Medical Policy

Policy Num:    05.001.052
Policy Name:  Tofersen (Qalsody)
Policy ID        [05.001.052] [Ac/L /M- / P-] 

Last Review:    September 25, 2025
Next Review:    September 20, 2026

Related Policies: None

    Tofersen (Qalsody)
 

Summary

Tofersen (Qalsody) is an antisense oligonucleotide indicated for the treatment of amyotrophic lateral sclerosis (ALS) in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene. This indication is approved under accelerated approval based on reduction in plasma neurofilament light chain observed in pati ents treated with tofersen (Qalsody). Continued approval for this  indication may be contingent upon verification of clinical benefit in confirmatory trial. 

Amyotrophic lateral sclerosis (ALS) is a debilitating disease caused by degeneration of cortical, brainstem, and spinal cord motor neurons and, in some cases, frontotemporal cortical neurons. The neurodegeneration results in progressive muscle weakness, muscle spasticity, dysarthria, dysphagia, cognitive and behavioral impairments, and other motor symptoms. 

Objective

To evaluate the evidence on safety, efficacy, and coverage considerations of tofersen (Qalsody) in the treatment of amyotrophic lateral sclerosis (ALS) with SOD1 mutations.

Policy Statement

The use of Qalsody (tofersen) is considered investigational for all indications, including ALS with SOD1 mutations, due to lack of conclusive evidence confirming clinical benefit.

Policy Guidelines

FDA Status: Accelerated approval granted (2023). Continued approval is contingent on confirmatory clinical benefit.
 
Evidence:
 
The VALOR phase 3 trial (n=108) showed reduction in SOD1 protein (CSF) and plasma neurofilament light chain but did not demonstrate statistically significant improvement in ALSFRS-R functional outcomes at 28 weeks.
 
Open-label extension suggested possible slower functional decline in early-start patients, but data remain preliminary.
 
 
Adverse Events: Serious neurological risks include:
 
Myelitis and radiculitis
 
Papilledema and intracranial hypertension
 
Aseptic meningitis

The American Academy of Neurology (AAN, reaffirmed 2020) and EFNS (2012) guidelines recommend riluzole as standard care.
 
Tofersen is not yet included in ALS guideline updates.

Benefit Application

Coverage determination is subject to contractual terms, state/federal mandates, and FDA status.
 
At this time, use remains investigational and coverage is not recommended outside of clinical trials.

Background

The efficacy of tofersen (Qalsody) was evaluated in a multicenter, randomized, double-blind, placebocontrolled trial (VALOR study). A total of 108 adult patients with SOD1 ALS were assigned 2:1 to receive either eight doses of tofersen 100 mg (3 loading doses at 14-day intervals followed by 5 maintenance doses at 28-day intervals) or placebo as an intrathecal bolus injection over a period of 24 weeks. Concomitant use of riluzole and edaravone was permitted. The primary end point was the change from baseline to week 28 in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale– Revised (ALSFRS-R; total scores are zero to 48 with higher scores indicating better function; see Definitions) among participants predicted to have faster-progressing disease. Secondary end points included changes in the total concentration of SOD1 protein in cerebrospinal fluid (CSF), in the concentration of neurofilament light chains in plasma, in slow vital capacity, and in handheld dynamometry in 16 muscles. A total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). In the fasterprogression subgroup, the change at week 28 in the ALSFRS-R score was −6.98 with tofersen and −8.14 with placebo (difference, 1.2 points; 95% confidence interval, −3.2 to 5.5; P=0.97). Tofersen demonstrated a reduction in concentrations of SOD1 in CSF (35% reduction for tofersen compared to 2% for placebo; P=<0.0001) and neurofilament light chains in plasma (55% reduction for tofersen compared to a 12% increase for placebo; P=<0.0001). Results for other secondary end points did not differ significantly between the two groups. Tofersen was further evaluated in an open-label extension phase. A total of 95 participants (88%) from the VALOR study entered the open-label tofersen extension; this population included patients that receive active drug therapy from the trial start (early-start) and those that switched from placebo to active drug at 28 weeks (delayed-start). At 52 weeks, the change in the ALSFRS-R score was −6.0 in the early-start cohort and −9.5 in the delayed-start cohort (difference, 3.5 points; 95% confidence interval, 0.4 to 6.7). The extension phase is ongoing, and final analysis scheduled to occur once participants have completed at least 3.5 years of follow-up. The most frequently reported adverse events were consistent with ALS disease progression or side effects of lumbar puncture and included procedural pain, headache, pain in the arms or legs, falls, and back pain. Four patients in the VALOR study and three patients in the open-label extension who received tofersen had a total of eight neurologic serious adverse events (e.g., myelitis, chemical/aseptic meningitis, lumbar radiculopathy, increased intracranial pressure, papilledema).

QALSODY can cause serious side effects, including:

• Inflammation of the spinal cord (myelitis) and/or irritation of the nerve roots (radiculitis), including serious cases, have been reported in patients treated with QALSODY. Six patients treated with QALSODY experienced inflammation of the spinal cord or irritation of the nerve roots in the clinical studies. Two patients stopped treatment with QALSODY and their symptoms resolved with treatment. In the remaining 4 patients, symptoms resolved without stopping QALSODY. If you experience common symptoms such as abnormal sensations (pins and needles), numbness, or weakness, please contact your healthcare provider. Your healthcare provider can help you determine how to address symptoms, and may recommend that you stop taking QALSODY.
• Swelling of the optic nerve (papilledema) and increased pressure inside the skull (elevated intracranial pressure), including serious cases, have been reported in patients treated with QALSODY. The optic nerve connects the eyes with the brain and is responsible for vision. Four patients developed increased pressure inside the skull and/or swelling of the optic nerve. All patients received treatment from their healthcare provider that resolved these symptoms, and no events led to stopping QALSODY. If you experience common symptoms of swelling of the optic nerve such as blurred vision, double vision, or vision loss, please contact your healthcare provider. If you experience symptoms of increased pressure inside the skull, such as headache, vomiting, or numbness or weakness, please contact your healthcare provider.
• Inflammation of the brain linings (aseptic meningitis, also called chemical meningitis or drug-induced aseptic meningitis), including serious cases, have been reported in patients treated with QALSODY. One patient experienced a serious side effect of inflammation of the brain linings, which led to the patient stopping QALSODY. One patient experienced a serious side effect of inflammation of the brain linings, which did not lead to the patient stopping QALSODY. In addition, nonserious side effects that can be signs of inflammation or infection have also been reported with QALSODY, including increased white blood cells and increased protein in the cerebrospinal fluid (the fluid around the spinal cord and the brain). If you experience symptoms such as headache, fever, vomiting, neck stiffness, nausea or vomiting, please contact your healthcare provider.

QALSODY can cause serious side effects, including:

• Inflammation of the spinal cord (myelitis) and/or irritation of the nerve roots (radiculitis), including serious cases, have been reported in patients treated with QALSODY. Six patients treated with QALSODY experienced inflammation of the spinal cord or irritation of the nerve roots in the clinical studies. Two patients stopped treatment with QALSODY and their symptoms resolved with treatment. In the remaining 4 patients, symptoms resolved without stopping QALSODY. If you experience common symptoms such as abnormal sensations (pins and needles), numbness, or weakness, please contact your healthcare provider. Your healthcare provider can help you determine how to address symptoms, and may recommend that you stop taking QALSODY.
• Swelling of the optic nerve (papilledema) and increased pressure inside the skull (elevated intracranial pressure), including serious cases, have been reported in patients treated with QALSODY. The optic nerve connects the eyes with the brain and is responsible for vision. Four patients developed increased pressure inside the skull and/or swelling of the optic nerve. All patients received treatment from their healthcare provider that resolved these symptoms, and no events led to stopping QALSODY. If you experience common symptoms of swelling of the optic nerve such as blurred vision, double vision, or vision loss, please contact your healthcare provider. If you experience symptoms of increased pressure inside the skull, such as headache, vomiting, or numbness or weakness, please contact your healthcare provider.
• Inflammation of the brain linings (aseptic meningitis, also called chemical meningitis or drug-induced aseptic meningitis), including serious cases, have been reported in patients treated with QALSODY. One patient experienced a serious side effect of inflammation of the brain linings, which led to the patient stopping QALSODY. One patient experienced a serious side effect of inflammation of the brain linings, which did not lead to the patient stopping QALSODY. In addition, nonserious side effects that can be signs of inflammation or infection have also been reported with QALSODY, including increased white blood cells and increased protein in the cerebrospinal fluid (the fluid around the spinal cord and the brain). If you experience symptoms such as headache, fever, vomiting, neck stiffness, nausea or vomiting, please contact your healthcare provider.

Rationale

Population Reference No. 1 Policy Statement

Evidence demonstrates strong biomarker response but uncertain clinical efficacy. Until confirmatory phase 3/4 trials validate functional benefits, coverage should remain investigational. FDA’s decision emphasizes unmet medical need in rare ALS subpopulations but requires post-marketing data. 

QALSODY is an antisense oligonucleotide indicated for the treatment of amyotrophic lateral sclerosis (ALS) in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene. This indication is approved under accelerated approval based on reduction in plasma neurofilament light chain observed in patients treated with QALSODY. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).  The exact etiology of ALS is unclear but is likely due to multiple genetic (e.g., C9orf72, TARDBP, SOD1, FUS genes) and environmental factors. The superoxide dismutase 1 (SOD1) gene mutation affects approximately 2% of ALS cases, which equates to about 500 patients in the United States. Onset typically occurs at age 50 to 75 years and is more frequently reported in males than females, with a lifetime risk of about 0.29% and 0.25%, respectively. Unfortunately, prognosis is poor with a median survival of 2 to 4 years, and respiratory insufficiency is the most common cause of death.

Suplemental Information

 Qalsody carries boxed warnings and clinical precautions for serious neurologic adverse events.

The U.S. Food and Drug Administration (FDA) has approved tofersen (Qalsody®) under the accelerated approval process for the treatment of amyotrophic lateral sclerosis (ALS) in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene. According to the prescribing information, continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory clinical trials. Grade 2 C.

Serious adverse reactions have occurred in patients receiving tofersen, including myelitis and/or radiculitis, papilledema and elevated intracranial pressure, and aseptic meningitis.

The American Academy of Neurology updated guidelines from 2009 (reaffirmed on January 11, 2020) titled “Update: The care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies” recommend that riluzole should be offered to slow the disease progression in patients with ALS. The European Federation of Neurological Sciences (EFNS) guidelines on clinical management of amyotrophic lateral sclerosis (MALS)-revised report of an EFNS task force, from 2012 also recommend riluzole in all patients. Neither set of guidelines have been updated to include the two most recent ALS drug approvals: Radicava® or Relyvrio™. There are no therapies listed specifically for ALS with SOD1 gene mutations

References

1. FDA Prescribing Information: Qalsody (tofersen), 2023.
 
 
2. Miller TM, Cudkowicz ME, Genge A, et al. Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. NEJM, 2022;387:1099-1110.
 
 
3. Miller T, et al. Phase 1-2 Trial of Tofersen. NEJM, 2020;383:109-119.
 
 
4. Kiernan MC, et al. Amyotrophic lateral sclerosis. Lancet, 2011;377:942–955.
 
 
5. AAN Guidelines: Care of ALS Patients. Neurology, 2009; reaffirmed 2020.
 
 
6. EFNS Guidelines: Management of ALS. Eur J Neurol, 2012.

Codes

Policy History