Phase 1b Study of ION356 to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics in Patients with Pelizaeus-Merzbacher Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ionis Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male

Therapeutic area

Diseases [C] - Nervous System Diseases [C10], Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

10 Apr 2024 → ongoing

Decision date (initial)

2023-11-06

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Ionis Pharmaceuticals Inc.

External identifiers

EU CT number

2022-502432-39-00

WHO UTN

U1111-1287-2044

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Safety, Others, Pharmacokinetic, Pharmacodynamic, Efficacy

To evaluate the safety and tolerability of ION356

Secondary objectives 1

1. 1. To characterize the CSF and plasma PK of ascending dose levels of multiple intrathecal (IT) administrations of ION356

Conditions and MedDRA coding

Pelizaeus-Merzbacher Disease

Regulatory references

Scientific advice from competent authorities

National Agency For The Safety Of Medicine And Health Products, Federal Institute For Drugs And Medical Devices

Plan to share IPD

Yes

IPD plan description

Ionis may share anonymized individual participant data, aggregated clinical data, and other types of data that support the results in this study. Data requests from qualified researchers will be considered once all three of the following criteria are met: (1) 12 months from marketing approval of the study drug in both the United States and European Union; (2) 18 months from conclusion of the study; and (3) 6 months from publication of study article. Access would be via a secure environment and is contingent upon approval of a research proposal and entry into an appropriate data use agreement. Requests to access data can be submitted via the website https://vivli.org/ourmember/ionis/

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. 1. Diagnosis of PMD with genetic confirmation of PLP1 gene duplication with molecular confirmation by a CLIA, CE-marked, or equivalent laboratory provided by the Investigator at Screening.
2. 2. Clinical phenotype and brain imaging consistent with a diagnosis of PMD
3. 3. Male between the ages of 2 and 17 years, inclusive, at the time of informed consent
4. 4. Able and willing to meet all study requirements (in the opinion of the Investigator), including travel to Study Center, procedures, measurements, and visits

Exclusion criteria 13

1. 01. > 2 copies of the PLP1 gene
2. 02. Clinically significant abnormalities in medical history (e.g., previous acute coronary syndrome or evidence of renal impairment within 6 months of Screening, major surgery within 3 months of Screening) or physical examination
3. 03. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator
4. 4. Any contraindication or unwillingness to undergo MRI (e.g., metal implants, claustrophobia, agitation, or motor symptoms of a severity to preclude MRI scans).
5. 05. Treatment with another investigational drug, biological agent, or device within 1 month of Screening, or 5 half-lives of the investigational agent, whichever is longer
6. 06. Previous treatment with an oligonucleotide (including small interfering ribonucleic acid) within 4 months of Screening if a single dose was received, or within 12 months of Screening if multiple doses were received; or history of hypersensitivity to ION356 or its excipients; or history of hypersensitivity to any ASO. This exclusion does not apply to vaccines (both mRNA and viral vector vaccines)
7. 07. History of gene therapy or cell transplantation, or any experimental brain surgery
8. 08. Current obstructive hydrocephalus
9. 09. Presence of a functional ventriculoperitoneal shunt for the drainage of CSF or an implanted CNS catheter
10. 10. Known brain or spinal disease or previous spinal surgery that would interfere with the LP process, CSF circulation, or safety assessment, including tumors or abnormalities by MRI or computed tomography, subarachnoid hemorrhage, spinal stenosis or curvature, Chiari malformation, syringomyelia, tethered spinal cord syndrome, and connective tissue disorders such as Ehlers-Danlos syndrome and Marfan syndrome
11. 11. History of severe post-LP headache and/or blood patch
12. 12. Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks prior to Screening or planned during the study
13. 13. Have any other conditions, that, in the opinion of the Investigator, would make the participant unsuitable for inclusion, or could interfere with participation in or completion of the study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 1. Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) from Day 1 to the final study visit over the course of the study • Incidence and frequency of TEAEs and SAEs • Change from Baseline over the course of the study in the following: − Laboratory assessments including clinical chemistry, hematology and coagulation in plasma/serum; urinalysis, and cerebrospinal fluid (CSF) safety panel − Neurological exam and vital signs − ECG − Concomitant medication use

Secondary endpoints 1

1. 1. ION356 concentrations in plasma and CSF over the course of the study • Maximum plasma concentration (Cmax), area under the concentration-time curve (AUC), elimination half-life (t½), and trough (pre-dose) and post-treatment ION356 concentrations, where appropriate • ION356 trough (pre-dose) and post-treatment concentrations in CSF • ION356 excretion in urine, percent of dose excreted, and renal clearance

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 14

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

Application history

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