Clinical trial NCT06430385: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Methyl CpG Binding Protein 2 (MECP2) Duplication Syndrome
Lead sponsor: Ionis Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2024-05-28
Enrollment: 48
Sex: MALE
Minimum age (years): 2
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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 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.

Eligibility criteria: Inclusion criteria for Part 1:

1. Males age ≥ 2 years to ≤ 65 years old, depending on specific cohort and group, at the time of informed consent.

   1. Group A: ≥ 8 to ≤ 65 years old
   2. Group B: 2 to 7 years old, inclusive
2. 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,
3. Participant has a documented diagnosis of MDS, with genetic confirmation of MECP2 duplication
4. Is currently receiving stable doses of concomitant medications for at least 3 months prior to baseline. If recent changes (\< 3 months stable) in medications, the participant may be allowed per Investigator judgment in consult with Sponsor Medical Monitor.
5. Able to complete all study procedures, measurements and visits and caregiver/participant has adequately supportive psychosocial circumstances, in the opinion of the Investigator.

Exclusion criteria for Part 1:

1. Documented diagnosis of complex MECP2 duplications 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.
2. Clinically significant vital sign or ECG abnormality at Screening \[including heart rate (HR) \< 45 beats per minute; systolic blood pressure \< 90 millimeters of mercury (mmHg); confirmed blood pressure readings \> 170/105 mmHg\]
3. 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.
4. 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.
5. Treatment with an investigational drug, biological agent, or device within 30 days of Screening, or 5 half-lives of investigational agent, whichever is longer.
6. 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.
7. 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.
8. Has a history of gene therapy or cell transplantation or any other experimental brain surgery.
9. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Baseline (Day 1).
10. Has experienced Status Epilepticus in the past 6 months.

Inclusion criteria for Part 2:

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

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).

Primary outcomes:
measure: Part 1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Up to approximately 36 weeks
measure: Part 1: Number of Participants With Clinically Significant Change From Baseline in Vital Signs
timeFrame: Baseline up to approximately 36 weeks
measure: Part 1: Number of Participants With Clinically Significant Change From Baseline in Physical and Neurological Examination Findings
timeFrame: Baseline up to approximately 36 weeks
measure: Part 1: Number of Participants With Clinically Significant Change from Baseline in Laboratory Assessments
timeFrame: Baseline up to approximately 36 weeks
measure: Part 1: Number of Participants With Clinically Significant Change From Baseline in Electrocardiogram (ECG)
timeFrame: Baseline up to approximately 36 weeks
measure: Part 2: Number of Participants With TEAEs
timeFrame: Up to approximately 192 weeks
measure: Part 2: Number of Participants With Clinically Significant Change From Baseline in Vital Signs
timeFrame: Baseline up to approximately 192 weeks
measure: Part 2: Number of Participants With Clinically Significant Change From Baseline in Physical and Neurological Examination Findings
timeFrame: Baseline up to approximately 192 weeks
measure: Part 2: Number of Participants With Clinically Significant Change from Baseline in Laboratory Assessments
timeFrame: Baseline up to approximately 192 weeks
measure: Part 2: Number of Participants With Clinically Significant Change From Baseline in ECG
timeFrame: Baseline up to approximately 192 weeks
Secondary outcomes:
measure: Part 1: Maximum Observed Concentration (Cmax) of ION440 in Plasma
timeFrame: Pre-dose and at multiple points post-dose up to Week 36
measure: Part 1: Area Under the Concentration-time Curve (AUC) of ION440 in Plasma
timeFrame: Pre-dose and at multiple points post-dose up to Week 36
measure: Part 1: Plasma Terminal Elimination Half-life (t½) of ION440
timeFrame: Pre-dose and at multiple points post-dose up to Week 36
measure: Part 1: Trough Concentration (Ctrough) of ION440 in Plasma and CSF
timeFrame: Pre-dose and at multiple points post-dose up to Week 36
measure: Part 1: Plasma Concentration of ION440
timeFrame: Pre-dose and at multiple points post-dose up to Week 36
measure: Part 2: Trough Concentration (Ctrough) of ION440 in Plasma and CSF
timeFrame: Up to approximately 192 weeks
Other outcomes:
Locations:
city: San Diego
country: United States
facility: Rady Children's Hospital
state: California
city: Saint Paul
country: United States
facility: Gillette Children's Specialty Healthcare
state: Minnesota
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
Study officials:
References: