Amyotrophic lateral sclerosis (ALS) degrades motor neurons, causing muscle atrophy, paralysis and death, usually within five years of diagnosis. It has no cure, and the only FDA-approved drug, riluzole (Rilutek), only slightly delays progression by reducing damage to motor neurons. Until the 1990s, researchers generally thought the disease was untreatable, and pharmaceutical companies were not invested in drug development for ALS. To stimulate more interest in studying the disease and in developing treatments, Massachusetts General Hospital researcher Merit Cudkowicz, MD, co-founded in 1995 a network group, now known as the Northeast ALS Consortium (NEALS), that comprises multidisciplinary and multi-institutional clinical networks, patient advocacy groups and funding agencies. The consortium’s efforts have resulted in a proliferation of basic and translational ALS research. They have also spurred the initiation of clinical trials testing investigational therapies and helped improve patient care, quality of life and longevity.
Genetic Discoveries in ALS
In 1993, a Massachusetts General Hospital team led by Robert Brown, MD, discovered the first genetic mutation in ALS, in a gene called superoxide dismutase (SOD1). The mutation causes a toxic gain of function independent of the enzyme’s normal activity. SOD1 accounts for 13 percent of familial ALS and 2 percent of all ALS patients.
ALS researchers have now identified 25 genes involved in different forms of ALS, suggesting that the disease is more heterogeneous and complex than previously thought. For example, C9orf72 accounts for about 40 percent of familial ALS but also 10 percent of sporadic cases. This and other findings are blurring the lines between inherited and acquired forms of ALS, suggesting a common biology in groups that were previously thought to be distinct. New animal models are helping to elucidate the diverse genetic pathways involved in motor neuron death for different mutations.
New Targeted Therapies
An investigational drug, ISIS 333611, which is an antisense oligonucleotide delivered intrathecally, targets the mutant SOD1 gene that was implicated earlier in ALS. The antisense technique silences SOD1 gene expression, thus reducing the SOD1 enzyme’s toxic gain of function. NEALS researchers led a Phase I study with ISIS 333611 in patients with ALS from mutations in SOD1. The compound, which proved safe in this Phase I study, will be tested in a larger trial for additional safety, dose finding and efficacy.
NEALS researchers are also working to identify potential biomarkers that can predict drug response and/or the progression of the disease, such as subtle changes in the motor cortex of ALS patients detected by brain imaging. Another, in collaboration with pharmaceutical companies, is to develop drugs that cross the blood-brain barrier, which prevents many drugs from entering the brain. Also, researchers are investigating stem cell transplant and anti-inflammatory strategies for treating ALS.
Clinical Trial Challenges
Two Phase III trials of ALS therapeutic strategies that looked promising in Phase II studies have recently failed—unfortunately a common occurrence in neurological disorders. One drug, dexpramipexole, is designed to increase mitochondrial function and slow motor decline. The other is a repurposed antibiotic, ceftriaxone, that modifies abnormal glutamate activity.
Dr. Cudkowicz, who was involved in both efforts, says that the lesson is similar to what cancer researchers have learned about targeted therapies for heterogeneous diseases: Some therapies may target a specific gene or protein that exists only in a small subset of patients in the trial, and such targeted therapies may fail in an unselected patient population. The researchers are analyzing the data to determine if a subset of participants responded favorably to the drug.
Novel Trial Designs
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Another challenge for ALS trials is the limited number of ALS patients and the large number of promising therapeutics to be tested. But novel trial designs, such as a multi-drug Phase II study and/or a multistage adaptive design for dosing, could expedite the advancement of the most promising compound at the most effective dose to Phase III studies. As in oncology, ALS may require different agents—or a cocktail of drugs—for different patients, and also for different stages of disease.
NEALS is also focused on improving the lives of patients currently living with the disease. The Red Flag Campaign aims to inform general practitioners of the early symptoms of ALS and encourage referral to a specialist, since earlier intervention might slow disease progression, and a new TeleHealth program being piloted in Maine addresses the shortage of ALS specialists in many areas.
Dr. Cudkowicz anticipates the advent of focused trials in different population cohorts of people with ALS subtypes, and improved targeted therapy development, as well as increasing team-based interactions among patients, physicians, drug companies, the FDA and funding groups. These developments show promise in improving patients’ quality of life and longevity.
|Merit E. Cudkowicz, MD