A Study To Investigate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of RO7248824 In Participants With Angelman Syndrome

Study Overview
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Brief Summary
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This is a Phase I, multicenter, non-randomized, adaptive, open label, multiple ascending, intra-participant, dose-escalation study with an LTE part. The objective of the study is to investigate the safety, tolerability, PK and PD of RO7248824 in participants administered IT 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 A4 (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-A4 preceding and gating the linked cohort B1-B5 (e.g., A1 precedes B1).

Official Title
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An Open-Label, Multicenter Study To Investigate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of RO7248824 In Participants With Angelman Syndrome

Conditions
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Angelman Syndrome

Intervention / Treatment
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* Drug: RO7248824


Participation Criteria
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Eligibility Criteria
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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 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 UBE3A mutation of the maternal allele or deletion on the maternally inherited chromosome 15q11q13 that includes the UBE3A gene and is less than 7 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: 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. 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. 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: UBE3A missense mutation of maternal allele 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. Medical history and concurrent disease Clinically relevant hematological, hepatic, cardiac or renal disease or event, in the judgement of the investigator. Pre-existing abnormal hepatic, renal or hematology lab tests must be discussed with the Sponsor Medical Monitor. 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, cerebrospinal fluid (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. Other Exclusion Criteria: Prior/Concurrent Clinical Study Experience 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.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Non-randomized, adaptive, open label, multiple ascending, intra-participant, dose-escalation study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A1 RO7248824<br>Participants 5-12 Years | Drug: RO7248824<br>* In the Multiple Ascending Dose 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 Long Term Extension part RO7248824 will be administered up to 10 doses as IT injection of selected dose levels with a minimum of approximately 16 weeks between each dose administration.<br>|
| Experimental: Cohort A2 RO7248824<br>Participants 5-12 Years | Drug: RO7248824<br>* In the Multiple Ascending Dose 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 Long Term Extension part RO7248824 will be administered up to 10 doses as IT injection of selected dose levels with a minimum of approximately 16 weeks between each dose administration.<br>|
| Experimental: Cohort A3 RO7248824<br>Participants 5-12 Years | Drug: RO7248824<br>* In the Multiple Ascending Dose 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 Long Term Extension part RO7248824 will be administered up to 10 doses as IT injection of selected dose levels with a minimum of approximately 16 weeks between each dose administration.<br>|
| Experimental: Cohort A4 RO7248824<br>Participants 5-12 Years | Drug: RO7248824<br>* In the Multiple Ascending Dose 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 Long Term Extension part RO7248824 will be administered up to 10 doses as IT injection of selected dose levels with a minimum of approximately 16 weeks between each dose administration.<br>|
| Experimental: Cohort A5 RO7248824<br>Participants 5-12 Years | Drug: RO7248824<br>* In the Multiple Ascending Dose 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 Long Term Extension part RO7248824 will be administered up to 10 doses as IT injection of selected dose levels with a minimum of approximately 16 weeks between each dose administration.<br>|
| Experimental: Cohort B1 RO7248824<br>Participants 1-4 Years | Drug: RO7248824<br>* In the Multiple Ascending Dose 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 Long Term Extension part RO7248824 will be administered up to 10 doses as IT injection of selected dose levels with a minimum of approximately 16 weeks between each dose administration.<br>|
| Experimental: Cohort B2 RO7248824<br>Participants 1-4 Years | Drug: RO7248824<br>* In the Multiple Ascending Dose 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 Long Term Extension part RO7248824 will be administered up to 10 doses as IT injection of selected dose levels with a minimum of approximately 16 weeks between each dose administration.<br>|
| Experimental: Cohort B3 RO7248824<br>Participants 1-4 Years | Drug: RO7248824<br>* In the Multiple Ascending Dose 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 Long Term Extension part RO7248824 will be administered up to 10 doses as IT injection of selected dose levels with a minimum of approximately 16 weeks between each dose administration.<br>|
| Experimental: Cohort B4 RO7248824<br>Participants 1-4 Years | Drug: RO7248824<br>* In the Multiple Ascending Dose 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 Long Term Extension part RO7248824 will be administered up to 10 doses as IT injection of selected dose levels with a minimum of approximately 16 weeks between each dose administration.<br>|
| Experimental: Cohort B5 RO7248824<br>Participants 1-4 Years | Drug: RO7248824<br>* In the Multiple Ascending Dose 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 Long Term Extension part RO7248824 will be administered up to 10 doses as IT injection of selected dose levels with a minimum of approximately 16 weeks between each dose administration.<br>|
| Experimental: Cohort EA1 RO7248824<br>New participants (age 5-12) enrolling directly in the LTE part | Drug: RO7248824<br>* In the Multiple Ascending Dose 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 Long Term Extension part RO7248824 will be administered up to 10 doses as IT injection of selected dose levels with a minimum of approximately 16 weeks between each dose administration.<br>|
| Experimental: Cohort EA2 RO7248824<br>Participants continuing from MAD cohorts A1 and A2 | Drug: RO7248824<br>* In the Multiple Ascending Dose 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 Long Term Extension part RO7248824 will be administered up to 10 doses as IT injection of selected dose levels with a minimum of approximately 16 weeks between each dose administration.<br>|
| Experimental: Cohort EA3 RO7248824<br>Participants continuing from MAD cohorts A3 and A4 | Drug: RO7248824<br>* In the Multiple Ascending Dose 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 Long Term Extension part RO7248824 will be administered up to 10 doses as IT injection of selected dose levels with a minimum of approximately 16 weeks between each dose administration.<br>|
| Experimental: Cohort EA4 RO7248824<br>Participants continuing from MAD Cohort A5 | Drug: RO7248824<br>* In the Multiple Ascending Dose 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 Long Term Extension part RO7248824 will be administered up to 10 doses as IT injection of selected dose levels with a minimum of approximately 16 weeks between each dose administration.<br>|
| Experimental: Cohort EB1 RO7248824<br>New participants (age 1-4) enrolling directly into the LTE | Drug: RO7248824<br>* In the Multiple Ascending Dose 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 Long Term Extension part RO7248824 will be administered up to 10 doses as IT injection of selected dose levels with a minimum of approximately 16 weeks between each dose administration.<br>|
| Experimental: Cohort EB2 RO7248824<br>Participants continuing from MAD cohorts B1 and B2 | Drug: RO7248824<br>* In the Multiple Ascending Dose 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 Long Term Extension part RO7248824 will be administered up to 10 doses as IT injection of selected dose levels with a minimum of approximately 16 weeks between each dose administration.<br>|
| Experimental: Cohort EB3 RO7248824<br>Participants continuing from MAD cohorts B3 and B4 | Drug: RO7248824<br>* In the Multiple Ascending Dose 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 Long Term Extension part RO7248824 will be administered up to 10 doses as IT injection of selected dose levels with a minimum of approximately 16 weeks between each dose administration.<br>|
| Experimental: Cohort EB4 RO7248824<br>Participants continuing from MAD Cohort B5 | Drug: RO7248824<br>* In the Multiple Ascending Dose 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 Long Term Extension part RO7248824 will be administered up to 10 doses as IT injection of selected dose levels with a minimum of approximately 16 weeks between each dose administration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency And Severity Of Adverse Events | MAD part: From the baseline MAD visit to the final MAD visit (D365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (D1092) or early withdrawal. | Baseline to last visit or early withdrawal | 
| Frequency And Severity Of Serious Adverse Events | MAD part: From the baseline MAD visit to the final MAD visit (D365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (D1092) or early withdrawal. | Baseline to last visit or early withdrawal | 
| Number of Participants Discontinued Treatment due to Adverse Events | MAD part: From the baseline MAD visit to the final MAD visit (D365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (D1092) or early withdrawal. | Baseline to last visit or early withdrawal | 
| Frequency Of Abnormal Laboratory Findings (Blood And Cerebrospinal Fluid [CSF]) | MAD part: From the baseline MAD visit to the final MAD visit (D365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (D1092) or early withdrawal. | Baseline to last visit or early withdrawal | 
| Frequency Of Abnormal Vital Signs | MAD part: From the baseline MAD visit to the final MAD visit (D365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (D1092) or early withdrawal. | Baseline to last visit or early withdrawal | 
| Frequency Of Abnormal ECG Values | MAD part: From the baseline MAD visit to the final MAD visit (D365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (D1092) or early withdrawal. | Baseline to last visit or early withdrawal | 
| Mean Changes From Baseline in Temperature Over Time | MAD part: From the baseline MAD visit to the final MAD visit (D365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (D1092) or early withdrawal. | Baseline to last visit or early withdrawal | 
| Mean Changes From Baseline in Systolic Blood Pressure Over Time | MAD part: From the baseline MAD visit to the final MAD visit (D365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (D1092) or early withdrawal. | Baseline to last visit or early withdrawal | 
| Mean Changes From Baseline In Diastolic Blood Pressure Over Time | MAD part: From the baseline MAD visit to the final MAD visit (D365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (D1092) or early withdrawal. | Baseline to last visit or early withdrawal | 
| Mean Changes From Baseline In Heartrate Over Time | MAD part: From the baseline MAD visit to the final MAD visit (D365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (D1092) or early withdrawal. | Baseline to last visit or early withdrawal | 
| Mean Changes From Baseline In Respiratory Rate Over Time | MAD part: From the baseline MAD visit to the final MAD visit (D365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (D1092) or early withdrawal. | Baseline to last visit or early withdrawal | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Maximum Concentration (Tmax) for RO7248824 | MAD part: From the baseline MAD visit to the final MAD visit (D365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (D1092) or early withdrawal. | Baseline to last visit or early withdrawal | 
| Maximum Plasma Concentration Observed (Cmax) for RO7248824 | MAD part: From the baseline MAD visit to the final MAD visit (D365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (D1092) or early withdrawal. | Baseline to last visit or early withdrawal | 
| AUC From Time 0 To Time Of Last Sampling Point Or Last Quantifiable Sample, Whichever Comes First (AUC last) for RO7248824 | MAD part: From the baseline MAD visit to the final MAD visit (D365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (D1092) or early withdrawal. | Baseline to last visit or early withdrawal | 
| AUC From Time 0 To Infinity (AUCinf) for RO7248824 | MAD part: From the baseline MAD visit to the final MAD visit (D365) or early withdrawal. LTE part: From the baseline LTE visit to final LTE visit (D1092) or early withdrawal. | Baseline to last visit or early withdrawal | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RO7248824; Angelman; ASO; LNA; Angelman syndrome