Clinical Pearls & Morning Reports
Miller et al. are conducting a three-part trial, and recently reported the results of part B, a phase 1–2, multiple ascending-dose, randomized, double-blind, placebo-controlled trial that evaluated the safety, pharmacokinetics, and pharmacodynamics of tofersen in adults with amyotrophic lateral sclerosis (ALS) due to SOD1 mutations. Participants were assigned to one of four dose cohorts (20, 40, 60, or 100 mg), which were assessed sequentially. Read the NEJM Original Article here.
Q: How common is ALS due to mutations in SOD1?
A: Up to 2% of all cases of ALS result from mutations in the gene encoding superoxide dismutase 1 (SOD1). More than 180 different SOD1 mutations have been identified in ALS. Disease penetration, progression rate, and prognosis are variable and may be mutation-specific.
Q: How do mutations in SOD1 cause degeneration of motor neurons in genetic ALS?
A: The mechanisms by which mutations in SOD1 cause degeneration of motor neurons in genetic ALS are not fully understood; a toxic gain of function has been considered to be the most likely mechanism in ALS caused by SOD1 mutations. Lowering the concentration of mutant SOD1 protein may be a potential target for therapeutic intervention. Tofersen is an antisense oligonucleotide that is under investigation for the treatment of ALS caused by SOD1 mutations. Tofersen has been designed to mediate RNase H–dependent degradation of SOD1 mRNA to reduce the synthesis of SOD1 protein.
A: The most common adverse events among the 38 participants who received one or more doses of tofersen were headache (in 16 participants), procedural pain (in 16), post–lumbar puncture syndrome (in 13), and falls (in 13). At baseline and during the trial, an elevated CSF protein concentration or CSF pleocytosis (or both) was observed. In the combined placebo group, 1 of 12 participants (8%) had at least one CSF white-cell count of more than 10 cells per cubic millimeter, as compared with 16 of 38 participants (42%) in the combined tofersen groups, with a maximum observed value of 144 cells per cubic millimeter. The cause of CSF pleocytosis and protein elevations remains unclear. Although myelitis with sensory and motor deficits was not seen in this trial, the clinical syndrome has been observed in the context of tofersen administration (unpublished data). The underlying cause of myelitis and the relationship to CSF pleocytosis and protein elevations are unknown. Changes in CSF variables and any manifestations of central nervous system inflammation are being monitored in ongoing trials.
A: The reduction from baseline in the total CSF SOD1 concentration was 3% in the placebo group and 36% in the group that received 100 mg of tofersen (the highest-dose group), with reductions in the lower-dose tofersen groups ranging from 1% to 27%. This trial was not powered to test an effect on clinical or biologic measures beyond the reduction in SOD1 concentration in CSF. With regard to some exploratory outcomes, there may have been evidence of a slowing in the decrease in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised score, the slow vital capacity, and the handheld dynamometry megascore with the 100-mg dose of tofersen, although no conclusions can be drawn from these descriptive outcomes.