Clinical Trials Register

Summary
EudraCT Number:	2020-000207-36
Sponsor's Protocol Code Number:	275AS101
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-12-04
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2020-000207-36

A.3

Full title of the trial

A Phase 1/2 Multiple-Ascending-Dose Study With a Long-Term Open-Label
Extension to Assess the Safety, Tolerability, Pharmacokinetics,
Pharmacodynamics, and Effect on Disease Progression of BIIB105
Administered Intrathecally to Adults With Amyotrophic Lateral Sclerosis
With or Without Poly-CAG Expansion in the Ataxin-2 Gene

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A Study to Assess the Safety, Tolerability, Pharmacokinetics,
Pharmacodynamics, and Effect on Disease Progression of BIIB105 in
Participants With Amyotrophic Lateral Sclerosis With or Without Polycytosine- adenine-guanine (CAG) Expansion in the Ataxin-2 Gene

A.3.2

Name or abbreviated title of the trial where available

ALSpire

A.4.1

Sponsor's protocol code number

275AS101

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Biogen Idec Research Limited
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Biogen Idec Research Limited
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Biogen
B.5.2	Functional name of contact point	Medical Director/Monitor
B.5.3	Address:
B.5.3.1	Street Address	Innovation house, 70 Norden Road
B.5.3.2	Town/ city	Maidenhead
B.5.3.3	Post code	SL6 4AY
B.5.3.4	Country	United Kingdom
B.5.6	E-mail	clinicialTrials@biogen.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	BIIB105
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intrathecal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BIIB105
D.3.9.2	Current sponsor code	BIIB105
D.3.9.3	Other descriptive name	BIIB105
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Intrathecal use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

ALS and ALS associated with ataxin-2 (ATXN2) poly-CAG expansion (polyQ-ALS)

E.1.1.1

Medical condition in easily understood language

Amyotrophic Lateral Sclerosis

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10002026
E.1.2	Term	Amyotrophic lateral sclerosis
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10052653
E.1.2	Term	Amyotrophic lateral sclerosis gene carrier
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

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; 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 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.

E.2.3

Trial contains a sub-study

E.3

Principal 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
superoxide 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 Federation 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 cytosine-adenine-guanine/cytosineadenine-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.
- No known presence or family history of mutations in the SOD1 or FUS genes.
- 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 (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, 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).
- 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.

E.4

Principal exclusion criteria

Key Exclusion Criteria:
Part 1:
- History or positive test result at Screening for 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 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
asymptomatic, 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 and
those intending to become pregnant during the study.
NOTE: Other protocol defined Exclusion criteria may apply.

E.5 End points

E.5.1

Primary end point(s)

Part 1: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
Part 2: Number of Participants with AEs and SAEs

E.5.1.1

Timepoint(s) of evaluation of this end point

Part 1: Up to Day 260
Part 2: Up to Day 820

E.5.2

Secondary end point(s)

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 in Plasma Levels of NfL
4.Change From Part 1 Baseline in Slow Vital Capacity (SVC)
5.Change From Part 1 Baseline in Amyotrophic Lateral Sclerosis
Functional Rating Scale – Revised (ALSFRS-R) Score
6.Change From Part 1 Baseline 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

E.5.2.1

Timepoint(s) of evaluation of this end point

Part 1:
1.Up to Day 176
2.Up to Day 259
3.Up to Day 176
4.Up to Day 176
5.Up to Day 176
6.Up to Day 176
7.Up to Day 176
8.Up to Day 259
Integrated Parts 1 and 2:
1.Up to Day 819
2.Up to Day 673
3.Up to Day 819
4.Up to Day 819
5.Up to Day 819
6.Up to Day 819
7.Up to Day 820
8.Up to Day 820
9.Up to Day 820

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

Yes

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Part 2 is an unblinded long term extension

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Canada

United States

Netherlands

Spain

Italy

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-06-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-11-18

P. End of Trial
P.	End of Trial Status	Ongoing

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IMP with orphan designation in the indication
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