Qalsody Approved for SOD1 Amyotrophic Lateral Sclerosis

The Food and Drug Administration (FDA) has granted accelerated approval to Qalsody^™ (tofersen) for the treatment of adults with amyotrophic lateral sclerosis (ALS) who have a mutation in the superoxide dismutase 1 (SOD1) gene. The indication was approved based on reduction in plasma neurofilament light chain (NfL), a marker of neurodegeneration.

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. The accelerated approval was based on data from the 28-week phase 3 VALOR study (ClinicalTrials.gov Identifier: NCT02623699), which compared the efficacy and safety of tofersen to placebo in 108 adults with ALS and a documented SOD1 mutation. Of these patients, 95 enrolled in the ongoing open-label extension (OLE) study (ClinicalTrials.gov Identifier: NCT03070119).

The primary endpoint of the study was the change from baseline to week 28 in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). While the results were not statistically significant, patients treated with tofersen experienced less decline from baseline in the ALSFRS-S compared with placebo (adjusted mean difference, 1.2 [95% CI, -3.2, 5.5]). Treatment with tofersen was associated with a nominally statistically significant reduction in total CSF SOD1 protein levels (P <.0001) and plasma NfL concentration (P <.0001) compared with placebo.

The most common adverse reactions reported with treatment included pain, fatigue, arthralgia, increased cerebrospinal fluid white blood cells, and myalgia.

Findings from an interim analysis at 52 weeks showed that early initiation of tofersen (at the start of VALOR) compared with delayed-start (6 months later in the OLE study) was associated with trends for reduction in decline on ALSRS-R, measures of respiratory function (as measured by slow vital capacity), muscle strength (as measured by the handheld dynamometry megascore), and risk of death or permanent ventilation. Similar reductions in NfL were observed in patients previously receiving placebo who initiated tofersen in the OLE and those who received tofersen in the 28-week study.

Continued approval of this indication is contingent upon confirmatory data from the phase 3 ATLAS trial (ClinicalTrials.gov Identifier: NCT04856982) of tofersen in clinically presymptomatic adults with SOD1 ALS. Qalsody is supplied as a 100mg/15mL solution in a single-dose vial and is administered intrathecally. It is expected to be available in approximately 1 week.