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)

NCT06430385 | Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: ION440-CS12023-507192-22U1111-1303-4105
• Study Type: interventional
• Target: 48
• Locations: 4 countries
• Sites: 11

Brief Summary

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

Conditions

Methyl CpG Binding Protein 2 (MECP2) Duplication Syndrome

Outcome Measures

Primary Outcomes (10)

• Part 1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

  Up to approximately 36 weeks

• Part 1: Number of Participants With Clinically Significant Change From Baseline in Vital Signs

  Baseline up to approximately 36 weeks

• Part 1: Number of Participants With Clinically Significant Change From Baseline in Physical and Neurological Examination Findings

  Baseline up to approximately 36 weeks

• Part 1: Number of Participants With Clinically Significant Change from Baseline in Laboratory Assessments

  Baseline up to approximately 36 weeks

• Part 1: Number of Participants With Clinically Significant Change From Baseline in Electrocardiogram (ECG)

  Baseline up to approximately 36 weeks

• Part 2: Number of Participants With TEAEs

  Up to approximately 192 weeks

• Part 2: Number of Participants With Clinically Significant Change From Baseline in Vital Signs

  Baseline up to approximately 192 weeks

• Part 2: Number of Participants With Clinically Significant Change From Baseline in Physical and Neurological Examination Findings

  Baseline up to approximately 192 weeks

• Part 2: Number of Participants With Clinically Significant Change from Baseline in Laboratory Assessments

  Baseline up to approximately 192 weeks

• Part 2: Number of Participants With Clinically Significant Change From Baseline in ECG

  Baseline up to approximately 192 weeks

Secondary Outcomes (6)

• Part 1: Maximum Observed Concentration (Cmax) of ION440 in Plasma

  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

  Pre-dose and at multiple points post-dose up to Week 36

• Part 1: Plasma Terminal Elimination Half-life (t½) of ION440

  Pre-dose and at multiple points post-dose up to Week 36

• Part 1: Trough Concentration (Ctrough) of ION440 in Plasma and CSF

  Pre-dose and at multiple points post-dose up to Week 36

• Part 1: Plasma Concentration of ION440

  Pre-dose and at multiple points post-dose up to Week 36

Study Arms (4)

Cohort 1: ION440 Dose A

EXPERIMENTAL

Participants will receive ION440 intrathecally at Dose A during Part 1/MAD, followed by ION440 Dose A during Part 2/LTE.

Drug: ION440

Cohort 2: ION440 Dose B

EXPERIMENTAL

Participants will receive ION440 intrathecally at Dose B during Part 1/MAD, followed by ION440 Dose B during Part 2/LTE.

Drug: ION440

Cohort 3: ION440 Dose C

EXPERIMENTAL

Participants will receive ION440 intrathecally at Dose C during Part 1/MAD, followed by ION440 Dose C during Part 2/LTE.

Drug: ION440

Sham Procedure

SHAM COMPARATOR

During the Part 1/MAD period, a lumbar procedure (LP) will be performed at the same frequency as ION440 administration. Participants will not receive ITB injections during this period. It will be followed by the open-label Part 2/LTE period, where participants will receive ION440 at the same dose as their enrolled cohort (e.g. Dose A, Dose B or Dose C).

Procedure: Sham procedure

Interventions

ION440 DRUG

ION440 will be administered by intrathecal bolus (ITB) injection.

Cohort 1: ION440 Dose A; Cohort 2: ION440 Dose B; Cohort 3: ION440 Dose C

Sham procedure PROCEDURE

An LP will be performed with CSF collection but will not be followed by the administration of study treatment by ITB injection.

Sham Procedure

Eligibility Criteria

• Age: 2 Years - 65 Years
• Gender Eligibility Details: Only males are included for this disease condition.
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.
• 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).
• \. 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).

Sponsors & Collaborators

• Ionis Pharmaceuticals, Inc.: lead

Study Sites (11)

Rady Children's Hospital

San Diego, California, 92123, United States

RECRUITING

University of Colorado Hopsital - Anschutz Medical Campus

Aurora, Colorado, 80045, United States

RECRUITING

Kennedy Krieger

Baltimore, Maryland, 21205, United States

RECRUITING

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

RECRUITING

Gillette Children's Specialty Healthcare

Saint Paul, Minnesota, 55101, United States

RECRUITING

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

RECRUITING

Baylor College of Medicine

Houston, Texas, 77030, United States

RECRUITING

Kepler University Hospital

Linz, 4040, Austria

RECRUITING

CHU Dijon Bourgogne

Dijon, 21079, France

RECRUITING

Hospital Saint Joan de Deu

Barcelona, 8950, Spain

RECRUITING

MeSH Terms

Conditions

Rett Syndrome

Condition Hierarchy (Ancestors)

X-Linked Intellectual Disability; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Heredodegenerative Disorders, Nervous System

Central Study Contacts

Ionis Pharmaceuticals

CONTACT

(844) 779-1497; IonisMECP2study@clinicaltrialmedia.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 21, 2024
• First Posted: May 28, 2024
• Study Start: October 21, 2024
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): April 1, 2030
• Last Updated: March 24, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share

Locations

AU (1); FR (1); US (8); ES (1)