Primary objective:x To evaluate the safety and tolerability of WVE-003 in patients with Huntington's disease (HD)Secondary objectives:x To characterize the pharmacokinetics (PK) of WVE-003 in plasma x To characterize the concentration of WVE-…
ID
Source
Brief title
Condition
- Congenital and hereditary disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety:
Adverse events, concomitant medications, physical examinations including
detailed neurological examination, vital signs, weight, 12-lead ECGs, clinical
laboratory evaluations (including clinical chemistry, hematology, and
urinalysis), CSF safety evaluations, MRI of the brain, and C-SSRS
Secondary outcome
Pharmacokinetics:
x Pharmacokinetic parameters of WVE-003 in plasma
x Concentration of WVE-003 in CSF
Pharmacodynamics:
x Change from baseline in the level of mHTT protein in CSF
x Change from baseline in the level of wtHTT protein in CSF
x Change from baseline in the level of tHTT protein in CSF
x Change from baseline in the level of NfL in CSF
x Change from baseline in the level of exploratory biomarkers in CSF, plasma,
and/or PBMC's
Clinical Effects Endpoint(s):
x Change from baseline in the UHDRS TFC
x Change from baseline in UHDRS total motor score
x Change from baseline in the UHDRS independence scale
x Change from baseline in Symbol Digit Modalities Test
x Change from baseline in Stroop word reading test
x Change from baseline in the composite UHDRS
x Change from baseline in the PBA-s
x Changes from baseline in MRI of the brain
Background summary
This is a Phase 1b/2a multicenter, randomized, double-blind, placebo-controlled
study to evaluate the safety, tolerability, PK, and PD of WVE-003 in adult
patients with early-manifest HD who carry the targeted single nucleotide
polymorphism (SNP) rs362273 (SNP3)
Study objective
Primary objective:
x To evaluate the safety and tolerability of WVE-003 in patients with
Huntington's disease (HD)
Secondary objectives:
x To characterize the pharmacokinetics (PK) of WVE-003 in plasma
x To characterize the concentration of WVE-003 in cerebrospinal fluid (CSF)
Exploratory objectives:
x To evaluate the pharmacodynamic (PD) effect of WVE-003 on the levels of
mutant huntingtin (mHTT) protein in CSF
x To evaluate the effect of WVE-003 on clinical measures of disease including
the Unified Huntington' s Disease Rating Scale (UHDRS) and Short Problem
Behaviors Assessment (PBA-s)
x To evaluate the PD effect of WVE-003 on other measures of PD activity, e.g.,
levels of wild type huntingtin (wtHTT) protein, total huntingtin (tHTT)
protein, and neurofilament light (NfL) in CSF
x To evaluate changes from baseline in magnetic resonance imaging (MRI) of the
brain
Study design
To participate in the study, patients must undergo prescreening to confirm they
are heterozygous for SNP3 with the A variant on the same allele as the
cytosine-adenine-guanine (CAG) triplet expansion. Prescreening can happen any
time before Screening. The prescreening testing process to confirm the presence
of SNP3 is expected to take up to 6 weeks. If patients meet these criteria,
they will continue to the Screening visit. The
prescreening assessment will have a separate informed consent form (ICF).
The study will include 2 distinct periods: Period 1 to evaluate single
ascending dose (SAD) cohorts and Period 2 to evaluate multiple ascending dose
(MAD) cohorts of WVE-003. Period 2 will not be initiated until nonclinical data
supportive of multiple dosing are approved by the local regulatory authorities.
Following this approval, the Sponsor intends to initiate Period 2. Patients may
participate in Period 1 (SAD) and Period 2 (MAD) or Period 2 (MAD) only. All
patients enrolled in Period 1 cohorts will have the opportunity to receive
multiple doses in Period 2.
Cohorts in both Period 1 and Period 2 will be enrolled, randomized, and dosed
in a sequential manner. Subsequent cohorts will not initiate until the
requirements for dose escalation are met (as defined below). This study will
utilize both a Dose Escalation Committee (DEC) and a Safety Monitoring
Committee (SMC). The DEC will be responsible for making recommendations
regarding dose escalation in Period 1, initiation of
multiple dosing in Period 2, and subsequent dose escalation in Period 2.
Decisions made by the DEC will be reviewed by the SMC.
WVE-003 will be administered intrathecally in a volume of 20 mL of artificial
CSF (aCSF).
Period 1: This period will consist of a single dose and a minimum of 12 weeks
of postdose follow-up.
Period 2: This period will consist of up to 12 weeks of treatment and 12 weeks
of follow-up.
Intervention
The currently planned starting dose level in Period 1 is 30 mg. The dose levels
in subsequent Period 1 cohorts and Period 2 will be determined based on the
findings in Period 1 and pending repeat-dose toxicity data from the GLP
studies. The dose levels will not exceed a maximum dose of 168 mg in Period 1
or the HED of the NOAEL from the 13-week GLP study in cynomolgus monkeys in
Period 2, unless addressed by a protocol amendment. In Period 2, doses will be
administered on Weeks 0, 2, and 4, and monthly thereafter (5 total doses).
WVE-003 will be provided as lyophilized powder for reconstitution and dilution
for IT injection. WVE-003 for injection will be prepared by reconstituting and
diluting the lyophilized powder with aCSF supplied by the Sponsor.
Placebo will be aCSF provided by the Sponsor. It will be a sterile,
preservative-free solution. Placebo will be visually identical in appearance to
the WVE-003 injection solution and administered intrathecally in order to
maintain the blind. Placebo will be administered in a volume of 20 mL.
Study burden and risks
Participation in the study requires amongst other the following of the subject:
- Visits: Prescreening, screening visit, period 1 (5 visits, including 1
overnight stay) and period 2 (8 visits)
- Possible side effects or adverse effects of the study drug, as described in
Section E9. WVE-003 has never been used in humans before.
- Experience discomfort from the measurements during the study, as described in
E9, like the lumbar puncture to draw CSF and administer the study drug
- Women should not get pregnant during the study or within 6 months following
the last dose of administration of WVE-003. Males should not conceive a child.
Huntington's disease is a rare, progressive neurological disease. Currently
available treatments for HD only mitigate symptoms and do not affect the
underlying HD pathology, the disease course, or life expectancy after diagnosis
of HD. No approved treatments exist that can cure, slow, or reverse the course
of HD. Based on the results of the nonclinical studies, WVE-003 has promise as
a disease-modifying agent for the treatment of patients with HD.
Chamberlain Square CS 1
Birmingham B3 3AX
GB
Chamberlain Square CS 1
Birmingham B3 3AX
GB
Listed location countries
Age
Inclusion criteria
1. Documented ability to understand the written study ICF(s) and consent, and
has provided signed written informed consent prior to any study procedures.
2. Ambulatory male or female
3. Age >=25 to <=60 years old
4. Body mass index (BMI) <=32 kg/m2
5. Documented CAG triplet repeats >=36 in the HTT gene
6. Documented heterozygosity at SNP3
7. Documented presence of the A variant of SNP3 on the same allele as the
pathogenic CAG triplet expansion
8. Clinical diagnostic motor features of HD, defined as UHDRS Diagnostic
Confidence Score = 4
9. UHDRS Total Functional Capacity (TFC) scores >=9 and <=13
10. In the opinion of the Investigator, the patient is able to tolerate all
study procedures, and is willing to comply with all other protocol requirements.
11. Willingness to practice highly effective contraception for the duration of
the study and for 5 months (i.e., 5 elimination half-lives) 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 completion of the
study.
Exclusion criteria
1. Malignancy or received treatment for malignancy, other than treated basal
cell or squamous cell carcinoma of the skin, within the previous 5 years.
2. Positive for Hepatitis B virus (HBV) or Hepatitis C virus (HCV).
3. Known to be positive for human immunodeficiency virus (HIV).
4. Clinically significant medical finding on the physical examination other
than HD that, in the judgment of the Investigator, will make the patient
unsuitable for participation in and/or completion of the study procedures.
5. Previously received tominersen.
6. Received prior treatment with viral or cellular-based gene therapy.
7. Received any other study drug, including an investigational oligonucleotide,
within the past 1 year or 5 half-lives of the drug, whichever is longer, with
the exception of the following:
a. Received WVE-120101 within the last 3 months (i.e., 5 half-lives); or
b. Received WVE-120102 within the last 3 months (i.e., 5 half-lives)
8. Implantable central nervous system device that may interfere with ability to
administer study drug via lumbar puncture or undergo MRI scan.
9. History of substance abuse disorder (except nicotine) within 6 months prior
to the Screening Visit.
10. Positive for opioids (unprescribed), cocaine, amphetamines, methadone,
barbiturates, methamphetamine, or phencyclidine at the Screening Visit.
11. Started or changed dose for concomitant medication for the treatment of HD
symptoms or psychiatric disorders within 30 days prior to the Screening Visit
(concomitant medications that have been administered on a stable regimen for
>=30 days are permitted).
12. Pregnant (as determined by a serum pregnancy test) or breast feeding at the
Screening Visit, or plans to become pregnant during the course of the study.
13. Clinically significant laboratory abnormality at Screening.
14. Clinically significant abnormality at Screening electrocardiogram (ECG),
including but not necessarily limited to a confirmed QT interval corrected for
heart rate (QTc) >=450 msec for males or >=470 msec for females.
15. Clinically significant cardiovascular, endocrine, hepatic, renal,
pulmonary, gastrointestinal, neurologic, malignant, metabolic, psychiatric, or
other condition that, in the opinion of the Investigator, precludes the
patient*s safe participation in the study or would interfere with the study
assessments. Mental status, psychiatric medical history, and eligibility for
the study must be documented in the screening questionnaire.
16. Bone, spine, bleeding, or other disorder that exposes the patient to risk
of injury or unsuccessful lumbar puncture.
17. Inability to undergo brain MRI (with or without sedation).
18. Deemed to be at significant risk for suicidal behavior based on any of the
following criteria:
a. The opinion of the Investigator; or
b. Answers *yes* to Actual Suicide Attempts or Suicidal Behaviors
in the Suicidal Behaviors section of the Columbia-Suicide Severity Rating
Scale (C-SSRS) with reference to a 2 year period prior to the Screening Visit;
or
c. Answers *yes* on any items in the Suicidal Ideation section of
the C-SSRS with reference to a 6-month period prior to the Screening Visit; or
d. Answers *yes* on any items in the Suicidal Ideation section of
the C-SSRS at the Baseline Visit since the last visit (Screening Visit).
19. Involved directly or indirectly in the conduct and administration of this
study as an Investigator, sub-investigator, study coordinator, or other study
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 study.
20. History of hypersensitivity to other antisense oligonucleotides and any
other drug that, in the opinion of the investigator, may preclude study
participation.
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 | EUCTR2020-004556-15-NL |
| ClinicalTrials.gov | NCT05032196 |
| CCMO | NL79700.000.22 |