Clinical Trial Results:
A Multicenter, Open-label Extension (OLE) Study to Evaluate the Safety, Pharmacodynamics, and Clinical Effects of WVE-004 in Patients with C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) and/or Frontotemporal Dementia (FTD)
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Summary
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EudraCT number |
2022-002267-29 |
Trial protocol |
NL IE BE |
Global end of trial date |
27 Jun 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
18 Apr 2025
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First version publication date |
18 Apr 2025
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
WVE-004-002
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT05683860 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Wave Life Sciences UK Limited
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Sponsor organisation address |
1 Chamberlain Square CS, Birmingham, United Kingdom, B3 3AX
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Public contact |
Daniel Paulson, Wave Life Sciences, +1 617-949-2900, info@wavelifesci.com
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Scientific contact |
Daniel Paulson, Wave Life Sciences, +1 617-949-2900, info@wavelifesci.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
27 Jun 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
27 Jun 2023
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To evaluate the safety and tolerability of long-term treatment with WVE-004 in participants with amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD) with a documented mutation in the C9orf72 gene.
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Protection of trial subjects |
The study was conducted according to the study protocol and standard operating procedures that meet the guidelines provided by the International Conference on Harmonisation for Good Clinical Practice in clinical studies, and any other applicable local regulatory requirements.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
14 Dec 2022
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 6
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Country: Number of subjects enrolled |
Belgium: 2
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Worldwide total number of subjects |
8
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EEA total number of subjects |
8
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
4
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From 65 to 84 years |
4
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85 years and over |
0
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Recruitment
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Recruitment details |
Following completion of WVE-004-001, eligible participants entered an open-label extension (OLE) study (WVE-004-002) regardless of whether they participated in only the single-dose phase, multiple-dose phase, or both parts of the study. | ||||||||||
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Pre-assignment
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Screening details |
A total of 8 participants were treated and none of the participants completed the study due to study termination by Sponsor. | ||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||
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Arms
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Arm title
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WVE-004 10 mg Q12W | ||||||||||
Arm description |
Eligible participants successfully completed the Phase 1b/2a WVE-004-001 study, met all inclusion criteria, and none of the exclusion criteria. Participants were administered 10 milligram (mg) of WVE-004 by intrathecal (IT) injection once every 12 weeks (Q12W) for 96 weeks. | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
WVE-004
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for injection
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Routes of administration |
Intrathecal use
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Dosage and administration details |
WVE-004 10 mg was administered IT by direct lumbar injection using an atraumatic needle Q12W for 96 weeks.
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Baseline characteristics reporting groups
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Reporting group title |
WVE-004 10 mg Q12W
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Reporting group description |
Eligible participants successfully completed the Phase 1b/2a WVE-004-001 study, met all inclusion criteria, and none of the exclusion criteria. Participants were administered 10 milligram (mg) of WVE-004 by intrathecal (IT) injection once every 12 weeks (Q12W) for 96 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
WVE-004 10 mg Q12W
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Reporting group description |
Eligible participants successfully completed the Phase 1b/2a WVE-004-001 study, met all inclusion criteria, and none of the exclusion criteria. Participants were administered 10 milligram (mg) of WVE-004 by intrathecal (IT) injection once every 12 weeks (Q12W) for 96 weeks. | ||
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End point title |
Number of Occurrences of Participants With Adverse Events (AEs), Severe AEs, Serious Adverse Events (SAEs), and Withdrawals Due to AEs [1] | ||||||||||||||
End point description |
A treatment-emergent adverse event (TEAE) is defined as any event not present before exposure to study treatment or any event already present that worsens in either intensity or frequency after exposure to study treatment. The safety population included all enrolled participants who have received at least 1 dose of study medication in the OLE.
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End point type |
Primary
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End point timeframe |
Day 1 to Week 120 (end of study)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive statistical analysis was performed for the primary end point. |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change From Baseline in Clinical Dementia Rating Plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration (CDR Plus NACC FTLD) | ||||||||
End point description |
Disease progression was measured using the CDR plus NACC FTLD scale. The evaluation included assessments of both cognitive and functional measures, including memory, orientation, judgment and problem-solving, involvement in community affairs, home and hobbies, personal care, language and behavior, and comportment and personality. The rating for each domain was scored using a scale of 0 (none) to 3 (severe) based on the participant's function in relation to cognitive ability (not impairment due to other factors) and past performance (or baseline level of functioning). The overall rating for each domain was summed to provide a global clinical measure of the disease. The CDR plus NACC FTLD score ranges from 0 to 24, with a higher score indicating more severe impairment. Analysis of the CDR plus NACC FTLD and its sum of boxes score by Mixed Model for Repeated Measures (MMRM) analysis model was conducted in the WVE-004-001 study only.
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End point type |
Secondary
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End point timeframe |
Day 1 to Week 120 (end of study)
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| Notes [2] - No participants were analyzed. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) | ||||||||
End point description |
ALSFRS-R is an instrument to monitor the function of participants with ALS and their disease progression. The components of the scale are grouped into 4 factors or domains that encompass gross motor tasks, fine motor tasks, bulbar functions, and respiratory functions. These components measure speech, salivation, swallowing, writing, feeding, dressing, turning, walking, climbing, breathing, dyspnea, orthopnea, and respiratory insufficiency. Each component is scaled from 0 to 4, with 4 being normal, and a total score is calculated. ALSFRS-R was not assessed for Study WVE-004-002.
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End point type |
Secondary
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End point timeframe |
Day 1 to Week 120 (end of study)
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| Notes [3] - No participants were analyzed. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Handheld Dynamometry (HHD) | ||||||||
End point description |
The HHD was used to provide an objective quantitative measurement of strength, a key hallmark of decline in ALS disease progression. For the HHD assessment, participants would be sitting in a hard-backed chair with armrests or a wheelchair. Muscle strength was tested using the HHD device. Measurements were recorded in pounds. A value of 0 was assigned to a given muscle if a participant could not assume the testing position due to weakness. HHD was not assessed for Study WVE-004-002 due to the early termination of the study.
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End point type |
Secondary
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End point timeframe |
Day 1 to Week 120 (end of study)
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| Notes [4] - No participants were analyzed. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Pulmonary Function Testing Forced Vital Capacity (FVC) | ||||||||
End point description |
Pulmonary function tests are tests that show how well your lungs are working. The tests measure lung volume, capacity, rates of flow, and gas exchange. FVC analysis was conducted in the WVE-004-001 study only.
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End point type |
Secondary
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End point timeframe |
Day 1 to Week 120 (end of study)
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| Notes [5] - No participants were analyzed. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ)-5 | ||||||||
End point description |
The ALSAQ-5 is specifically used to provide a brief assessment of the impacts of ALS on participants. Participants were asked to think about the difficulties they have experienced during the reporting period and scale each event as never/rarely/sometimes/often/always or cannot do at all. ALSAQ-5 was not assessed for Study WVE-004-002 due to the early termination of the study.
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End point type |
Secondary
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End point timeframe |
Day 1 to Week 120 (end of study)
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| Notes [6] - No participants were analyzed. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in the Concentration of Poly-glycine-proline (Poly-GP) Levels in the Cerebrospinal Fluid (CSF) | ||||||||||||
End point description |
CSF samples were collected to determine the concentration of poly-GP levels in CSF. The safety population included all enrolled participants who had received at least 1 dose of study medication in the OLE.
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End point type |
Secondary
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End point timeframe |
From Baseline to Week 12
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
TEAE period in the OLE consisted of up to 96 weeks of treatment (at a maximum frequency of once every 4 weeks) followed by 24 weeks of follow-up.
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Adverse event reporting additional description |
The Safety population included all participants who were enrolled in the OLE study.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24.0
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Reporting groups
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Reporting group title |
WVE-004 (Dose A)
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Reporting group description |
WVE-004 is a stereopure antisense oligonucleotide. It is administered via intrathecal injection. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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13 Oct 2022 |
Extended the duration of treatment from 12 weeks to 96 weeks. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| Due to lack of clinical benefit, development of WVE-004 was stopped. | |||
