ION440 for MECP2 duplication syndrome (MDS)

Inclusion criteria

• {"criterion_text":"- Part 1: Males aged ≥ 2 to ≤ 65 years, depending on specific cohort and group, at the time of informed consent. − Group A: ≥ 8 to ≤ 65 years − Group B: 2 to 7 years, inclusive\n- Part 1: Participant has at least one parent or caregiver ≥ 18 years of age capable of providing informed consent (signed and dated) and able to attend all scheduled study visits and provide feedback regarding the participant’s symptoms and performance as described in the protocol, and able to comply with all study requirements and activities\n- Part 1: Participant has a documented diagnosis of MDS, with genetic confirmation of MECP2 duplication.\n- Part 1: Able to complete all study procedures, measurements and visits to support primary and secondary endpoints, and the caregiver/participant has adequately supportive psychosocial circumstances, in the opinion of the Investigator.\n- Part 1: Is currently receiving stable doses of concomitant medications for at least 1 month prior to Screening.\n- Part 2: Participants in ION440-CS1 Part 1/MAD who received at least one dose of Study Drug/Sham in Part 1/MAD, missed no more than 1 study visit, and attended the Followup visit (Visit 6).\n- Part 2: All inclusion criteria in Part 1/MAD apply (participants will not be required to undergo Screening blood collections additional to those scheduled on Part 1/MAD Visit 6 [Day 253])."}

Exclusion criteria

• {"criterion_text":"- Part 1: Confirmed (by repeat measurement) clinically significant vital sign or ECG abnormality at Screening including: a. Heart rate (HR) < 45 beats per minute b. QTcF > 450 milliseconds c. Blood pressure exceeding the 95th percentile for age, sex, and height plus 12 mmHg, or blood pressure meeting hypertension diagnostic criteria for children per European Society of Hypertension (ESH) guidelines for children and adolescents, or blood pressure > 140/90 mmHg d. Blood pressure below the 5th percentile for age, sex, and height per ESH guidelines for children and adolescents.\n- Part 2: Has developed any concomitant disease (e.g., gastrointestinal, renal, hepatic, endocrine, respiratory, or cardiovascular system disease) or condition or circumstance, or any finding during Part 1/MAD that, in the opinion of the Investigator, makes the participant unsuitable for continued treatment (e.g. could interfere with the conduct of the study or that would pose an unacceptable risk to the participant in this study).\n- Part 1: Documented diagnosis of severe MECP2 duplication including terminal duplication and/or translocation or MECP2 triplication OR clinical features associated with severe variant structure including (a) onset of seizures prior to aged 5 years (for those 5 years and above at signing of ICF), (b) oxygen dependence, and (c) microcephaly, IF MECP2 genetic structure information is unavailable.\n- Part 1: Known brain or spinal disease that would interfere with the LP procedure, or CSF circulation or presence of other factors would affect the safety of the LP procedure.\n- Part 1: Has any concomitant disease or condition or circumstance, or any finding at Screening that, in the opinion of the Investigator, makes the participant unsuitable for enrollment or that could interfere with the conduct of the study or that would pose an unacceptable risk to the participant in this study\n- Part 1: Treatment with an investigational drug, biological agent, or device within 30 days of Screening, or 5 half-lives of investigational agent, whichever is longer.\n- Part 1: Previous treatment with an oligonucleotide (including siRNA) within 4 months of Screening if single dose received, or within 12 months of Screening if multiple doses received (this exclusion does not apply to vaccines - both mRNA and viral vector vaccines are allowed including COVID-19). For centrally administered ASOs, a minimum of 12 months washout is required irrespective of the number of doses received.\n- Part 1: Has experienced Status Epilepticus in the past 6 months.\n- Part 1: Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to BL (Day 1).\n- Part 1: Has a history of gene therapy or cell transplantation or any other experimental brain surgery."}

Primary endpoints

• {"endpoint_text":"- Incidence of treatment-emergent adverse events (TEAEs) and clinically significant change from Baseline (BL) in vital signs, physical and neurological examination, laboratory assessments, and electrocardiogram (ECG) over the course of the study.","definition_or_measurement_approach":"Monitoring and recording incidence of TEAEs and clinically significant changes from Baseline in vital signs, physical and neurological examinations, laboratory assessments and ECG throughout study visits (as stated in the endpoint description)."}

Secondary endpoints

• {"endpoint_text":"- Maximum plasma concentration (Cmax), area under the concentration-time curve (AUC), elimination half-life (t½), and trough (pre-dose) and post-treatment ION440 concentrations, where appropriate","definition_or_measurement_approach":"Pharmacokinetic measurements in plasma including Cmax, AUC, t½, and pre-dose and post-treatment concentrations of ION440."}
• {"endpoint_text":"- ION440 trough (pre-dose) and post-treatment concentrations in CSF","definition_or_measurement_approach":"Pharmacokinetic measurements of ION440 in cerebrospinal fluid (CSF), including trough (pre-dose) and post-treatment concentrations."}

Spain

Earliest CTIS Part Ii Submission Date

09-07-2024

Latest Decision Or Authorization Date

23-03-2026

Processing Time Days

622

Number Of Sites

1

Number Of Participants

6

France

Earliest CTIS Part Ii Submission Date

28-06-2024

Latest Decision Or Authorization Date

20-03-2026

Processing Time Days

600

Number Of Sites

1

Number Of Participants

6

Austria

Earliest CTIS Part Ii Submission Date

19-06-2025

Latest Decision Or Authorization Date

24-03-2026

Processing Time Days

278

Number Of Sites

1

Number Of Participants

4

Primary sponsor

Full Name

Ionis Pharmaceuticals Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Propharma Group LLC

Responsibilities

On site monitoring, Regulatory expertise

Name

Medpace Reference Laboratories LLC

Responsibilities

Transportation management; laboratory services and sample handling

Name

Invicro LLC

Responsibilities

Core lab activities, MRI Analysis

Third parties

• {"country":"United States","full_name":"Invicro LLC","duties_or_roles":"Core lab activities, MRI Analysis","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"Clouds of Care","duties_or_roles":"EEG","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Ambry Genetics Corp.","duties_or_roles":"Lab analysis - Array CGH","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Ionis Pharmaceuticals Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Pyxant Labs Inc.","duties_or_roles":"","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United Kingdom","full_name":"Chillibean Limited","duties_or_roles":"Video assessment Services","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medpace Reference Laboratories LLC","duties_or_roles":"Transportation management","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Propharma Group LLC","duties_or_roles":"On site monitoring, Regulatory expertise","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Charles River Laboratories Edinburgh Limited","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Sitero LLC","duties_or_roles":"Medical Term Coding","organisation_type":"Pharmaceutical company"}