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.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Angelman Syndrome	Drug: ION582	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 51 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: HALOS: A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered ION582 in Patients With Angelman Syndrome
• Actual Study Start Date: December 22, 2021
• Estimated Primary Completion Date: March 2029
• Estimated Study Completion Date: March 2029

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

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

Eligibility Criteria

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

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.

Contacts and Locations

Locations

United States, California

Rady Children's Hospital

San Diego, California, United States, 92123

United States, Colorado

Colorado Children's Hospital Research Institute

Aurora, Colorado, United States, 80045

United States, Illinois

Rush University Medical Center

Chicago, Illinois, United States, 60612

United States, Massachusetts

Boston Children's Hospital

Boston, Massachusetts, United States, 02215

United States, North Carolina

University of North Carolina at Chapel Hill School of Medicine

Carrboro, North Carolina, United States, 27510

United States, Texas

Texas Children's Hospital

Houston, Texas, United States, 77030

Australia

Sydney Children's Hospital, Kids Cancer Centre

Randwick, Australia, NSW 2031

France

Necker-Enfants Malades Hospital

Paris, France, 75015

Israel

Sheba Medical Center

Ramat Gan, Israel, 5262100

Italy

Azienda Ospedaliera Universitaria Pisana

Pisa, Italy, 56126

United Kingdom

STRONG Group University of Oxford

Oxford, Oxfordshire, United Kingdom, OX3 9DU

Sponsors and Collaborators

Ionis Pharmaceuticals, Inc.

Biogen

More Information

• Responsible Party: Ionis Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT05127226
• Other Study ID Numbers: ION582-CS1; 2021-003009-23 ( EudraCT Number )
• First Posted: November 19, 2021
• Last Update Posted: March 20, 2024
• Last Verified: March 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Additional relevant MeSH terms:

Angelman Syndrome; Syndrome; Disease; Pathologic Processes; Movement Disorders; Central Nervous System Diseases; Nervous System Diseases; Abnormalities, Multiple; Congenital Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn; Imprinting Disorders