Amyotrophic Lateral SclerosisPhase 3VALOR (Part C)NCT02623699
An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
A Phase 3 study testing Tofersen in people with Amyotrophic Lateral Sclerosis, run by Biogen at 40 sites in 12 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Amyotrophic Lateral Sclerosis
- What is being tested?
- Tofersen
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 176 participants
- Where
- 40 sitesin 12 countries
- Study dates
- 20 Jan 2016to 16 Jul 2021
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
- 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.
Who cannot join
- 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.
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- Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system (DPS) during the study period.
- 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.
Trial locations and contacts
40 sites in 12 countries.
40 sites in 12 countries
United States20 sites
Emory University Hospital
Atlanta, Georgia, 30322
Johns Hopkins University
Baltimore, Maryland, 21287
Massachusetts General Hospital
Boston, Massachusetts, 02114
Northwestern University Feinberg School of Medicine
Chicago, Illinois, 60611
The Cleveland Clinic Foundation
Cleveland, Ohio, 44106
Henry Ford Hospital
Detroit, Michigan, 48202
Methodist Neurological Institute
Houston, Texas, 77030
Mayo Clinic in Florida
Jacksonville, Florida, 32224
New Orleans Center for Clinical Research/Volunteer Research Group, an AMR Company
Knoxville, Tennessee, 37920
University of California San Diego Medical Center
La Jolla, California, 92093
Neurology Associates, P.C.
Lincoln, Nebraska, 68506
University of Miami School of Medicine
Miami, Florida, 33136
Columbia University Medical Center
New York, New York, 10032
Bioclinica Research
Orlando, Florida, 32806
University of Pennsylvania
Philadelphia, Pennsylvania, 19104
Barrow Neurological Institute
Phoenix, Arizona, 85013
Providence ALS Center
Portland, Oregon, 97213
Mayo Clinic - Rochester
Rochester, Minnesota, 55905
California Pacific Medical Center
San Francisco, California, 94115
Washington University School of Medicine
St Louis, Missouri, 63110
Japan5 sites
The University of Tokyo Hospital
Bunkyō City
Research Site
Fukuoka
Research Site
Kagoshima
Research Site
Shinjuku-ku
Research Site
Suita-Shi
Canada4 sites
University of Calgary - Health Sciences Centre
Calgary, Alberta, T2N 1N4
Research Site
Edmonton, Alberta, T6G 2G3
Montreal Neurological Institute
Montreal, Quebec, H3A 2B4
Sunnybrook Health Sciences Centre
Toronto, Ontario, M4N 3M5
South Korea2 sites
Research Site
Seoul, 04763
Research Site
Yangsan, Gyeongsangnam-do, 50612
United Kingdom2 sites
Research Site
London, Greater London, SE5 9RS
Research Site
Sheffield, South Yorkshire, S10 2HQ
Italy1 site
ALS Center - Dept. of Neuroscience "Rita Levi Montalcini", University of Turin
Torino, 10126
About this study
Official title: 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
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.
Read the 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.
- Conditions
- Amyotrophic Lateral Sclerosis
- Being tested
- Tofersen, Placebo
- Keywords
- IONIS-SOD1Rx, SOD1, ALS
- Medical subject headings
- Amyotrophic Lateral Sclerosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TofersenDrug
Also called BIIB067, QALSODY
Administered as specified in the treatment arm.
PlaceboDrug
Administered as specified in the treatment arm.
| Study group | Role | What they receive |
|---|---|---|
| Part A-SAD: Combined Placebo | Placebo comparator | Participants will be administered tofersen-matching placebo once by intrathecal bolus injection on Day 1 of Cohorts 1, 2, 3, and 4 respectively. Receives: Drug: Placebo |
| Part A-SAD: Cohort 1: Tofersen 10 mg | Experimental | Participants will be administered tofersen 10 mg once by intrathecal bolus injection on Day 1. Receives: Drug: Tofersen |
| Part A-SAD: Cohort 2: Tofersen 20 mg | Experimental | 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. Receives: Drug: Tofersen |
| Part A-SAD: Cohort 3: Tofersen 40 mg | Experimental | 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. Receives: Drug: Tofersen |
| Part A-SAD: Cohort 4: Tofersen 60 mg | Experimental | 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. Receives: Drug: Tofersen |
| Part B-MAD: Combined Placebo | Placebo comparator | 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. Receives: Drug: Placebo |
| Part B-MAD: Cohort 5: Tofersen 20 mg | Experimental | 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. Receives: Drug: Tofersen |
| Part B-MAD: Cohort 6: Tofersen 40 mg | Experimental | 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. Receives: Drug: Tofersen |
| Part B-MAD: Cohort 7: Tofersen 60 mg | Experimental | 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. Receives: Drug: Tofersen |
| Part B-MAD: Cohort 8: Tofersen 100 mg | Experimental | 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. Receives: Drug: Tofersen |
| Part C-Pivotal: Placebo | Placebo comparator | 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. Receives: Drug: Placebo |
| Part C-Pivotal: Tofersen 100 mg | Experimental | 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. Receives: Drug: Tofersen |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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)
Measured: 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)
Measured: 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)
Measured: 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)
Measured: 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)
Measured: 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)
Measured: 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)
Measured: 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.
Measured: Baseline, Week 28 (Day 197)
Secondary outcomes (8)
Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline
Total CSF SOD1 protein ratio to baseline was calculated.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: Baseline up to Week 28 (Day 197)
Part C: Time to Death
Measured: 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.
Measured: First dose up to Day 236
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Dec 2015 (estimated)
- Study start20 Jan 2016
- Primary completion16 Jul 2021
- Study completion16 Jul 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Amyotrophic Lateral SclerosisStudies of the same condition, open and under way.
- More trials run by BiogenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 176 participants (actual)
Sponsor and investigators
- Lead sponsor
- Biogen
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Ionis Pharmaceuticals, Inc.
- Responsible party
- Sponsor
- Investigators
- Medical Director, Study director, Biogen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02623699
- Sponsor's protocol ID
- 233AS101
- Other IDs
- 2015-004098-33, 2015
- Acronym
- VALOR (Part C)
- Status last verified
- Jul 2023
- First submitted
- 24 Nov 2015
- Last updated
- 28 Jul 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on http://clinicalresearch.biogen.com/
Publications
Guise AJ, Sellon MT, Roemer SF, Monine M, Comfort Harris NT, Bartlett D, David E, Xu S, Jandreski L, Malek S, Garafalo S, Nestorov I, Ireland MD, King A, Bowser RP, Korobeynikov V, Ravits J, Shaw PJ, Highley JR, Ferguson TA, Fradette S, Graham DL, Sorenson EJ, Oskarsson B, Reichard RR, Dickson DW, Paganoni S, Babu S, Oakley DH, Frosch MP, Miller TM, Bucelli RC, Perrin RJ, Ly CV, Plowey ED. Antisense Oligonucleotide Tofersen Distribution in the Central Nervous System of SOD1-ALS Autopsy Tissue Donors. JAMA Neurol. 2026 Jul 6:e262195. doi: 10.1001/jamaneurol.2026.2195. Online ahead of print.
PubMed 42406382Miller TM, Cudkowicz ME, Shaw PJ, Genge A, Sobue G, Bucelli RC, Chio A, Van Damme P, Ludolph AC, Glass JD, Andrews JA, Babu S, Benatar M, McDermott CJ, Salachas F, Bruneteau G, Al-Chalabi A, Amorin M, Nestorov I, Graham D, Lin L, Sun P, McNeill M, Malek S, Inra J, Garafalo S, Fradette S; VALOR and OLE Working Group. Long-Term Tofersen in SOD1 Amyotrophic Lateral Sclerosis. JAMA Neurol. 2026 Feb 1;83(2):115-125. doi: 10.1001/jamaneurol.2025.4946.
PubMed 41661214Miller TM, Cudkowicz ME, Genge A, Shaw PJ, Sobue G, Bucelli RC, Chio A, Van Damme P, Ludolph AC, Glass JD, Andrews JA, Babu S, Benatar M, McDermott CJ, Cochrane T, Chary S, Chew S, Zhu H, Wu F, Nestorov I, Graham D, Sun P, McNeill M, Fanning L, Ferguson TA, Fradette S; VALOR and OLE Working Group. Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2022 Sep 22;387(12):1099-1110. doi: 10.1056/NEJMoa2204705.
PubMed 36129998Miller T, Cudkowicz M, Shaw PJ, Andersen PM, Atassi N, Bucelli RC, Genge A, Glass J, Ladha S, Ludolph AL, Maragakis NJ, McDermott CJ, Pestronk A, Ravits J, Salachas F, Trudell R, Van Damme P, Zinman L, Bennett CF, Lane R, Sandrock A, Runz H, Graham D, Houshyar H, McCampbell A, Nestorov I, Chang I, McNeill M, Fanning L, Fradette S, Ferguson TA. Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2020 Jul 9;383(2):109-119. doi: 10.1056/NEJMoa2003715.
PubMed 32640130
Study at a glance
From the registry record, last updated by the sponsor on 28 Jul 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT02623699
- Acronym / sponsor ID
- VALOR (Part C) / 233AS101
- Conditions
- Amyotrophic Lateral Sclerosis
- Keywords
- IONIS-SOD1Rx, SOD1, ALS
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 176 participants (actual)
- Lead sponsor
- BiogenIndustry (pharma, biotech, devices)
- Collaborators
- Ionis Pharmaceuticals, Inc.
- Study start
- 20 Jan 2016 (actual)
- Primary completion
- 16 Jul 2021 (actual)
- Study completion
- 16 Jul 2021 (actual)
- First posted
- 8 Dec 2015 (estimated)
- Results
- Posted 28 Jul 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 12
| Arm | Type | Receives |
|---|---|---|
| Part A-SAD: Combined Placebo | Placebo comparator | Drug: PlaceboParticipants will be administered tofersen-matching placebo once by intrathecal bolus injection on Day 1 of Cohorts 1, 2, 3, and 4 respectively. |
| Part A-SAD: Cohort 1: Tofersen 10 mg | Experimental | Drug: TofersenParticipants will be administered tofersen 10 mg once by intrathecal bolus injection on Day 1. |
| Part A-SAD: Cohort 2: Tofersen 20 mg | Experimental | Drug: TofersenParticipants will be administered tofersen 20 mg once by intrathecal bolus injection on Day 1 of Cohort 2 after the safety review of Cohort 1. |
| Part A-SAD: Cohort 3: Tofersen 40 mg | Experimental | Drug: TofersenParticipants will be administered tofersen 40 mg once by intrathecal bolus injection on Day 1 of Cohort 3 after the safety review of Cohort 2. |
| Part A-SAD: Cohort 4: Tofersen 60 mg | Experimental | Drug: TofersenParticipants will be administered tofersen 60 mg once by intrathecal bolus injection on Day 1 of Cohort 4 after the safety review of Cohort 3. |
| Part B-MAD: Combined Placebo | Placebo comparator | Drug: PlaceboParticipants 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. |
| Part B-MAD: Cohort 5: Tofersen 20 mg | Experimental | Drug: TofersenParticipants 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. |
| Part B-MAD: Cohort 6: Tofersen 40 mg | Experimental | Drug: TofersenParticipants 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. |
| Part B-MAD: Cohort 7: Tofersen 60 mg | Experimental | Drug: TofersenParticipants 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. |
| Part B-MAD: Cohort 8: Tofersen 100 mg | Experimental | Drug: TofersenParticipants 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. |
| Part C-Pivotal: Placebo | Placebo comparator | Drug: PlaceboParticipants 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. |
| Part C-Pivotal: Tofersen 100 mg | Experimental | Drug: TofersenParticipants 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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.
- Weakness attributable to ALS and confirmed SOD1 mutation at Screening Visit.
Key exclusion criteria (15 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TofersenAlso: BIIB067, QALSODYAdministered as specified in the treatment arm. | Drug | Part A-SAD: Cohort 1: Tofersen 10 mg, Part A-SAD: Cohort 2: Tofersen 20 mg, Part A-SAD: Cohort 3: Tofersen 40 mg, Part A-SAD: Cohort 4: Tofersen 60 mg, Part B-MAD: Cohort 5: Tofersen 20 mg, Part B-MAD: Cohort 6: Tofersen 40 mg, Part B-MAD: Cohort 7: Tofersen 60 mg, Part B-MAD: Cohort 8: Tofersen 100 mg, Part C-Pivotal: Tofersen 100 mg |
| PlaceboAdministered as specified in the treatment arm. | Drug | Part A-SAD: Combined Placebo, Part B-MAD: Combined Placebo, Part C-Pivotal: Placebo |
Primary outcome
Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Part A: Up to Day 57; Part B: Up to Day 169
Clinically significant neurological examination abnormalities included hyporeflexia.
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
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
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
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
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
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
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
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
Part C: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score at Week 28
Time frame: 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.
8 secondary outcomes
Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline
Time frame: Day 85
Part C: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline
Time frame: Week 28 (Day 197)
Part C: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline
Time frame: Baseline, Day 197 (Week 28)
Part C: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 28
Time frame: Baseline, Week 28 (Day 197)
Part C: Change From Baseline in Handheld Dynamometry (HHD) Megascore as Measured by the HHD Device at Week 28
Time frame: Baseline, Week 28 (Day 197)
Part C: Time to Death or Permanent Ventilation
Time frame: Baseline up to Week 28 (Day 197)
Part C: Time to Death
Time frame: Baseline up to Week 28 (Day 197)
Part C: Number of Participants Experiencing AEs and SAEs
Time frame: First dose up to Day 236
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Jul 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 42406382Guise AJ, Sellon MT, Roemer SF, Monine M, Comfort Harris NT, Bartlett D, David E, Xu S, Jandreski L, Malek S, Garafalo S, Nestorov I, Ireland MD, King A, Bowser RP, Korobeynikov V, Ravits J, Shaw PJ, Highley JR, Ferguson TA, Fradette S, Graham DL, Sorenson EJ, Oskarsson B, Reichard RR, Dickson DW, Paganoni S, Babu S, Oakley DH, Frosch MP, Miller TM, Bucelli RC, Perrin RJ, Ly CV, Plowey ED. Antisense Oligonucleotide Tofersen Distribution in the Central Nervous System of SOD1-ALS Autopsy Tissue Donors. JAMA Neurol. 2026 Jul 6:e262195. doi: 10.1001/jamaneurol.2026.2195. Online ahead of print.
- Derived from this study: PubMed 41661214Miller TM, Cudkowicz ME, Shaw PJ, Genge A, Sobue G, Bucelli RC, Chio A, Van Damme P, Ludolph AC, Glass JD, Andrews JA, Babu S, Benatar M, McDermott CJ, Salachas F, Bruneteau G, Al-Chalabi A, Amorin M, Nestorov I, Graham D, Lin L, Sun P, McNeill M, Malek S, Inra J, Garafalo S, Fradette S; VALOR and OLE Working Group. Long-Term Tofersen in SOD1 Amyotrophic Lateral Sclerosis. JAMA Neurol. 2026 Feb 1;83(2):115-125. doi: 10.1001/jamaneurol.2025.4946.
- Derived from this study: PubMed 36129998Miller TM, Cudkowicz ME, Genge A, Shaw PJ, Sobue G, Bucelli RC, Chio A, Van Damme P, Ludolph AC, Glass JD, Andrews JA, Babu S, Benatar M, McDermott CJ, Cochrane T, Chary S, Chew S, Zhu H, Wu F, Nestorov I, Graham D, Sun P, McNeill M, Fanning L, Ferguson TA, Fradette S; VALOR and OLE Working Group. Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2022 Sep 22;387(12):1099-1110. doi: 10.1056/NEJMoa2204705.
- Derived from this study: PubMed 32640130Miller T, Cudkowicz M, Shaw PJ, Andersen PM, Atassi N, Bucelli RC, Genge A, Glass J, Ladha S, Ludolph AL, Maragakis NJ, McDermott CJ, Pestronk A, Ravits J, Salachas F, Trudell R, Van Damme P, Zinman L, Bennett CF, Lane R, Sandrock A, Runz H, Graham D, Houshyar H, McCampbell A, Nestorov I, Chang I, McNeill M, Fanning L, Fradette S, Ferguson TA. Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2020 Jul 9;383(2):109-119. doi: 10.1056/NEJMoa2003715.
- Individual participant dataSharing planned: Yes. In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on http://clinicalresearch.biogen.com/
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Director study director
Biogen
40 sites in 12 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Tofersen in people with Amyotrophic Lateral Sclerosis, run by Biogen at 40 sites in 12 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Jul 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 40 sites in United States, Japan, Canada, South Korea, United Kingdom and 7 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 28 Jul 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) (time frame: Part A: First dose up to Day 63; Part B: First dose up to Day 289). The study lists 14 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02623699, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Jul 2023.