A Study to Investigate the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of RO7248824 in Participants With Angelman Syndrome (AS)

NCT ID: NCT04428281

Last Updated: 2025-08-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 74 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-08-19
• Study Completion Date: 2025-07-31

Brief Summary

This is a phase I, multicenter, non-randomized, adaptive, open-label, multiple ascending, intra-participant, dose-escalation study with a long-term extension (LTE) part and an optional open-label extension (OOE) part. The objective of the study is to investigate the safety, tolerability, PK and PD of RO7248824 administered intrathecally (IT) in participants with AS. Two linked sets of dose escalation cohorts are planned based on two different age groups, namely participants with AS aged ≥ 5 to ≤ 12 years in cohorts A1 to A5 (with at least 2 participants ≤ 8 years old in each cohort) and AS participants aged ≥ 1 to ≤ 4 years in cohorts B1 to B5. The two sets of cohorts will be run in parallel, with each cohort A1 to A5 preceding and gating the linked cohort B1 to B5 (e.g., A1 precedes B1).

Conditions

Angelman Syndrome

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cohort A1 RO7248824

Participants 5-12 years

Group Type: EXPERIMENTAL

RO7248824

Intervention Type: DRUG

In the MAD part, RO7248824 will be administered as IT injection of varing dose levels over a period of 8 weeks, with a minimum of approximately 4 weeks between each dose administration. In the LTE part, RO7248824 will be administered as IT injection of varying dose levels over a period of 144 weeks, with a minimum of approximately 16 weeks between each dose administration. In the OOE part, participants will receive RO7248824 as an IT injection with the same dosing regime as the LTE part over a period of up to 48 weeks.

Cohort A2 RO7248824

Participants 5-12 years

Group Type: EXPERIMENTAL

RO7248824

Intervention Type: DRUG

In the MAD part, RO7248824 will be administered as IT injection of varing dose levels over a period of 8 weeks, with a minimum of approximately 4 weeks between each dose administration. In the LTE part, RO7248824 will be administered as IT injection of varying dose levels over a period of 144 weeks, with a minimum of approximately 16 weeks between each dose administration. In the OOE part, participants will receive RO7248824 as an IT injection with the same dosing regime as the LTE part over a period of up to 48 weeks.

Cohort A3 RO7248824

Participants 5-12 years

Group Type: EXPERIMENTAL

RO7248824

Intervention Type: DRUG

In the MAD part, RO7248824 will be administered as IT injection of varing dose levels over a period of 8 weeks, with a minimum of approximately 4 weeks between each dose administration. In the LTE part, RO7248824 will be administered as IT injection of varying dose levels over a period of 144 weeks, with a minimum of approximately 16 weeks between each dose administration. In the OOE part, participants will receive RO7248824 as an IT injection with the same dosing regime as the LTE part over a period of up to 48 weeks.

Cohort A4 RO7248824

Participants 5-12 years

Group Type: EXPERIMENTAL

RO7248824

Intervention Type: DRUG

In the MAD part, RO7248824 will be administered as IT injection of varing dose levels over a period of 8 weeks, with a minimum of approximately 4 weeks between each dose administration. In the LTE part, RO7248824 will be administered as IT injection of varying dose levels over a period of 144 weeks, with a minimum of approximately 16 weeks between each dose administration. In the OOE part, participants will receive RO7248824 as an IT injection with the same dosing regime as the LTE part over a period of up to 48 weeks.

Cohort A5 RO7248824

Participants 5-12 years

Group Type: EXPERIMENTAL

RO7248824

Intervention Type: DRUG

In the MAD part, RO7248824 will be administered as IT injection of varing dose levels over a period of 8 weeks, with a minimum of approximately 4 weeks between each dose administration. In the LTE part, RO7248824 will be administered as IT injection of varying dose levels over a period of 144 weeks, with a minimum of approximately 16 weeks between each dose administration. In the OOE part, participants will receive RO7248824 as an IT injection with the same dosing regime as the LTE part over a period of up to 48 weeks.

Cohort B1 RO7248824

Participants 1-4 years

Group Type: EXPERIMENTAL

RO7248824

Intervention Type: DRUG

In the MAD part, RO7248824 will be administered as IT injection of varing dose levels over a period of 8 weeks, with a minimum of approximately 4 weeks between each dose administration. In the LTE part, RO7248824 will be administered as IT injection of varying dose levels over a period of 144 weeks, with a minimum of approximately 16 weeks between each dose administration. In the OOE part, participants will receive RO7248824 as an IT injection with the same dosing regime as the LTE part over a period of up to 48 weeks.

Cohort B2 RO7248824

Participants 1-4 years

Group Type: EXPERIMENTAL

RO7248824

Intervention Type: DRUG

In the MAD part, RO7248824 will be administered as IT injection of varing dose levels over a period of 8 weeks, with a minimum of approximately 4 weeks between each dose administration. In the LTE part, RO7248824 will be administered as IT injection of varying dose levels over a period of 144 weeks, with a minimum of approximately 16 weeks between each dose administration. In the OOE part, participants will receive RO7248824 as an IT injection with the same dosing regime as the LTE part over a period of up to 48 weeks.

Cohort B3 RO7248824

Participants 1-4 years

Group Type: EXPERIMENTAL

RO7248824

Intervention Type: DRUG

In the MAD part, RO7248824 will be administered as IT injection of varing dose levels over a period of 8 weeks, with a minimum of approximately 4 weeks between each dose administration. In the LTE part, RO7248824 will be administered as IT injection of varying dose levels over a period of 144 weeks, with a minimum of approximately 16 weeks between each dose administration. In the OOE part, participants will receive RO7248824 as an IT injection with the same dosing regime as the LTE part over a period of up to 48 weeks.

Cohort B4 RO7248824

Participants 1-4 years

Group Type: EXPERIMENTAL

RO7248824

Intervention Type: DRUG

In the MAD part, RO7248824 will be administered as IT injection of varing dose levels over a period of 8 weeks, with a minimum of approximately 4 weeks between each dose administration. In the LTE part, RO7248824 will be administered as IT injection of varying dose levels over a period of 144 weeks, with a minimum of approximately 16 weeks between each dose administration. In the OOE part, participants will receive RO7248824 as an IT injection with the same dosing regime as the LTE part over a period of up to 48 weeks.

Cohort B5 RO7248824

Participants 1-4 years

Group Type: EXPERIMENTAL

RO7248824

Intervention Type: DRUG

In the MAD part, RO7248824 will be administered as IT injection of varing dose levels over a period of 8 weeks, with a minimum of approximately 4 weeks between each dose administration. In the LTE part, RO7248824 will be administered as IT injection of varying dose levels over a period of 144 weeks, with a minimum of approximately 16 weeks between each dose administration. In the OOE part, participants will receive RO7248824 as an IT injection with the same dosing regime as the LTE part over a period of up to 48 weeks.

LTE: Cohort EA1 RO7248824

New participants (age 5-12) enrolling directly in the LTE part

Group Type: EXPERIMENTAL

RO7248824

Intervention Type: DRUG

In the MAD part, RO7248824 will be administered as IT injection of varing dose levels over a period of 8 weeks, with a minimum of approximately 4 weeks between each dose administration. In the LTE part, RO7248824 will be administered as IT injection of varying dose levels over a period of 144 weeks, with a minimum of approximately 16 weeks between each dose administration. In the OOE part, participants will receive RO7248824 as an IT injection with the same dosing regime as the LTE part over a period of up to 48 weeks.

LTE: Cohort EA2 RO7248824

Participants continuing from multiple ascending dose (MAD) cohorts A1 and A2

Group Type: EXPERIMENTAL

RO7248824

Intervention Type: DRUG

In the MAD part, RO7248824 will be administered as IT injection of varing dose levels over a period of 8 weeks, with a minimum of approximately 4 weeks between each dose administration. In the LTE part, RO7248824 will be administered as IT injection of varying dose levels over a period of 144 weeks, with a minimum of approximately 16 weeks between each dose administration. In the OOE part, participants will receive RO7248824 as an IT injection with the same dosing regime as the LTE part over a period of up to 48 weeks.

LTE: Cohort EA3 RO7248824

Participants continuing from MAD cohorts A3 and A4

Group Type: EXPERIMENTAL

RO7248824

Intervention Type: DRUG

In the MAD part, RO7248824 will be administered as IT injection of varing dose levels over a period of 8 weeks, with a minimum of approximately 4 weeks between each dose administration. In the LTE part, RO7248824 will be administered as IT injection of varying dose levels over a period of 144 weeks, with a minimum of approximately 16 weeks between each dose administration. In the OOE part, participants will receive RO7248824 as an IT injection with the same dosing regime as the LTE part over a period of up to 48 weeks.

LTE: Cohort EA4 RO7248824

Participants continuing from MAD Cohort A5

Group Type: EXPERIMENTAL

RO7248824

Intervention Type: DRUG

In the MAD part, RO7248824 will be administered as IT injection of varing dose levels over a period of 8 weeks, with a minimum of approximately 4 weeks between each dose administration. In the LTE part, RO7248824 will be administered as IT injection of varying dose levels over a period of 144 weeks, with a minimum of approximately 16 weeks between each dose administration. In the OOE part, participants will receive RO7248824 as an IT injection with the same dosing regime as the LTE part over a period of up to 48 weeks.

LTE: Cohort EB1 RO7248824

New participants (age 1-4) enrolling directly into the LTE

Group Type: EXPERIMENTAL

RO7248824

Intervention Type: DRUG

In the MAD part, RO7248824 will be administered as IT injection of varing dose levels over a period of 8 weeks, with a minimum of approximately 4 weeks between each dose administration. In the LTE part, RO7248824 will be administered as IT injection of varying dose levels over a period of 144 weeks, with a minimum of approximately 16 weeks between each dose administration. In the OOE part, participants will receive RO7248824 as an IT injection with the same dosing regime as the LTE part over a period of up to 48 weeks.

LTE: Cohort EB2 RO7248824

Participants continuing from MAD cohorts B1 and B2

Group Type: EXPERIMENTAL

RO7248824

Intervention Type: DRUG

In the MAD part, RO7248824 will be administered as IT injection of varing dose levels over a period of 8 weeks, with a minimum of approximately 4 weeks between each dose administration. In the LTE part, RO7248824 will be administered as IT injection of varying dose levels over a period of 144 weeks, with a minimum of approximately 16 weeks between each dose administration. In the OOE part, participants will receive RO7248824 as an IT injection with the same dosing regime as the LTE part over a period of up to 48 weeks.

LTE: Cohort EB3 RO7248824

Participants continuing from MAD cohorts B3 and B4

Group Type: EXPERIMENTAL

RO7248824

Intervention Type: DRUG

In the MAD part, RO7248824 will be administered as IT injection of varing dose levels over a period of 8 weeks, with a minimum of approximately 4 weeks between each dose administration. In the LTE part, RO7248824 will be administered as IT injection of varying dose levels over a period of 144 weeks, with a minimum of approximately 16 weeks between each dose administration. In the OOE part, participants will receive RO7248824 as an IT injection with the same dosing regime as the LTE part over a period of up to 48 weeks.

LTE: Cohort EB4 RO7248824

Participants continuing from MAD Cohort B5

Group Type: EXPERIMENTAL

RO7248824

Intervention Type: DRUG

In the MAD part, RO7248824 will be administered as IT injection of varing dose levels over a period of 8 weeks, with a minimum of approximately 4 weeks between each dose administration. In the LTE part, RO7248824 will be administered as IT injection of varying dose levels over a period of 144 weeks, with a minimum of approximately 16 weeks between each dose administration. In the OOE part, participants will receive RO7248824 as an IT injection with the same dosing regime as the LTE part over a period of up to 48 weeks.

OOE: RO7248824

Participants in the LTE part of the study will be given the opportunity to participate in the OOE part.

Group Type: EXPERIMENTAL

RO7248824

Intervention Type: DRUG

In the MAD part, RO7248824 will be administered as IT injection of varing dose levels over a period of 8 weeks, with a minimum of approximately 4 weeks between each dose administration. In the LTE part, RO7248824 will be administered as IT injection of varying dose levels over a period of 144 weeks, with a minimum of approximately 16 weeks between each dose administration. In the OOE part, participants will receive RO7248824 as an IT injection with the same dosing regime as the LTE part over a period of up to 48 weeks.

Interventions

RO7248824

In the MAD part, RO7248824 will be administered as IT injection of varing dose levels over a period of 8 weeks, with a minimum of approximately 4 weeks between each dose administration. In the LTE part, RO7248824 will be administered as IT injection of varying dose levels over a period of 144 weeks, with a minimum of approximately 16 weeks between each dose administration. In the OOE part, participants will receive RO7248824 as an IT injection with the same dosing regime as the LTE part over a period of up to 48 weeks.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• The participant has a parent, caregiver or legal representative (hereinafter "caregiver") who is reliable, competent and at least 18 years of age. The caregiver is willing and able to accompany the participant to clinic visits and to be available to the Investigational Site by phone or email if needed and who (in the opinion of the Investigator) is and will remain sufficiently knowledgeable of participant's ongoing condition to respond to any inquiries about the participant from personnel from the Study Site.
• A caregiver must be able to consent for the participant according to International Council on Harmonisation (ICH) and local regulations.
• Ability to comply with all study requirements.
• Have adequate supportive psychosocial circumstances.
• Able to tolerate blood draws.
• Able to undergo lumbar puncture (LP) and IT injection, under sedation or anesthesia if needed and as determined appropriate by the Investigator.
• Stable medical status for at least 4 weeks prior to Screening and at the time of enrollment.
• Body weight of ≥ 7 kg
• Participant must be ≥ 1 to ≤ 12 years of age at the time of signing of the informed consent by the caregiver.
• Clinical diagnosis of AS confirmed by a molecular diagnosis with genotypic classification of either Ubiquitin-protein ligase E3A (UBE3A) mutation of the maternal allele or deletion on the maternally inherited chromosome 15q11q13 that includes the UBE3A gene and is less than 7 megabyte (Mb) in size.

Reproductive Status:

Some of the provisions that follow may have limited applicability based on the age range of study participants (i.e., up to the age of 12) and the nature of the disease understudy. These provisions are nonetheless included for purposes of completeness in order:

A) Female Participants

A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

• Women of non-childbearing potential.
• Women of childbearing potential who agree to remain abstinent (refrain from heterosexual intercourse) or use acceptable contraceptive methods during the treatment period and for at least 6 months after the final dose of RO7248824 (RG6091). The following are acceptable contraceptive methods: bilateral tubal occlusion/ ligation, male sexual partner who is sterilized, established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and copper intrauterine devices, male or female condom with or without spermicide; and cap, diaphragm, or sponge with spermicide.

B) Male Participants

During the treatment period and for at least 6 months after the final dose of RO7248824 (RG6091), consent has to be provided to:

• Remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures such as a condom, with a female partner of childbearing potential, or pregnant female partner, to avoid exposing the embryo.

The reliability of sexual abstinence for male and/or female enrollment eligibility needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of preventing drug exposure.

• Current or prior participations in the LTE part of Study BP41674.

Exclusion Criteria

Diagnostic Assessments

• Clinically-significant laboratory, vital sign or electrocardiography (ECG) abnormalities at Screening

Type of Participants and Disease Characteristics

• Molecular diagnosis of AS with genotypic classification: Paternal Uniparental Disomy (UPD) of 15q11-13; UBE3A Imprinting center defect (ID); A partial molecular diagnosis of AS, that cannot exclude (UPD)or ID despite appropriate genetic testing.
• Clinically relevant hematological, hepatic, cardiac or renal disease or event, in the judgement of the Investigator.
• Any concomitant condition that might interfere with the clinical evaluation of AS and that is not related to AS.
• Known history of human immunodeficiency virus (HIV) or hepatitis B virus (HBV) or hepatitis C virus (HCV).
• Any condition that increases risk of meningitis.
• History of bleeding diathesis or coagulopathy.
• A medical history of brain or spinal disease that would interfere with the LP process, CSF circulation or safety assessment
• History of clinically significant post-lumbar-puncture headache of moderate or severe intensity and/or blood patch
• Malignancy within 5 years of Screening
• Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned during the study
• Have any other conditions, which, in the opinion of the Investigator, would make the participant unsuitable for inclusion or could interfere with the participant participating in or completing the study, including any contraindication to administration of intrathecal therapy.
• Premature birth with gestational age at birth below 34 weeks.
• History of hypersensitivity to the investigational medicinal product (IMP), antisense oligonucleotides, or any excipients.

Prior Therapy

• Allowed sleep medications have not been stable for 4 weeks prior to screening and at the time of enrollement.
• Allowed medications for treatment of epilepsy have not been stable for 12 weeks prior to screening and at the time of enrollment.
• Use of antiplatelet or anticoagulant therapy for 2 weeks prior to screening and at the time of enrollment.
• Concurrent psychotropic medications have not been stable for 4 weeks prior to screening and at the time of enrollment.

• Received an investigational drug within 90 days or 5 times the half-life of the investigational drug (whichever is longer) or participation in a study testing an investigational medical device within 90 days prior to first dosing or if the device is still active.
• Concurrent or planned concurrent participation in any clinical study (including observational, non-drug and non-interventional studies) without a signed data sharing agreement in place between the other clinical study and the Sponsor.
• Previous participation in a cellular therapy, or gene therapy, or gene editing clinical study.

• Participants who never enrolled in Study BP41674, or who discontinued participation due to safety reasons, are not eligible for the OOE part.

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 12 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

UCLA Neuropsychiatric Institute

Los Angeles, California, United States

Rady Children's Hospital - San Diego

San Diego, California, United States

Rush Medical Center

Chicago, Illinois, United States

Mayo Clinic - Rochester

Rochester, Minnesota, United States

Columbia University Medical Center

New York, New York, United States

Carolina Institute for Development DisabilitiesUniversity of North Carolina/School of Medicine

Carrboro, North Carolina, United States

Baylor College of Med

Houston, Texas, United States

Ospedale Pediatrico Bambino Gesù

Rome, Lazio, Italy

Erasmus MC / location Sophia Kinderziekenhuis

Rotterdam, , Netherlands

Hospital Sant Joan De Deu

Esplugues de Llobregas, Barcelona, Spain

Corporacio Sanitaria Parc Tauli

Sabadell, Barcelona, Spain

Hospital Universitario Virgen del Rocío

Seville, , Spain

Countries

United States; Italy; Netherlands; Spain

References

Hipp JF, Bacino CA, Bird LM, Bruenig-Traebert I, Chan D, de Wit MC, Fontoura P, Hooper G, Jagasia R, Krishnan ML, Murtagh L, Noci A, Martinez AR, Schwab D, Serrano M, Shen MD, Tillmann J, Tjeertes J, Vincenzi B, Berry-Kravis E, Bonni A; Rugonersen Study Group; all TANGELO investigators. The UBE3A-ATS antisense oligonucleotide rugonersen in children with Angelman syndrome: a phase 1 trial. Nat Med. 2025 Sep;31(9):2936-2945. doi: 10.1038/s41591-025-03784-7. Epub 2025 Jul 11.

Reference Type: DERIVED

PMID: 40646322 (View on PubMed)

Other Identifiers

2019-003787-48

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

RG6091

Identifier Type: OTHER

Identifier Source: secondary_id

BP41674

Identifier Type: -

Identifier Source: org_study_id