Part 1: The primary objective is to evaluate the safety and tolerability of BIIB105 in participants with amyotrophic lateral sclerosis (ALS) or poly-CAG expansion (polyQ)-ALS.Part 2: The primary objective is to evaluate the long-term safety and…
ID
Source
Brief title
Condition
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part 1: Number of Participants with Adverse Events (AEs) and Serious
Adverse Events (SAEs)
Part 2: Number of Participants with AEs and SAEs
Secondary outcome
Part 1:The secondary objectives are to assess the pharmacokinetic (PK) profile
in serum and cerebrospinal fluid (CSF), and to evaluate the
biomarker effect of BIIB105 in participants with ALS or polyQ-ALS.
Parts 1 and 2:The secondary objectives are to assess the long-term PK profile
of BIIB105 in serum and CSF of participants with ALS or polyQALS;
to evaluate the long-term biomarker effect of BIIB105 in participants with ALS
or polyQ-ALS, and, where relevant, to assess the impact of earlier initiation
of BIIB105 (i.e., at start of Part 1) compared with delayed initiation of
BIIB105 (i.e., at start of Part 2) on biomarkers; to evaluate the long-term
effect of BIIB105 on measures of clinical function and, where relevant to
assess the impact of earlier initiation of
BIIB105 (i.e., at start of Part 1) compared with delayed initiation of
BIIB105 (i.e., at start of Part 2) on measures of clinical function.
Part 1:
1. Serum Concentration of BIIB105
2. CSF Concentrations of BIIB105
3. Area Under the Serum Concentration-Time Curve from Time Zero to Infinity
(AUCinf)
4. Area Under the Serum Concentration-Time Curve From Time Zero to Time of the
Last Measurable Concentration (AUClast)
5. Maximum Observed Serum Concentration (Cmax)
6. Time to Reach Maximum Observed Serum Concentration (Tmax)
7. Elimination Half-Life (t1/2) in Serum
8. Change From Baseline in Plasma Levels of Neurofilament Light Chain
(NfL)
Integrated Parts 1 and 2:
1.CSF Through PK Concentration of BIIB105
2.Serum PK Concentration of BIIB105
3.Change From Part 1 Baseline (Cohorts D1, D2) or part 2 baseline (Cohorts A,
B, C1, C2) in Plasma Levels of NfL
4.Change From Part 1 Baseline (Cohorts D1, D2) or part 2 baseline (Cohorts A,
B, C1, C2) in Slow Vital Capacity (SVC)
5.Change From Part 1 Baseline (Cohorts D1, D2) or part 2 baseline (Cohorts A,
B, C1, C2) in Amyotrophic Lateral Sclerosis Functional Rating
Scale - Revised (ALSFRS-R) Score
6.Change From Part 1 Baseline (Cohorts D1, D2) or part 2 baseline (Cohorts A,
B, C1, C2) in Muscle Strength, as Measured by Handheld
Dynamometry (HHD)
7.Time to Death or Permanent Ventilation
8.Time to Death
9.Time to Death, Incorporating Post-Study Withdrawal or Study Completion Vital
Status Data
Background summary
Amyotrophic lateral sclerosis (ALS) is a disease that causes the nerve cells
that control muscles (also known as motor neurons) to gradually break down and
die. Motor neurons are responsible for muscle movements. In patients with ALS,
as the motor neurons die, control over muscle movement is lost. In most
patients, the cause of ALS is not known, and doctors describe patients in this
group as *sporadic ALS* patients. In a separate small group of ALS patients,
the disease may be at least partially caused by a mutation in a gene called
Ataxin-2 (ATXN2), also known as polyQ-ALS. It has been shown that people with a
mutation in the ATXN2 gene (called polyQ mutations) are at a higher risk of
developing more aggressive ALS. Animal studies have shown that decreasing
levels of ATXN2 were related to increased survival and improved motor function
in mice.
BIIB105 is a novel ASO being developed for the treatment of ALS. The ASO
targets the ATXN2-mRNA for degradation, as a means to decrease ATXN2 protein.
Study objective
Part 1: The primary objective is to evaluate the safety and tolerability of
BIIB105 in participants with amyotrophic lateral sclerosis (ALS) or poly-
CAG expansion (polyQ)-ALS.
Part 2: The primary objective is to evaluate the long-term safety and
tolerability of BIIB105 in participants with ALS or polyQ-ALS.
Parts 1 and 2: The primary objective is to evaluate the long-term safety and
tolerability of BIIB105 in participants with ALS or polyQ-ALS.
Study design
This is a Phase 1, randomized, double-blind, placebo-controlled, MAD evaluation
of the safety, tolerability, and PK of BIIB105, administered IT to
approximately 70 participants
(48 participants with ALS and 22 participants with polyQ-ALS) at approximately
13 sites globally. Up to 4 dose levels of BIIB105 will be administered up to 5
times over approximately 3 months.
Additionally, participants with polyQ-ALS (Cohort D2) must complete a 4-month
or longer Natural History Run-in Period (inclusive of the Screening Period)
prior to dosing.
Intervention
Participants with ALS:
• Cohort A: BIIB105 5 mg (6 participants) or placebo (2 participants)
• Cohort B: BIIB105 20 mg (6 participants) or placebo (2 participants)
• Cohort C1: BIIB105 60 mg (9 participants) or placebo (3 participants)
• Cohort D1: BIIB105 120 mg (15 participants) or placebo (5 participants)
Participants with polyQ-ALS:
• Cohort C2: BIIB105 60 mg (3 participants) or placebo (1 participant)
• Cohort D2: BIIB105 120 mg (12 participants) or placebo (6 participants)
Participants in each cohort will receive 3 loading doses administered every 2
weeks (on Days 1, 15, and 29), followed by 2 maintenance doses administered
once every 4 weeks (on Days 57 and 85), for a total of 5 doses over
approximately 12 weeks.
Study burden and risks
Participants are not expected to receive therapeutic benefit from participation
in the study. The study has been designed with appropriate dose escalation,
safety monitoring, and stopping rules to minimize risks to participants.
The results of this study may offer key insights into the development of a
disease-modifying therapy for ALS. This is a first in human study, thus the
risk in humans is unknown.
Nonclinical work with Atxn2 homozygous knockout mice suggests that ATXN2
reduction could be associated with risks of metabolic complications
(adult-onset obesity and insulin resistance) and subtle neurological deficits
such as motor hyperactivity and abnormal fear conditioning [Huynh 2009; Kiehl
2006; Lastres-Becker 2008]. Human data from the Genome-Wide Association Studies
database suggest that variation in ATXN2 could be associated with changes in
blood pressure and cardiometabolic phenotypes [Auburger 2014]. From the
nonclinical safety studies in NHPs, the adverse effect level was considered to
be 60 mg based on severe but reversible and monitorable clinical signs: 1 of 3
animals exhibited increased muscle tone, whole body spasms, and tremors that
required administration of diazepam. The animal fully recovered by 24 hours. No
adverse metabolic effects were seen in toxicology studies. Participants will be
monitored in the clinical setting with neurological and physical examinations
and careful monitoring of blood chemistries, among other safety assessments.
Although LP is generally considered a safe procedure, certain complications can
occur in a subset of patients. These may include, but are not limited to, back
pain, headache, nausea, infection, bleeding, radicular pain and numbness, and
bruising or injury at the injection site. These potential risks can be
mitigated by using atraumatic needles, avoiding contraindicated medications,
and testing coagulation and platelet counts prior to the procedure.
Importantly, life-threatening cerebral herniation is a possible complication of
a lumbar puncture procedure.
Innovation House, 70 Norden Road 70
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Innovation House, 70 Norden Road 70
Maidenhead SL6 4AY
GB
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Age
Inclusion criteria
Key Inclusion Criteria:
Part 1:
- Ability of the participant to understand the purpose and risks of the study
and indicate informed consent, and the ability of the participant or the
participant's legally authorized representative to provide signed and dated
informed consent and authorization to use protected health information in
accordance with national and local privacy regulations.
- All women of childbearing potential and all men must ensure that highly
effective contraception is used during the study and for at least 6 months for
female participants and 8 months for male participants after their last dose of
study treatment.
- No known presence or family history of mutations in the the dismutase 1
(SOD1) or fused in sarcoma (FUS) genes.
- Participants in Cohorts A, B, C1 and D1, must meet the laboratory supported
probable, probable, or definite criteria for diagnosing ALS according to the
World Federati of Neurology El Escorial criteria (revised according to the
Airlie House Conference 1998 [Brooks 2000]). Participants in Cohort C2 and D2,
must meet any of the prior conditions, but may also only meet clinically
possible criteria for diagnosing ALS, or exhibit weakness attributable to ALS
in the presence of ataxin-2 protein (ATXN2) intermediate repeats.
- In participants in Cohorts C2 and D2, confirmed intermediate cytosineadenine-
uanine/cytosine-adenine-adenine (CAG/CAA) repeat expansion in the ataxin-2 gene
or RNA (ATXN2) gene as defined by at least 1 allele carrying 30 to 33 CAG/CAA
repeats.
- Slow vital capacity (SVC) criteria:
- In participants in Cohorts A, B, C1, and D1, SVC >=60% of predicted value as
adjusted for sex, age, and height (from the sitting position).
- In participants in Cohorts C2 and D2, SVC >=50% of predicted value as adjusted
for sex, age, and height (from the sitting position).
- 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,
unless the Investigator determines that it should be discontinued for medical
reasons, in which case it may not be restarted during the study.
- Participants taking concomitant edaravone at study entry must be on a stable
dose for >=60 days prior to the first dose of study treatment (Day1).
Participants taking concomitant edaravone must be willing to continue with the
same dose regimen throughout the study, 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.
- Screening values of coagulation parameters including platelet count,
international normalized ratio (INR), prothrombin time (PT), and activated
partial thromboplastin time (aPTT) should be within normal ranges.
- Has an informant/caregiver who, in the Investigator's judgment, has frequent
and sufficient contact with the participant as to be able to provide accurate
information about the participant's cognitive and functional abilities at
screening.
Part 2:
- Ability of the participant to understand the purpose and risks of the study
and indicate informed consent, and the ability of the participant or the
participant's legally authorized representative to provide signed and dated
informed consent and authorization to use protected health information in
accordance with national and local privacy regulations
- Participants must have completed Study 275AS101 Part 1 through Week 25 (Day
175 Visit for Cohorts A, B, C1, C2; Day 176 Visit for Cohorts D1, D2).
- Participants from Cohorts A, B, C1, and C2 must have a washout of >=16 weeks
between the last dose of study treatment received in Study 275AS101 Part 1 and
the first dose of BIIB105 received in Study 275AS101 Part 2. Participants from
Cohorts D1 and D2 do not require a washout period.
- 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,
unless the Investigator determines that it should be discontinued for medical
reasons, in which case it may not be restarted during the
study.
- Participants taking concomitant edaravone at study entry must be on a stable
dose for >= 60 days prior to the first dose of study treatment (Day 1).
Participants taking concomitant edaravone must be willing to continue with the
same dose regimen throughout the study, 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.
- Screening values of coagulation parameters including platelet count,INR, PT,
and aPTT should be within normal ranges.
NOTE: Other protocol defined Inclusion criteria may apply.
Exclusion criteria
Key Exclusion Criteria:
Part 1 :
- History or positive test result at Screening for human immunodeficiency virus
(HIV).
- Current hepatitis C infection.
- Current hepatitis B infection.
- History of alcohol or substance abuse <=6 months of Screening that would limit
participation in the study, as determined by the Investigator.
- Current or anticipated need, in the opinion of the Investigator, of a
diaphragm pacing system during the study period.
- Presence of tracheostomy.
- In participants from Cohorts A, B, C1, and D1, history of myocardial
infarction, as determined by the Investigator.
- In participants from Cohorts A, B, C1, and D1, poorly controlled type 1 or 2
diabetes mellitus defined as HbA1c >=8% during Screening.
- In participants in Cohorts A, B, and C1, prescreening ALSFRS-R slope >- 0.4
points/month, where prescreening ALSFRS-R slope is defined as: (ALSFRS-R score
at Screening - 48) / (months from date of symptom onset to date of Screening).
This criterion is not applicable for Cohorts C2, D1, and D2.
- Treatment with another investigational drug (including investigational drugs
for ALS through compassionate use programs) or biological agent within 1 month
or 5 half-lives of study agent, whichever is longer, before Screening.
-Treatment with an approved disease-modifying therapy for ALS other than
riluzole or edaravone within 1 month or 5 half-lives of therapy, whichever is
longer, before completion of screening.
- Treatment with an antiplatelet or anticoagulant therapy that cannot safely be
interrupted for lumbar puncture (LP) according to local standard of care and/or
institutional guidelines, in the opinion of the Investigator or Prescriber.
- Female participants who are pregnant or currently breastfeeding and those
intending to become pregnant during the study.
Part 2:
- History or positive test result at Screening for HIV. If participants from
Cohorts D1 and D2 who would seamlessly roll from Part 1 into Part 2 test
positive for HIV during screening for Part 2 but are clinically symptomatic,
they may enroll in Part 2 at the discretion of the Investigator.
-Current hepatitis C infection. If participants from Cohorts D1 and D2 who
would seamlessly roll from Part 1 into Part 2 test positive for hepatitis C
during screening for Part 2 but are clinically asymptomatic, they may enroll in
Part 2 at the discretion of the Investigator.
- Current hepatitis B infection. If participants from Cohorts D1 and D2 who
would seamlessly roll from Part 1 into Part 2 test positive for hepatitis B
during screening for Part 2 but are clinically asymptomatic, they may enroll in
Part 2 at the discretion of the Investigator.
- History of alcohol or substance abuse <= 6 months of Screening that would
limit participation in the study, as determined by the Investigator.
- Current or anticipated need, in the opinion of the Investigator, of a
diaphragm pacing system during the study period.
- In participants from Cohorts A, B, C1, and D1, history of myocardial
infarction, as determined by the Investigator.
- In participants from Cohorts A, B, C1, and D1, poorly controlled type 1 or 2
diabetes mellitus defined as HbA1c >= 8% during Screening.
-Treatment with another investigational drug (including investigational drugs
for ALS through compassionate use programs; excluding BIIB105) or biological
agent within 1 month or 5 half-lives of study agent, whichever is longer,
before Screening.
- Treatment with an antiplatelet or anticoagulant therapy that cannot safely be
interrupted for LP according to local standard of care and/or institutional
guidelines, in the opinion of the Investigator or Prescriber.
- Female participants who are pregnant or currently breastfeeding andthose
intending to become pregnant during the study.
NOTE: Other protocol defined Exclusion criteria may apply.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-000207-36-NL |
| CCMO | NL73598.000.20 |