- An urgent need exists in ALS research for biological indicators called biomarkers that can be used for diagnostic purposes, to measure disease progression and to assess drug performance in clinical trials.
- Imaging has advanced to the point where some techniques are now being utilized in ALS studies.
- Other potential biomarkers include those based on electrical activity in the brain, spinal cord and muscles; proteins in the blood, urine, spinal fluid, muscles or other tissues.
- The use of biomarkers in clinical trials allows for more informed decisions and better odds of a return on investment, and has become crucial to late-stage development of promising drug candidates.
An urgent need exists for biomarkers — biological indicators — in ALS research that can be used:
- for diagnostic purposes;
- to measure disease progression; and
- to reliably assess the effects of experimental drugs in clinical trials.
“If you compare a disease like ALS to multiple sclerosis [MS], you’ll find that the MS field is much further along in developing effective therapies that ameliorate disease progression,” says neurologist Bryan Traynor, head of the Neuromuscular Diseases Research Unit at the National Institutes of Health in Bethesda, Md.
Traynor notes that MS clinical trials have been facilitated by the availability of a reliable MS biomarker that can quickly reveal whether or not an experimental therapy is effective. Having an MS biomarker has made development of drugs easier and cheaper by reducing the amount of time spent in testing.
In MS, researchers can assess the brain lesions that signal the state of the disease by using the common imaging tool, magnetic resonance imaging (MRI).
Biomarkers detectable through MRI and other measuring techniques also are under study for use in ALS.
Advances in technology have led to increased sensitivity in imaging techniques that can now show what is going on in the brain or spinal cord.
In November 2010, the first Neuroimaging Symposium in ALS was held at St. Edmund Hall, Oxford University, United Kingdom. There, consensus guidelines were developed for how to properly utilize four different MRI techniques in ALS studies.
Voxel-based morphometry provides high-resolution, three-dimensional brain scans. It’s used to measure disease progression in Alzheimer’s disease and Huntington’s disease, and appears to be especially good for detecting changes in areas of the brain that correspond with frontotemporal dementia (FTD), a condition sometimes seen in ALS.
Diffusion tensor imaging is used to measure the movement of water in the brain, which changes with ALS progression. Its use can be complicated by the fact that other disorders sometimes cause similar changes in the brain.
Functional MRI can indicate changes in brain activity and connectivity through the measurement of blood flow.
Magnetic resonance spectroscopy can be used to measure the presence of small molecules called metabolites in the brain. For example, levels of a metabolite called n-acetyl aspartate (NAA), which is produced by healthy neurons, often are reduced in some areas of the brain in people with ALS. Measurement of NAA levels is under investigation for use in estimating the extent of motor neuron loss. The process is complicated by the fact that levels of NAA are not always reliable indicators.
Biomarkers detected with imaging techniques likely will be more useful in determining disease presence and progression than in evaluating treatments in clinical trials. They also could be used in combination with other types of biomarkers better suited to detecting drug-based effects. (For more on neuroimaging, read Seeing Is Understanding, Quest, Summer 2012.)
The conduction of electrical signals in the nervous system also is under investigation as a diagnostic biomarker in ALS. Two tests commonly used as part of the diagnostic work-up for ALS are nerve conduction velocity (NCV) and electromyography (EMG).
NCV tests are used by physicians to evaluate weakness in the limbs. Physicians use electrodes to stimulate nerves and then measure the amount of time it takes for a particular muscle to respond, as well as the strength of the signal. Nerve signals typically conduct electrical impulses at a standard speed and strength; deviations can be indicative of disease or damage.
EMG measures the electrical activity of skeletal muscles while at rest and during contraction, and is used to help determine the health of muscles and neuromuscular junctions (the connections between muscle and nerve).
During an electromyogram, a needle is inserted into a muscle and transmits the muscle signal to a device that provides a readout that can be used in the diagnosis of muscle diseases and diseases like ALS that involve nerve cells.
An additional test — motor unit number estimation (MUNE) — is based on the techniques of NCV and EMG and can quantify the number of motor units in a given muscle. MUNE measurements over time can detect a decline in the number of motor units, reflecting motor neuron loss. MUNE has been used as a secondary outcome measure in some clinical trials.
Measurement of protein levels in blood, spinal fluid, muscle or other tissues can provide insight about the state of disease and also about characteristics that may make someone more or less likely to respond to a treatment. For example, spinal fluid levels of four different interleukin proteins and a protein called granulocyte-monocyte colony stimulating factor have been found to be significantly higher in people with ALS compared to people without ALS.
Protein levels are commonly measured using a test called ELISA (enzyme-linked immunosorbent assay), in which scientists use immune system cells called antibodies to target and bind to the specific protein. After processing, a visual indicator signals the amount of protein in a given sample.
In some cases, the amount of protein may be measured for increase or decrease. In other cases, the measurement might be made to determine the ratio of one protein to another.
Biomarkers in clinical trials
A long line of clinical trials has been conducted for drugs that worked in mice but failed to produce an effect in humans.
“There’ve been huge numbers of failures in ALS clinical trials, and on one hand the failure could be that we just picked the wrong mechanism for people with the disease,” explains neurologist Jeffrey Rothstein, director of both the Robert Packard Center for ALS Research and the MDA/ALS Center at Johns Hopkins University in Baltimore. “That’s one possibility, but the other possibility is that the standard pharmaceutical approach to drug development has not been efficiently used in ALS.”
The standard approach Rothstein refers to, called “target engagement,” is to ask two questions when testing a drug: Does it get to its target, and does it do what it’s supposed to do?
“If you do a trial and the drug, for whatever reason, only works in 10 percent of trial participants,” Rothstein says, “you may miss the valid effects because it’ll fail in the vast majority of patients.”
Rothstein currently is working to develop an experimental therapy designed to target the C9ORF72 gene responsible for some cases of ALS. At the same time, the therapy under development — antisense oligonucleotides, or ASOs — also is being used by Rothstein as a tool to help identify biomarkers able to show whether the treatment is working or not. (See C9ORF72: Bound to Repeat Itself and Antisense Against C9ORF72 in this issue.)
Late-stage drug development
The use of biomarkers as tools in clinical trials allows for more informed decisions and better odds for avoiding a late-stage failure in a drug trial.
Having a readout early in the process can indicate whether the drug is getting to its target and doing what it’s supposed to do. That’s the first step, Rothstein says, toward a better drug trial with a higher chance of success.
In ALS, for example, there may be a number of proteins whose levels are increased in the brain and can be measured in cerebrospinal fluid. If an experimental treatment causes those protein levels to go down, then it’s an indication the treatment may be working.
Such a sign is crucial to late-stage development of promising drug candidates. Most companies working on therapies for diseases such as ALS won’t move forward until they can discover a biomarker that can tell them whether their drug is working or not, Rothstein says. “They don’t want to gamble.”