Evaluation of ION373 Efficacy and Safety in Alexander Disease: A Phase 1-3 Double-Blind, Randomized, Placebo-Controlled Study

Trial ID: 2024-510603-11-00
Protocol: ION373-CS1
Sponsor: Ionis Pharmaceuticals Inc.

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Diseases & Conditions

Alexander disease

Objectives

The primary objective of this study is to evaluate the **efficacy** of ION373 in improving or stabilizing gross motor function in patients with **Alexander Disease**. This is clinically relevant as gross motor function is a critical aspect of daily living and quality of life for patients affected by this rare neurological disorder. The ability to improve or maintain motor function can significantly impact patient outcomes and disease progression.

Secondary objectives include further evaluation of the efficacy of ION373 in improving or stabilizing disease manifestations across a range of affected domains. These domains include gross and fine motor skills, communication, swallowing, autonomic and other gastrointestinal functions, as well as nutritional and growth status. Addressing these secondary objectives is important for a comprehensive understanding of the potential benefits of ION373 in managing the multifaceted symptoms of Alexander Disease.

Participants

The clinical trial involves a total of **42 participants** diagnosed with **Alexander Disease**, a rare neurological disorder. The study population includes both male and female subjects, with an age range from **2 to 65 years**. Participants were selected based on specific criteria, including a clinical phenotype and brain imaging consistent with Alexander Disease, as well as a documented genetic mutation in the GFAP gene. The trial includes individuals who are able to comply with study requirements, such as travel to the study center and participation in necessary procedures and visits. Participants are required to have stable medications, nutritional support, and therapies for at least three months prior to screening. The study also considers lifestyle factors, requiring that participants maintain stable physical, occupational, speech, and respiratory therapies. The trial population includes vulnerable groups, such as children under 18, who must have a reliable trial partner to accompany them to visits. The selection process ensures that participants are capable of meeting all study requirements, as determined by the investigator.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of intrathecally administered ION373 in patients with **Alexander Disease**. The trial is structured into four distinct periods: a 60-week Double-Blind Treatment Period, a 60-week Open-Label Treatment Period, a 120-week open-label long-term extension (LTE), and a 28-week Post-Treatment Follow-Up Period. The overall duration of the trial is estimated to conclude by March 2029, with recruitment having commenced in November 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, clinical phenotype, and genetic mutation in the GFAP gene. Following successful screening, participants will be randomized to receive either ION373 or a placebo. The primary endpoint is the percent change from baseline to Week 61 in the 10-Meter Walk Test (10MWT) for patients in Stratum 1. Secondary endpoints include changes in various clinical and patient-reported outcomes from baseline to Week 61.

Study visits will occur at regular intervals throughout the trial, including follow-up visits every 12 weeks during the Double-Blind and Open-Label Treatment Periods. The end-of-study visit will mark the conclusion of the participant's involvement, which is expected to last up to 268 weeks, depending on the specific treatment and follow-up periods. Conditions that may lead to early termination from the study include non-compliance with study requirements, adverse events, or withdrawal of consent by the participant.

Treatment

The clinical trial involves the administration of **ION373**, an experimental medication designed to evaluate its efficacy, safety, pharmacokinetics, and pharmacodynamics in patients with Alexander disease. **ION373** is a **2'-O-(2-methoxyethyl)-D-ribose antisense oligonucleotide** targeting glial fibrillary acidic protein messenger ribonucleic acid. The pharmaceutical form of **ION373** is an injection, and it is administered via the **intrathecal route**. The dosing schedule and frequency of administration are determined by the study protocol, and participant compliance is monitored throughout the trial. **ION373** is classified as a chemical antisense oligonucleotide and is not a pediatric formulation. It has been designated as an orphan drug under the designation number EU/3/19/2206.

In addition to the experimental treatment, the study utilizes **Artificial Cerebrospinal Fluid (aCSF) for injection** as a placebo comparator. The **aCSF** serves as a control to evaluate the effects of **ION373** against a non-active substance. The pharmaceutical form and route of administration for **aCSF** are consistent with those of **ION373**, ensuring a double-blind study design. The use of **aCSF** allows for the assessment of the true efficacy and safety profile of **ION373** in the context of Alexander disease treatment. Compliance with the administration of the placebo is also monitored to maintain the integrity of the trial results.

Efficacy

The efficacy of ION373 in patients with Alexander disease will be assessed through a series of primary and secondary endpoints. The primary endpoint is the percent change from baseline to Week 61 in the 10-Meter Walk Test (10MWT) for patients in Stratum 1. Secondary endpoints include changes from baseline to Week 61 or values at Week 61 for various measures. These measures encompass patients' self-identified most bothersome symptom using a Likert scale, PedsQL Generic Core Scales, Patient Global Impression of Severity (PGIS), Patient Global Impression of Change (PGIC), and Clinical Global Impression of Change (CGIC).

Additional secondary endpoints involve the Gross Motor Function Measure-88 (GMFM-88) for patients under 5 years old, the 10MWT for patients 5 years and older, the 9-Hole Peg Test (9HPT) for patients 8 years and older, and the Vineland-3 Motor Skills Domain for patients under 8 years old. Other assessments include the PedsQL Gastrointestinal Symptoms Scales, Vineland-3 Adaptive Behavior Composite (ABC) Score for patients under 18, Composite Autonomic Symptom Score 31 (COMPASS-31) for patients 18 and older, and cerebrospinal fluid (CSF) **GFAP** levels. The Alexander Disease Patient Domain Impression of Severity (AxD-PDIS) and Change (AxD-PDIC), as well as body weight percentiles for patients under 18 or body weight for those 18 and older, will also be evaluated.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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
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.
Clinical phenotype and brain imaging consistent with a diagnosis of AxD
Documented genetic mutation in the GFAP gene
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)
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
Stable medications, nutritional support and physical, occupational, speech, and respiratory therapy for at least 3 months prior to Screening
Able and willing to meet all study requirements (in the opinion of the Investigator), including travel to Study Center, procedures, measurements and visits
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

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Exclusion Criteria

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
Platelet count (defined as < 100,000/mm3 ) or any other clinically significant laboratory abnormalities that would render a patient unsuitable for inclusion
History of bleeding diathesis or coagulopathy
Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1
Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator
Any contraindication or unwillingness to undergo MRI (e.g., metal implants, claustrophobia, agitation or motor symptoms of a severity that precludes MRI scans)
Known history of, or positive test for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B
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
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
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)
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).
History of gene therapy or cell transplantation or any other experimental brain surgery
Current obstructive hydrocephalus
Presence of a functional ventriculoperitoneal shunt for the drainage of CSF or an implanted CNS catheter
Any condition that increases risk of meningitis unless patient is receiving appropriate prophylactic treatment
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
History of severe post-LP headache and/or blood patch
Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks prior to Screening or planned during the study
Recent history of, or current drug or alcohol abuse
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
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