Last Review Date: 06/01/2023

Date of Origin: 06/01/2023

Dates Reviewed: 06/2023

1. Description of Procedure or Service ¹

Tofersen is an antisense oligonucleotide that causes degradation of SOD1 mRNA through binding to SOD1 mRNA, which results in a reduction of SOD1 protein synthesis.

2. Policy

Qalsody™ (tofersen) is considered not medically necessary for all indications including treatment of amyotrophic lateral sclerosis (ALS) in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene.

Note: There is insufficient clinical evidence for demonstrated efficacy

3. Key Points

ALS, also known as Lou Gehrig’s disease, affects an estimated 16,000 to 32,000 people in the United States, according to the Centers for Disease Control and Prevention (CDC). Approximately 2% of cases of amyotrophic lateral sclerosis (ALS) are associated with mutations in the gene encoding superoxide dismutase 1 (SOD1).

4. Clinical Trials and FDA Review ^1,2

The accelerated approval was based on the phase 3 VALOR trial (NCT02623699), which showed a reduction in plasma neurofilament light chain (NfL), a biomarker of nerve injury and neurodegeneration that was believed to be reasonably likely to predict a clinical benefit in SOD1-ALS. This was the first time a biomarker has been used as a surrogate endpoint in ALS.

The VALOR trial was a 28-week, randomized, double-blind, placebo-controlled clinical study that randomly assigned 108 patients to receive either tofersen 100 mg or placebo for 24 weeks (three loading doses followed by five maintenance doses). Adults with SOD1 ALS were randomly assigned in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over a period of 24 weeks, 72 patients were assigned to the tofersen arm (39 predicted to have faster progression) while 36 patients were assigned to the placebo arm (21 predicted to have faster progression). Patients in the trial were permitted to use riluzole and/or edaravone concomitantly. 

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) in patients who were predicted to have faster-progressing disease.

Secondary end points included changes in the following: total concentration of SOD1 protein in cerebrospinal fluid (CSF), concentration of neurofilament light chains in plasma, slow vital capacity, and handheld dynamometry in 16 muscles.

Qalsody failed to demonstrate a statistically significant benefit over placebo on the primary efficacy endpoint, change from baseline to Week 28 in the ALSFRS-R in the prespecified analysis population. However, it did show improvements in multiple secondary and exploratory endpoints. In the overall intent-to-treat population (n = 108), the tofersen arm had greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. Patients who received Qalsody experienced a 55% reduction in plasma NfL compared to a 12% increase in placebo-treated patients (nominal p-value <0.0001), while levels of cerebrospinal fluid SOD1 protein, an indirect measure of target engagement, were reduced by 35% in the Qalsody-treated group compared to 2% in the placebo group (nominal p-value <0.0001). The most common side effects in the clinical trial were pain, fatigue, arthralgia, cerebrospinal fluid white blood cell increased, and myalgia.

The authors concluded that in persons with SOD1 ALS, tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events.

5. Billing Code/Availability Information

HCPCS Code:

• J3490 - Unclassified drugs (Discontinue use on 01/01/2024)
• J1304 – Injection, tofersen, 1 mg; 1 billable unit = 1 mg (Effective 01/01/2024)
• C9157 – Injection, tofersen, 1 mg; 1 billable unit = 1 mg (Discontinue use on 01/01/2024)

NDC:

• 100 mg/15 mL solution in a single-dose glass vial (preservative free): 64406-0109-xx

6. References

1. Qalsody [package insert]. Cambridge, MA; Biogen MA, Inc; April 2023. Accessed May 2023.
2. Miller TM, Cudkowicz ME, Genge A, et al; VALOR and OLE Working Group. Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2022 Sep 22;387(12):1099-1110. doi: 10.1056/NEJMoa2204705.
3. Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci. 1999 Oct 31;169(1-2):13-21.
4. Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009 Oct 13;73(15):1218-26.
5. Siddique N, Siddique T. Amyotrophic Lateral Sclerosis Overview. GeneReviews. Initial Posting: March 23, 2021; Last Revision: September 30, 2021; Accessed on June 7, 2022. http://www.ncbi.nlm.nih.gov/books/NBK1450/.
6. Hardiman O, van den Berg LH, Kiernan MC. Clinical diagnosis and management of amyotrophic lateral sclerosis. Nat Rev Neurol. 2011 Oct 11;7(11):639-49.
7. Costa J, Swash M, de Carvalho M. Awaji criteria for the diagnosis of amyotrophic lateral sclerosis: a systematic review. Arch Neurol. 2012 Nov;69(11):1410-6.
8. Pinto S, de Carvalho M. SVC Is a Marker of Respiratory Decline Function, Similar to FVC, in Patients With ALS. Front Neurol. 2019 Feb 28;10:109. doi: 10.3389/fneur.2019.00109. PMID: 30873101; PMCID: PMC6403463.

Appendix 1 – Covered Diagnosis Codes

Appendix 2 – Centers for Medicare and Medicaid Services (CMS)

Medicare coverage for outpatient (Part B) drugs is outlined in the Medicare Benefit Policy Manual (Pub. 100-2), Chapter 15, §50 Drugs and Biologicals. In addition, National Coverage Determination (NCD), Local Coverage Determinations (LCDs), and Local Coverage Articles (LCAs) may exist and compliance with these policies is required where applicable. They can be found at: https://www.cms.gov/Medicare-Coverage-Database/search.aspx. Additional indications may be covered at the discretion of the health plan.

Medicare Part B Covered Diagnosis Codes (applicable to existing NCD/LCD/LCA): N/A