Study of the Safety and Biologic Activity of AL01211 in Treatment Naive Males With Classic Fabry Disease

A Phase II, Open-label Study to Evaluate the Safety, Pharmacodynamics, Pharmacokinetics, and Efficacy in Males With Classic Fabry Disease Who Have Never Received Any Treatment

This is a Phase II, open-label study designed to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of AL01211 in male subjects with classic Fabry disease who have never received any treatment (eg. ERT or chaperone therapy). Eligible subjects will receive 182 days (26 weeks) of study treatment as the primary study period followed by an extension period. The total study duration for a subject is up to at most 2 years including the primary period of 26 weeks.

Inclusion Criteria:

• Male subjects with classic Fabry mutations with between 18 and 60 years of age, inclusive, at screening.
• Have never received any Fabry disease-specific treatment (eg. ERT, chaperone therapy).
• Signed and dated informed consent prior to any study mandated procedure.
• Confirmed diagnosis of Fabry disease as documented by the presence of a Fabry genetic variant of known significance and documented (within 10 years prior to study entry) leukocyte αGAL activity of <4 nmol/hr/mg or plasma αGAL activity of <1.5 nmol/hr/mL. If the genetic variant is not known or available, genetic test will be done to document the genetic variation after obtaining the patient's informed consent. If documented leukocyte or plasma αGAL activity is unavailable, the subject must consent to plasma αGAL activity screening.
• eGFR ≥50 mL/min/1.73 m2 by CKD-EPI Creatinine-Cystatin Equation (2021) at the screening visit.
• Subject agrees to comply with all procedural requirements as presented in the protocol, including participation in observational period which extends beyond the planned 52-week treatment duration of the study and 1 month follow-up visit.
• For subjects receiving renin-angiotensin-aldosterone system (RAAS) inhibitors/blockers (ACEIs, ARBs, aldosterone receptor antagonists) or sodium-glucose cotransporter-2 (SGLT2) inhibitors, the dose should be stable (ie, prescribed dose and frequency) for at least the immediate 3 months prior to screening.
• Symptom or clinical finding of ≥1 of the characteristic features of Fabry disease, such as, but not limited to, neuropathic pain, symptoms of gastrointestinal, renal, or cardiac dysfunction.
• Willing to undergo opthalmological examination with photodocumentation at baseline and at specified times during the study.
• Plasma Lyso GL3 ≥25 ng/mL.

Exclusion Criteria:

• Subject on regular dialysis for the treatment of chronic kidney disease or has undergone a kidney transplant.
• Clinically significant abnormal liver function judged by the investigator, including but not limited to serum total bilirubin > 1.5 the upper limit of normal [ULN], serum alanine aminotransferase > 2 times the ULN, or aspartate aminotransferase >2 times the ULN).
• Scheduled in-patient hospitalization, including elective surgery, during the study.
• A positive result on any of the following tests: hepatitis B surface antigen (HBsAg) (If HBsAg is positive, hepatitis B virus DNA needs to be tested, and the copy number >ULN), antihepatitis C virus antibodies, anti-human immunodeficiency virus 1 and 2 antibodies.
• A cortical cataract (COR) >one quarter of the lens circumference (Grade COR-2) or a posterior subcapsular cataract (PSC) with about 30% opacity (Grade PSC-2), according to World Health Organization grading. Subjects with nuclear cataracts are not excluded.
• Currently receiving, or has received within the past month, potentially cataractogenic medications, including a chronic regimen (more frequently than once every 2 weeks) of any route of corticosteroids (limited to medium and high-potency topical steroids; intranasal steroids are acceptable) or any medication that may cause cataracts (such as phenothiazines and miotics, amiodarone, allopurinol and phenytoin) according to the Prescribing Information.
• Male subjects with partners of child-bearing potential who do not agree to use a medically accepted, highly effective method of contraception during the study until 3 months after the last administration of study drug. Male subjects must be willing to withhold from any sperm donation during the study and up to 3 months after the last dose of study treatment.
• Presence of any medical, emotional, behavioral, or psychological condition that, in the judgment of the investigator, would interfere with the subject's compliance with the requirements of the study or interpretation of the results.
• Prior participation in a study involving an investigational drug within 90 days since the end of the study or within 5 half lives since the last dose of investigational drug, whichever is longer.
• Unwilling to comply with the requirements of the protocol.
• Known and documented cardiovascular event (eg, myocardial infarction, unstable angina), cerebrovascular event (eg, stroke, transient ischemic attack), or clinically significant unstable cardiac disease (eg, uncontrolled symptomatic arrhythmia or congestive heart failure of New York Heart Association Class III or IV) in the 6 months prior to screening.
• Any cardiac disease that could mimic Fabry disease or confound cardiac measurement, such as (non-Fabry related) hypertrophic cardiomyopathy or the presence of a pacemaker or implantable cardioverter/defibrillator; any contraindications to MRI measurement (eg, cerebral aneurysm clips).
• History of acute kidney injury in the 12 months prior to screening, including specific kidney diseases (eg, acute interstitial nephritis, acute glomerular and vasculitic renal diseases), nonspecific conditions (eg, ischemia and toxic injury), and extrarenal pathology (eg, prerenal azotemia and acute postrenal obstructive nephropathy).
• Subjects received herbal medicines within 14 days prior to screening.
• The participant had received strong or moderate inducers or inhibitors of Cytochrome P450 3A4 (CYP3A4) within 14 days prior to enrollment or within 5 times the elimination half-life or PD half-life of the medication, whichever is longer; Ingested grapefruit, grapefruit juice, or grapefruit products within 72 hours prior to initial administration, or were unwilling to avoid grapefruit, grapefruit juice, or grapefruit products during treatment.
• Any other situations that the investigator considers unsuitable for the patient to participate in this study.