took approximately 24 months and $2.5 million.
Perrin attributes the reduction in cost and time to a number of factors: funding from multiple sources; focus on a single disease; commitment of all resources to ALS drug development; and the development of a complete preclinical package that “fills in all the gaps.”
“It doesn’t have to be as complicated or time consuming or expensive as the industry standard,” Perrin said, “and I think you’re going to see that change over time.”
The next quarterly ALS TDI research update will take place July 20 at 6 p.m. EDT.
To view the archived May 18 webcast, visit www.als.net; click on the “Get Involved” tab, followed by the “webinar: The ALS CRISIS” banner; then click on the Q1 2010 Research Update Webcast link in the schedule section. (You must register to view the webcast.)