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Cautious Optimism for Newly Approved Drug for Rare Form of Genetic ALS

Article In Brief

The Food and Drug Administration approved tofersen for SOD1-mutant amyotrophic lateral sclerosis (ALS) largely on the basis of a phase 3 trial, which found it reduced two biomarkers for ALS. Experts say the drug appears promising, but more data are needed to determine its impact on disease progression.

The Food and Drug Administration (FDA) granted accelerated approval to tofersen (Qalsody) in late April for patients with amyotrophic lateral sclerosis (ALS) caused by a mutation in the superoxide dismutase 1 (SOD1) gene.

The new drug was approved largely based on data showing significant reduction of two biomarkers associated with the genetic form of ALS, but the degree to which the drug will make a clinically meaningful difference is not clear. ALS specialists not involved with the tofersen studies expressed cautious optimism that the drug potentially could help slow the disease's progression.

Tofersen, the first approved treatment for a genetic cause of ALS, is an antisense oligonucleotide that targets the messenger RNA produced from a mutated SOD1 gene, stopping the synthesis of toxic SOD1 proteins. SOD1-linked ALS affects approximately 2 percent of ALS patients.

The drug is administered by intrathecal injection, unlike other ALS treatments, which are either administered through IV infusion or orally. Patients receive three initial doses administered at 14-day intervals, followed by a maintenance dose every 28 days. The price for the new drug has not yet been confirmed.

“This is a milestone for the ALS community,” said Shafeeq Ladha, MD, professor of neurology and director of the Gregory W. Fulton ALS and Neuromuscular Disorders Center at the Barrow Neurological Institute in Phoenix, which was involved in the VALOR trial that led to the FDA's approval. “ALS is one of the most devastating and debilitating diseases, and it is my hope this new drug therapy will pave the way to developing even more treatment options for patients living with the condition.”

The VALOR trial assessed tofersen's efficacy in a randomized, double-blinded study involving 108 patients 23 to 78 years of age with SOD1-linked ALS; the findings were published Sept. 22, 2022, in the New England Journal of Medicine. Over the 28 weeks of the trial, tofersen failed to show a statistically significant change in the primary endpoint—the change from baseline in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R); the difference between the ALSFRS-R scores among those taking tofersen and placebo was 1.2 points (p= 0.97).

Under the accelerated approval pathway, however, the FDA can approve a drug based on surrogate endpoints to allow for earlier access to therapies for serious conditions with unmet needs.

In the overall intent-to-treat population (n=108), the tofersen group experienced a 55 percent reduction in plasma neurofilament light chain (NfL), a blood-based biomarker of axonal injury and neurodegeneration, compared with a 12 percent increase in placebo-treated participants (p<0.0001). Levels of SOD1 protein in the cerebrospinal fluid (CSF), an indirect measure of target engagement, were reduced by 35 percent in the group receiving the experimental drug compared with 2 percent in the corresponding placebo group (p<0.0001).

“The declines in SOD1 protein and NfL were fairly dramatic, so we see a bit of a disconnect between the functional scores at 28 weeks and the biomarker response,” Dr. Ladha said. “We know that the SOD1 protein is bad, and intuitively, if you can reduce it, that's got to be good. So what's going on? In subgroup post-hoc analyses, they found that people who started on the drug earlier seemed to experience a functional benefit.”

One-year data from both the phase 3 trial and an ongoing open-label extension study found that tofersen led to a significant and clinically meaningful slowing of ALS progression. Compared with patients who were initially assigned a placebo and then switched to tofersen in the extension study, those who were always on the active drug experienced a smaller decline in their ALSFRS-R scores—6 vs. 9.5—at one year.

The researchers also reported significant differences in measures of lung function and muscle strength, while the early-start group—those who started the drug at trial entry—also experienced significant extensions in survival and in time to death or permanent ventilation.

“This analysis included all genotypes of SOD1, whereas the primary endpoint was just the fast-progressing genotypes; this would appear to help explain the differences in the outcomes,” said Stephen Goutman, MD, associate professor of neurology, director of the Pranger ALS Clinic, and associate director of the ALS Center of Excellence at University of Michigan.

Post-hoc analyses, reported in 2022 at a meeting of the Northeast ALS Consortium, also suggested that reductions in blood NfL levels over the first four months of treatment predicted slower declines in measures of function and disease severity in a dose-dependent manner: every 10 picogram/mL drop in NfL blood levels up to day 113 predicted a 0.77-point slower reduction in ALSFRS-R scores up to day 197.

Cautious Optimism

ALS specialists who spoke with Neurology Today all expressed cautious optimism about the potential for tofersen to make a meaningful difference in the lives of patients with SOD1-linked ALS. “If the initial VALOR study had been longer and larger, I think we would now know with more certainty whether or not tofersen works. I do think that it does,” said Bjorn Oskarsson, MD, FAAN, an associate professor of neurology at Mayo Clinic in Jacksonville, FL. “I believe that the benefit shown in the extension trial analyses is real. There are people living today taking tofersen who, statistically speaking, would be unlikely to still be alive. That, of course, is almost anecdotal evidence, but matched with the NfL findings, it is very promising. If I had SOD1 ALS, I would want to take tofersen, no doubt about it.”

“The open-label extension findings suggest that the reduction of NfL in the plasma precedes a slowing in patients' decline,” said Sarah Berth, MD, PhD, assistant professor of neurology at the Johns Hopkins Health System in Baltimore. “I am testing all of my ALS patients for genetic causes of ALS, and for those who do have the SOD1 mutation, I plan to offer tofersen. I'm interested in seeing how well it will work for my patients and how they respond.”

“The reduction in the SOD1 CSF protein does give some evidence that the drug is doing what it's intended to do, which I think is really important,” said Dr. Goutman.

“We don't know at this point how effective this drug is going to be, and I think our clinical experience is going to help inform us of that, but based on the changes in biomarkers, I remain optimistic that this drug will have a clinically meaningful effect. After 11 years of caring for individuals with ALS and having participated on the benefits/risk working group of the ALS Association as new FDA guidelines were being drafted, I have learned that people living with ALS are willing to take on a much greater degree of risk with drugs than we might imagine.”

The most common side effects were pain, fatigue, arthralgia, increased CSF white blood cells, and myalgia. “They were generally mild. People could have pain from the intrathecal delivery, headaches, post-lumbar puncture syndrome, and fatigue,” Dr. Berth said. “Increases in white blood count and protein in the CSF did occur in some patients, and a small percentage of those patients experienced myelitis, radiculitis, or meningitis. That is something to watch out for, although I would note that it did not lead to a discontinuation of tofersen for most of these patients.”

The VALOR findings also point to the importance of early initiation of therapy. “For many drug products we test in ALS, there seems to be some sign of benefit when you begin treating patients as early in the disease course as possible, but later on there may be no perceptible difference,” Dr. Oskarsson said.

“These findings emphasize the need to screen and diagnose people earlier and potentially start drug treatments sooner,” Dr. Goutman said. “The earlier we can treat, the more there is to salvage. We have a lot of work to do to speed up the ALS diagnostic process and make it more recognizable earlier on in the disease, and that will become even more important as new drugs come out that may have even greater clinical efficacy.”

A New Biomarker

Although the FDA's Peripheral and Central Nervous System Drugs Advisory Committee had mixed opinions on the evidence of tofersen's efficacy, voting 3-5 (with one abstention) that the clinical data from the VALOR trial did not provide convincing evidence of the drug's effectiveness, they were unanimously convinced of the validity of NfL as a biomarker. In a 9-0 vote, they agreed that the available evidence was sufficient to conclude that reducing plasma NfL was reasonably likely to predict tofersen's clinical benefit in SOD1-linked ALS. That conclusion also led them to unanimously recommend the accelerated approval.

“ALS is a disease that is deadly yet difficult for us to measure. This has been a problem for drug development since forever,” Dr. Oskarsson said. “Even in a rapidly progressing disease like ALS, you need to do trials that are at least a year if not more to assess any effect on survival. We have come up with different ways of trying to measure function, but while our functional scales are improving, they have historically had poor methodological quality. The ALSFRS-R is the best we have, and I use it, but it is not necessarily a particularly good tool. Until now, we have not had a measure that relates to nerve cell death that we could measure in the blood.”

One of the problems with the ALSFRS-R score for the purposes of assessing the efficacy of a drug is the fact that it does not change rapidly, Dr. Ladha said. “NfL has been a lead candidate biomarker for quite some time. It's still not perfect because the disease is quite heterogeneous and the mechanism within patients varies enough that it would be nearly impossible to find a uniform perfect biomarker that mirrors the disease, affects all patients to an equal degree, and changes with a speed that would affect clinical trial development.”

The search for additional biomarkers in ALS continues. “What we will look for in the future is biomarkers that are predominant in different subtypes of ALS to allow us to funnel different patients with different primary mechanisms of disease into a trial of a drug that attacks the associated mechanism,” Dr. Ladha said.

The Costs of Care

Biogen has not confirmed a price for the drug but said that it will be “within a range comparable to other recently launched ALS treatments.” Industry publications have estimated that the cost will be $14,230 per dose, which would amount to under $200,000 in the first year (14 doses) and approximately $185,000 in subsequent years (13 doses). By comparison, sodium phenylbutyrate/taurursodiol (Relyvrio), which the FDA approved in 2022 for the treatment of ALS, is priced at about $158,000 annually, and edaravone (Radicava), originally approved in 2017 as an infusion drug and released in 2022 in an oral suspension form, is priced at about $171,000 per year.

The annual cost calculations for tofersen are for the drug only and do not include any costs related to administration, which could be substantial given its intrathecal delivery method. These costs, along with logistical challenges of any scaled-up implementation of therapeutics with that method of administration, could pose a challenge for ALS centers in the future.

“We are fortunate in a sense in that this patient population is small, but we do have other intrathecal treatments in the pipeline that are aimed at all patients. If any of them are successful and we start doing significantly more of these, at some point it could completely overwhelm our ability to do that many injections,” Dr. Ladha said. “We don't have a real plan for that yet.”

Multidisciplinary ALS centers are already overburdened because the approval process for treating patients with any of the newer agents requires a lot of staff hours. “We already see that with Relyvrio and Radicava,” Dr. Ladha said, “and with an intrathecal procedure, these challenges will be multiplied. Scheduling those procedures takes a lot of time and is not really reimbursed well by payors, so costs to the centers will be high.”

With funding from drugmaker Amylyx, a number of ALS neurologists, including Dr. Ladha, have worked with a lobbying firm to push for adoption of legislation that would revamp the Medicare reimbursement system for multidisciplinary ALS centers by creating a supplemental, facility-based payment to qualified facilities. The AAN supports the legislation, which Reps. Jan Schakowsky (IL-09), Mike Quigley (IL-05), Brian Fitzpatrick (PA-01), and Jason Crow (CO-06) introduced in the US House of Representatives in December 2022.

Positive Signs for the Future

Although tofersen treats a very small percentage of people with ALS (estimated by the Centers for Disease Control and Prevention to be fewer than 500 people in the US today), experts agree that the approval also holds promise for patients with other forms of ALS.

“If the extension trials confirm tofersen's efficacy for SOD1 ALS, that would be proof of principle that antisense oligonucleotide therapy is effective in this disease and could be applied to other forms of ALS as well,” Dr. Berth said.

Indeed, two promising trials underway are assessing the efficacy of antisense oligonucleotide therapies in sporadic ALS, Dr. Berth said. “This is now a bona fide class of drugs that we are now learning how to use, and what we have learned and continue to learn from the tofersen study—as well as from other antisense oligonucleotide successes, such as nusinersen for spinal muscular atrophy—will help us more rapidly advance the field.”

“There is a lot of hope and excitement out there that this drug may have a meaningful impact for people with this rare genetic form of ALS,” Dr. Goutman said. “We as a field are hopeful that this is just the first in a line of drugs that can target the underlying genetic mechanisms of this disease.”


Dr. Oskarsson has received consulting fees for Columbia University from Tsumura Inc., MediciNova, Biogen, Amylyx, and Mitsubishi. Drs. Berth and Goutman had no disclosures.

Link Up for More Information

• Miller TM, Cudkowicz ME, Genge A, et al; for the VALOR and OLE Working Group. Trial of antisense oligonucleotide tofersen for SOD1 ALS N Engl J Med 2022;387:1099–1110.
• Supplement: Proceedings of the 21st annual meeting of the Northeast ALS Consortium Muscle Nerve 2022;66(S2): S1–S63.