HALOS: A Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of Multiple Ascending Doses of ION582 in Participants With Angelman Syndrome

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety and tolerability of ascending doses of ION582 administered intrathecally in participants with Angelman syndrome.

Detailed Description
-----------------
This is a Phase 1-2a, open-label study consisting of 2 parts. Part 1 is a multiple ascending dose (MAD) study, consisting of a 13-week MAD Treatment Period and a minimum 12-week but up to 32-week Post-MAD Follow-Up Period. Part 2 is the Long-Term Extension (LTE) Period including a 49-week LTE Treatment Period, where participants who completed Part 1 will receive IT bolus doses of ION582 and a 32-week Post-LTE Follow-Up Period. The study will enroll approximately 44, and up to 55 participants.

Official Title
-----------------
HALOS: A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered ION582 in Patients With Angelman Syndrome

Conditions
-----------------
Angelman Syndrome

Intervention / Treatment
-----------------
* Drug: ION582


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participant has a documented and certified diagnosis of Angelman syndrome (AS) (ubiquitin-protein ligase E3A [UBE3A] deletion or UBE3A mutation) Male or female between the ages of 2-50 years of age, with signed informed consent from parent(s) or legal guardian(s) Currently receiving stable standard of care treatments such as, stable doses of anti-epileptic medication, behavioral management medications, sleep medications, gabapentin, cannabidiol, and including special diets, supplements or nutritional support for at least 3 months prior to first dose. Follow good study practice and not participate in the sharing of personal or study information on social media platforms, such as any website or social media site (e.g., Facebook, Instagram, Twitter, YouTube, etc.) until notified that the study is completed. Exclusion Criteria: Has documented molecular AS confirmation of paternal uniparental disomy (UPD) or imprinting defect (ID). Any clinically significant (CS) cardiovascular, endocrine, hepatic, renal, pulmonary, gastrointestinal, neurologic, malignant, metabolic, psychiatric, or other condition that, in the judgment of the Investigator, will pose a safety risk, will make the patient unsuitable for participation in, and/or unable to complete the study procedures. Has poorly controlled seizures as determined by the Investigator or has documented Status Epilepticus in the past 6 months that could pose a safety risk while on study. Known bone, spine, bleeding, or other disorder that exposes the patient to risk of injury or unsuccessful lumbar puncture. Previous treatment with an oligonucleotide (including small interfering ribonucleic acid, antisense oligonucleotide [ASOs]). COVID-19 vaccinations are allowed. Any prior use of gene therapy. Have any other conditions, which, in the opinion of the Investigator would make the participant unsuitable for inclusion or could interfere with the participant taking part in or completing the study.

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 MAD: Cohort A<br>ION582 will be administered as IT injection over a period of 13 weeks, with a minimum of approximately 4 weeks between each dose administration. | Drug: ION582<br>* ION582 will be administered by IT injection.<br>|
| Experimental: Part 1 MAD: Cohort B<br>ION582 will be administered as IT injection over a period of 13 weeks, with a minimum of approximately 4 weeks between each dose administration. | Drug: ION582<br>* ION582 will be administered by IT injection.<br>|
| Experimental: Part 1 MAD: Cohort C<br>ION582 will be administered as IT injection over a period of 13 weeks, with a minimum of approximately 4 weeks between each dose administration. | Drug: ION582<br>* ION582 will be administered by IT injection.<br>|
| Experimental: Part 1 MAD: Cohort D<br>ION582 will be administered as IT injection over a period of 13 weeks, with a minimum of approximately 4 weeks between each dose administration. | Drug: ION582<br>* ION582 will be administered by IT injection.<br>|
| Experimental: Part 1 MAD: Cohort E<br>ION582 will be administered as IT injection of over a period of 13 weeks, with a minimum of approximately 4 weeks between each dose administration. | Drug: ION582<br>* ION582 will be administered by IT injection.<br>|
| Experimental: Part 2 LTE: Group 1<br>ION582 will be administered as IT injection of over a period of 49 weeks, with additional dosing intervals. | Drug: ION582<br>* ION582 will be administered by IT injection.<br>|
| Experimental: Part 2 LTE: Group 2<br>ION582 will be administered as IT injection of over a period of 49 weeks, with additional dosing intervals. | Drug: ION582<br>* ION582 will be administered by IT injection.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the safety and tolerability of single and multiple doses of ION582 (incidence, severity, and dose-relationship of adverse effects and changes in the laboratory parameters). | The safety and tolerability of ION582 will be assessed by determining the incidence, severity, and dose relationship of adverse effects and changes in the laboratory parameters by dose. | Part 1: Up to Week 45; Part 2: Up to Week 81 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of ION582 |  | Part 1: Up to Week 45; Part 2: Up to Week 81 | 
| Time to Reach Maximal Plasma Concentration (Tmax) of ION582 |  | Part 1: Up to Week 45; Part 2: Up to Week 81 | 
| Plasma Elimination Half-Life (t1/2λz) of ION582 |  | Part 1: Up to Week 45; Part 2: Up to Week 81 | 
| Concentration ION582 in CSF |  | Part 1: Up to Week 13; Part 2: Up to Week 49 |