New Hope for ALS

Pauline Anderson

July 09, 2020

Two early studies are raising hopes that some genetic forms of amyotrophic lateral sclerosis (ALS) can be treated.

Both studies investigated potential benefits of suppressing the toxic activity in cells of a mutant gene (SOD1) that encodes superoxide dismutase 1 (SOD1) in patients with ALS.

One study investigated the antisense oligonucleotide (ASO) tofersen (Biogen); the other study examined viral vector–mediated gene suppression.

The studies' promising results signal "the beginning of a new precision medicine–based approach towards treating ALS," Orla Hardiman, MD, consultant neurologist and professor of neurology, Trinity College and Beaumont Hospital, Dublin, Ireland, told Medscape Medical News.

Hardiman co-authored an editorial that accompanied the two studies, which were published July 9 in The New England Journal of Medicine.

Genetic Culprits

ALS is a disorder of progressive degeneration of upper and lower motor neurons. It typically leads to death from ventilatory failure within 5 years of symptom onset.

Genetic factors are responsible for about half the risk variance of ALS. In populations of European origin, variants in SOD1 account for an estimated 13% to 20% of familial ALS, although this rate varies around the world.

Although SOD1 is not the most common variant in ALS, it is the one that researchers are most familiar with and has been studied in an animal model.

In the first study, investigators evaluated the safety, pharmacokinetics, and pharmacodynamics of the ASO tofersen in adults with ALS.

Dr Toby Ferguson

An ASO is a small piece of nucleic acid that enters neurons in the spinal cord and brain, co-investigator Toby A. Ferguson, MD, PhD, vice president and head of the neuromuscular development unit at Biogen, told Medscape Medical News.

ASO binds to the SOD1 gene and knocks down the SOD1 protein, which is the "toxic engine [that] drives the disease, kills neurons, and causes patients to have loss of function and eventually to die," said Ferguson.

"The ASO turns off the motor that produces that toxic protein," he added.

Animal studies have shown that ASOs that target SOD1 messenger RNA transcripts prolong survival, improve motor performance, and reduce SOD1 protein concentrations.

The new phase 1/2 double-blind study included 50 adults at 18 sites in the United States, Canada, and four European countries. All had muscle weakness attributed to ALS and a documented SOD1 mutation.

Participants were randomly assigned to receive one of four doses of tofersen ― 20, 40, 60, or 100 mg ― or placebo. Treatment was administered via a lumbar intrathecal bolus injection.

The study included a screening period followed by a 12-week intervention period and a 12-week follow-up.

Adverse Events

A primary outcome was the incidence of adverse events (AEs) and serious AEs. Results showed that all participants reported one or more AEs.

The most common AEs were headache, pain at the injection site, post–lumbar puncture syndrome, and falls.

Three deaths occurred, one in the placebo group, one in the 20-mg dose group, and one in the 60-mg dose group. There were no serious AEs in the 100-mg group.

Although the investigators found an increase in cerebrospinal fluid (CSF) protein and white cell counts, there was no clear association between these observations and higher doses of tofersen or longer duration of exposure.

"We don't know the implications of this, and it's something we need to keep an eye on as we move these studies forward," Ferguson said.

None of the adverse events or CSF abnormalities led to trial discontinuation.

A secondary outcome was change in SOD1 protein concentration in CSF at day 85.

The study showed that SOD1 concentrations decreased by 36% among the participants who received tofersen 100 mg and by lesser amounts in the patients who received lower doses. Concentrations in the placebo group were reduced by 3%.

The 36% reduction in the highest dose group is likely meaningful and "foundational to the concept of what this molecule can do," Ferguson said.

"If the number one cause of SOD1 ALS is accumulation of toxic SOD1 protein, then the demonstration that we can reduce SOD1 protein in the CSF...is saying that's the first step on the way to showing the molecule is doing what it should do," he added.

Emerging Tool

In patients with ALS, neurofilament concentrations typically increase as the disease progresses. However, this study documented a reduction in these CSF concentrations.

"One interpretation of that could be that there is less neurodegeneration or neuro injury" in patients treated with tofersen, Ferguson said.

He noted that neurofilament is "an emerging tool" for understanding neurodegeneration. It could also "be another sort of biochemical signal that the molecule is doing something important," he added.

However, he noted that neurofilament concentration is still an exploratory marker.

Exploratory analyses suggested a possible slowing of functional loss, as measured by the ALS Functional Rating Scale–Revised (ALSFRS-R) score and the handheld dynamometry megascore. The latter assesses strength in 16 muscle groups in the arms and legs.

The investigators note that no conclusions can be drawn from these outcomes.

A post hoc analysis showed that among patients with SOD1 mutations associated with a fast-progressing disease course, the slope of clinical decline might have been gentler, and there was a greater decrease in CSF neurofilament concentration compared among those whose disease followed a slower course.

This suggests that "if you pick the right target," even patients with severe disease can be treated, Ferguson said.

He acknowledged that in a relatively short study such as this one, it may be easier to see benefits in patients whose disease is progressing rapidly. However, he's convinced that the treatment "would work for all SOD1 ALS patients, not just fast patients."

Ferguson said the study investigators are encouraged by the new data, which "really suggest that we may be developing a meaningful treatment for SOD1 ALS."

However, "it's still early" in terms of rolling out this therapy for patients with ALS, he said.

The safety and efficacy of tofersen are currently being evaluated in a phase 3, randomized, double-blind, placebo-controlled trial.

Limitations of the current study were the small number of participants, the short duration of treatment and follow-up, the exploratory nature of efficacy outcomes, and the post hoc methods for defining the fast-progressing subgroup.

Although an advantage of tofersen is that it can enter the nucleus of the cell, perhaps boosting effectiveness, a drawback might be that patients need several treatments administered via lumbar puncture. Following three initial doses, the drug is given every month.

An alternative approach might be a viral vector approach.

"Stunning" Finding

In the second study, investigators assessed the safety of a single intrathecal infusion of a viral vector therapy designed to target SOD1 in two patients with familial ALS. The two patients were a 22-year-old man whose mother had died of ALS at age 45 and a 56-year-old man who had a family history of ALS.

Dr Robert H. Brown, Jr

The aim of the viral vector therapy is to continually suppress mutant gene activity, study co-investigator Robert H. Brown, Jr, MD, professor of neurology, University of Massachusetts Medical School, Worcester, told Medscape Medical News.

"The virus essentially drops off a piece of DNA, and that DNA keeps making the agent that suppresses the gene," Brown said.

He noted that the first patient had a mutation that causes a rapidly developing, "horribly devastating" disease.

Initially, the patient's right leg, in which movement had been worsening over several weeks, "seemed to get stronger and remain strong for quite a long time. I've never seen that in this kind of mutation," said Brown.

The patient died of ALS. At autopsy, there was evidence of suppression of SOD1 in the spinal cord. There was some preservation of motor neurons on the right side of the spinal cord, which Brown called a "stunning" finding.

"We have never seen preservation of motor neurons in an autopsy of a patient with this kind of mutation before," he said.

Prior to the patient's death, there were some initial signs of a decrease of SOD1 in CSF. However, the patient developed an inflammatory response in the lining of the CSF known as meningoradiculitis.

"In that setting, the SOD1 level went back up, so we could not say that we produced a significant lasting decrease," Brown said.

One and Done

Because meningoradiculitis occurred in the first patient, immunosuppressive drugs were administered to the second patient.

The functional status and vital capacity of the second patient were relatively stable during a 60-week period, a course that could be typical of the slow disease progression in patients with this SOD1 genotype.

As with the first patient, this man did not experience a substantial change in SOD1 protein levels in CSF, and he did not show clinical improvement.

The main advantage of a viral gene therapy is that it could be a one-time treatment; ideally, it could be used to replace a single missing gene in conditions such as cystic fibrosis.

"The hope is that the virus will drop off the gene modulator or the gene itself of interest, depending on the disease, and that the gene will be there more or less indefinitely," said Brown. "So the cliché is, 'one and done' ― if all goes well."

This small study illustrates that gene therapy safely "turns off genes and that the extent of suppression of genes can be significant," said Brown.

Most SOD1 mutations could be treated with this microRNA viral vector, he added. More than 180 such mutations have been identified in ALS.

Additional studies are now needed to determine the results of this method in a larger number of patients who have ALS with SOD1 mutations, the investigators write.

Within Reach

Both studies are encouraging in that they show that a precision-medicine approach to ALS associated with single mutated genes "may be within reach," said Hardiman.

She noted that gene therapies have been used successfully in other motor neuron conditions.

For example, an ASO and a viral vector have "very significant efficacy" in a form of spinal muscular atrophy that occurs in infants. "So the underlying proof of principle is already there."

The reduction in SOD1 levels among the highest-dose tofersen group in the first study indicates "target engagement," Hardiman said.

In that study, the documented decreased protein in the CSF appeared to be dose related, as was the effect for neurofilaments, which is biomarker evidence of neuronal damage, she noted.

In the second study, the pathologic evidence from the first patient also suggests "evidence of target engagement," Hardiman said.

However, she added, "We don't know very much about the outcome of the second case other than immunosuppression seemed to be beneficial."

New Hope

Both studies have caveats, said Hardiman. For example, it is unclear whether the treatments would be beneficial for every variant in SOD1.

"These are very expensive therapies, and we will need to have some level of certainty in order to be able to determine whether this should be a treatment for a patient or not," said Hardiman.

She also noted that the studies were not powered to provide evidence of efficacy and that they raise questions about the accuracy of the ALSFRS-R.

One issue is that the respiratory part of that scale is "very insensitive"; another is that the scale doesn't capture nonmotor elements, such as cognition and behavior, she said.

Utilizing a combination of the ALSFRS-R slope and survival would "probably be more beneficial," Hardiman said.

Understanding how to alter the genetic influence in a disorder is important to be able to identify successful treatments, Hardiman added. For example, the discovery of the BRCA gene led oncologists to develop a precision medicine approach to the treatment of breast cancer.

In regard to ALS, by starting with subgroups that have specific genomic features, "investigators are providing new hope for patients at genetic risk for this devastating fatal disease," said Hardiman.

The first study was funded by Biogen. The second study was funded by a fellowship grant from the Alzheimer's Association, a Jack Satter Foundation Award, the ALS Association, the Angel Fund for ALS Research, ALS Finding a Cure, ALS-One, Project ALS, the Massachusetts General Hospital, the Max Rosenfeld and Cellucci Funds for ALS Research, and several senior members of Bain Capital. Ferguson is employed by and holds stock in Biogen. Brown receives grant support from the National Institute of Neurological Disorders and Stroke. He is also co-founder of Apic Bio. Hardiman is the editor in chief of the Journal of Amyotrophic Lateral Sclerosis and Frontotemporal Degenerations, has consulted for Cytokinetics, Mitsubishi, and Wave, and holds research grants from Novartis and Merck. During the past 2 years, she has also been a principal investigator on ALS clinical trials sponsored by Orion and Cytokinetics and is currently on the data and safety monitoring board of Accelsior.

N Engl J Med. Published online July 9, 2020. Study 1, Abstract; Study 2, Abstract; Editorial

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