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

• ClinicalTrials.gov Identifier: NCT05127226
• Recruitment Status: Active, not recruiting
• First Posted: November 19, 2021
• Last Update Posted: March 20, 2024
• Sponsor: Ionis Pharmaceuticals, Inc.
• Collaborator: Biogen
• Information provided by (Responsible Party): Ionis Pharmaceuticals, Inc.

Tracking Information

• First Submitted Date: November 9, 2021
• First Posted Date: November 19, 2021
• Last Update Posted Date: March 20, 2024
• Actual Study Start Date: December 22, 2021
• Estimated Primary Completion Date: March 2029 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 6, 2023)

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). [ Time Frame: Part 1: Up to Week 45; Part 2: Up to Week 81 ]

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.

Original Primary Outcome Measures (submitted: November 9, 2021)

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). [ Time Frame: From Baseline up to 47 weeks ]

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.

Current Secondary Outcome Measures (submitted: January 6, 2023)

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

Original Secondary Outcome Measures (submitted: November 9, 2021)

• Maximum Observed Plasma Concentration (Cmax) of ION582 [ Time Frame: Over weeks 1-47 ]
• Time to Reach Maximal Plasma Concentration (Tmax) of ION582 [ Time Frame: Over weeks 1-47 ]
• Plasma Elimination Half-Life (t1/2λz) of ION582 [ Time Frame: Over weeks 1-47 ]
• Concentration ION582 in CSF [ Time Frame: Over weeks 1-13 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: HALOS: A Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of Multiple Ascending Doses of ION582 in Participants With Angelman Syndrome
• Official Title: HALOS: A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered ION582 in Patients With Angelman Syndrome
• 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 3 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 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. The study will enroll approximately 44, and up to 55, participants.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Angelman Syndrome

Intervention

Drug: ION582

ION582 will be administered by IT injection.

Study Arms

• 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.
  Intervention: Drug: ION582
• 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.
  Intervention: Drug: ION582
• 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.
  Intervention: Drug: ION582
• 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.
  Intervention: Drug: ION582
• 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.
  Intervention: Drug: ION582
• Experimental: Part 2 Group 1
  ION582 will be administered as IT injection of over a period of 49 weeks, with additional dosing intervals.
  Intervention: Drug: ION582
• Experimental: Part 2 Group 2
  ION582 will be administered as IT injection of over a period of 49 weeks, with additional dosing intervals.
  Intervention: Drug: ION582
• Experimental: Part 3 Group 1
  ION582 will be administered as IT injection of over a period of 145 weeks, with additional dosing intervals.
  Intervention: Drug: ION582
• Experimental: Part 3 Group 2
  ION582 will be administered as IT injection of over a period of 145 weeks, with additional dosing intervals.
  Intervention: Drug: ION582

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: December 7, 2023): 51
• Original Estimated Enrollment (submitted: November 9, 2021): 44
• Estimated Study Completion Date: March 2029
• Estimated Primary Completion Date: March 2029 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 2-50 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.

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Years to 50 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, France, Israel, Italy, United Kingdom, United States

Administrative Information

• NCT Number: NCT05127226
• Other Study ID Numbers: ION582-CS1; 2021-003009-23 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Ionis Pharmaceuticals, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Ionis Pharmaceuticals, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Biogen
• Investigators: Not Provided
• PRS Account: Ionis Pharmaceuticals, Inc.
• Verification Date: March 2024