Long-Term Evaluation of BIIB067 (Tofersen)

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. An 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. TEAEs were defined as any AEs or SAE with an onset date and time that was on or after the first dose of study drug, or any pre-existing condition that worsened in severity after the first dose of study drug.

This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on the data collected from both 233AS101 and 233AS102 studies. This is reported as a part of the final integrated analyses. Baseline is defined as the Day 1 of 233AS101 Part C. Data has been reported for Weeks 52, 104 and 148 from the 233AS101 Part C baseline.

This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on the data collected from both 233AS101 and 233AS102 studies. This is reported as a part of the final integrated analyses. Baseline is defined as the Day 1 of 233AS101 Part C. Data has been reported for Weeks 52, 104 and 148 from the 233AS101 Part C baseline.

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). The ALSFRS-R total score was calculated as the sum of the 4 functional domain scores, ranging from 0 to 48, where higher scores representing better function. Negative change from baseline indicates disease progression. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on the data collected from both 233AS101 and 233AS102 studies. This is reported as a part of the final integrated analyses. Baseline is defined as the Day 1 of 233AS101 Part C. Data has been reported for Weeks 52, 104 and 148 from the 233AS101 Part C baseline.

Vital capacity was measured by means of an SVC test, administered in the upright position. Upright SVC was determined by performing 3 to 5 measures, in accordance with criteria established by the American Thoracic Society and the European Respiratory Society. The percent predicted SVC was calculated as [observed SVC divided by predicted SVC]*100%. The predicted SVC was adjusted by sex, age, height, which was programmed into and performed by the equipment used. Negative change from baseline indicated worsening of respiratory capacity. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on the data collected from both 233AS101 and 233AS102 studies. This is reported as a part of the final integrated analyses. Baseline is defined as the Day 1 of 233AS101 Part C. Data has been reported for Weeks 52, 104 and 148 from the 233AS101 Part C baseline.

Quantitative muscle strength was evaluated using the HHD Megascore, which tests isometric strength of multiple muscles using standard participant positioning. Approximately 8 muscle groups were examined (per each side) 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. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on the data collected from both 233AS101 and 233AS102 studies. This is reported as a part of the final integrated analyses. Baseline is defined as the Day 1 of 233AS101 Part C. Data has been reported for Weeks 52, 104 and 148 from the 233AS101 Part C baseline.

Individual muscle strength was evaluated using handheld dynamometer which tests the isometric strength of multiple muscles using standard participant positioning. Eight muscle groups were examined (per each side) in both upper and lower extremities. Negative change from baseline=decreased muscle strength. The analyses was based on observed data. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on data collected from both 233AS101 & 233AS102 studies. This is reported as a part of final integrated analyses.

Permanent ventilation was defined as ≥ 22 hours of mechanical ventilation [invasive or noninvasive] per day for ≥ 21 consecutive days. An event of permanent ventilation was based on an adjudicated event (i.e., adjudicated by the Endpoint Adjudication Committee (EAC) as having met the permanent ventilation criteria defined in the protocol). Time to death or permanent ventilation was defined as the time to the earliest occurrence of death or permanent ventilation. The start date for calculating time to death or permanent ventilation in days was date of first dose. Participants without an event were censored at the last known alive dates. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on data collected from both 233AS101 & 233AS102 studies. This is reported as a part of final integrated analyses. Time to permanent ventilation or death was summarized using the Kaplan-Meier product limit method.

Time to death was defined as the time from first dose received in 233AS101 to death. Participants who do not meet the endpoint definition were censored at the participant's last known alive date. Only events that were adjudicated by the EAC are included. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on data collected from both 233AS101 & 233AS102 studies. This is reported as a part of final integrated analyses. Time to death was summarized using the Kaplan-Meier product limit method.