A Phase 1-2, Double-Blind, MAD Study of ION440 in MDS

Phase 1/2

Recruiting

• Conditions: Methyl CpG binding protein 2 (MECP2) Duplication Syndrome (MDS)

• Registration Number: 2023-507192-22-00
• Lead Sponsor: Ionis Pharmaceuticals Inc.

Brief Summary

To assess the safety and tolerability of ION440 (Part 1 and 2)

Detailed Description

This is a phase 1-2 randomized, double-blind, sham-controlled, multiple-ascending dose (MAD) study to evaluate ION440 in pediatric and adult participants with MECP2 Duplication Syndrome (MDS) and will be conducted in two parts. During Part 1 (MAD) (36 weeks), participants will be randomized in a 3:1 ratio to receive ION440 or sham. Individuals who complete Part 1 may enter Part 2, an open label long-term extension study (LTE), where they will receive ION440 for up to approximately 156 weeks. Multiple dose cohorts (Dose A, Dose B, and Dose C) will be evaluated in the study.

All dosing cohorts will be further subdivided by age. Sub cohort A will include participants 8 years of age and older and sub cohort B will include participants 2 through 7 years of age. Dosing cohorts will be enrolled sequentially with sub cohort A initiating prior to sub cohort B.

Study Timeline

• Study First Submitted: 2024-05-21
• Study First Submitted QC: 2024-05-21
• Study First Posted: 2024-05-28
• Study Start: 2024-10-21
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-01
• Last Update Posted: 2025-07-03
• Primary Completion: 2026-05
• Study Completion: 2030-04-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Male
• Target Recruitment: 12

Inclusion Criteria

Part 1: Males age ≥ 2 years to ≤ 65 years old, depending on specific cohort and group, at the time of informed consent. − Group A: ≥ 8 to ≤ 65 years old − Group B: 2 to 7 years old, inclusive

Part 1: Participant has at least one parent or caregiver ≥ 18 years old 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

Part 1: Participant has a documented diagnosis of MDS, with genetic confirmation of MECP2 duplication.

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.

Part 1: Is currently receiving stable doses of concomitant medications for at least 3 months prior to BL.

Part 2: Completed ION440-CS1, Part 1/MAD. Completers are defined as participants who received at least one dose of Study Drug and attended all study visits through Follow Up (Visit 6)

Part 2: All inclusion criteria in Part 1/MAD apply (participants will not be required to undergo new Screening bloodwork)

Exclusion Criteria

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 msec 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.

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).

Part 1: Documented diagnosis of MECP2 duplication including terminal duplication and/or translocation or MECP2 triplication OR clinical features associated with complex variant structure including (a) onset of seizures prior to age 5 (for those age 5 and above at signing of ICF), (b) oxygen dependence, (c) microcephaly, IF MECP2 genetic structure information is unavailable.

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.

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

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.

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.

Part 1: Has experienced Status Epilepticus in the past 6 months.

Part 1: Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to BL (Day 1).

Part 1: Has a history of gene therapy or cell transplantation or any other experimental brain surgery.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Primary Outcome Measures

Name	Time	Method
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.		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.

Secondary Outcome Measures

Name	Time	Method
ION440 trough (pre-dose) and post-treatment concentrations in CSF		ION440 trough (pre-dose) and post-treatment concentrations in CSF
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		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

Trial Locations

Locations (6)

Rady Children's Hospital; 🇺🇸 San Diego, California, United States

University of Colorado Hopsital - Anschutz Medical Campus; 🇺🇸 Aurora, Colorado, United States

Gillette Children's Specialty Healthcare; 🇺🇸 Saint Paul, Minnesota, United States

Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

Baylor College of Medicine; 🇺🇸 Houston, Texas, United States