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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ionis Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male

Therapeutic area

Phenomena and Processes [G] - Genetic Phenomena [G05]

Trial duration

24 Oct 2025 → ongoing

Decision date (initial)

2025-07-14

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Ionis Pharmaceuticals Inc

External identifiers

EU CT number

2023-507192-22-00

WHO UTN

U1111-1303-4105

ClinicalTrials.gov

NCT06430385

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Safety, Others, Pharmacokinetic

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

Secondary objectives 1

1. To characterize the pharmacokinetics of ION440 in the cerebrospinal fluid (CSF) and plasma (Part 1 and 2)

Conditions and MedDRA coding

Methyl CpG binding protein 2 (MECP2) Duplication Syndrome (MDS)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. 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
2. 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
3. Part 1: Participant has a documented diagnosis of MDS, with genetic confirmation of MECP2 duplication.
4. 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.
5. Part 1: Is currently receiving stable doses of concomitant medications for at least 1 month prior to Screening.
6. 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).
7. 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 10

1. 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.
2. 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.
3. 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.
4. 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
5. 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.
6. 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.
7. Part 1: Has experienced Status Epilepticus in the past 6 months.
8. Part 1: Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to BL (Day 1).
9. Part 1: Has a history of gene therapy or cell transplantation or any other experimental brain surgery.
10. 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).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 endpoints 2

1. 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
2. ION440 trough (pre-dose) and post-treatment concentrations in CSF

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ionis Pharmaceuticals Inc.

Sponsor organisation

Ionis Pharmaceuticals Inc.

Address

2855 Gazelle Court

City

Carlsbad

Postcode

92010-6670

Country

United States

Scientific contact point

Organisation

Ionis Pharmaceuticals Inc.

Contact name

Global Regulatory Affairs

Public contact point

Organisation

Ionis Pharmaceuticals Inc.

Contact name

Global Regulatory Affairs

Third parties 12

Locations

3 EU/EEA countries · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 34 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications