Serious Neurologic Adverse Events in Tofersen Clinical Trials for Amyotrophic Lateral Sclerosis

Abstract

Introduction/aims: Tofersen is approved for the treatment of amyotrophic lateral sclerosis (ALS) due to superoxide dismutase 1 mutations (SOD1-ALS). Here we report serious neurologic adverse events (AEs) that occurred in the tofersen clinical trials in people with SOD1-ALS.

Methods: Serious neurologic AEs of myelitis, radiculitis, aseptic meningitis, and papilledema reported in the tofersen clinical trials are described. Serious AEs were defined according to International Conference for Harmonization guidelines, and neurologic AEs in clinical trials were diagnosed by investigators based on symptoms, clinical examination findings, and diagnostic workup.

Results: Ten participants (approximately 7% of tofersen 100-mg-treated trial participants) experienced a total of 12 serious neurologic AEs-4 of myelitis, 2 of radiculitis, 2 of aseptic meningitis, and 4 of intracranial hypertension (ICH) and/or papilledema. All events but one resolved either spontaneously, with dosing interruption/modification, or with concomitant therapies. One event was ongoing but improved as of December 2022. While 3 events led to tofersen treatment discontinuation, all other participants were able to remain on treatment. No event was life-threatening or fatal.

Discussion: Some antisense oligonucleotides (ASOs) have been described as having pro-inflammatory properties. Aseptic meningitis has been reported with nusinersen; however, myelitis, radiculitis, increased intracranial pressure, and papilledema have not been reported with ASO treatment. These neurologic AEs should be considered when assessing the overall benefit/risk of tofersen treatment for SOD1-ALS. Safety data from the open-label extension and expanded access program will continue to characterize these events and further inform the safety profile of tofersen in SOD1-ALS.

Keywords: SOD1‐ALS; VALOR; myelitis; serious adverse events; tofersen.

FIGURE 1

Clinical trial participants who received tofersen 100 mg. N = 147 inclusive of all participants with SOD1‐ALS who received at least 1 dose of tofersen 100 mg. 20 participants enrolled in the SAD, 50 participants enrolled in the MAD (including 2 participants who were previously enrolled in the SAD following washout periods of 32 and 42 weeks) [8], and 108 participants enrolled in VALOR (72 in the tofersen 100 mg treatment group and 36 in the placebo group) [9]. Of the 68 participants enrolled in the SAD and/or MAD studies, 43 participants received at least 1 dose of tofersen 100 mg in the MAD and/or OLE studies. Of the 36 participants who received placebo in the VALOR study, 32 participants subsequently enrolled in the OLE and received at least 1 dose of tofersen 100 mg. MAD, multiple ascending dose; OLE, open‐label extension; SAD, single ascending dose.

FIGURE 2

CSF protein (A) and WBC (B) levels across the VALOR and OLE studies by visit as of July 15, 2022. Shaded boxes represent the 25th to 75th percentile, whiskers represent furthest data point. Outliers are denoted by a + or °, depending on whether the participant was in the early‐start tofersen group vs. delayed‐start tofersen group, respectively. Number of participants with data at the specified visit is indicated below each sub‐figure. Yellow dashed line indicates the end of VALOR and the start of the OLE. Delayed‐start tofersen 100‐mg participants (blue) received placebo in VALOR followed by tofersen 100 mg in the OLE; early‐start tofersen 100‐mg participants (red) received tofersen 100 mg in VALOR and the OLE. Outliers identified as data entry errors are not included in this figure. CSF, cerebrospinal fluid; DS, delayed‐start; ES, early‐start; OLE, open‐label extension; tof, tofersen; W, week; WBC, white blood cell.

FIGURE 3

Peak CSF protein (A) and peak CSF WBC (B) Levels for each individual participant across the VALOR and OLE studies as of July 15, 2022. The peak value for each CSF WBC and protein, whether in tube 1 or tube 2, is indicated in these plots for each individual participant. Participants 2, 7, and 8 had higher CSF WBC and/or CSF protein values at the time of the event (Table 1) than their peak values in the clinical trial database; these values were diagnostic values obtained outside of the clinical trial, and at shorter intervals than typically measured at the scheduled clinical trial visits. Data points that were identified as data entry errors were excluded, and the next highest peak value for the same participant was utilized for this plot. CSF, cerebrospinal fluid; OLE, open‐label extension; WBC, white blood cell.