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

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

The purpose of this study is to evaluate the safety and tolerability of ascending doses of ION582 administered intrathecally in participants with Angelman syndrome.

Study Overview

• Status: Active, not recruiting
• Conditions: Angelman Syndrome
• Intervention / Treatment: Drug: ION582

Detailed Description

This is a Phase 1-2a, open-label study consisting of 3 parts in approximately 70 participants. Part 1 is a multiple ascending dose (MAD) study, consisting of a 13-week MAD Treatment Period and a minimum 12-week Post-MAD Follow-Up Period. Part 2 is a multi-center 49-week study where participants who completed Part 1 will receive IT bolus doses of ION582 followed by a minimum 12-week Part 2 follow up period. Part 3 extends the treatment period for participants who completed Part 2 for up to an additional 3 years followed by a 32-week post-LTE follow up period.

• Study Type: Interventional
• Enrollment (Actual): 71
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • Randwick, Australia, NSW 2031
    • Sydney Children's Hospital, Kids Cancer Centre
• France
  • Paris, France, 75015
    • Necker-Enfants Malades Hospital
• Israel
  • Ramat Gan, Israel, 5262100
    • Sheba medical center
• Italy
  • Pisa, Italy, 56126
    • Azienda Ospedaliera Universitaria Pisana
• United Kingdom
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX3 9DU
      • STRONG Group University of Oxford
• United States
  • California
    • San Diego, California, United States, 92123
      • Rady Children's Hospital
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Colorado Children's Hospital Research Institute
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Boston Children's Hospital
  • North Carolina
    • Carrboro, North Carolina, United States, 27510
      • University of North Carolina at Chapel Hill School of Medicine
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 50 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Participant has a documented and certified diagnosis of Angelman syndrome (AS) (ubiquitin-protein ligase E3A [UBE3A] deletion or UBE3A mutation)
2. Male or female between the ages of 0-50 years of age, with signed informed consent from parent(s) or legal guardian(s)
3. 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.
4. 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.

Key Exclusion Criteria:

1. Has documented molecular AS confirmation of paternal uniparental disomy (UPD) or imprinting defect (ID).
2. 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.
3. 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.
4. 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1 MAD: Cohort A; 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; ION582 will be administered by IT injection.
Experimental: Part 1 MAD: Cohort B; 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; ION582 will be administered by IT injection.
Experimental: Part 1 MAD: Cohort C; 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; ION582 will be administered by IT injection.
Experimental: Part 1 MAD: Cohort D; 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; ION582 will be administered by IT injection.
Experimental: Part 1 MAD: Cohort E; 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; ION582 will be administered by IT injection.
Experimental: Part 2 Group 1; ION582 will be administered as IT injection of over a period of 49 weeks, with additional dosing intervals.	Drug: ION582; ION582 will be administered by IT injection.
Experimental: Part 2 Group 2; ION582 will be administered as IT injection of over a period of 49 weeks, with additional dosing intervals.	Drug: ION582; ION582 will be administered by IT injection.
Experimental: Part 3 Group 1; ION582 will be administered as IT injection of over a period of 145 weeks, with additional dosing intervals.	Drug: ION582; ION582 will be administered by IT injection.
Experimental: Part 3 Group 2; ION582 will be administered as IT injection of over a period of 145 weeks, with additional dosing intervals.	Drug: ION582; ION582 will be administered by IT injection.
Experimental: Part 1 MAD: Cohort F; ION582 will be administered as IT injection over a period of 13 weeks, with a minimum of approximately 12 weeks between each dose administration.	Drug: ION582; ION582 will be administered by IT injection.

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	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

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.
• Collaborators: Biogen

Study record dates

Study Major Dates

• Study Start (Actual): December 22, 2021
• Primary Completion (Estimated): March 1, 2029
• Study Completion (Estimated): March 1, 2029

Study Registration Dates

• First Submitted: November 9, 2021
• First Submitted That Met QC Criteria: November 9, 2021
• First Posted (Actual): November 19, 2021

Study Record Updates

• Last Update Posted (Actual): August 20, 2026
• Last Update Submitted That Met QC Criteria: August 19, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Imprinting Disorders; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Congenital Abnormalities; Movement Disorders; Abnormalities, Multiple; Chromosome Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Angelman Syndrome
• Other Study ID Numbers: ION582-CS1; 2021-003009-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Ionis may share anonymized individual participant data, aggregated clinical data, and other types of data that support the results in this study. Data requests from qualified researchers will be considered once all three of the following criteria are met: (1) 12 months from marketing approval of the study drug in both the United States and European Union; (2) 18 months from conclusion of the study; and (3) 6 months from publication of study article. Access would be via a secure environment and is contingent upon approval of a research proposal and entry into an appropriate data use agreement. Requests to access data can be submitted via the website https://vivli.org/ourmember/ionis/.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No