Amyotrophic lateral sclerosis (ALS) falls easily into the Food and Drug Administration definition of “rare disease.” With an estimated prevalence in the United States of fewer than 20,000 cases,1 ALS sits comfortably below the cutoff of 200,000 cases that serves to define a disease as “rare.”
After a recent steep climb, there are something on the order of 50 therapies, across more than 10 drug classes, in clinical trials for the treatment of ALS.2 This bounty represents exciting progress toward the development of targeted therapies for a characteristically fatal disease.
That headway is coupled with a sobering limitation, however: Relatively few ALS patients are being enrolled.
The knotty problem with therapeutic trials for ALS
“Trials are generally designed for patients with adequate functional reserve and predicted survival, to ensure that a signal of benefit can be seen,” said Nicholas John Maragakis, MD, director of the ALS Clinical Trials Unit at Johns Hopkins University, Baltimore. “Many of my patients are too severely affected at presentation.”
Dr. Nicholas Maragakis
Dr. Maragakis hasn’t calculated the precise percentage of patients he is enrolling in one of the many available trials available at the Johns Hopkins center. He estimates that it is less than 20%, however.
That percentage is comparable to what is reported by Stephen Scelsa, MD, and Daniel J. Macgowan, MD, who share much of the ALS caseload in a dedicated, comprehensive ALS center at Mount Sinai Beth Israel, New York. Both are on the faculty at the Icahn School of Medicine at Mount Sinai.
“The considerable delay in the diagnosis of ALS remains a challenge,” Dr. Scelsa acknowledges. Like Dr. Maragakis, he reports that, by the time patients develop symptoms that make referral to a comprehensive ALS center like Mount Sinai Beth Israel appropriate, many no longer meet eligibility criteria for most experimental treatments.
Some therapeutic targets in clinical trials, such as neuroinflammation, offer potential benefit even in advancing disease, but it is prevention that is usually the goal of experimental ALS therapies. This approach is associated with far more promise than attempting to reverse existing neurologic damage, which might not be possible, according to both Dr. Scelsa and Dr. Macgowan.
Dr. Stephen Scelsa
“The clinical trials are typically looking for patients with less than 2 years since the onset of symptoms and at least 60% of predicted respiratory function,” Dr. Macgowan said.
Because of these or other similarly restrictive criteria, coupled with common delays before patients arrive at a center where trials are available, “the window for clinical research closes very quickly,” Dr. Macgowan added, and “the band of patients who are eligible is relatively narrow.”
At Hennepin Healthcare in Minneapolis, which, like Johns Hopkins and Mount Sinai, offers an advanced multidisciplinary approach to ALS care in a dedicated clinic, the problem of late referrals is no different. Samuel Maiser, MD, chair of neurology, does attempt to counter this delay by moving quickly.
“I almost always offer a therapeutic trial to a patient with early-stage ALS,” he said. He does so earlier, rather than later, and explains: “I do not want to delay that conversation, because any delay might reduce the chance for getting into a trial.”