Primary objective:• Evaluate the safety and tolerability of WVE-004 in patients with ALS or FTD with a documented mutation in the C9orf72 gene.Secondary objectives:• Characterize the pharmacokinetics (PK) of WVE-004 in plasma.• Characterize…
ID
Source
Brief title
Condition
- Neuromuscular disorders
- Dementia and amnestic conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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.
Secondary outcome
Secondary Endpoint(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
Exploratory Endpoint(s)
Biomarker Assessments:
• Change from baseline in concentration of neurodegeneration markers
(including, but not limited to, neurofilament light chain in CSF and/or plasma,
or the extracellular domain of the P75 neurotrophin receptor [P75NTRECD] in
urine)
Laboratory Assessments of Clinical Effects:
• Change from baseline on electrocardiogram
• Change from baseline on pulmonary function tests
• Change from baseline in magnetic resonance imaging (MRI)
Clinical Assessments:
• Change from baseline in the following assessments of clinical signs and
symptoms:
Functional Assessments
* CDR® plus NACC FTLD
* ALS Functional Rating Scale-Revised (ALSFRS-R)
* Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40)
* Hand-held dynamometry (HHD)
* Neuropsychiatric Inventory Questionnaire (NPI-Q)©
Cognitive Assessments
* Trails Making A and B
* Stroop Test
* Verbal Fluency
* Symbol Digit Modalities Test (SDMT)
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
Primary objective:
• Evaluate the safety and tolerability of WVE-004 in patients with ALS or FTD
with a documented mutation in the C9orf72 gene.
Secondary objectives:
• 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-GP in CSF.
Exploratory objectives:
• Evaluate the PD effects of WVE-004 via assessment of markers of
neurodegeneration.
• Evaluate the effect of WVE-004 on signs and symptoms of ALS and FTD.
• Characterize changes in brain imaging in patients receiving WVE-004
Study design
Period 1: Up to 4 dose cohorts (P1C1, P1C2, P1C3, and P1C4) are planned. The
planned initial dose in P1C1 is 10 mg. Patients will receive a single dose.
Period 2: Up to 4 dose cohorts (P2C1, P2C2, P2C3, and P2C4) are planned. The
planned initial dose in P2C1 is 10 mg, administered at a maximum frequency of
once monthly.
The maximum dose level in Period 1 and Period 2 and the maximum dose frequency
in Period 2 will not exceed those currently recommended by the Dose Escalation
Committee (DEC)/Data Safety Monitoring Board (DSMB).
Intervention
The study will include two distinct periods. Period 1 will evaluate single
ascending doses (SAD), and Period 2 will evaluate multiple ascending doses
(MAD) of WVE-004.
Period 2 cohorts will be based upon available clinical biomarker and safety
data alongside nonclinical data. The maximum dose in Period 2 will not exceed a
monthly dose of 11.2 mg, which is the human equivalent dose (HED) of the no
observed adverse effect level (NOAEL) as established in the ongoing 13-week
Good Laboratory Practice (GLP) study in cynomolgus monkeys. Dose escalation
beyond the NOAEL established in the 13-week repeat dose toxicity study (11.2 mg
monthly) will not occur until the supportive nonclinical data from subsequent
chronic toxicity studies are submitted in a substantial amendment to the IMPD
and approved by the competent authorities.
Patients may participate in Period 1 (SAD) and Period 2 (MAD) or Period 2 only.
All patients enrolled in Period 1 cohorts will have the opportunity to receive
multiple doses in Period 2. All cohorts will include both ALS and FTD patients,
and sentinel patients may be diagnosed with either ALS or FTD.
The Sponsor will continue to evaluate available nonclinical and clinical data
to optimize the dose level and frequency for multiple dosing but intends to
evaluate up to 4 dose levels in Period 1 and Period 2, and 2 dose frequencies
in Period 2.
Cohorts in both Period 1 and Period 2 will be enrolled and dosed in a
sequential manner. Cohorts that follow the initial dose cohort in Period 1 and
Period 2 will not initiate until the requirements for dose escalation are met
(as defined in the protocol on page 4-8). This study will utilize both a Dose
Escalation Committee (DEC) and a Data Safety Monitoring Board (DSMB). WVE-004
will be administered IT in a volume of 20 mL of artificial cerebrospinal fluid
(aCSF). Prior to administration, approximately 20 mL of CSF should be
withdrawn.
Study burden and risks
Burden:
Period 1
Study visits 10x; 5x Phone visits, Genetic testing for C9orf72 gene 1x; Blood
collection 15x; Screening questionnaire 1x; Lumbar puncture 7x, first lumbar
puncture is to collect CSF and for study drug administration and the other
lumber punctures are only for CSF collection; Questionnaires 10x; Physical
examination 10x; Targeted postdose physical examination 6x; MRI 1x; Lungtest
(forced vital capacity (FVC)) 10x; and ECG 6x
Sentinel subjects will have one extra visit on day 3. These subjects will have
an extra: C-SSRS, FVC, physical examination, targeted postdose physical
examination, blood collection, and ECG.
Period 2
Study visits 10x; Genetic testing for C9orf72 gene 1x; Blood collection 15x;
Lumbar puncture 7x, up to 4 lumbar puncture for CSF collection and study drug
administration and the other lumber punctures are only for CSF collection;
Questionnaires 10x; Physical examination 9x; Targeted postdose physical
examination 10x; MRI 1x; Lungtest (forced vital capacity (FVC)) 9x; Actipgraph
wear 3 x 2 weeks, and ECG 11x.
Sentinel subjects will have one extra visit on day 3. These subjects will have
an extra: C-SSRS, FVC, physical examination, targeted postdose physical
examination, blood collection, and ECG.
IP related risks:
In studies in animals (rats and monkeys) using WVE-004, there were short-term
effects on motor functioning (weakness of the legs, changes in mobility and
walking), as well as slower neuro-reflexes. These effects resolved within 24-48
hours. Subjects will therefore remain 4 hours after each dose for careful
monitoring by the investigator.
WVE-004 is a type of drug called an antisense oligonucleotide. Based on what we
know about other, similar drugs, there may be a risk of potential damage to
subject's liver or kidneys, changes in their blood (a decrease in platelets
which are involved in clotting and an increase in the time it takes for their
blood to clot), and immune reactions that can cause inflammation. An
independent Data and Safety Monitoring Committee will review safety data from
this
study. The subject will be made aware of any new risks if they arise.
Procedure related risks:
Subjects will be tested for hepatitis B, hepatitis C, HIV, and pregnancy and
subjects will be updated about the outcome of these tests.
The subjects will undergo a lumbar puncture. This may include the following
risks: mild to severe headache which may last for several days
, pain at the site where the needle entered the spinal canal, meningitis (an
infection of the nervous system), bleeding, spinal fluid leakage, nerve damage,
paralysis.
As mention above a blood collection will be performed this may include the
following risks: pain and discomfort at the site where the needle enters the
skin, fainting
bruising, swelling, an infection may develop at the site where the needle
enters the skin (on rare occasions)
In addition a MRI will be performed and this may include the following risks:
you be confined in a small, partially enclosed space, sound of the machine may
be loud, people who are claustrophobic (fear of being in small spaces) can
sometimes have anxiety during an MRI.
The subject will be asked to wear the Actigraph device for 2 weeks following
the Period 2 Screening visit, and for 2 weeks prior to the Period 2 Day 85
(Week 12) and Day 169 (Week 24) visits. The Actigraph device measures how the
subject moves throughout the day and is worn around the wrist like a watch.
There are no known risk for wearing the device. If the device becomes
uncomfortable to wear, hot, or causes skin irritation, it should be removed and
the study doctor should be contacted immediately. Do not wear the device over
any open wounds or irritated skin. The device does not capture or record the
location. The device is designed and manufactured by Actigraph. Actigraph will
receive data from the device, will analyse this data, and will provide this
analysis to the study Sponsor for assessment of changes in movement.
Finally, a ECG will be performed. Skin irritation, such as redness or itching,
is rare, but could occur during an ECG from the electrodes or gel that is used.
The ECG is painless and takes about 5 minutes.
Chamberlain Square CS 1
Birmingham B3 3AX
GB
Chamberlain Square CS 1
Birmingham B3 3AX
GB
Listed location countries
Age
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 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 the last dose.
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:
i. Renal insufficiency, which is defined 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 diseas, 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.
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 | EUCTR2020-005193-94-NL |
| CCMO | NL76122.000.21 |