Tofersen (Qalsody)

Number: 1031

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses tofersen (Qalsody) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification: 

Precertification of tofersen (Qalsody) is required of all Aetna participating providers and members in applicable plan designs. For precertification of tofersen (Qalsody), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

Note: Unless member's health plan has elected not to require, gene and cellular therapies must be administered at an Aetna Institutes^® Gene Based, Cellular and Other Innovative Therapy (GCIT^®) Network. For tofersen (Qalsody), see Aetna Institutes® GCIT Designated Centers.  

1. Prescriber Specialties

   This medication must be prescribed by or in consultation with a neurologist, neuromuscular specialist or physician specializing in the treatment of amyotrophic lateral sclerosis (ALS).

2. Criteria for Initial Approval

   Aetna considers tofersen (Qalsody) medically necessary for the treatment of amyotrophic lateral sclerosis (ALS) when all of the following criteria are met:

   1. Member is 18 year of age or older; and
   2. Member has weakness attributable to ALS (e.g., medical history and/or diagnostic testing including nerve conduction studies, imaging and laboratory values to support the diagnosis); and
   3. Member has an superoxide dismutase 1 (SOD1) mutation confirmed via genetic testing; and
   4. Member has a forced vital capacity (FVC) or slow vital capacity (SVC) greater than or equal to 45% of predicted value for gender, height and age; and
   5. Member does not have a tracheostomy.

   Aetna considers all other indications as experimental, investigational, or unproven.

3. Continuation of Therapy

   Aetna considers continuation of tofersen (Qalsody) therapy medically necessary for the treatment of ALS when both of the following criteria are met:  

   1. Member has had a documented clinical benefit from therapy with the requested medication; and
   2. Invasive ventilation or tracheostomy is not required.  

4. Related Policies

   1. CPB 0715 - Pharmacogenetic and Pharmacodynamic Testing
   2. CPB 0918 - Edaravone (Radicava)

Dosage and Administration

Qalsody (tofersen) is supplied as 100 mg/15 mL (6.7 mg/mL) solution in a single-dose vial for intrathecal use.

The recommended dosage is 100 mg (15 mL) per administration.

Qalsody is administered intrathecally using a lumbar puncture by, or under the direction of, healthcare professionals experienced in performing lumbar punctures. 

Per label, Qalsody treatment is initiated with 3 loading doses administered at 14-day intervals. A maintenance dose should be administered once every 28 days thereafter.

Source: Biogen, 2023c

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
96450	Chemotherapy administration, into CNS (eg, intrathecal), requiring and including spinal puncture
HCPCS codes covered for indications listed in the CPB:
J1304	Injection, tofersen, 1 mg
ICD-10 codes covered for indications listed in the CPB:
G12.21	Amyotrophic lateral sclerosis

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

• Qalsody is 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).

Tofersen is branded as Qalsody (Biogen MA Inc.). Tofersen is an antisense oligonucleotide (ASO) designed to bind to SOD1 mRNA to reduce SOD1 protein production.

Tofersen carries labeled warnings and precautions for myelitis and/or radiculitis, papilledema and elevated intracranial pressure, and aseptic meningitis. In clinical studies, 6 patients treated with tofersen experienced myelitis or radiculitis, 2 discontinued treatment and required symptomatic management with full resolution of symptoms. In the remaining 4 patients, symptoms resolved without discontinuation of the medication. Four patients developed elevated intracranial pressure and/or papilledema. All patients received treatment with standard of care with resolution of symptoms, and no events led to discontinuation of tofersen.  One patient experienced a serious adverse reaction of chemical meningitis, which led to discontinuation of the medication. One patient experienced a serious adverse reaction of aseptic meningitis, which did not lead to discontinuation of the medication. In addition, nonserious adverse drug reactions of cerebrospinal fluid (CSF) white blood cell increased, and CSF protein increased were also reported with use (Biogen, 2023c). 

The most common adverse reactions (10% or more treated with tofersen and greater than placebo) included pain, fatigue, arthralgia, cerebrospinal fluid white blood cell increase, and myalgia. 

Safety and effectiveness in pediatric patients have not been established.

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a progressive neurodegenerative disorder that affects motor neurons which results in muscle weakness, disability and eventual death. There is no cure and treatment has consisted of symptom management and supportive care. Currently, there are a few FDA-approved medications on the market that either help extend survival by a few months and/or time to tracheostomy, or help slow the decline in clinical assessment of daily functioning.

For most ALS cases, the cause is not known. Cases appear to occur sporadically with no clear associated risk factors and no family history of the disease. However, approximately 10 percent of all cases are found to be inherited and referred to as familial ALS. About 12 to 20 percent of familial cases result from mutations in the superoxide dismutase 1 (SOD1) gene that is involved in production of the enzyme copper-zinc SOD1 (NIH, 2023). Most of these cases are inherited in an autosomal dominant manner. Approximately 50 percent of individuals with pathogenic variants are symptomatic by age 46, and 90 percent are symptomatic by age 70 (McCluskey and Ladha, 2022). 

Genetic testing has not routinely been performed to confirm an ALS diagnosis, as testing had offered little or no additional value in making the diagnosis and would not impact medical management or treatment options. Testing has generally been reserved for "rare cases of early-stage disease (i.e., clinically suspected and clinically possible ALS by El Escorial criteria), with or without a family history of ALS" and provide "risk information and subsequent counseling for unaffected at-risk family members". Genetic testing may provide prognostic information for ALS patients with a family history suggesting autosomal dominant inheritance. Individuals with ALS who do not have a positive family history may also consider genetic testing, as some sporadic cases have also been reported to carry this pathogenic genetic variant (McCluskey and Ladha, 2022). Genetic testing for SOD1 is now encouraged to confirm familial ALS diagnosis in adults, as a genotype-specific therapy, tofersen (Qalsody), has become available as a treatment option. 

In April 2023, the FDA granted accelerated approval of tofersen, brand Qalsody (Biogen MA, Inc.), 100 mg/15mL injection for the treatment of ALS in adults who have a mutation in the SOD1 gene. This indication is approved under accelerated approval based on reduction in plasma neurofilament light chain (NfL), a blood-based biomarker of axonal injury and neurodegeneration, observed in patients treated with Qalsody in the VALOR trial and open-label extension study (OLE). Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s). Qalsody is the first approved treatment to target a genetic cause of ALS.

Miller et al (2022) conducted a phase 3, randomized, placebo-controlled study (VALOR) to evaluate intrathecally administered tofersen in patients with ALS-associated mutations in SOD1 (SOD1 ALS). Adult patients (n=108) with SOD1 ALS were randomly assigned in a 2:1 ratio to receive eight doses (3 loading doses followed by 5 maintenance doses) of tofersen (100 mg) or placebo over a period of 24 weeks. Concomitant riluzole and/or edaravone use was permitted. The primary end point was the change from baseline to week 28 in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) 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 (NfL) in plasma, in slow vital capacity, and in handheld dynamometry in 16 muscles. A combined analysis of the randomized component of the trial and its open-label extension (OLE) at 52 weeks compared the results in participants who started tofersen at trial entry (early-start cohort) with those in participants who switched from placebo to the drug at week 28 (delayed-start cohort). In the trial, a total of 72 patients received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). The authors found that tofersen led to greater reductions in concentrations of SOD1 in CSF and of NfL in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (p = 0.97). Results for secondary clinical end points did not differ significantly between the two groups. A total of 95 participants (88%) entered the OLE. 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; non-multiplicity-adjusted differences favoring early-start tofersen were seen for other end points. Lumbar puncture-related adverse events were common. Neurologic serious adverse events occurred in 7% of tofersen recipients. The authors concluded that in patients with SOD1 ALS, tofersen reduced concentrations of SOD1 in CSF and of NfL in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events. The authors note that the potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the extension phase. 

The clinical study included 3 parts (Part A, B, and C). Key inclusion criteria for all 3 parts were weakness attributable to ALS and documented SOD1 mutation. Part A and B required a forced vital capacity (FVC) greater than or equal to 50% of predicted value for gender, height and age. For Part C, if the patient was taking edaravone, the patient must have initiated edaravone 60 days or more (2 treatment cycles) prior to Day 1 and expected to remain at that dose until the final study visit, unless the Investigator determined that edaravone should be discontinued for medical reasons, in which case it may not be restarted during the study.

Tofersen is currently being studied in an ongoing phase 3, randomized, placebo-controlled ATLAS study to evaluate whether tofersen can delay clinical onset when initiated in pre-symptomatic individuals with SOD1-ALS.

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References