Amyotrophic Lateral Sclerosis
Conditions
Keywords
IONIS-SOD1Rx, SOD1, ALS
Brief summary
The primary objectives of Parts A and B of this study are to evaluate the safety, tolerability, and pharmacokinetics (PK) of ascending doses of tofersen in adults with ALS and a documented superoxide dismutase 1 (SOD1) mutation. The primary objective of Part C of this study is to evaluate the clinical efficacy of tofersen administered to adults with ALS and a confirmed SOD1 mutation. The secondary objective of Parts A and B of this study is to evaluate the effects of tofersen on levels of total SOD1 protein in the cerebrospinal fluid (CSF). The secondary objectives of Part C are to evaluate the safety, tolerability, pharmacodynamic (PD), and biomarker effects of tofersen.
Detailed description
This is a 3-part study to examine the efficacy, safety, tolerability, PK, and PD of tofersen. Part A is the single ascending dose (SAD) component of the study, Part B is the multiple ascending dose (MAD) component of study and Part C is the fixed dose component of the study. Hence, the overall phase of development of the study is 1/2/3. The study completed on 16 Jul 2021. In total, the study enrolled 176 participants, of which 108 enrolled in Part C.
Interventions
DRUGTofersen
Administered as specified in the treatment arm.
DRUGPlacebo
Administered as specified in the treatment arm.
Sponsors
Ionis Pharmaceuticals, Inc.
Biogen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: Part A and B * Weakness attributable to ALS and documented SOD1 mutation at Screening Visit 2. * A forced vital capacity (FVC) ≥50% of predicted value as adjusted for sex, age, and height (from the sitting position). Participants with stable FVC \<50% but ≥45%, whose FVC has not declined by more than 5% in the last 6 months may be considered for inclusion, at the discretion of the Investigator. * If taking riluzole, participant must be on a stable dose for ≥30 days prior to Day 1 and expected to remain at that dose until the final study visit. * Medically able to undergo the study procedures, and to adhere to the visit schedule at the time of study entry, as determined by the Investigator. Key
Exclusion criteria
Part A and B * History of or positive test result for human immunodeficiency virus. * History of, or positive test result at Screening, for hepatitis C virus antibody. * Current hepatitis B infection (defined as positive for hepatitis B surface antigen \[HBsAg\] and/or hepatitis B core antibody \[HBcAb\]). Participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive hepatitis B surface antibody immunoglobulin G, and positive HBcAb) or vaccination (defined as positive anti-HBs) are eligible to participate in the study. * Treatment with another investigational drug, biological agent, or device within 1 month or 5 half-lives of study agent, whichever is longer. Specifically, no prior treatment with small interfering ribonucleic acid, stem cell therapy, or gene therapy is allowed. * Current enrollment in any other interventional study. * Current or recent (within 1 month) use, or anticipated need, in the opinion of the Investigator, of copper (II) (diacetyl-bis (N4-methylthiosemicarbazone)) or pyrimethamine. * Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system (DPS) during the study period. Key Inclusion Criteria: Part C * Weakness attributable to ALS and confirmed SOD1 mutation at Screening Visit. * If taking riluzole, participant must be on a stable dose for ≥30 days prior to Day 1 and expected to remain at that dose until the final study visit. * If taking edaravone, participant must have initiated edaravone ≥60 days (2 treatment cycles) prior to Day 1 and expected to remain at that dose until the final study visit, unless the Investigator determines that edaravone should be discontinued for medical reasons, in which case it may not be restarted during the study. Edaravone may not be administered on dosing days of this study. * Medically able to undergo the study procedures and to adhere to the visit schedule at the time of study entry, as determined by the Investigator. Key
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part C: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score at Week 28 | Baseline, Week 28 (Day 197) | 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. |
| Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities | Part A: Up to Day 57; Part B: Up to Day 169 | — |
| Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax) | Part A: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1; Part B: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1 and 1, 2, 4, 6 hrs post-dose on Day 85 | — |
| Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax) | Part A: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1; Part B: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1 and 1, 2, 4, 6 hrs post-dose on Day 85 | — |
| Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h) | Parts A and B: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1 | — |
| Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) | Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169 | — |
| Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) | Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169 | — |
| Parts A and B: PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2) | Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169 | — |
| Parts A and B: PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2) | Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169 | — |
| Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) | Part A: First dose up to Day 63; Part B: First dose up to Day 289 | 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. |
| Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Part A: Up to Day 57; Part B: Up to Day 169 | Clinical laboratory assessments included hematology, chemistry, and urinalysis. |
| Parts A and B: Number of Participants With Clinically Significant Vital Sign Abnormalities | Part A: Up to Day 57; Part B: Up to Day 169 | 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. |
| Parts A and B: Number of Participants With Clinically Significant Physical Examination Abnormalities | Part A: Up to Day 57; Part B: Up to Day 169 | Clinically significant physical examination abnormalities included weight decreased. |
| Parts A and B: Number of Participants With Clinically Significant Neurological Examination Abnormalities | Part A: Up to Day 57; Part B: Up to Day 169 | Clinically significant neurological examination abnormalities included hyporeflexia. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part C: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline | Week 28 (Day 197) | Total CSF SOD1 protein ratio to baseline was calculated and LS Geometric Mean ratio to baseline was reported. |
| Part C: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline | Baseline, Day 197 (Week 28) | NfL is a biomarker whose concentration was assessed in plasma. Plasma NfL ratio to baseline was calculated. |
| Part C: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 28 | Baseline, Week 28 (Day 197) | Vital capacity was measured by means of an SVC test, administered in the upright position. |
| Part C: Change From Baseline in Handheld Dynamometry (HHD) Megascore as Measured by the HHD Device at Week 28 | Baseline, Week 28 (Day 197) | 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. |
| Part C: Time to Death or Permanent Ventilation | Baseline up to Week 28 (Day 197) | 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). |
| Part C: Time to Death | Baseline up to Week 28 (Day 197) | — |
| Part C: Number of Participants Experiencing AEs and SAEs | First dose up to Day 236 | 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. |
| Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline | Day 85 | Total CSF SOD1 protein ratio to baseline was calculated. |
Countries
Australia, Belgium, Canada, Denmark, France, Germany, Italy, Japan, Poland, South Korea, United Kingdom, United States
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Part A-SAD: Combined Placebo Participants were administered BIIB067-matching placebo once by intrathecal bolus injection on Day 1 of Cohorts 1, 2, 3, and 4 respectively. | 5 |
| Part A-SAD: Cohort 1: BIIB067 10 mg Participants were administered BIIB067 10 mg once by intrathecal bolus injection on Day 1. | 3 |
| Part A-SAD: Cohort 2: BIIB067 20 mg Participants were administered BIIB067 20 mg once by intrathecal bolus injection on Day 1 of Cohort 2 after the safety review of Cohort 1. | 3 |
| Part A-SAD: Cohort 3: BIIB067 40 mg Participants were administered BIIB067 40 mg once by intrathecal bolus injection on Day 1 of Cohort 3 after the safety review of Cohort 2. | 3 |
| Part A-SAD: Cohort 4: BIIB067 60 mg Participants were administered BIIB067 60 mg once by intrathecal bolus injection on Day 1 of Cohort 4 after the safety review of Cohort 3. | 6 |
| Part B-MAD: Combined Placebo Participants were administered BIIB067-matching placebo, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection. | 12 |
| Part B-MAD: Cohort 5: BIIB067 20 mg Participants were administered BIIB067 20 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection. | 9 |
| Part B-MAD: Cohort 6: BIIB067 40 mg Participants were administered BIIB067 40 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection after the safety and PK review of Cohort 5. | 8 |
| Part B-MAD: Cohort 7: BIIB067 60 mg Participants were administered BIIB067 60 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection after the safety, PK review and SOD1 PD review of Cohort 6. | 9 |
| Part B-MAD: Cohort 8: BIIB067 100 mg Participants were administered BIIB067 100 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection after the safety, PK review and SOD1 PD review of Cohort 7. | 10 |
| Part C-Pivotal: Placebo Participants were administered BIIB067-matching placebo, 3 loading doses administered once every 2 weeks on Days 1, 15, 29 followed by 5 maintenance doses administered once every 4 weeks on Days 57, 85, 113, 141, 169 up to 24 weeks by intrathecal bolus injection. | 36 |
| Part C-Pivotal: BIIB067 100 mg Participants were administered BIIB067 100 mg, 3 loading doses administered once every 2 weeks on Days 1, 15, 29 followed by 5 maintenance doses administered once every 4 weeks on Days 57, 85, 113, 141, 169 up to 24 weeks by intrathecal bolus injection. | 72 |
| Total | 176 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Part A (Up to 63 Days) | Consent Withdrawn | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part B (Up to 289 Days) | Consent Withdrawn | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part B (Up to 289 Days) | Death | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 1 | 0 | 0 | 0 |
| Part B (Up to 289 Days) | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Part C (Up to 236 Days) | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
| Part C (Up to 236 Days) | Consent Withdrawn | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 2 |
| Part C (Up to 236 Days) | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Part C (Up to 236 Days) | Disease Progression | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 3 |
Baseline characteristics
| Characteristic | Part A-SAD: Cohort 4: BIIB067 60 mg | Part B-MAD: Combined Placebo | Part B-MAD: Cohort 5: BIIB067 20 mg | Part B-MAD: Cohort 6: BIIB067 40 mg | Part B-MAD: Cohort 7: BIIB067 60 mg | Part B-MAD: Cohort 8: BIIB067 100 mg | Part A-SAD: Cohort 3: BIIB067 40 mg | Part A-SAD: Combined Placebo | Part A-SAD: Cohort 1: BIIB067 10 mg | Part A-SAD: Cohort 2: BIIB067 20 mg | Part C-Pivotal: Placebo | Part C-Pivotal: BIIB067 100 mg | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 45.0 years STANDARD_DEVIATION 12.82 | 49.2 years STANDARD_DEVIATION 11.04 | 42.1 years STANDARD_DEVIATION 11.19 | 57.5 years STANDARD_DEVIATION 11.75 | 45.6 years STANDARD_DEVIATION 10.71 | 48.9 years STANDARD_DEVIATION 10.8 | 49.0 years STANDARD_DEVIATION 3.61 | 58.4 years STANDARD_DEVIATION 9.29 | 50.3 years STANDARD_DEVIATION 7.64 | 55.3 years STANDARD_DEVIATION 17.62 | 51.2 years STANDARD_DEVIATION 11.57 | 48.1 years STANDARD_DEVIATION 12.64 | 49.2 years STANDARD_DEVIATION 12.02 |
| Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) | — | — | — | — | — | — | — | — | — | — | 35.4 score on a scale STANDARD_DEVIATION 5.66 | 36.0 score on a scale STANDARD_DEVIATION 6.4 | 35.78 score on a scale STANDARD_DEVIATION 6.109 |
| Cerebrospinal Fluid (CSF) Levels of Total SOD1 Protein Concentration | — | 70.40 nanograms per milliliter (ng/mL) | 102.00 nanograms per milliliter (ng/mL) | 125.00 nanograms per milliliter (ng/mL) | 82.80 nanograms per milliliter (ng/mL) | 135.86 nanograms per milliliter (ng/mL) | — | — | — | — | 107.07 nanograms per milliliter (ng/mL) | 103.32 nanograms per milliliter (ng/mL) | 104.64 nanograms per milliliter (ng/mL) |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 4 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 9 Participants | 4 Participants | 5 Participants | 4 Participants | 7 Participants | 1 Participants | 4 Participants | 3 Participants | 3 Participants | 28 Participants | 47 Participants | 120 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 5 Participants | 3 Participants | 5 Participants | 3 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 7 Participants | 21 Participants | 51 Participants |
| Handheld Dynamometry (HHD) Megascore as Measured by the HHD Device | — | — | — | — | — | — | — | — | — | — | 0.0 score on a scale STANDARD_DEVIATION 0.6 | 0.0 score on a scale STANDARD_DEVIATION 0.67 | -0.007 score on a scale STANDARD_DEVIATION 0.6396 |
| Neurofilament Light Chain (NfL) Concentration in Plasma | — | — | — | — | — | — | — | — | — | — | 92.7 picograms per mL (pg/mL) | 121.8 picograms per mL (pg/mL) | 110.49 picograms per mL (pg/mL) |
| Percentage Predicted Slow Vital Capacity (SVC) | — | — | — | — | — | — | — | — | — | — | 83.7 percent predicted STANDARD_DEVIATION 17.87 | 80.3 percent predicted STANDARD_DEVIATION 14.22 | 81.50 percent predicted STANDARD_DEVIATION 15.533 |
| Race/Ethnicity, Customized Race Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 5 Participants | 10 Participants |
| Race/Ethnicity, Customized Race Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Not Reported | 1 Participants | 3 Participants | 5 Participants | 3 Participants | 5 Participants | 3 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 7 Participants | 21 Participants | 51 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Race White | 5 Participants | 7 Participants | 4 Participants | 4 Participants | 4 Participants | 7 Participants | 1 Participants | 4 Participants | 3 Participants | 3 Participants | 25 Participants | 44 Participants | 111 Participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 3 Participants | 5 Participants | 3 Participants | 6 Participants | 1 Participants | 2 Participants | 3 Participants | 0 Participants | 17 Participants | 29 Participants | 78 Participants |
| Sex: Female, Male Male | 2 Participants | 7 Participants | 6 Participants | 3 Participants | 6 Participants | 4 Participants | 2 Participants | 3 Participants | 0 Participants | 3 Participants | 19 Participants | 43 Participants | 98 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 6 | 1 / 12 | 1 / 10 | 0 / 9 | 1 / 9 | 0 / 10 | 0 / 36 | 1 / 72 |
| other Total, other adverse events | 2 / 5 | 2 / 3 | 3 / 3 | 3 / 3 | 6 / 6 | 11 / 12 | 10 / 10 | 9 / 9 | 9 / 9 | 10 / 10 | 34 / 36 | 68 / 72 |
| serious Total, serious adverse events | 0 / 5 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 6 | 2 / 12 | 2 / 10 | 1 / 9 | 2 / 9 | 0 / 10 | 5 / 36 | 13 / 72 |
Outcome results
Primary
Part C: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score at Week 28
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.
Time frame: Baseline, Week 28 (Day 197)
Population: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part A-SAD: Combined Placebo | Part C: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score at Week 28 | -8.1 score on scale | Standard Error 1.79 |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Part C: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score at Week 28 | -7.0 score on scale | Standard Error 1.42 |
Comparison: Joint rank test combining function and mortality were used for statistical inference and the estimates were from the Analysis of covariance (ANCOVA) for change from baseline. Multiple imputation was used to handle missing data for withdrawals other than death in the joint rank analysis. Multiple imputation was used to handle all missing data in the ANCOVA for change from baseline.p-value: =0.968995% CI: [-3.19, 5.53]Joint rank
Primary
Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)
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.
Time frame: Part A: First dose up to Day 63; Part B: First dose up to Day 289
Population: Safety population included all randomized participants who received at least 1 dose or a part of 1 dose of study treatment (BIIB067 or placebo) in Part A or B.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A-SAD: Combined Placebo | Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 2 Participants |
| Part A-SAD: Combined Placebo | Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 2 Participants |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 3 Participants |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 3 Participants |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 6 Participants |
| Part B-MAD: Combined Placebo | Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 2 Participants |
| Part B-MAD: Combined Placebo | Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 12 Participants |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 2 Participants |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 10 Participants |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 9 Participants |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
| Part B-MAD: Cohort 7: BIIB067 60 mg | Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 9 Participants |
| Part B-MAD: Cohort 7: BIIB067 60 mg | Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 2 Participants |
| Part B-MAD: Cohort 8: BIIB067 100 mg | Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 10 Participants |
| Part B-MAD: Cohort 8: BIIB067 100 mg | Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
Primary
Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities
Time frame: Part A: Up to Day 57; Part B: Up to Day 169
Population: Safety population included all randomized participants who received at least 1 dose or a part of 1 dose of study treatment (BIIB067 or placebo) in Part A or B.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A-SAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities | Maximum Post-baseline QTcF > 480 to 500 ms | 0 Participants |
| Part A-SAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities | Maximum Increase From Baseline QTcF > 30 to 60 ms | 0 Participants |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities | Maximum Post-baseline QTcF > 480 to 500 ms | 0 Participants |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities | Maximum Increase From Baseline QTcF > 30 to 60 ms | 0 Participants |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities | Maximum Post-baseline QTcF > 480 to 500 ms | 0 Participants |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities | Maximum Increase From Baseline QTcF > 30 to 60 ms | 0 Participants |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities | Maximum Post-baseline QTcF > 480 to 500 ms | 0 Participants |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities | Maximum Increase From Baseline QTcF > 30 to 60 ms | 0 Participants |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities | Maximum Post-baseline QTcF > 480 to 500 ms | 0 Participants |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities | Maximum Increase From Baseline QTcF > 30 to 60 ms | 0 Participants |
| Part B-MAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities | Maximum Increase From Baseline QTcF > 30 to 60 ms | 3 Participants |
| Part B-MAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities | Maximum Post-baseline QTcF > 480 to 500 ms | 1 Participants |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities | Maximum Post-baseline QTcF > 480 to 500 ms | 0 Participants |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities | Maximum Increase From Baseline QTcF > 30 to 60 ms | 1 Participants |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities | Maximum Post-baseline QTcF > 480 to 500 ms | 0 Participants |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities | Maximum Increase From Baseline QTcF > 30 to 60 ms | 2 Participants |
| Part B-MAD: Cohort 7: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities | Maximum Increase From Baseline QTcF > 30 to 60 ms | 2 Participants |
| Part B-MAD: Cohort 7: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities | Maximum Post-baseline QTcF > 480 to 500 ms | 0 Participants |
| Part B-MAD: Cohort 8: BIIB067 100 mg | Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities | Maximum Increase From Baseline QTcF > 30 to 60 ms | 3 Participants |
| Part B-MAD: Cohort 8: BIIB067 100 mg | Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities | Maximum Post-baseline QTcF > 480 to 500 ms | 0 Participants |
Primary
Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities
Clinical laboratory assessments included hematology, chemistry, and urinalysis.
Time frame: Part A: Up to Day 57; Part B: Up to Day 169
Population: Safety population included all randomized participants who received at least 1 dose or a part of 1 dose of study treatment (BIIB067 or placebo) in Part A or B.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A-SAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Eosinophilia | 0 Participants |
| Part A-SAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Blood Phosphorus Decreased | 0 Participants |
| Part A-SAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Pleocytosis | 0 Participants |
| Part A-SAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Urine Output Decreased | 0 Participants |
| Part A-SAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF White Blood Cell Count Increased | 0 Participants |
| Part A-SAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Gamma-Glutamyltransferase Increased | 0 Participants |
| Part A-SAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF Protein Increased | 0 Participants |
| Part A-SAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF White Blood Cell Count Positive | 0 Participants |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF White Blood Cell Count Positive | 0 Participants |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF White Blood Cell Count Increased | 0 Participants |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Eosinophilia | 0 Participants |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF Protein Increased | 0 Participants |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Pleocytosis | 0 Participants |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Blood Phosphorus Decreased | 0 Participants |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Gamma-Glutamyltransferase Increased | 0 Participants |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Urine Output Decreased | 0 Participants |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Blood Phosphorus Decreased | 0 Participants |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF Protein Increased | 0 Participants |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Urine Output Decreased | 0 Participants |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Gamma-Glutamyltransferase Increased | 0 Participants |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Pleocytosis | 0 Participants |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF White Blood Cell Count Positive | 0 Participants |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Eosinophilia | 0 Participants |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF White Blood Cell Count Increased | 0 Participants |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF White Blood Cell Count Increased | 0 Participants |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Blood Phosphorus Decreased | 0 Participants |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Urine Output Decreased | 0 Participants |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Pleocytosis | 0 Participants |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF Protein Increased | 0 Participants |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Gamma-Glutamyltransferase Increased | 0 Participants |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF White Blood Cell Count Positive | 0 Participants |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Eosinophilia | 0 Participants |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Gamma-Glutamyltransferase Increased | 0 Participants |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Pleocytosis | 0 Participants |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Eosinophilia | 0 Participants |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF Protein Increased | 0 Participants |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Urine Output Decreased | 0 Participants |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF White Blood Cell Count Increased | 0 Participants |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF White Blood Cell Count Positive | 0 Participants |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Blood Phosphorus Decreased | 0 Participants |
| Part B-MAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF White Blood Cell Count Positive | 0 Participants |
| Part B-MAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Gamma-Glutamyltransferase Increased | 0 Participants |
| Part B-MAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF Protein Increased | 1 Participants |
| Part B-MAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Blood Phosphorus Decreased | 0 Participants |
| Part B-MAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Urine Output Decreased | 1 Participants |
| Part B-MAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF White Blood Cell Count Increased | 0 Participants |
| Part B-MAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Pleocytosis | 0 Participants |
| Part B-MAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Eosinophilia | 0 Participants |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF White Blood Cell Count Increased | 0 Participants |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF White Blood Cell Count Positive | 0 Participants |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Blood Phosphorus Decreased | 0 Participants |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF Protein Increased | 0 Participants |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Gamma-Glutamyltransferase Increased | 1 Participants |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Urine Output Decreased | 0 Participants |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Eosinophilia | 0 Participants |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Pleocytosis | 2 Participants |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF Protein Increased | 0 Participants |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Eosinophilia | 0 Participants |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Gamma-Glutamyltransferase Increased | 0 Participants |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF White Blood Cell Count Increased | 1 Participants |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Pleocytosis | 1 Participants |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Urine Output Decreased | 0 Participants |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF White Blood Cell Count Positive | 0 Participants |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Blood Phosphorus Decreased | 0 Participants |
| Part B-MAD: Cohort 7: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF White Blood Cell Count Increased | 3 Participants |
| Part B-MAD: Cohort 7: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Blood Phosphorus Decreased | 1 Participants |
| Part B-MAD: Cohort 7: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Pleocytosis | 0 Participants |
| Part B-MAD: Cohort 7: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Eosinophilia | 0 Participants |
| Part B-MAD: Cohort 7: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF Protein Increased | 4 Participants |
| Part B-MAD: Cohort 7: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF White Blood Cell Count Positive | 0 Participants |
| Part B-MAD: Cohort 7: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Gamma-Glutamyltransferase Increased | 0 Participants |
| Part B-MAD: Cohort 7: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Urine Output Decreased | 0 Participants |
| Part B-MAD: Cohort 8: BIIB067 100 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF White Blood Cell Count Positive | 1 Participants |
| Part B-MAD: Cohort 8: BIIB067 100 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF White Blood Cell Count Increased | 0 Participants |
| Part B-MAD: Cohort 8: BIIB067 100 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | CSF Protein Increased | 1 Participants |
| Part B-MAD: Cohort 8: BIIB067 100 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Eosinophilia | 1 Participants |
| Part B-MAD: Cohort 8: BIIB067 100 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Pleocytosis | 0 Participants |
| Part B-MAD: Cohort 8: BIIB067 100 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Blood Phosphorus Decreased | 0 Participants |
| Part B-MAD: Cohort 8: BIIB067 100 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Urine Output Decreased | 0 Participants |
| Part B-MAD: Cohort 8: BIIB067 100 mg | Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Gamma-Glutamyltransferase Increased | 0 Participants |
Primary
Parts A and B: Number of Participants With Clinically Significant Neurological Examination Abnormalities
Clinically significant neurological examination abnormalities included hyporeflexia.
Time frame: Part A: Up to Day 57; Part B: Up to Day 169
Population: Safety population included all randomized participants who received at least 1 dose or a part of 1 dose of study treatment (BIIB067 or placebo) in Part A or B.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A-SAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant Neurological Examination Abnormalities | 0 Participants |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Parts A and B: Number of Participants With Clinically Significant Neurological Examination Abnormalities | 0 Participants |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant Neurological Examination Abnormalities | 0 Participants |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant Neurological Examination Abnormalities | 0 Participants |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant Neurological Examination Abnormalities | 1 Participants |
| Part B-MAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant Neurological Examination Abnormalities | 0 Participants |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant Neurological Examination Abnormalities | 0 Participants |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant Neurological Examination Abnormalities | 0 Participants |
| Part B-MAD: Cohort 7: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant Neurological Examination Abnormalities | 0 Participants |
| Part B-MAD: Cohort 8: BIIB067 100 mg | Parts A and B: Number of Participants With Clinically Significant Neurological Examination Abnormalities | 0 Participants |
Primary
Parts A and B: Number of Participants With Clinically Significant Physical Examination Abnormalities
Clinically significant physical examination abnormalities included weight decreased.
Time frame: Part A: Up to Day 57; Part B: Up to Day 169
Population: Safety population included all randomized participants who received at least 1 dose or a part of 1 dose of study treatment (BIIB067 or placebo) in Part A or B.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A-SAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant Physical Examination Abnormalities | 0 Participants |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Parts A and B: Number of Participants With Clinically Significant Physical Examination Abnormalities | 0 Participants |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant Physical Examination Abnormalities | 0 Participants |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant Physical Examination Abnormalities | 0 Participants |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant Physical Examination Abnormalities | 0 Participants |
| Part B-MAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant Physical Examination Abnormalities | 1 Participants |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant Physical Examination Abnormalities | 0 Participants |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant Physical Examination Abnormalities | 0 Participants |
| Part B-MAD: Cohort 7: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant Physical Examination Abnormalities | 0 Participants |
| Part B-MAD: Cohort 8: BIIB067 100 mg | Parts A and B: Number of Participants With Clinically Significant Physical Examination Abnormalities | 1 Participants |
Primary
Parts A and B: Number of Participants With Clinically Significant Vital Sign Abnormalities
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.
Time frame: Part A: Up to Day 57; Part B: Up to Day 169
Population: Safety population included all randomized participants who received at least 1 dose or a part of 1 dose of study treatment (BIIB067 or placebo) in Part A or B.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A-SAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 Participants |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Parts A and B: Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 Participants |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 Participants |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 Participants |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 Participants |
| Part B-MAD: Combined Placebo | Parts A and B: Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 Participants |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 Participants |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 Participants |
| Part B-MAD: Cohort 7: BIIB067 60 mg | Parts A and B: Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 Participants |
| Part B-MAD: Cohort 8: BIIB067 100 mg | Parts A and B: Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 Participants |
Primary
Parts A and B: PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2)
Time frame: Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169
Population: PK population is the subset of the ITT population with at least 1 post-dose PK measurement in Part A or B.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A-SAD: Combined Placebo | Parts A and B: PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2) | NA hours |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2) | NA hours |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2) | NA hours |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2) | NA hours |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2) | NA hours |
| Part B-MAD: Combined Placebo | Parts A and B: PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2) | NA hours |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2) | NA hours |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2) | NA hours |
Primary
Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h)
Time frame: Parts A and B: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1
Population: PK population is the subset of the ITT population with at least 1 post-dose PK measurement in Part A or B.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part A-SAD: Combined Placebo | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h) | 879.86 hour*ng/mL |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h) | 1027.18 hour*ng/mL |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h) | 2873.77 hour*ng/mL |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h) | 5196.11 hour*ng/mL |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h) | 1009.85 hour*ng/mL |
| Part B-MAD: Combined Placebo | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h) | 2875.13 hour*ng/mL |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h) | 4289.16 hour*ng/mL |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h) | 11344.47 hour*ng/mL |
Primary
Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf)
Time frame: Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169
Population: PK population is the subset of the ITT population with at least 1 post-dose PK measurement in Part A or B.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part A-SAD: Combined Placebo | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) | NA hour*ng/mL |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) | NA hour*ng/mL |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) | NA hour*ng/mL |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) | NA hour*ng/mL |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) | NA hour*ng/mL |
| Part B-MAD: Combined Placebo | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) | NA hour*ng/mL |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) | NA hour*ng/mL |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) | NA hour*ng/mL |
Primary
Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast)
Time frame: Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169
Population: PK population is the subset of the ITT population with at least 1 post-dose PK measurement in Part A or B.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part A-SAD: Combined Placebo | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) | NA hour*ng/mL |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) | NA hour*ng/mL |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) | NA hour*ng/mL |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) | NA hour*ng/mL |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) | NA hour*ng/mL |
| Part B-MAD: Combined Placebo | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) | NA hour*ng/mL |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) | NA hour*ng/mL |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) | NA hour*ng/mL |
Primary
Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax)
Time frame: Part A: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1; Part B: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1 and 1, 2, 4, 6 hrs post-dose on Day 85
Population: PK population is the subset of the ITT population (all randomized participants who received at least 1 dose or a part of 1 dose of study treatment) of participants with at least 1 post-dose PK measurement in Part A or B. Data was not collected for participants on Day 85 for Part A of the study.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Part A-SAD: Combined Placebo | Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax) | Day 1 | 64.94 ng/mL |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax) | Day 1 | 75.06 ng/mL |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax) | Day 1 | 202.09 ng/mL |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax) | Day 1 | 529.63 ng/mL |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax) | Day 85 | 112.74 ng/mL |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax) | Day 1 | 80.75 ng/mL |
| Part B-MAD: Combined Placebo | Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax) | Day 1 | 229.41 ng/mL |
| Part B-MAD: Combined Placebo | Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax) | Day 85 | 199.69 ng/mL |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax) | Day 1 | 437.28 ng/mL |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax) | Day 85 | 411.00 ng/mL |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax) | Day 85 | 1181.83 ng/mL |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax) | Day 1 | 1031.74 ng/mL |
Primary
Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax)
Time frame: Part A: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1; Part B: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1 and 1, 2, 4, 6 hrs post-dose on Day 85
Population: PK population is the subset of the ITT population with at least 1 post-dose PK measurement in Part A or B. Data was not collected for participants on Day 85 for Part A of the study.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Part A-SAD: Combined Placebo | Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax) | Day 1 | 4.58 hours |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax) | Day 1 | 4.16 hours |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax) | Day 1 | 6.00 hours |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax) | Day 1 | 2.70 hours |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax) | Day 85 | 3.93 hours |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax) | Day 1 | 7.01 hours |
| Part B-MAD: Combined Placebo | Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax) | Day 1 | 3.68 hours |
| Part B-MAD: Combined Placebo | Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax) | Day 85 | 3.97 hours |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax) | Day 1 | 2.44 hours |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax) | Day 85 | 3.12 hours |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax) | Day 85 | 3.82 hours |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax) | Day 1 | 3.67 hours |
Primary
Parts A and B: PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2)
Time frame: Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169
Population: PK population is the subset of the ITT population with at least 1 post-dose PK measurement in Part A or B.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A-SAD: Combined Placebo | Parts A and B: PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2) | NA hours |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Parts A and B: PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2) | NA hours |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Parts A and B: PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2) | NA hours |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Parts A and B: PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2) | NA hours |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Parts A and B: PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2) | NA hours |
| Part B-MAD: Combined Placebo | Parts A and B: PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2) | NA hours |
| Part B-MAD: Cohort 5: BIIB067 20 mg | Parts A and B: PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2) | NA hours |
| Part B-MAD: Cohort 6: BIIB067 40 mg | Parts A and B: PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2) | NA hours |
Secondary
Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline
Total CSF SOD1 protein ratio to baseline was calculated.
Time frame: Day 85
Population: PD population is the subset of the ITT population with at least 1 post-dose PD measurement in Part B.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part A-SAD: Combined Placebo | Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline | 0.97 ratio |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline | 0.99 ratio |
| Part A-SAD: Cohort 2: BIIB067 20 mg | Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline | 0.73 ratio |
| Part A-SAD: Cohort 3: BIIB067 40 mg | Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline | 0.79 ratio |
| Part A-SAD: Cohort 4: BIIB067 60 mg | Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline | 0.64 ratio |
Comparison: Difference in LS geometric mean ratio (BIIB067:Placebo) was calculated.p-value: <0.000195% CI: [0.53, 0.84]Wilcoxon rank sum test
Comparison: Difference in LS geometric mean ratio (BIIB067:Placebo) was calculated.p-value: =0.000295% CI: [0.6, 0.95]Wilcoxon rank sum test
Comparison: Difference in LS geometric mean ratio (BIIB067:Placebo) was calculated.p-value: =0.064195% CI: [0.65, 1.02]Wilcoxon rank sum test
Comparison: Difference in LS geometric mean ratio (BIIB067:Placebo) was calculated.p-value: <0.000195% CI: [0.53, 0.84]Wilcoxon rank sum test
Secondary
Part C: Change From Baseline in Handheld Dynamometry (HHD) Megascore as Measured by the HHD Device at Week 28
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 frame: Baseline, Week 28 (Day 197)
Population: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part A-SAD: Combined Placebo | Part C: Change From Baseline in Handheld Dynamometry (HHD) Megascore as Measured by the HHD Device at Week 28 | -0.37 score on a scale | Standard Error 0.096 |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Part C: Change From Baseline in Handheld Dynamometry (HHD) Megascore as Measured by the HHD Device at Week 28 | -0.34 score on a scale | Standard Error 0.073 |
p-value: =0.83995% CI: [-0.207, 0.255]ANCOVA
Secondary
Part C: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 28
Vital capacity was measured by means of an SVC test, administered in the upright position.
Time frame: Baseline, Week 28 (Day 197)
Population: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part A-SAD: Combined Placebo | Part C: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 28 | -22.20 percent predicted | Standard Error 4.771 |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Part C: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 28 | -14.31 percent predicted | Standard Error 3.557 |
Comparison: Joint rank test combining function and mortality were used for statistical inference and the estimates were from the ANCOVA for change from baseline. Multiple imputation was used to handle missing data for withdrawals other than death in the joint rank analysis. Multiple imputation was used to handle all missing data in the ANCOVA for change from baseline.p-value: =0.323395% CI: [-3.528, 19.322]Joint rank
Secondary
Part C: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline
Total CSF SOD1 protein ratio to baseline was calculated and LS Geometric Mean ratio to baseline was reported.
Time frame: Week 28 (Day 197)
Population: 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.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A-SAD: Combined Placebo | Part C: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline | 1.16 ratio |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Part C: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline | 0.71 ratio |
Comparison: The ANCOVA model included covariates for the corresponding baseline value i.e. log value, baseline disease duration since symptom onset, and use of riluzole or edaravone. Multiple imputation was used to handle missing data for withdrawals. Difference in LS geometric mean ratio to baseline (BIIB067:Placebo) was calculated.p-value: <0.000195% CI: [0.49, 0.78]ANCOVA
Secondary
Part C: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline
NfL is a biomarker whose concentration was assessed in plasma. Plasma NfL ratio to baseline was calculated.
Time frame: Baseline, Day 197 (Week 28)
Population: 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.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A-SAD: Combined Placebo | Part C: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline | 1.20 ratio |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Part C: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline | 0.40 ratio |
Comparison: Difference in LS geometric mean ratio (BIIB067:Placebo) was calculated.p-value: <0.000195% CI: [0.25, 0.45]ANCOVA
Secondary
Part C: Number of Participants Experiencing AEs and SAEs
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.
Time frame: First dose up to Day 236
Population: Safety population included all participants in Part C who were randomized and received at least one dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A-SAD: Combined Placebo | Part C: Number of Participants Experiencing AEs and SAEs | AEs | 34 Participants |
| Part A-SAD: Combined Placebo | Part C: Number of Participants Experiencing AEs and SAEs | SAEs | 5 Participants |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Part C: Number of Participants Experiencing AEs and SAEs | AEs | 69 Participants |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Part C: Number of Participants Experiencing AEs and SAEs | SAEs | 13 Participants |
Secondary
Part C: Time to Death
Time frame: Baseline up to Week 28 (Day 197)
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A-SAD: Combined Placebo | Part C: Time to Death | NA days |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Part C: Time to Death | NA days |
Secondary
Part C: Time to Death or Permanent Ventilation
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).
Time frame: Baseline up to Week 28 (Day 197)
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A-SAD: Combined Placebo | Part C: Time to Death or Permanent Ventilation | NA days |
| Part A-SAD: Cohort 1: BIIB067 10 mg | Part C: Time to Death or Permanent Ventilation | NA days |