ATTUNE: A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intrathecally-Administered ION440 in Participants With Methyl CpG Binding Protein 2 (MECP2) Duplication Syndrome (MDS)

Official title

A Phase 1-2, Double-Blind, Sham-Controlled Multiple Ascending Dose Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intrathecally-Administered ION440 in Patients With MECP2 Duplication Syndrome

Overview

The primary purpose of this study is to evaluate the safety and tolerability of ION440.

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 through 65 years of age, 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.

Interventions

• Drug ION440
  ION440 will be administered by intrathecal bolus (ITB) injection.
• Procedure Sham procedure
  An LP will be performed with CSF collection but will not be followed by the administration of study treatment by ITB injection.

Primary outcome measures

• Part 1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [Time frame: Up to approximately 36 weeks]
• Part 1: Number of Participants With Clinically Significant Change From Baseline in Vital Signs [Time frame: Baseline up to approximately 36 weeks]
• Part 1: Number of Participants With Clinically Significant Change From Baseline in Physical and Neurological Examination Findings [Time frame: Baseline up to approximately 36 weeks]
• Part 1: Number of Participants With Clinically Significant Change from Baseline in Laboratory Assessments [Time frame: Baseline up to approximately 36 weeks]
• Part 1: Number of Participants With Clinically Significant Change From Baseline in Electrocardiogram (ECG) [Time frame: Baseline up to approximately 36 weeks]
• Part 2: Number of Participants With TEAEs [Time frame: Up to approximately 192 weeks]
• Part 2: Number of Participants With Clinically Significant Change From Baseline in Vital Signs [Time frame: Baseline up to approximately 192 weeks]
• Part 2: Number of Participants With Clinically Significant Change From Baseline in Physical and Neurological Examination Findings [Time frame: Baseline up to approximately 192 weeks]
• Part 2: Number of Participants With Clinically Significant Change from Baseline in Laboratory Assessments [Time frame: Baseline up to approximately 192 weeks]
• Part 2: Number of Participants With Clinically Significant Change From Baseline in ECG [Time frame: Baseline up to approximately 192 weeks]

Secondary outcome measures (6)

• Part 1: Maximum Observed Concentration (Cmax) of ION440 in Plasma [Time frame: Pre-dose and at multiple points post-dose up to Week 36]
• Part 1: Area Under the Concentration-time Curve (AUC) of ION440 in Plasma [Time frame: Pre-dose and at multiple points post-dose up to Week 36]
• Part 1: Plasma Terminal Elimination Half-life (t½) of ION440 [Time frame: Pre-dose and at multiple points post-dose up to Week 36]
• Part 1: Trough Concentration (Ctrough) of ION440 in Plasma and CSF [Time frame: Pre-dose and at multiple points post-dose up to Week 36]
• Part 1: Plasma Concentration of ION440 [Time frame: Pre-dose and at multiple points post-dose up to Week 36]
• Part 2: Trough Concentration (Ctrough) of ION440 in Plasma and CSF [Time frame: Up to approximately 192 weeks]

Eligibility criteria

Key Inclusion criteria for 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 old
• Group B: 2 to 7 years old, inclusive
• Participant has at least one parent or caregiver ≥ 18 years old capable of providing informed consent and able to comply with all study requirements and activities.
• Participant has a documented diagnosis of MDS with genetic confirmation of MECP2 duplication.
• Is currently receiving stable doses of concomitant medications for at least 1 month prior to screening.
• Able to complete all study procedures, measurements and visits to support primary and secondary endpoints, in the opinion of the Investigator.

Key Exclusion criteria for Part 1:

• Documented diagnosis of severe MECP2 duplications including terminal duplication and/or translocation or MECP2 triplication OR clinical features associated with severe variant structure including (a) onset of seizures prior to age 5 (for those aged 5 and above at signing of ICF), (b) oxygen dependence, (c) microcephaly, IF MECP2 genetic structure information is unavailable.
• Clinically significant vital sign or ECG abnormality at Screening
• 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.
• 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.
• Treatment with an investigational drug, biological agent, or device within 30 days of Screening, or 5 half-lives of investigational agent, whichever is longer.
• 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.
• Currently enrolled in a clinical trial of an investigational agent or device or has used any investigational agent or device within 5 half-lives of investigational agent, whichever is longer.
• Has a history of gene therapy or cell transplantation or any other experimental brain surgery.
• Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Baseline (Day 1).
• Has experienced Status Epilepticus in the past 6 months.

Key Inclusion criteria for 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 Follow Up visit (Visit 6).
• All inclusion criteria in Part 1/MAD apply (participants will not be required to undergo new Screening bloodwork).

Key Exclusion criteria for Part 2:

1\. 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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 8 centers

• Rady Children's Hospital — San Diego
• University of Colorado Hopsital - Anschutz Medical Campus — Aurora
• Kennedy Krieger — Baltimore
• Boston Children's Hospital — Boston
• Gillette Children's Specialty Healthcare — Saint Paul
• Children's Hospital of Philadelphia — Philadelphia
• Vanderbilt University Medical Center — Nashville
• Baylor College of Medicine — Houston

Austria · 1 center

• Kepler University Hospital — Linz

France · 1 center

• CHU Dijon Bourgogne — Dijon

Spain · 1 center

• Hospital Saint Joan de Deu — Barcelona

Identifiers

NCT: NCT06430385 · ION440-CS1 · 2023-507192-22 · U1111-1303-4105

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗