Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered ION373 in Patients with Alexander Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ionis Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

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

Trial duration

8 Apr 2021 → ongoing

Decision date (initial)

2024-06-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Ionis Pharmaceuticals, Inc.

External identifiers

EU CT number

2024-510603-11-00

EudraCT number

2020-000976-40

WHO UTN

U1111-1303-1396

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Pharmacodynamic, Safety

To evaluate the efficacy of ION373 in improving or stabilizing gross motor function in patients with Alexander disease

Secondary objectives 1

1. To further evaluate the efficacy of ION373 in improving or stabilizing disease manifestations across the full range of affected domains (gross and fine motor, communication, swallowing, autonomic and/or other gastrointestinal functions, nutritional/growth status) in patients with Alexander disease

Conditions and MedDRA coding

Alexander Disease

Study design 4 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Must have given written informed consent (and assent, if indicated per patient’s age and institutional guidelines) and any authorizations required by local law and be able to comply with all study requirements
2. Patients who, in the opinion of the Investigator, have reached reproductive maturity, must satisfy 1 of the following: Females must be non-pregnant and non-lactating, and either: i. Surgically sterile (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy) ii. Postmenopausal (defined as 12 months of spontaneous amenorrhea without an alternative medical cause; in females ≤ 55 years of age not using hormonal contraception or hormonal replacement therapy, a high follicle stimulating hormone (FSH) level in the postmenopausal range for the laboratory involved will be used to confirm a postmenopausal state) iii. Abstinent* or iv. If engaged in sexual relations of childbearing potential, agree to use highly effective contraceptive methods (refer to Section 6.3.1) from the time of signing the informed consent form until at least 40 weeks after the last dose of Study Drug (ION373 or placebo) and agree to receive a pregnancy test at Screening, Day 1, every 12 weeks during the Double-Blind and Open-Label Treatment Periods, and at the last study visit Males must be abstinent*; surgically sterile (i.e., bilateral orchidectomy); or if engaged in sexual relations with a woman of childbearing potential (WOCBP), a highly effective contraceptive method (refer to Section 6.3.1) must be used from the time of signing the informed consent form until at least 40 weeks after the last dose of Study Drug (ION373 or placebo). * Abstinence (i.e., refraining from heterosexual intercourse throughout the duration of study participation) is only acceptable as true abstinence, i.e., when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), withdrawal, and declaration of abstinence for the duration of a trial are not acceptable methods of contraception.
3. Clinical phenotype and brain imaging consistent with a diagnosis of AxD
4. Documented genetic mutation in the GFAP gene
5. Aged ≥ 2 to 65 years old at the time of informed consent (eligibility for main study) or aged < 2 years old at the time of informed consent (eligibility for the open-label sub study)
6. If aged ≥ 2 and < 5 years old, must be able to sit with minimal assistance (using only own hands for support) for at least 10 seconds, or must be ambulatory (defined as able to complete the 10MWT in 5 minutes or less [assistive walking devices such as braces, canes, walkers permitted]); if aged ≥ 5 years old, must be ambulatory
7. Stable medications, nutritional support and physical, occupational, speech, and respiratory therapy for at least 3 months prior to Screening
8. Able and willing to meet all study requirements (in the opinion of the Investigator), including travel to Study Center, procedures, measurements and visits
9. Patients < 18 years old at Screening must have a trial partner (parent, caregiver or other) who is reliable, competent and at least 18 years of age, is willing to accompany the patient to the trial visits and to be available to the Study Center by phone if needed, and who (in the opinion of the Investigator) is and will remain sufficiently knowledgeable of patient’s ongoing condition to respond to Study Center inquiries about the patient

Exclusion criteria 21

1. Clinically significant abnormalities in medical history (e.g., previous acute coronary syndrome within 6 months of Screening, major surgery within 3 months of Screening) or physical examination
2. Platelet count (defined as < 100,000/mm3 ) or any other clinically significant laboratory abnormalities that would render a patient unsuitable for inclusion
3. History of bleeding diathesis or coagulopathy
4. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1
5. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator
6. Any contraindication or unwillingness to undergo MRI (e.g., metal implants, claustrophobia, agitation or motor symptoms of a severity that precludes MRI scans)
7. Known history of, or positive test for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B
8. Uncontrolled hypertension defined as: i. for patients < 13 years old, BP ≥ 95th percentile + 12 mmHg, or ≥ 140/90 mmHg, whichever is lower ii. for patients ≥ 13 years old, BP ≥ 140/90 mmHg
9. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix that has been successfully treated or benign pediatric tumors. Patients with a history of other malignancies that have been treated with curative intent and which have no recurrence within 5 years may also be eligible if approved by the Sponsor Medical Monitor
10. Treatment with another investigational drug, biological agent, or device within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer; concurrent participation in any other clinical study (including observational and non-interventional studies)
11. Previous treatment with an oligonucleotide (including small interfering ribonucleic acid [siRNA]) within 4 months of Screening if single dose received, or within 12 months of Screening if multiple doses received; or history of hypersensitivity to ION373 or its excipients; or history of hypersensitivity to any ASO. This exclusion does not apply to vaccines (both mRNA and viral vector vaccines).
12. History of gene therapy or cell transplantation or any other experimental brain surgery
13. Current obstructive hydrocephalus
14. Presence of a functional ventriculoperitoneal shunt for the drainage of CSF or an implanted CNS catheter
15. Any condition that increases risk of meningitis unless patient is receiving appropriate prophylactic treatment
16. Known brain or spinal disease 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
17. History of severe post-LP headache and/or blood patch
18. Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks prior to Screening or planned during the study
19. Recent history of, or current drug or alcohol abuse
20. Antiplatelet or anticoagulant therapy within the 14 days prior to Screening or anticipated use during the study, including but not limited to aspirin (unless ≤ 81 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban and apixaban
21. Have any other conditions, which, in the opinion of the Investigator would make the patient unsuitable for inclusion, or could interfere with the patient participating in or completing the study, such as the presence of a chronic condition which places the patient at higher risk from procedural sedation or anesthesia if this is deemed necessary by the Investigator for completion study procedures including the lumbar punctures and/or brain MRI scans

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Percent change from Baseline to Week 61 in the 10MWT in patients who are in Stratum 1.

Secondary endpoints 4

1. Change from Baseline to Week 61 or value at Week 61 for the following: • Patients' self-identified most bothersome symptom (based on a Likert scale for change; all patients) • PedsQL Generic Core Scales (all patients) • Patient Global Impression of Severity (PGIS; all patients) • Patient Global Impression of Change (PGIC; all patients) • Clinical Global Impression of Change (CGIC; all patients)
2. Change from Baseline to Week 61 or value at Week 61 for the following: • Gross Motor Function Measure-88, Dimensions C, D and E (GMFM-88, Dimensions C-E; patients < 5 years old at Screening) or 10MWT (patients ≥ 5 years old at Screening) • 9-Hole Peg Test (9HPT; patients ≥ 8 years old at Screening) • Vineland-3 Motor Skills Domain (patients < 8 years old at Screening) • PedsQL Gastrointestinal Symptoms Scales (all patients)
3. Change from Baseline to Week 61 or value at Week 61 for the following: Vineland-3 Adaptive Behavior Composite (ABC) Score (patients < 18 years old at Screening) • Composite Autonomic Symptom Score 31 (COMPASS-31; patients ≥ 18 years old at Screening) • CSF GFAP levels (all patients) • Clinical Global Impression of Severity (CGIS; all patients)
4. Change from Baseline to Week 61 or value at Week 61 for the following: • Alexander Disease Patient Domain Impression of Severity (AxD-PDIS; all patients) •Alexander Disease Patient Domain Impression of Change (AxD-PDIC; all patients) • Body weight percentile (for patients < 18 years old at Screening) or body weight (for patients ≥ 18 years old at Screening

Investigational products

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

Test 1

Placebo 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 13

Locations

2 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 39 files

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

Application history

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