A Safety and Efficacy of Intrathecally Administered ION283 in Patients With Lafora Disease

Prior treatment

• Clinically significant abnormalities in medical history (e.g., previous stroke within 6 months of Screening, major surgery within 3 months of Screening) or physical examination
• Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1
• 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 ION283 or its excipients; or history of hypersensitivity to any ASO. This exclusion criterion does not apply to COVID-19 mRNA vaccinations
• Has enrolled in any clinical trial or used any investigational agent or device, or has participated in any investigational procedure, within the 30 days, or within 5 half-lives of investigational agent, whichever is longer, before screening or does so concurrently with this study
• Use of antiplatelet or anticoagulant therapy within the 14 days prior to Screening (with the exception of aspirin ≤ mg/day) or anticipated use during the study, including but not limited to clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban, and apixaban

Other illness

• History of bleeding diathesis or coagulopathy
• Known history of, or positive test for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B
• Moderate-to-severe hepatic impairment or renal impairment.
• 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's Medical Monitor
• History of alcohol or drug abuse within 12 months of Screening, or current drug or alcohol abuse

Lab values

• Platelet count \< 80,000/mm3 or any other clinically significant laboratory abnormalities that would render a patient unsuitable for inclusion.

Age

• Uncontrolled hypertension defined as:
  • for patients \< 13 years old, BP ≥ 95th percentile + 12 mmHg, or ≥ 140/90 mmHg, whichever is lower for patients ≥ 13 years old, BP ≥ 140/90 mmHg

Other

• Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator
• Contraindication or unwillingness to undergo lumbar puncture

• General Inclusion Criteria
• Must give written informed consent (and assent if indicated by patient's age and in accordance with local requirements) and be willing/able to comply with all study requirements.
• Aged 10-18 (inclusive) years old at the time of informed consent.
• Non-pregnant and non-lactating females
• All male participants and women of childbearing potential must refrain from sperm/egg donation from the time of signing the informed consent/assent form until at least 12 weeks (approximately 5 half-lives of ION283) after the dose of Study Drug.
• For participants engaged in sexual relations of childbearing potential, highly effective contraception must be used from the time of signing the informed consent/assent form until at least 12 weeks (approximately 5 half-lives of ION283) after receiving Study Drug.
  • Target Inclusion Criteria
• Genetically confirmed diagnosis of Lafora disease before or at enrollment (documented pathogenic mutations in known causative genes (EPM2A/laforin, EPM2B/NHLRC1/malin)
• Must have LDPS score ≥ 9 and LDPS motor subscore of ≥ 2 (independent ambulation- walking 10 steps independently)