Clinical Trials Register

Summary
EudraCT Number:	2020-005193-94
Sponsor's Protocol Code Number:	WVE-004-001
National Competent Authority:	Ireland - HPRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-03-25
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

Ireland - HPRA

A.2

EudraCT number

2020-005193-94

A.3

Full title of the trial

A Multicenter, Randomized, Double-blind, Placebo-controlled, Phase 1b/2a Study of WVE-004 Administered Intrathecally to Patients with C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) or Frontotemporal Dementia (FTD)

A.3.1

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

Phase 1b/2a Study of WVE-004 in Patients with C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) or Frontotemporal Dementia (FTD)

A.4.1

Sponsor's protocol code number

WVE-004-001

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04931862

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	Wave Life Sciences UK 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	Wave Life Sciences UK 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	Medpace, Inc.
B.5.2	Functional name of contact point	Regulatory Submissions
B.5.3	Address:
B.5.3.1	Street Address	5375 Medpace Way
B.5.3.2	Town/ city	Cincinnati
B.5.3.3	Post code	OH 45227
B.5.3.4	Country	United States
B.5.4	Telephone number	0015135799911
B.5.5	Fax number	0015135790444
B.5.6	E-mail	regsubmissions@medpace.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	WVE-004
D.3.4	Pharmaceutical form	Powder for 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	not yet assigned
D.3.9.1	CAS number	N/A
D.3.9.2	Current sponsor code	WVE-004
D.3.9.3	Other descriptive name	Synthetic stereopure antisense oligonucleotide targeting human C9orf72 hexanucleotide repeat-containing mRNA transcripts
D.3.9.4	EV Substance Code	SUB219364
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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	Yes
D.3.11.13.1	Other medicinal product type	antisense oligonucleotide

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

Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

E.1.1.1

Medical condition in easily understood language

Motor neuron disease; dementia where the front and sides of the brain has been affected

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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10068968
E.1.2	Term	Frontotemporal dementia
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluate the safety and tolerability of WVE-004 in patients with ALS or FTD with a documented mutation in the C9orf72 gene.

E.2.2

Secondary objectives of the trial

• Characterize the pharmacokinetics (PK) of WVE-004 in plasma.
• Characterize cerebrospinal fluid (CSF) concentration of WVE-004.
• Evaluate the pharmacodynamic (PD) effect of WVE-004 via measurement of poly-glycine-proline (poly GP) in CSF.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

ALS-Specific Inclusion Criteria:
1. Diagnosis of ALS based on clinical manifestations.
2. ALS: Clinically diagnosed possible, laboratory supported probable, probable, or definite criteria for diagnosing ALS according to the World Federation of Neurology revised El Escorial criteria.
3. Patients receiving riluzole have been on a stable dose for a minimum of 30 days.
4. Patients on edaravone have received a minimum of 1 cycle (28 days).
5. Patients discontinuing riluzole or edaravone had the last dose administered ≥1 month prior to Screening.
FTD-Specific Inclusion Criteria:
6. FTD: Must have Global Clinical Dementia Rating – Frontotemporal Lobar Degeneration (CDR® plus NACC FTLD) score of 0.5 or 1.
7. FTD: Able to undergo periodic magnetic resonance imaging (MRI) of the brain. Patients with mixed phenotype (ALS and FTD) need not undergo MRI if their ALS symptoms prevent it.
Mixed Phenotype (ALS and FTD) Inclusion Criteria:
8. Patients who are mixed phenotype (ALS and FTD) must meet both the ALS-specific and FTD-specific criteria.
Inclusion Criteria Common to Both Diseases:
9. Patient must have the ability and be willing to provide written informed consent prior to any trial-related procedures.
10. Documented mutation (GGGGCC [G4C2] repeat expansion) in the first intronic region of the C9orf72 gene.
11. Body mass index (BMI) ≤32 kg/m2.
12. Forced vital capacity (FVC) of >50% predicted.
13. Age of ≥18 and ≤80 years at Screening visit.
14. Willing and able to comply with scheduled visits, drug administration plan, laboratory tests, trial restrictions, and all trial procedures.
15. Willingness to practice highly effective contraception for the duration of the trial and for 5 months after the last dose of study drug if patients or their partners are of childbearing potential. Non-childbearing potential and highly effective methods of contraception will be defined in the protocol. In addition, willingness to forego sperm or ova (egg) donation for the duration of the study and 5 months after last dose.

E.4

Principal exclusion criteria

Exclusion Criteria:
1. Clinically significant medical finding on the physical examination other than C9orf72-associated ALS or FTD that, in the judgment of the Investigator, will make the patient unsuitable for participation in, and/or completion of the trial procedures, including, but not limited to:
a. Prior or ongoing medical conditions, including acute illness, within 28 days of Screening visit;
b. Clinically significant abnormality on laboratory testing at Screening,
including, but not limited to:
Renal insufficiency, which is defined as creatinine clearance <40
mL/min.
2. Positive hepatitis B surface antigen or hepatitis C antibody test.
3. Known to be positive for human immunodeficiency virus (HIV).
4. History of substance use disorder (except nicotine) within 6 months prior to the Screening Visit.
5. Significant cognitive impairment; or unstable psychiatric illness, including active psychosis, active suicidal ideation, recent suicide attempt, or untreated major depression, within the last 90 days, as determined by the Investigator. Mental status, psychiatric medical history, and eligibility for the study must be documented in the screening questionnaire.
6. Pregnant (as determined by a serum pregnancy test) or breast feeding at the Screening Visit, or plans to become pregnant during the trial.
7. Clinically significant abnormality on Screening electrocardiogram (ECG), including, but not limited to, a confirmed QT interval using Fridericia’s correction method (QTcF) of ≥450 msec for males or ≥470 msec for females.
8. Bone, spine, bleeding (e.g. hemophilia, Von Willenbrand disease, liver disease), or other disorder that exposes the patient to risk of injury or unsuccessful lumbar puncture.
9. Dementia due to a condition other than C9orf72-associated ALS or FTD, including, but not limited to, Alzheimer disease, Parkinson disease, dementia with Lewy bodies, Huntington's disease, or vascular dementia.
Prior or Concomitant Medications
10. Positive for opioids (unprescribed), cocaine, amphetamines, methadone, barbiturates, methamphetamine, and phencyclidine at the Screening Visit.
11. Changes in nutritional or herbal supplements or concomitant medications within 1 month prior to Screening visit or plans to modify dose or regimen during the trial.
12. Received prior treatment with viral or cellular-based gene therapy.
13. Received any other investigational drug, biological agent, or device within 1 month of 5 half-lives of study agent, whichever is longer. Received an investigational oligonucleotide, within the past 6 months or 5 half-lives of the drug, whichever is longer. Received prior treatment with investigational product BIIB078.
14. Anticipates using antiplatelet or anticoagulant therapy during the course of the study. Patients who received antiplatelet or anticoagulant therapy must complete one of the following washout periods before the Screening Visit:
a. A 7-day washout period for antiplatelet therapy,
b. A 1-day washout period for anticoagulants (except warfarin), or
c. A 5-day washout period for warfarin.
Trial Compliance
15. Implantable central nervous system (CNS) device that may interfere with ability to administer trial drug via lumbar puncture or undergo MRI scan.
16. Deemed to be at significant risk for suicidal behavior based on Investigator assessment and/or active suicidal ideation.
17. Known hypersensitivity to any oligonucleotide, as demonstrated by a systemic allergic reaction, such as changes in pulse, blood pressure, breathing function, etc., or any other drug that in the opinion of the Investigator may preclude study participation.
18. Patient is directly or indirectly involved in the conduct and administration of this trial as an Investigator, sub investigator, trial coordinator, or other trial staff member, or the patient is a first-degree family member, significant other, or relative residing with one of the above persons involved directly or indirectly in the trial.

E.5 End points

E.5.1

Primary end point(s)

Incidence of patients with AEs, the incidence of patients with severe AEs, incidence of patients with SAEs, and the incidence of patients who withdraw due to AEs.

E.5.1.1

Timepoint(s) of evaluation of this end point

Period 1: week 1 - 24
Period 2: week 1 - 24

E.5.2

Secondary end point(s)

• Pharmacokinetic parameters of WVE-004 in plasma
• CSF concentration of WVE-004
• Change from baseline in concentration of poly-GP levels in the CSF

E.5.2.1

Timepoint(s) of evaluation of this end point

Period 1: week 1 - 24
Period 2: week 1 - 24

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

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

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

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Period 1: Single Ascending Dose, Period 2 Multiple Ascending Dose

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

Australia

Canada

New Zealand

United States

Sweden

Netherlands

Germany

Belgium

Ireland

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

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

Last patient Last Visit ( Including Follow-up Visit)

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)

Depending on the results of this study, subjects might be able to participate in an extension study ( after study approval by the authorities)

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

2021-06-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-08-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-06-28

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