An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BIIB067 Administered to Adult Subjects With Amyotrophic Lateral Sclerosis and Confirmed Superoxide Dismutase 1 Mutation

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: Tofersen
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 Exclusion Criteria: Part C History of or positive test result for human immunodeficiency virus. Current hepatitis C infection (defined as positive hepatitis C virus [HCV] antibody and detectable HCV ribonucleic acid [RNA]). Participants with positive HCV antibody and undetectable HCV RNA are eligible to participate in the study (United States Centers for Disease Control and Prevention). Current hepatitis B infection (defined as positive for HBsAg and/or anti-HBc). participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive anti-HBc, and positive anti-HBs) or vaccination (defined as negative HBsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate in the study. Treatment with another investigational drug (including investigational drugs for ALS through compassionate use programs), biological agent, or device within 1 month or 5 half-lives of study agent, whichever is longer. Specifically, no prior treatment with small interfering RNA, 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 DPS during the study period. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Part A-SAD: Combined Placebo<br>Participants will be administered tofersen-matching placebo once by intrathecal bolus injection on Day 1 of Cohorts 1, 2, 3, and 4 respectively. | Drug: Placebo<br>* Administered as specified in the treatment arm.<br>|
| Experimental: Part A-SAD: Cohort 1: Tofersen 10 mg<br>Participants will be administered tofersen 10 mg once by intrathecal bolus injection on Day 1. | Drug: Tofersen<br>* Administered as specified in the treatment arm.<br>* Other names: QALSODY;|
| Experimental: Part A-SAD: Cohort 2: Tofersen 20 mg<br>Participants will be administered tofersen 20 mg once by intrathecal bolus injection on Day 1 of Cohort 2 after the safety review of Cohort 1. | Drug: Tofersen<br>* Administered as specified in the treatment arm.<br>* Other names: QALSODY;|
| Experimental: Part A-SAD: Cohort 3: Tofersen 40 mg<br>Participants will be administered tofersen 40 mg once by intrathecal bolus injection on Day 1 of Cohort 3 after the safety review of Cohort 2. | Drug: Tofersen<br>* Administered as specified in the treatment arm.<br>* Other names: QALSODY;|
| Experimental: Part A-SAD: Cohort 4: Tofersen 60 mg<br>Participants will be administered tofersen 60 mg once by intrathecal bolus injection on Day 1 of Cohort 4 after the safety review of Cohort 3. | Drug: Tofersen<br>* Administered as specified in the treatment arm.<br>* Other names: QALSODY;|
| Placebo Comparator: Part B-MAD: Combined Placebo<br>Participants will be administered tofersen-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. | Drug: Placebo<br>* Administered as specified in the treatment arm.<br>|
| Experimental: Part B-MAD: Cohort 5: Tofersen 20 mg<br>Participants will be administered tofersen 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. | Drug: Tofersen<br>* Administered as specified in the treatment arm.<br>* Other names: QALSODY;|
| Experimental: Part B-MAD: Cohort 6: Tofersen 40 mg<br>Participants will be administered tofersen 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. | Drug: Tofersen<br>* Administered as specified in the treatment arm.<br>* Other names: QALSODY;|
| Experimental: Part B-MAD: Cohort 7: Tofersen 60 mg<br>Participants will be administered tofersen 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. | Drug: Tofersen<br>* Administered as specified in the treatment arm.<br>* Other names: QALSODY;|
| Experimental: Part B-MAD: Cohort 8: Tofersen 100 mg<br>Participants will be administered tofersen 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. | Drug: Tofersen<br>* Administered as specified in the treatment arm.<br>* Other names: QALSODY;|
| Placebo Comparator: Part C-Pivotal: Placebo<br>Participants will be administered tofersen-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. | Drug: Placebo<br>* Administered as specified in the treatment arm.<br>|
| Experimental: Part C-Pivotal: Tofersen 100 mg<br>Participants will be administered tofersen 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. | Drug: Tofersen<br>* Administered as specified in the treatment arm.<br>* Other names: QALSODY;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Part A: First dose up to Day 63; Part B: First dose up to Day 289 | 
| Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities | Clinical laboratory assessments included hematology, chemistry, and urinalysis. | Part A: Up to Day 57; Part B: Up to Day 169 | 
| 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. | Part A: Up to Day 57; Part B: Up to Day 169 | 
| Parts A and B: Number of Participants With Clinically Significant Physical Examination Abnormalities | Clinically significant physical examination abnormalities included weight decreased. | Part A: Up to Day 57; Part B: Up to Day 169 | 
| Parts A and B: Number of Participants With Clinically Significant Neurological Examination Abnormalities | Clinically significant neurological examination abnormalities included hyporeflexia. | Part A: Up to Day 57; Part B: Up to Day 169 | 
| 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 | 
| 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. | Baseline, Week 28 (Day 197) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline | Total CSF SOD1 protein ratio to baseline was calculated. | Day 85 | 
| 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. | Week 28 (Day 197) | 
| 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. | Baseline, Day 197 (Week 28) | 
| 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. | Baseline, Week 28 (Day 197) | 
| 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. | Baseline, Week 28 (Day 197) | 
| 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). | Baseline up to Week 28 (Day 197) | 
| Part C: Time to Death |  | Baseline up to Week 28 (Day 197) | 
| 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. | First dose up to Day 236 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ALS, IONIS-SOD1Rx, SOD1