Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS.

BACKGROUND: The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in SOD1 (SOD1 ALS). METHODS: In this phase 3 trial, we randomly assigned adults with SOD1 ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over a period of 24 weeks. 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 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 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). RESULTS: A total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains 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 (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; 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 open-label extension. 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 (difference, 3.5 points; 95% CI, 0.4 to 6.7); 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. CONCLUSIONS: 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. The potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the extension phase. (Funded by Biogen; VALOR and OLE ClinicalTrials.gov numbers, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.).

Characterization of Adult Patients With SMA Treated in US Hospital Settings: A Natural History Study in the Premier Healthcare Database.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare genetic disease characterized by progressive muscular weakness and atrophy resulting from motor neuron degeneration. Limited information is available on disease progression among older SMA patients, particularly adults. OBJECTIVE: This study sought to characterize the natural history of SMA among adult patients in US hospital settings through the assessment of symptoms, complications, costs, and healthcare resource utilization (HRU) over 3 years before the availability of disease-modifying therapies. METHODS: The study population included adult (≥18 years) patients with inpatient and/or hospital-based outpatient discharge records and ≥2 primary or secondary SMA ICD-9 codes ≥30 days apart in the Premier Healthcare Database during the main study period (2007-2014). Index date was the date of the first SMA ICD-9 code. The frequency of SMA-related symptoms and complications was assessed 1 year preindex through 2 years postindex to characterize disease progression. Costs and HRU were also assessed across the study period. RESULTS: A total of 446 adult patients from 337 US hospitals met inclusion criteria for these analyses. All evaluated SMA-related symptoms and complications increased steadily over time, from 1 year preindex to 2 years postindex both overall and in each age group. Adult patients with SMA had increasing total costs and HRU over the 3-year study period: total costs were $1,759 preindex and $12,308 by 2 years postindex. CONCLUSIONS: Findings are consistent with increasing disease burden over time and support the progressive nature of SMA for adult patients with hospital interactions.