Trial Outcomes & Findings for An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS) (NCT NCT02623699)

Participants were enrolled at the investigative sites in the Belgium, Canada, Denmark, France, Germany, Italy, Japan, United Kingdom, and the United States from 20 January 2016 to 16 July 2021.

Study included SAD (Part A), MAD (Part B) and pivotal portions (Part C). Total 176 participants were randomized: 20 into Part A, 50 into Part B including 2 participants who completed Part A, were randomized in Part B after 12-week washout period, hence 2 participants were analysed in both Parts A, B (for total of 68 in Parts A, B), Part C randomized 108 participants.

Modified ITT (mITT) population included all participants who met the prognostic enrichment criteria for rapid disease progression in Part C who were randomized and received at least 1 dose of study treatment. This measure was only analyzed for Part C arms groups.

An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE is any untoward medical occurrence that at any dose results in death, life-threatening event, requires inpatient hospitalization, significant disability/incapacity or congenital anomaly.

Clinical laboratory assessments included hematology, chemistry, and urinalysis.

The criteria for clinically significant vital sign abnormalities include: Temperature: \>38 degree Celsius (°C) or an increase from baseline of ≥1°C; Pulse: \>120 beats per minute (bpm) or an increase from baseline of \>20 bpm, \<50 bpm or a decrease from baseline of \>20 bpm; Systolic blood pressure (BP): \>180 mmHg or an increase from baseline of \>40 mmHg, \<90 mmHg or a decrease from baseline of \>30 mmHg; Diastolic BP: \>105 mmHg or an increase from baseline of \>30 mmHg, \<50 mmHg or a decrease from baseline of \>20 mmHg.

Clinically significant physical examination abnormalities included weight decreased.

Clinically significant neurological examination abnormalities included hyporeflexia.

The ALSFRS-R measures 4 functional domains, including respiratory, bulbar function, gross motor skills, and fine motor skills. There are 12 questions, each scored from 0 (no function) to 4 (full function), for a total possible score of 48. Scores decline with disease progression. ALSFRS-R scores calculated at diagnosis can be compared to scores throughout time to determine the speed of progression. Higher scores represent better function, negative change from baseline indicates disease progression.

Total CSF SOD1 protein ratio to baseline was calculated.

Total CSF SOD1 protein ratio to baseline was calculated and LS Geometric Mean ratio to baseline was reported.

NfL is a biomarker whose concentration was assessed in plasma. Plasma NfL ratio to baseline was calculated.

Vital capacity was measured by means of an SVC test, administered in the upright position.

Quantitative muscle strength was evaluated using HHD, which tests isometric strength of multiple muscles using standard participant positioning. Sixteen muscle groups were evaluated in both upper and lower extremities. The muscle strength values were normalized to Z scores as (post-baseline measurements - mean)/SD and averaged to provide HHD overall megascore. The overall megascore was created by averaging all eight bilateral measurement Z scores, if no more than 10 (≤ 10) measures are missing. A negative change from baseline indicated decreased muscle strength.

Time to Death or Permanent Ventilation is defined as the time to the earliest occurrence of one of the following events that were adjudicated by an independent committee: Death; Permanent ventilation (≥22 hours of mechanical ventilation \[invasive or noninvasive\] per day for ≥21 consecutive days).

An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE is any untoward medical occurrence that at any dose results in death, life-threatening event, requires inpatient hospitalization, significant disability/incapacity or congenital anomaly.