Qalsody (tofersen) for ALS

Last updated June 6, 2024, by Ines Martins, PhD
Fact-checked by Patricia Silva, PhD

What is Qalsody for ALS?

Qalsody (tofersen) is an injection therapy conditionally approved in the U.S. for the treatment of amyotrophic lateral sclerosis (ALS) associated with mutations in the SOD1 gene (SOD1-ALS).

The therapy was shown in clinical trials to significantly slow disease progression and extend survival, but the approval was based on biomarker data that the regulatory agency said is reasonably likely to predict a clinical benefit in patients.

Ionis Pharmaceuticals first developed Qalsody, but Biogen acquired the rights to the medication in 2018. The treatment also is approved in the European Union under exceptional circumstances and is under regulatory review for possible SOD1-ALS approval in Canada.

Therapy Snapshot

How does Qalsody work in ALS?

ALS is a progressive neurodegenerative disorder in which motor neurons — the nerve cells that control muscle movement — are progressively damaged and die off, ultimately leading to loss of muscle control and paralysis.

The exact cause of the disease is unknown, but up to 20% of familial ALS cases and as many as 2% of sporadic cases are associated with mutations in the gene SOD1, which codes for an enzyme called superoxide dismutase (SOD1).

The SOD1 enzyme neutralizes free radicals, which are byproducts of normal cellular processes that are harmful to cells, preventing a form of cellular damage called oxidative stress. Mutations in the SOD1 gene, however, lead to the production of an abnormal form of the SOD1 protein that cannot properly clear the free radicals and is prone to form toxic clumps, leading to nerve cell damage.

Qalsody is an RNA-based therapy designed to prevent the toxic SOD1 protein from being made. It works by binding to and promoting the degradation of SOD1 mRNA molecules, which are the intermediate molecules produced from the gene that are used as a template for protein production.

By reducing toxic SOD1 levels, the therapy is expected to slow disease progression and potentially extend survival in ALS patients carrying mutations in this gene.

Who can use Qalsody?

The U.S. Food and Drug Administration conditionally approved Qalsody in April 2023 for the treatment of adults with ALS who carry a mutation in the SOD1 gene. This marked the first conditional approval for ALS in the country.

The approval was based on reductions in the levels of neurofilament light chain (NfL), a marker of nerve damage, seen in patients who received the drug in clinical trials. However, continued approval for this indication will require confirmation of Qalsody’s clinical benefits in ongoing trials.

Qalsody also was approved under exceptional circumstances in the European Union in May 2024. This approval pathway can be recommended for therapies with a positive risk-benefit, but when comprehensive data are unlikely to be obtained given the rarity of the disease.

Who should not use Qalsody?

The prescribing information for Qalsody lists no contraindications. However, individuals taking the medication might be at an increased risk of complications such as inflammation on the spinal cord and the meninges, which are the membrane layers that protect the brain and spinal cord, and should be monitored for symptoms as clinically needed. Patients also should be monitored for elevated intracranial pressure as needed.

How is Qalsody administered in ALS?

Qalsody is administered directly into the spinal canal — called an intrathecal injection — at a recommended dose of 100 mg (15 mL) per administration.

When starting treatment with Qalsody, patients first receive three loading doses of the medication, each given two weeks apart. Maintenance doses are then administered every 28 days (almost monthly) thereafter.

Each injection lasts about 1-3 minutes and should be given by a healthcare professional with experience in performing lumbar punctures, also known as a spinal tap. Before giving the medication, the professional also should remove about 10 mL of spinal fluid to account for the extra fluid that will be injected into the spinal canal.

If a dose is missed, patients should receive the medication as soon as possible, and the following dose should be given according to the approved schedule — two weeks later if the missed dose was the second loading dose. In cases in which the third loading dose or a maintenance dose is missed, Qalsody also should be administered as soon as possible, and the next dose should be given one month later.

Qalsody in ALS clinical trials

Qalsody’s approval in the U.S. was based on data from the three-part Phase 1/2/3 VALOR trial (NCT02623699) and its ongoing open-label extension study (NCT03070119).

VALOR Phase 1/2 parts

The first parts of VALOR tested single and multiple ascending doses of Qalsody in people with SOD1-ALS. Phase 1 investigated a single intrathecal injection of the drug at doses ranging from 10 to 60 mg, while the Phase 2 part randomly assigned participants to one of four doses — 20, 40, 60, or 100 mg — or a placebo, given in five injections over 12 weeks, or about three months.

Data from the second part showed that Qalsody was generally well tolerated and able to lower SOD1 and NfL protein levels in the cerebrospinal fluid (CSF), the liquid surrounding the brain and spinal cord.

While the trial was not powered to detect significant changes in clinical outcomes, the data showed that patients who received the now approved dose (100 mg) experienced slower declines in functional ability, lung function, and muscle strength over 12 weeks compared with those given a placebo. A slower disease progression was particularly evident in a subgroup of patients with fast-progressing disease.

VALOR Phase 3 portion

In the Phase 3 part, a total of 108 patients were randomly assigned to receive eight injections of either 100 mg Qalsody or a placebo over six months.

The main goal was to evaluate the effects of 28 weeks (about seven months) of treatment on the ALS Functional Rating Scale Revised (ALSFRS-R) scores — a measure of functional disability — especially in the 60 participants with rapidly progressing ALS.

Top-line data demonstrated that fast-progressing patients given Qalsody or a placebo had similar ALSFRS-R declines over the course of treatment, failing to meet the trial’s main goal.

However, trends supporting Qalsody were observed in some secondary measures, including muscle strength, quality of life , and lung function. Also, patients given the medication experienced marked drops in their CSF SOD1 protein levels and in blood NfL levels, while levels increased among those on a placebo.

Open-label extension

Individuals who completed the VALOR trial were invited to participate in an open-label extension study, in which all are receiving Qalsody for up to seven years.

Data spanning the Phase 3 trial and the extension period showed that treatment with Qalsody led to a significant and clinically meaningful slowing of ALS progression. Patients who continuously received the medication for one year experienced a six-point decline in the ALSFRS-R scores, compared with a 9.5-point decline among those who started on Qalsody seven months later.

Early treatment also resulted in smaller declines in lung function (9.4% vs. 18.6%) and muscle strength (0.17 vs. 0.45 points), and in a significant, 73% reduction in the risk of death and 64% reduction in the risk of death or permanent ventilation.

Patients on continuous Qalsody experienced sustained reductions in their CSF SOD1 and blood NfL levels. While similar reductions were observed after patients on a placebo switched to Qalsody, these drops were less pronounced at one year compared with those reported for patients always on Qalsody.

Further analysis demonstrated that early reductions in blood NfL levels — within the first four months of treatment — predicted slower reductions in ALSFRS-R scores up to 6.5 months. Such early drops also were linked to slower declines in other measures of function and disease severity.

Qalsody received its approval via the FDA’s accelerated approval pathway, which allowed the agency to give conditional marketing authorization to the medication based on early NfL clinical trial data. Continuous approval, however, may be contingent on data from ongoing clinical trials that are evaluating the therapy’s clinical efficacy.

ATLAS trial

The still-recruiting ATLAS Phase 3 trial (NCT04856982) will serve as the confirmatory trial. It is testing Qalsody in people who have not yet experienced symptoms of ALS but carry SOD1 mutations associated with rapidly progressing disease and who show signs of neuronal damage, as defined by elevated NfL levels.

A total of 150 adults are expected to enroll at sites worldwide. They will be randomly assigned to receive either 100 mg Qalsody or a placebo, given via three intrathecal injections over the first month, followed by monthly injections for up to two years.

The main goal is to determine the proportion of patients who develop ALS symptoms in the first 12 months of treatment. Secondary measures include time to first symptoms, changes in ALSFRS-R scores and lung function, and survival. Top-line data are expected in 2026.

Common side effects of Qalsody

The most common side effects associated with Qalsody in clinical trials include:

• pain
• fatigue
• joint and muscle pain
• increase in white blood cell counts in the cerebrospinal fluid.

Inflammation in nerves and meninges

Some patients who received Qalsody experienced serious cases of inflammation in the spinal cord (myelitis), and of pain radiating along specific peripheral nerves due to inflammation at the root of its connection to the spinal column (radiculitis).

There also were reports of serious aseptic meningitis, or inflammation in the membranes covering the brain and spinal cord — called the meninges — usually without the presence of bacteria in the CSF.

Patients on the medication should be monitored for symptoms consistent with any of these conditions. If any such signs do develop, diagnostic workups and treatments should be initiated accordingly.

Elevated brain pressure and optic nerve swelling

Cases of serious increases in intracranial pressure and consequent swelling of the optic disc (papilledema) may occur during Qalsody treatment. If symptoms of these complications become evident, patients should undergo diagnostic procedures and treatment according to standard of care.

Pregnancy and breastfeeding

In animal models, administering Qalsody during pregnancy or before mating had no toxic effects on the developing fetus, but the medication was found in the milk of lactating mice following an under-the-skin (subcutaneous) injection.

Yet, the medication has not been thoroughly studied in human patients who were pregnant or breastfeeding. Individuals who are or plan to become pregnant or breastfeed while on the medication are advised to discuss this topic with their healthcare team.

ALS News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.