Alpha-1 Antitrypsin Deficiency (AATD)
Conditions
Brief summary
This study is the first study in the RestorAATion clinical program. The purpose of this first-in human (FIH), double-blind, randomized, placebo-controlled, single ascending dose (SAD) and multiple-dose Phase 1 study is to assess the safety, tolerability, and pharmacokinetics (PK) of WVE-006 compared to placebo in healthy participants following a single dose (Period 1) and multiple doses (Period 2) of WVE-006. This information will be used to determine doses and regimes that have the potential to be pharmacologically active in patients with Alpha-1 antitrypsin deficiency in the RestorAATion 2 study, and the maximum safe and tolerable dose that may be given to these patients.
Interventions
DRUGWVE-006
RNA editing oligonucleotide
Sponsors
Wave Life Sciences Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy as determined by the Investigator, based on a medical evaluation. * Genetic testing confirming PI\*MM. * Participant has been a non-smoker for at least 1 year prior to screening.
Exclusion criteria
* Participant has a history of multiple drug allergies or of allergic reaction to an oligonucleotide or to N-acetylgalactosamine (GalNAc). * Participant has a history of intolerance or any medical condition that might interfere with subcutaneous injections. * Any ongoing or recent infections. * Any recent or planned vaccinations during the study. * Participant has a history of regular alcohol consumption exceeding 14 standard drinks/week. * Unwilling to abstain from alcohol for 48 hours prior to dosing at each of the dosing visits. * Participant has a history of caffeine consumption exceeding 8 cups of coffee/day. * Use of prescription or non-prescription medications, including vitamin, dietary, and herbal supplements (including St John's Wort) within 7 days prior to the first dose of study treatment unless, in the opinion of the Investigator and Sponsor, the medication will not interfere with interpretation of study assessments. Contraception and hormone replacement therapy (HRT) are permitted. If needed, over-the-counter (OTC) medications such as paracetamol/acetaminophen may be used acutely. * Any recent or planned major surgery during the study. * Donation of blood or blood products in excess of 500 mL within 12 weeks prior to Screening Visit and/or unwilling to refrain from blood donation for the duration of the study. * Participant has received an investigational agent within 3 months of the Screening Visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of Participants With Adverse Events | Adverse events are collected from the date of consent until up to 85 days after the dose in Period 1 and up to 113 days after the first dose in Period 2. | The number of participants who reported an adverse event (AE) will be summarised. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Single Ascending Dose (Period 1) - Area Under the Plasma Concentration Time Curve for WVE-006 From Time of Dosing to the Last Measurable Concentration (AUClast) | Samples collected at the following timepoints: Day 1 pre-dose, 30 mins, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr & 12 hr post-Day 1 dose, Day 2: 24 hr & 36 hr post-Day 1 dose, Day 3: 48 hr post-Day 1 dose, Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78 & 85. | Plasma samples were obtained in order to evaluate defined plasma pharmacokinetic parameters for WVE-006. This endpoint will report the summary of derived pharmacokinetic parameters for the Area under the plasma concentration time curve for WVE-006 from time of dosing to the last measurable concentration (AUClast) of WVE-006 in plasma for participants in Period 1 of the study. |
| Single Ascending Dose - Maximum Concentration of WVE-006 in Plasma (Cmax) | Samples collected at the following timepoints: Day 1 pre-dose, 30 mins, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr & 12 hr post-Day 1 dose, Day 2: 24 hr & 36 hr post-Day 1 dose, Day 3: 48 hr post-Day 1 dose, Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78 & 85. | Plasma samples were obtained in order to evaluate defined plasma pharmacokinetic parameters for WVE-006. This endpoint will report the summary of derived pharmacokinetic parameters for the Maximum concentration of WVE-006 in plasma (Cmax) of WVE-006 in plasma for participants in Period 1 of the study. |
| Multiple Ascending Doses - Area Under the Plasma Concentration Time Curve for WVE-006 From Time of Dosing to the Last Measurable Concentration (AUClast) - Day 1 | Samples collected at the following timepoints for Day 1 measurement: Day 1 pre-dose, 30 mins, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 hr & 24 hr post-dose. | Plasma samples were obtained in order to evaluate defined plasma pharmacokinetic parameters for WVE-006. This endpoint will report the summary of derived pharmacokinetic parameters for the Area under the plasma concentration time curve for WVE-006 from time of dosing to the last measurable concentration (AUClast) of WVE-006 in plasma for participants in Period 2 of the study. |
| Multiple Ascending Doses - Maximum Concentration of WVE-006 in Plasma (Cmax) - Day 1 | Samples collected at the following timepoints for Day 1 measurement: Day 1 pre-dose, 30 mins, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 hr & 24 hr post-dose. | Plasma samples were obtained in order to evaluate defined plasma pharmacokinetic parameters for WVE-006. This endpoint will report the summary of derived pharmacokinetic parameters for the Maximum concentration of WVE-006 in plasma (Cmax) of WVE-006 in plasma for participants in Period 2 of the study. |
| Multiple Ascending Doses - Area Under the Plasma Concentration Time Curve for WVE-006 From Time of Dosing to the Last Measurable Concentration (AUClast) - Day 29 | Samples collected at the following timepoints for Day 29 measurement: Day 29 pre-dose, 30 mins, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 hr & 24 hr post-dose. | Plasma samples were obtained in order to evaluate defined plasma pharmacokinetic parameters for WVE-006. This endpoint will report the summary of derived pharmacokinetic parameters for the Area under the plasma concentration time curve for WVE-006 from time of dosing to the last measurable concentration (AUClast) of WVE-006 in plasma for participants in Period 2 of the study. |
| Multiple Ascending Doses - Maximum Concentration of WVE-006 in Plasma (Cmax) - Day 29 | Samples collected at the following timepoints for Day 29 measurement: Day 29 pre-dose, 30 mins, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 hr & 24 hr post-dose. | Plasma samples were obtained in order to evaluate defined plasma pharmacokinetic parameters for WVE-006. This endpoint will report the summary of derived pharmacokinetic parameters for the Maximum concentration of WVE-006 in plasma (Cmax) of WVE-006 in plasma for participants in Period 2 of the study. |
Countries
United Kingdom
Contacts
STUDY_DIRECTORCynthia Caracta, MD
Wave Life Sciences
Participant flow
Recruitment details
Study recruitment was undertaken at one site in the United Kingdom. The recruitment process began in November 2023 and concluded in October 2024. A sufficient number of volunteers were screened in order to successfully recruit 46 completing participants (with one participant withdrawal).
Pre-assignment details
Participants were screened to the inclusion/exclusion of the protocol. The following assessments were performed: Consent, Demographics, Medical History, Prior/Concomitant Medications, AAT Testing, Pregnancy/FSH, Vital signs, Physical examination, Laboratory Safety Testing, ECG, Urine Drugs of Abuse Testing . The study included 2 distinct periods: Period 1 (SAD) and Period 2 (multiple dose). A total of 39 participants were randomised to Period 1 and 8 participants were randomised to Period 2.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Age, Continuous | 34.0 Years STANDARD_DEVIATION 8.7 |
| Body Mass Index | 25.496 Kilograms per metre 2 STANDARD_DEVIATION 1.853 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 46 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Height | 1.740 Metres STANDARD_DEVIATION 0.103 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Region of Enrollment United Kingdom | 47 participants |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 6 Participants |
| Weight | 78.17 Kilograms STANDARD_DEVIATION 12.54 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 6 | 0 / 5 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 2 |
| other Total, other adverse events | 8 / 10 | 5 / 6 | 4 / 5 | 3 / 6 | 3 / 6 | 3 / 6 | 2 / 6 | 1 / 2 |
| serious Total, serious adverse events | 0 / 10 | 0 / 6 | 0 / 5 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 2 |
Outcome results
None listed