US Pharm. 2023;48(11):37-41.

ABSTRACT: Amyotrophic lateral sclerosis (ALS), an incurable, progressive neurodegenerative disorder, is the most common motor neuron disease, affecting approximately 31,000 adults in the United States. Until recently, the only drugs that were approved for the management of ALS were riluzole, edaravone, and sodium phenylbutyrate/taurursodiol. However, on April 25, 2023, the FDA granted accelerated approval to tofersen (Qalsody), an antisense oligonucleotide, indicated to treat patients with ALS associated with a mutation in the SOD1 (superoxide dismutase 1) gene. Study surrogate endpoint data are available that have not demonstrated a statistically significant benefit from the use of tofersen over placebo. However, trends have indicated that tofersen reduces cerebrospinal fluid (CSF) concentrations of SOD1 and plasma concentrations of neurofilament light chains, especially when it is administered early in the disease course. The most common adverse events associated with tofersen include pain, fatigue, arthralgia, CSF white blood cell increases, and myalgia. Confirmatory studies are needed to verify the clinical benefit of tofersen in familial ALS secondary to a SOD1 mutation.

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is the most common motor neuron disease in adults. It involves the progressive degeneration of upper and lower motor neurons.1-3 While the pathogenesis of ALS is not completely understood, it is thought to involve neuronal damage triggered by protein misfolding, oxidative stress, mitochondrial dysfunction, RNA-processing impairment, neurofilament aggregation, loss of axonal transport, disruption of the neuromuscular junction, and axon demyelination. Protein aggregates of TDP43 have been found in the neuronal cytoplasm of 97% of ALS patients.4

ALS Symptoms and Prevalence

Symptoms of ALS include muscle fasciculations, muscle cramps, spasticity, muscle weakness, slurred and nasal speech, dysphagia, dysarthria, and paralysis, with patients eventually requiring ventilatory support.3 Up to one-half of patients develop cognitive and/or behavioral impairment, including frontotemporal dementia.1

Based on data from 2018 from the National ALS Registry, 21,665 persons in the United States had confirmed or likely ALS, for a prevalence rate of 6.6 per 100,000 persons. However, after accounting for missing data, the adjusted prevalence rate is 9.1 per 100,000.5 The lifetime risk of ALS is estimated to be one in 350 people.1 There are over 31,000 persons living with ALS in the U.S.6

Nongenetic ALS Risk Factors

Age, biological sex, race, and military involvement are risk factors associated with the development of ALS.3 Those aged >65 years (>65 years 21.4/100,000 vs. 1.1/100,000 for those aged 18-50 years); males (8.1 cases/100,000 males vs. 5.2/100,000 females); and whites (6.1/100,000 vs. 2.8/100,000 in blacks, 4.5/100,000 in other races) have the highest prevalence rate compared with other patient populations.5 Veterans may have been exposed to lead, pesticides, and other environmental toxins that may have put them at risk of developing ALS.3,4 Athleticism, smoking, and viruses are also being investigated as possible risk factors of ALS.4

Genetic Risk Factors

Although most cases of ALS occur sporadically (i.e., at random with no known risk factors or family history), about 5% to 15% of cases are familial and are either autosomal dominant, autosomal recessive, or X-linked.1,3 Sporadic ALS tends to develop at a later age than familial ALS.4

Over 40 genes have been associated with the development of ALS, with four genes, C90RF72, SOD1, TARDBPM, and FUS, accounting for >70% of familial ALS cases.1

The first familial ALS pathogenic gene, the SOD1 (superoxide dismutase 1) gene, was discovered in 1993.1 This gene is involved in the production of the enzyme copper-zinc superoxide dismutase 1.3 There are over 200 mutations to the SOD1 gene, and they affect the age of onset and survival time of ALS.1 Mutations in the SOD1 gene occur in about 2% of ALS cases.4 Approximately 70% of familial ALS patients and about 15% of spontaneous ALS cases have mutations in known ALS genes.1

Prognosis for Patients With ALS

A poorer prognosis is associated with older age, bulbar onset, early respiratory dysfunction, and a lower score on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) compared with younger patients and those with limb-onset ALS.4 Death, which typically occurs within 3 to 5 years from the onset of symptoms, usually results from respiratory failure. However, about 10% of those with ALS survive for a decade or longer.3


Unfortunately, there is no cure for ALS. Treatment is mainly supportive and is designed to keep patients with ALS mobile, comfortable, and independent as long as possible.3 Factors such as the lack of knowledge about the pathogenesis of ALS, heterogeneity of the disease progression, limitations of study design, and pharmacogenetic interactions (e.g., genetic variants in the C9orf72 gene) have complicated drug development for ALS.4

Prior to 2023, the only drugs for ALS that were approved by the FDA were riluzole, edaravone, and sodium phenylbutyrate/taurursodiol (P/T).7 Riluzole, a glutamate antagonist approved in 1995, has been associated with an increased time to tracheostomy or death compared with placebo. Its use is associated with a 2- to 3-month survival benefit based on clinical trials and up to 21 months based on real-world evidence. However, it does not improve measures of muscle strength and neurologic function.8 Riluzole appears to be associated with a 35% reduction in mortality in ALS, with the drug prolonging stage 4 (late stage) ALS in a dose-dependent manner. There is no apparent prolongation of stages 2 or 3, even though it is recommended to start therapy upon diagnosis of ALS.4,9

Edaravone is an antioxidant and free radical scavenger that is thought to act by reducing excessive oxidative stress and cell death.4 The decline in the ALSFRS-R from baseline to 24 weeks for edaravone was significantly less than for placebo.10 However, overall data supporting the use of edaravone have been mixed. Edaravone is thought to preserve function and delay motor deterioration early in the course of the disease.4 A post hoc analysis of a P/T trial demonstrated longer median overall survival in the treatment group compared with placebo.11

On April 25, 2023, the FDA approved tofersen (Qalsody), an antisense oligonucleotide, to treat patients with ALS associated with a mutation in SOD1 gene (SOD1-ALS).12 This indication is approved under accelerated approval based on reduction in plasma neurofilament light chain (NfL) observed in patients treated with tofersen.13

Evidence Supporting the Use of Tofersen

Surrogate endpoints used to support the accelerated approval of tofersen included the effect of tofersen on total cerebrospinal fluid (CSF) SOD1 protein, which is an indirect measure of target engagement and plasma NfL levels, a blood-based biomarker of axonal injury and neurodegeneration.13

Use of NfL as a therapeutic trial outcome has been associated with a significant reduction in sample size and in an earlier detection of disease-slowing compared with the ALSFRS-R.14 In ALS, higher blood NfL levels have been associated with a statistically significant elevated risk of death (for high vs. low NfL level: hazard ratio = 4.51, 95% CI [2.45-8.32], P <.01).15 Although NfL is a validated, reproducible, easily accessible surrogate marker of axonal loss that has prognostic value in ALS, it has been shown to have a sensitivity of 0.77, 95% CI (0.68-0.85) and a specificity of 0.75 (CI 0.55-0.89), corresponding to a positive predictive value of 0.92 (CI 0.84-0.97) and negative predictive value of only 0.48 (CI 0.32-0.63).16,17 NfL can be used to stratify patients with ALS by disease activity and as a biomarker in therapeutic trials.18

Overproduction of toxic SOD1 proteins have been observed in ALS patients with mutations in the SOD1 gene. Tofersen reduces the synthesis of SOD1 proteins by mediating the RNase H-dependent degradation of SOD1 messenger RNA.19

Tofersen gained FDA accelerated approval based on the three-part VALOR trial in which the first two parts (NCT02623699) were dose-escalation trials to assess the dose of tofersen to be used in part C (i.e., a phase III trial; NCT03070119).19,20 Part A involved the use of a single ascending dose, and Part B involved the use of multiple ascending doses of tofersen.19

Fifty patients with ALS due to SOD1 mutations were enrolled in the international phase I-II, placebo-controlled, ascending-dose trial in which the effects of 20, 40, 60, or 100 mg of tofersen or placebo were evaluated in a 3:1 ratio, with five doses administered intrathecally for 12 weeks on Days 1, 15, 29, 57, and 85.19

In addition to having the SOD1 mutation, study participants had to have normal coagulation variables and a forced vital capacity (VC) of at least 50% of the predicted value after adjustments for sex, age, and height. Patients were allowed to receive stable doses of riluzole, but the use of edaravone was prohibited.

The primary outcomes were the incidence of adverse events and serious adverse events; abnormalities in laboratory data and vital signs; neurologic physical exam findings; Mini-Mental State Examination; and electrocardiogram, which were safety outcomes. Other outcomes included tofersen pharmacokinetic measures in plasma and the CSF. The secondary outcome was the change from baseline of the CSF SOD concentration by day 85. Additional exploratory outcomes included changes from baseline in the total score on the ALSFRS-R; the percentage of predicted slow VC; the handheld dynamometry megascore, which assessed muscle strength in the arms and legs; and neurofilament concentrations (phosphorylated neurofilament heavy chains and post hoc analysis of NfL).

A fast-progression subgroup was identified as patients with ALS who had a SOD1 mutation that had one of 10 prespecified mutations, a mean disease duration of <3 years, and a decline in the ALSFRS-R score of at least 0.2 points per month.

Study participants were followed for 31 weeks, which included a 7-week screening period followed by a 12-week intervention and 12-week follow-up period.

Of the 50 patients, 48 received all five doses of tofersen. The 100-mg dose was found to be the most effective, with a 33%-point decrease in CSF SOD1 concentrations. Adverse events occurred in all patients, with most events being lumbar puncture–related adverse events (e.g., headache, injection pain, falls). Three deaths occurred, including one in the placebo group (from respiratory failure), one in the 20-mg tofersen group (due to pulmonary embolism), and one in the 60-mg tofersen group (from respiratory failure). While elevations in CSF white blood cell counts (WBCs) and/or CSF protein were more common in the tofersen group, there was no association between higher doses of tofersen or longer duration of exposure to tofersen and these elevated levels; the significance of these findings is unclear.

Unfortunately, this study only reported descriptive statistics without P values, so interpretation of its findings is difficult.19

Following the completion of the VALOR phase I-II trials, the phase III trial commenced. This trial’s results were used to gain accelerated approval status.13 This trial enrolled 108 patients with ALS, including 72 participants who received tofersen and 36 who received placebo. These patients were not the same as those in the phase I-II trial. Within these groups, 60 patients were predicted to have the “faster progression” type of ALS. They had a slow VC >65% of predicted value and had met the prognostic enrichment criteria based on their ALSFRS-R score decline and SOD1 mutation type.

This trial included a 4-week screening period followed by a 24-week treatment period and a 4- to 8-week follow-up period. Tofersen 100 mg (15 mL) or placebo was randomly assigned in a 2:1 ratio and administered via intrathecal bolus. For the placebo group, an equivalent volume of artificial CSF was administered. Patients were stratified by use of edaravone, riluzole, or both, by disease progression status (i.e., fast progression), and by baseline plasma NfL concentrations. After the completion of the phase III study, 95 patients enrolled in the 236-week, open-extension trial.

The primary efficacy endpoint was the change from baseline to Week 28 in the faster-progression group ALSFRS-R total score. The prespecified secondary endpoints included the change from baseline in the total concentration of SOD1 protein in the CSF, the concentration of NfL chains in plasma, the percentage of the predicted VC, the handheld dynamometry megascore, time to death or persistent ventilation (>22 hours/day of mechanical ventilation for >21 consecutive days), time to death, and safety. These were the same endpoints for the open-label extension trial.

Patients randomized to the tofersen group had higher baseline concentrations of NfL and a faster rate of decline in the ALSFRS-R score. Among the study patients, 62% received riluzole and 8% were on edaravone.

There was no statistically significant difference in the primary or clinical secondary outcomes between the tofersen group and placebo. There was one death in the tofersen group. As for the secondary endpoints, change from baseline at Week 28 in plasma NfL and CSF SOD1 protein were nominally statistically significantly different in favor of tofersen between the treatment and placebo groups. There was a reduction in total CSF SOD1 protein by 35% in the tofersen-treated group versus a 2% decrease from baseline in the placebo group. Mean plasma NfL was also reduced by 55% in the treatment group compared with a 12% increase in the placebo group. There was a similar reduction in phosphorylated neurofilament heavy chains and reductions in both CSF and plasma concentrations.13

At Week 52 in the open-label extension, the difference between the early-start tofersen group (i.e., those who had received active treatment in the randomized trial) compared with the delayed-start tofersen group (i.e., those who received tofersen for the first time during the open extension trial) favored early-start tofersen in terms of change in the ALSFRS-R score from baseline, change in the percentage of predicted slow VC from baseline, and change in the handheld dynamometry megascore, although these findings were not statistically significant. The hazard ratio for time to death or permanent ventilation for the early-start versus the delayed-start tofersen group was 0.36 (95% CI 0.14-0.94) and for time to death was 0.27 (95% CI 0.08-0.89); however, the median time to death or permanent ventilation or median time to death could not be calculated due to the limited number of occurrences. This represented a nonstatistically significant trend toward a reduction of the risk of death or permanent ventilation in the tofersen group.

Adverse Event Profile

Neurologic serious adverse events occurred in 7% of tofersen-treated patients and were consistent with disease progression, expected occurrence in the general population, or effects from the lumbar puncture procedure. Among the neurologic adverse events observed in the tofersen group were myelitis, aseptic meningitis, lumbar radiculopathy, increased intracranial pressure, and papilledema. Increases in CSF WBC and CSF protein concentrations were greater in the tofersen group during both the randomized phase III trial and the open-extension trial.

The authors concluded that tofersen reduced CSF concentrations of SOD1 and plasma concentrations of NfL chains over 28 weeks, but it did not improve clinical endpoints, and it was associated with adverse events.13,20

Despite these limited positive effects, tofersen was approved by accelerated approval based on a surrogate endpoint that it is reasonably likely to predict clinical benefit in patients, i.e., based on a reduction in plasma NfL.12

The findings from the open-extension trial that indicated that the early-start group demonstrated a trend toward greater benefit with tofersen compared with the delayed-start group led to the initiation of the phase III ATLAS study, a global, randomized, placebo-controlled study with a natural history run-in and open-label extension (NCT04856982). Inclusion criteria for ATLAS are age >18 years; possession of the SOD1 variant (most commonly A5V carriers); and presence of an elevated plasma NfL level (i.e., plasma NfL >44 pg/mL and an increase of >10 pg/mL from Part A baseline).21 The primary objective of the ATLAS study is to evaluate the efficacy of tofersen in presymptomatic adult carriers of an SOD1 mutation with elevated neurofilament. The secondary objectives are to evaluate the safety and tolerability of tofersen and to evaluate the effect of tofersen on pharmacodynamics/treatment response biomarkers when initiated before the manifestation of symptoms of ALS.

ATLAS commenced May 17, 2021, and is expected to complete August 7, 2027. If patients develop manifestations of ALS, they can enroll in the open-label tofersen trial.21,22

Dosage and Administration

Tofersen is administered intrathecally as a 100-mg (15-mL) dose. Treatment is initiated with three loading doses (LDs) given at 14-day intervals. Upon completion of the LD, a maintenance dose of 100 mg (15 mL) is administered once every 28 days. In the event that the second LD is missed, tofersen should be administered as soon as possible with the subsequent dose given 14 days later. However, if the third LD or a maintenance dose is missed, tofersen should be administered as soon as possible, but the following dose should not be given until 28 days later.13

Tofersen is available in a preservative-free, single-dose vial. Prior to administration, the drug needs to be warmed to room temperature without using an external heat source. To accommodate the volume of tofersen, about 10 mL of CSF should be withdrawn prior to administration. Tofersen is administered as an intrathecal bolus over 1 to 3 minutes. Since tofersen contains no preservatives, it must be administered no later than within 4 hours of drawing up the dose into the syringe or it must be discarded.13


When administered intrathecally, tofersen becomes distributed throughout the CSF and into central nervous system tissue. It is transferred from the CSF into the systemic circulation with a median time to maximum plasma concentrations of 2 to 6 hours. It is not metabolized via the CYP450 system, nor is it a substrate of transporters. It is thought to be metabolized through exonuclease (3’-5’)–mediated hydrolysis. It is unclear how the drug is eliminated from the body.13

Safety of Tofersen

The warnings and precautions section of the product labeling indicates that serious neurologic adverse events, including myelitis and/or radiculitis, papilledema and elevated intracranial pressure, and aseptic meningitis have been reported following administration of tofersen.13

The most common adverse events, reported in >10% of patients who received tofersen in clinical trials compared to placebo, include pain, fatigue, CSF WBC increase, and myalgia. Tofersen does not prolong the QT interval.13

There is no information on the use of tofersen in pregnant or lactating women, in pediatric patients, or in patients with hepatic or renal impairment. Although only about 14% of study participants were aged 65 years or older, there is no evidence of differences in safety or effectiveness between younger and older patients and no dosage alterations are needed in this age group.13  


Tofersen may be stored in its original carton at <86°F for up to 14 days. However, once it is removed from the original carton, unopened vials can be removed and returned to the refrigerator for no more than 6 hours/day at <86°F for a maximum of 6 hours for 6 days for a total of 36 hours.13 


Although data are preliminary, tofersen may offer hope to patients with familial ALS who have a mutation in the SOD1 gene. Since the drug was approved via the accelerated approval process, it is essential that confirmatory clinical trials be conducted to help further define tofersen’s place in therapy in the management of familial ALS with a mutation in SOD1.


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