Two dozen researchers from academia, government, biotechnology, and the pharmaceutical industry met recently to discuss how to push forward with development of biomarkers in order to speed ALS clinical trials. The one-day meeting ended with new commitments to improve infrastructure and standardize collection of biospecimens, and new appreciation of how far the field has come, yet how much remains to be done to develop robust markers for ALS. “We are moving closer to solving this important problem,” said Lucie Bruijn, Ph.D., M.B.A., ALS Association Chief Scientist and co-host of the meeting, along with Steven Perrin, Ph.D., President of the ALS Therapy Development Institute in Cambridge, Massachusetts.
A biomarker is a measurable quantity, such as cholesterol in the blood or the brightness of a spot on an x-ray, that correlates with some aspect of a disease process. The use of a biomarker has the potential to allow clinical trials to be smaller and faster, thus allowing more new therapies to be tested rapidly.
Disease Subtypes and Types of Biomarkers
A major challenge in ALS is the diversity of the disease itself, noted Robert Brown, M.D., Ph.D., of University of Massachusetts Medical Center. There are 35 genes and counting known to cause or increase the risk of ALS and multiple different clinical subtypes. This all suggests there may be different disease processes at work in different individuals. It would be valuable to have biomarkers for each of those processes.
The existence of subtypes in ALS is one likely reason that clinical trials have had such difficulty demonstrating benefit of new treatments. If a treatment is beneficial in only one subtype, but the trial enrolls all subtypes, the beneficial signal will be diluted out, and the overall result will not be positive. Biomarkers for subtypes of ALS, especially those connected to different disease processes, would be very valuable for stratifying individuals in a trial, to measure the treatment effect within each group, said Merit Cudkowicz, M.D., of Massachusetts General Hospital.
Some progress has been made. Recently, groups competing for the Prize4Life challenge in ALS showed that rate of disease progression could be predicted from a small set of blood-based markers. Using those in future trials should allow researchers to more finely analyze whether treatment slowed progression versus what would have been expected for each individual person, based on their baseline level of these markers. “The biggest fear is that we are missing effective treatments in subpopulations,” Dr. Cudkowicz said.
Biomarkers that determine whether a drug is “hitting its target” in the central nervous system are also valuable. Dr. Cudkowicz noted that two new trials, one of the anti-inflammatory tocilizumab and the other of anti-epileptic retigabine, will be using this type of biomarker.
Other disease process-related biomarkers that involve inflammation were discussed at the meeting, including newly discovered candidates presented by several researchers. These promising developments will be explored in more detail in the lab in order to gauge their utility in clinical trials.
Motor unit number estimation (MUNE) measures electrical properties of muscle-nerve interaction to determine the degree of loss of motor neurons, a direct measure of the disease process. Measurement of MUNE can be done easily in the clinic and is painless for the subject. It is less subject to fluctuation than the ALS Functional Rating Scale, the measure typically used in clinical trials to track disease progression. MUNE has been used on trials and may become more widely employed. In addition, EIM, or electrical impedance myography, is an emerging measure that has attractive attributes for following disease progression, included excellent reproducibility and ease of measurements, as well as a clear pattern of change with disease state.
Several members of the group spoke about efforts underway in other neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Much of those efforts center on imaging, using markers for accumulation of toxic proteins in the brain. An unmet need in ALS is to develop such a marker for accumulation of the TDP-43 protein, which aggregates in most people with ALS, and might be useful for tracking disease progression.
The Importance of Biosamples
Those at the meeting agreed that current efforts at collecting biosamples from people with ALS should be continued and strengthened. Samples such as blood and cerebrospinal fluid collected during a trial can be analyzed, even well after the end of the trial, to determine if some aspect of the disease process was altered by treatment. The Northeast ALS Consortium (NEALS), the clinical trial consortium, is standardizing collection procedures for biosamples, a critical part of the process to ensure that the samples are preserved the same way at different centers. In conjunction with these efforts, NEALS through its NeuroBank initiative, has developed a web-based patient identification system, so that individual samples collected at different times from the same person can be correlated, even if the samples are in different centers and were collected in different trials.
Cerebrospinal fluid (CSF) has yielded “probably the best characterized biomarkers in ALS,” according to Robert Bowser, Ph.D., of Barrow Neurologic Institute. Neurofilaments, which are part of the cell’s structural skeleton, are also found in the CSF. The amount and types of specific neurofilaments in the CSF are characteristic of ALS and may find use in early diagnosis. They may also be useful for establishing prognosis early on.
Cooperation and Directions for the Future
Members agreed that increased cooperation could speed development of multiple initiatives. Standardization of operating procedures in biosample collection will be worked on by members of the group. Harmonizing data collection during studies will also be useful, as it will allow analysis of larger data sets in the future. Opportunities exist for federal funds to catalyze these efforts.
“This is an extraordinary moment in ALS, with advances in genetics and significant work on biomarker development,” Dr. Brown said. “We are poised for major progress here.”