NEW YORK – Researchers at the Mayo Clinic are studying whether a protein biomarker that's been linked with neurodegeneration can help guide treatment decisions for patients with amyotrophic lateral sclerosis (ALS).
Physicians and patients will review data on neurofilament light (NfL) as they decide whether to continue testing an experimental drug, MediciNova's ibudilast, in what researchers say is a first-of-its-kind study.
ALS, better known as Lou Gehrig's disease, is a fatal and progressive neurodegenerative disorder characterized by muscle weakness and loss of muscle control, though patients can have a variety of clinical symptoms. It's a heterogeneous disease with links to mutations in more than 40 genes, though the majority of cases are sporadic.
In the fall, the Mayo Clinic's Florida campus in Jacksonville was awarded a $22 million grant from the US National Institutes of Health's National Institute of Neurological Disorders and Stroke (NINDS) to study ibudilast in ALS. The Mayo Clinic will take $12 million of the grant and distribute the remainder to other collaborators.
In the trial underway, researchers are testing whether ibudilast, a drug that inhibits phosphodiesterase type-4 and inflammatory cytokines, can slow ALS progression. Physicians will use a blood test in the trial to monitor how patients' NfL levels are changing as they receive ibudilast and, based on that, decide whether to keep giving patients the drug.
The Mayo Clinic is giving patients ibudilast within this clinical trial through the US Food and Drug Administration's expanded access program. The FDA's EAP, also known as the "compassionate use" program, offers a path for patients with serious diseases to get experimental medical products when they're out of treatment options.
For this study, the Mayo Clinic is working with WideTrial, an organization that leverages the EAP to garner experimental drugs for clinical trials. Physicians at other institutions treating ALS patients can join a network managed by the Mayo Clinic and WideTrial to gain access to ibudilast. The goal is to enable patients who aren't eligible for other clinical trials of ALS drugs to get access to a promising treatment, said Björn Oskarsson, a neurologist and director of the Mayo Clinic's ALS Center of Excellence, who is the lead investigator on this project.
La Jolla, California-based MediciNova is currently studying ibudilast within the randomized-controlled Phase IIb/III COMBAT-ALS trial, enrolling patients who experienced ALS onset within the past year and a half. Oskarsson is also a principal investigator on the COMBAT-ALS trial but said the EAP-enabled study will open access to a broader population of patients. "This is a way of trying to include a larger swath of people with ALS in some kind of research," he said, adding that most clinical trials in ALS "are very restrictive in who we can enroll."
A 2019 analysis published in Neurology found that on average 60 percent of ALS patients may be excluded from clinical trials due to stringent eligibility criteria.
Clinical trials tend to focus on patients with earlier-stage disease, Oskarsson said. That's in part because the "gold standard" functional outcome measures used to assess disease progression and treatment response tend to perform better in patients with early ALS and rapidly progressing disease but don't work as well at assessing change in progression for patients with more advanced disease or whose disease is advancing more slowly.
"That has led to a lot of frustration on the part of patients," Oskarsson said. The "gold standard" for clinical trial endpoints in ALS therapies is a change in function for daily activities, according to a 2019 FDA guidance, which is often measured using a scale like the Revised ALS Functional Rating Scale (ALSFRS-R). This is the scale MediciNova is using to measure ibudilast's efficacy in the COMBAT-ALS trial.
That's part of the reason NfL is so exciting for Oskarsson, since it could potentially provide a useful outcome measure to monitor disease in patients at various stages of ALS. In the Mayo Clinic-led study, researchers will primarily assess ibudilast's effect on disease progression using blood tests to measure NfL, a protein that can indicate damage to neurons. This is the first study in which NfL will be measured and the results will be shared with patients and physicians to guide decision-making within ALS, Oskarsson said. While researchers have used NfL as a surrogate endpoint in other clinical trials, they have not used it to guide treatment decisions.
Interest in NfL as a biomarker of response has ramped up since it was used as a surrogate endpoint to support the accelerated approval of Biogen's Qalsody (tofersen), an antisense oligonucleotide designed to treat a rare genetic form of ALS caused by mutations in the SOD1 gene. The FDA's accelerated approval pathway enables the regulator to quickly review data on drugs that treat serious conditions based on intermediate or surrogate endpoints that it deems "reasonably likely" to predict a clinical benefit, even if evidence of a link between the surrogate endpoint and clinical benefit isn't fully established yet.
Even though Qalsody had failed to improve patients' physical functions in a Phase III trial, the FDA approved it based on findings that the drug had led to a reduction in NfL for patients — representing the first time that an ALS drug had been approved by the FDA using NfL as a surrogate endpoint. And other biopharmaceutical companies are using NfL as an exploratory biomarker within their clinical trials. UniQure, for instance, is using NfL as a secondary outcome measure within a Phase I/II trial of a gene therapy it is developing for SOD1-ALS and measuring NfL within a Phase I/II trial evaluating its Huntington's disease gene therapy as an exploratory biomarker for disease progression and treatment response.
Kuldip Dave, senior VP of research at the ALS Association, has seen industry interest in NfL ramp up after the FDA accepted it as a surrogate endpoint in Biogen's Qalsody trial in SOD1-ALS. "ALS is a heterogeneous disease," Dave said. "When you see a patient with ALS, their symptoms are very distinct from another patient living with ALS." To Dave, that begs the question as to whether there is an objective biomarker, such as NfL, that could provide insight into how ALS patients are progressing regardless of their specific clinical symptoms.
The Mayo Clinic expects researchers to treat around 200 patients with ibudilast through the EAP-enabled study. Ibudilast was approved more than two decades ago in Japan as a treatment for asthma and post-stroke complications and is known to address inflammation and stimulate cell repair. At MediciNova, the drug is also known as MN-166 and is in late-stage clinical testing in various neurodegenerative diseases.
Within the ALS study at the Mayo Clinic, physicians will measure patients' NfL levels at baseline and then again at least three months and six months after treatment to assess how the drug is affecting neurodegeneration. Doctors will be able to discuss those tests' results with their patients and use the data to inform whether a patient should continue to take the drug.
That will provide a somewhat personalized treatment strategy, Oskarsson said. "All treating physicians are well aware that a single [test result] doesn't tell the full story; there's always more to it," he said. "But I think this is a useful marker."
NfL doesn't provide insight into whether a patient has early- or late-stage disease, nor does it predict a patient's survival, Oskarsson said. However, when evaluated over time, NfL can act like a "speedometer," providing a signal into how quickly a disease is progressing and whether a treatment is working.
"We're following their ALS and using the neurofilament light test as a guide to try to get an idea of whether their disease is speeding up or slowing down," Oskarsson said. "Patients will actually see their own [neurofilament] levels and will be able to work with their own doctors to see if it seems like this treatment might be helping them or the opposite."
NfL is considered a "nonspecific" biomarker, he added. The protein is associated with axonal injury and neurodegeneration because NfL is released when neurons are damaged. High levels of the biomarker can be detected in blood or cerebrospinal fluid tests, which can be beneficial to treating physicians.
Increases in NfL can signal neurodegeneration in the peripheral and central nervous systems. Changes in NfL levels can also occur when patients have different types of ALS and reflect various clinical presentations of the disease, and the biomarker isn't associated with a particular genetic mutation or subtype. But NfL's association with numerous conditions beyond ALS is also what makes changes in biomarker levels difficult to interpret.
A 2021 paper, for example, found that NfL could be useful for diagnosing and managing various neurodegenerative disorders, including frontotemporal degeneration (FTD) and Parkinson's disease with dementia.
Other organizations have been advancing plans to establish the use of NfL in these disease settings, too. The Foundation for the National Institutes of Health (FNIH), an independent nonprofit that was established by Congress in 1990 to create public-private partnerships that support the NIH's mission, has been studying NfL as a biomarker for FTD, a rare and progressive form of dementia, and plans to establish its application in drug development through the FDA's biomarker qualification program.
In the spring, the FNIH announced that the FDA had indicated that the group could move forward and develop a biomarker qualification plan to continue to study NfL. The group had sent a letter of intent — the first step in qualifying a biomarker within this program — outlining its intention to establish NfL for identifying patients at risk of developing FTD, which the FDA accepted. The FNIH has said it will also examine the role of the biomarker in ALS as part of the project, since this neurodegenerative disease is biologically related to FTD.
The ALS Association's Dave foresees a variety of clinical uses for NfL. As researchers continue to build evidence, the most immediate use cases for NfL will likely be for monitoring disease progression or treatment response. One day, it could also potentially be used as a biomarker to support diagnosis, such as to pinpoint disease onset in patients with known genetic risk variants.
Dave noted that's one component of the first ALS prevention trial, known as the ATLAS trial, in which investigators at the University of Miami are using NfL to identify presymptomatic ALS patients. As part of the study, patients with certain SOD1 mutations, but no clinical symptoms of ALS, will receive either Qalsody or placebo once they reach a certain threshold of NfL. Investigators are exploring whether treatment with Qalsody can delay onset of ALS in these presymptomatic patients.
NfL "is a surrogate biomarker for neuronal cell death — that's the hypothesis," Dave said. "It's really exciting for it to be used as a biomarker for ALS."