Genetic Testing for ALS, Now a Standard, Creates a Path Toward Individualized Care

September 25, 2024|Neurology Reviews

Early Treatment Presumed More Effective

“We think that earlier treatment in the course of ALS is probably better for gene therapies as well,” Dr. Fournier said. She cautioned that follow-up is not yet long enough to confirm a survival benefit with tofersen, but she said it is reasonable to anticipate better and longer response when neurologic damage is limited. Citing the effect of gene therapy in spinal muscular atrophy (SMA), where progression is halted if gene therapy is initiated early in life, Dr. Fourier suggested that the emphasis on early treatment stems from the low likelihood for treatments to reverse functional impairments.

“It is conceivable that future treatments might be developed to reverse symptoms, but current drug development is largely aimed at slowing progression,” she explained. Under some circumstances, halting progression has the potential to allow some function to be regained, but as the etiologies of ALS and the pathways of progression are better understood, she believes that all targeted therapy will be started as early as possible to prevent rather than treat neurological damage.

Tofersen, the gene therapy for SOD1-ALS, has provided an opportunity to test the idea that it may be possible to prevent ALS. In a phase 3 trial called ATLAS, unaffected carriers of SOD1 variants that are associated with aggressive disease and high or complete penetrance are enrolled for a run-in phase (Part A) during which participants are followed for a rise in neurofilament light chain (NfL) levels. Based on a previous natural history study called the Pre-Symptomatic Familial ALS (Pre-fALS) study, NfL rises in the serum of unaffected SOD1 carriers prior to phenoconversion. A low NfL is an entry criterion for ATLAS.

ATLAS End Point Is Reduction in Phenoconversion to Clinically Manifest ALS

People in whom NfL rises above a predefined threshold during the run-in stage will be eligible for randomization (Part B) to receive either tofersen or placebo. Efficacy will be measured by comparing the rates of phenoconversion to clinically manifest ALS between those who receive placebo and those who receive tofersen.

Two other groups enrolled in ATLAS will be followed on open-label tofersen. One comprises people who phenoconvert during Part B and the other comprises those who develop ALS during the run-in and therefore are not enrolled in Part B. These patients, forming Parts C and D of the study, provide another set of data to evaluate whether earlier rather than later introduction of therapy provides better outcomes.

“There is a lot of interest and optimism about the trial,” said Dr. Fournier, who praised the trial design and thinks the hypothesis being explored “makes sense.”

Michael Benatar, MD, PhD, professor of neurology and public health, University of Miami School of Medicine, Miami, Florida, is the principal investigator of ATLAS and also leads the Pre-Symptomatic Familial ALS study together with a colleague, Joanne Wuu, Associate Director of Research at the University of Miami ALS Center. The hope from these initiatives, according to Dr. Fournier, is that ATLAS will offer broader learnings beyond just the SOD1 population, providing critical information about the optimal timing of treatment initiation.

The benefit from targeting genes considered causative for ALS is not yet a sure thing. A clinical trial targeting C9orf72, for example, failed to support an approvable therapy. There is a trial of a gene therapy for the FUS variant that is ongoing. Yet, the introduction of a gene therapy for SOD1 variant ALS has already established that highly targeted therapies can be effective, an important step forward after so many failed treatment trials with nonspecific drugs.

“We are seeing more and more therapies being developed to address specific ALS biology,” said Dr. Fournier, who predicts a pivot toward conceptualizing ALS as an array of pathologies rather than one disorder driven by a single mechanism. More effort is being directed to recognizing phenotypes as well as genotypes. Hopefully, more biomarkers that distinguish between ALS variants will emerge and help in individualizing treatment.

“We are not there yet, but I think many of us in the field see this as a way forward,” she said.

Multidisciplinary Care, Symptomatic Management, and Palliative Care Are Still Essential for ALS

Disease-modifying therapies are the ultimate goal in ALS, but Dr. Fournier said that the other side of the equation is multidisciplinary and palliative care. To the extent that almost all ALS therapies only modify the course of disease modestly, palliative care remains the cornerstone of day-to-day care.

“Multidisciplinary and palliative care are not necessarily novel, but they are still critically important. There are clear data to show that multidisciplinary care improves functional status and quality of life, and that this is meaningful to patients,” Dr. Fournier said.

There have been numerous improvements in the areas of multidisciplinary and palliative care, some of which can be credited to advancing technology. In centers of excellence, the multidisciplinary approach has been focused on helping patients sustain a sense of independence and self-worth.

Now robotics, devices, and software are being increasingly employed to extend patient capabilities even in relatively advanced stages of disease, according to Dr. Fournier. As one example, she cited current work in brain-computer interfaces to record electrical activity in the central nervous system to allow patients to communicate even when speech is impaired.

A focus on patient-centered clinical care is appropriate because it is the best current opportunity to improve the lives of patients with ALS. Clinically, this work is very rewarding, according to Dr. Fournier, who described ALS patients overall as generally ”very invested in advocacy and research initiatives and motivated to help others,” Dr. Fournier said.

“The diagnosis can be tough, but there is satisfaction in helping these patients navigate toward an acceptable and meaningful quality of life. They typically give a lot back,” she added.

Overall, there is a sense of progress in ALS, even though it remains a uniformly fatal disease. Dr. Fournier expressed hope that clinical research is reaching a tipping point and an emphasis on targeted treatments after a long list of failed trials over the past 30 years. However, with only one approved therapy modifying an ALS-associated gene, this approach is still in its early stages.

Dr. Fournier has financial relationships with Amylyx, Biogen, Corcept, Denali, Mitsubishi QurAlis, and Tanabe.

Genetic Testing for ALS, Now a Standard, Creates a Path Toward Individualized Care

Early Treatment Presumed More Effective

ATLAS End Point Is Reduction in Phenoconversion to Clinically Manifest ALS

Multidisciplinary Care, Symptomatic Management, and Palliative Care Are Still Essential for ALS

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