Primaire Objective: - To evaluate the safety and tolerability of long-term treatment with the study drug in patients with ALS or FTD with a documented mutation in the C9orf72 geneSecondary Objective: - To evaluate the clinical and pharmacodynamic (…
ID
Source
Brief title
Condition
- Neuromuscular disorders
- Dementia and amnestic conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint:
- Incidence of patients with adverse events (AEs), severe AEs, serious
adverse events (SAEs), withdrawals due to AEs
Secondary outcome
Secondary Endpoints:
Clinical Assessments:
- Clinical Dementia Rating plus National Alzheimer*s Coordinating Center
Frontotemporal Lobar Degeneration (CDR® plus NACC FTLD)
- ALS Functional Rating Scale-Revised (ALSFRS-R)
- Handheld dynamometry (HHD)
- Pulmonary function testing (forced vital capacity [FVC])
- Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ)-5
Pharmacodynamic Effects:
- Change from baseline in concentration of poly-glycine-proline (poly-GP)
levels in the cerebrospinal fluid (CSF)
Background summary
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND)
in some regions, is a progressive, fatal, motor neuropathy. Frontotemporal
Dementia (FTD) is a degenerative disorder of the frontal and anterior temporal
lobes. ALS and FTD are both associated with the G4C2 expansion in the C9orf72
gene. At this moment in the EU there is only 1 approved drug, Rilutek®
(riluzole), for ALS which extends patient survival by 3 to 6 months. For FTD
there is no disease-modifying drug, only the symptoms are currently treated.
The study drug, WVE-004, is an antisense oligonucleotide (ASO) that promotes
RNase H-mediated degradation of C9orf72*s pathogenic mRNA variants. WVE-004 has
the potential to reduce either RNA-based or protein-based toxicity and slow the
progression of ALS or FTD.
Study objective
Primaire Objective:
- To evaluate the safety and tolerability of long-term treatment with the
study drug in patients with ALS or FTD with a documented mutation in the
C9orf72 gene
Secondary Objective:
- To evaluate the clinical and pharmacodynamic (PD) effects of the study drug
in patients with ALS or FTD with a documented mutation in the C9orf72
gene
Study design
All patients will receive intrathecal (IT) doses of WVE-004 starting at Week 0.
Patients will continue to attend clinic visits every 12 weeks to undergo safety
monitoring and assessment of clinical effects through Week 96. In addition,
patients will receive monthly telephone calls for safety monitoring. Patients
will return to the clinic for follow-up visits on Week 108 and Week 120.
Intervention
All patients will receive intrathecal (IT) doses of the study drug starting at
Week 0.
The initial dose level is planned to be 10 mg of the study drug administered no
more often than every 12 weeks. However, as the main study is ongoing and data
are continuing to emerge, the Sponsor may decide to modify the dose level and
frequency being evaluated in this study to ensure patients are receiving one
that is optimized.
The dose level and frequency will not exceed the dose levels and associated
frequencies evaluated in the WVE-004-001 study, which are recommended by the
independent Data Safety Monitoring Board (DSMB) for that study. Dose
modification will occur at the next dosing visit. If dosing occurs less often
than every 12 weeks, dosing will still align with the currently planned visits
(e.g., dosing may occur on some, but not all, of the planned visits on Weeks
12, 24, 36 etc.). If more than 1 dose level or dosing frequency combination is
selected, patients will be randomized across the dosing cohorts using a fixed
block size. The Sponsor is extending treatment with this amendment (Amendment
1.0) for up to 2 years. Patients will not be dosed beyond the 12-week duration
specified in the original protocol until this protocol amendment and associated
nonclinical data are approved.
Study burden and risks
While patients may receive treatments that are intended to help manage specific
symptoms of ALS and FTD, none of these drugs are intended to address the
underlying cause of these diseases. As such, a significant unmet medical need
exists for effective treatments for ALS and FTD, particularly disease-modifying
agents with the potential to impact the course of the disease.
The study drug has the potential to be a disease-modifying treatment to address
the common genetic cause of C9orf72-associated ALS and FTD that gives rise to
the devastating manifestations of both disorders. Initial clinical data
following single doses of the study drug demonstrated a statistically
significant reduction in poly-GP, supporting the potential benefit for
patients. Nonclinical data available to date have not identified potential
risks that would prevent the evaluation of the study drug in patients with ALS
or FTD.
In nonclinical toxicity studies of study drug, impacts on motor function and
neuroreflexes have been identified as potential risks and, in addition, ataxia
resulting in the early euthanasia of several animals at the highest doses and
frequencies administered. These potential risks should be monitored, as
outlined in the study assessments.
Given the significant unmet need for treatments that slow or prevent the
progression of disease in ALS and FTD patients, the risk/benefit profile of the
study drug appears favorable for continued development.
Chamberlain Square CS 1
Birmingham B3 3AX
GB
Chamberlain Square CS 1
Birmingham B3 3AX
GB
Listed location countries
Age
Inclusion criteria
1. Patient has the ability and is willing to provide informed consent prior to
any study procedures. In instances where signed written informed consent is
unable to be obtained it is acceptable for the patient to provide consent with
legally authorized representative signing on the patient*s behalf.
2. Patient successfully completed the Phase 1b/2a study with WVE-004,
WVE-004-001.
3. In the opinion of the Investigator, the patient is able to tolerate all
study procedures, is willing to comply with all other protocol requirements,
and tolerated study drug in the parent study.
4. Patient is willing to practice highly effective contraception for the
duration of the study and for 5 months after the last dose of study drug if the
patient or their partner are of childbearing potential. Non-childbearing
potential and highly effective methods of contraception are defined in the
protocol. In addition, willingness to forego sperm or ova (egg) donation for
the duration of the study and 5 months after completion of the study.
5. Patient has identified a study partner(s) for the duration of the study.
Exclusion criteria
1. Patient has a clinically significant medical finding on the physical
examination other than C9orf72-associated ALS or FTD that, in the judgment
of the Investigator or Sponsor, will make the patient unsuitable for
participation in and/or completion of the trial procedures.
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. Patient has a positive hepatitis B surface antigen or hepatitis C antibody
test.
3. Patients who are pregnant (as determined by a serum pregnancy test) or
breast feeding at the Screening visit or plans to become pregnant
during the trial.
4. Patients deemed to be at significant risk for suicidal behavior based on
Investigator assessment and/or active suicidal ideation.
5. Patient has a bone, spine, bleeding (e.g., hemophilia, Von Willebrand
disease, or liver disease), or other disorder that exposes the patient to a
risk of injury or unsuccessful LP.
6. Patient received prior treatment with viral or cellular-based gene therapy.
7. Patient received any other investigational drug, biological agent, or device
within 1 month or 5 half-lives of study agent, whichever is longer.
Patient received an investigational oligonucleotide within the past 6
months or 5 half-lives of the drug, whichever is longer.
8. Patient 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.
9. Patient was noncompliant in the opinion of the Investigator or Sponsor when
participating in study WVE-004-001.
10. 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.
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 | EUCTR2022-002267-29-NL |
| CCMO | NL81832.000.22 |