Safety, Tolerability, and Pharmacodynamic Exploration of Orelabrutinib in Patients With Amyotrophic Lateral Sclerosis (ALS)

Prior treatment

• Unable to swallow or tolerate oral medication at screening.
• Prior or current malignancy.
• Major surgery within 6 weeks before screening, or need for major surgery during the study period.
• Prior exposure to BTK pathway inhibitors.
• Current use of moderate or strong CYP3A inhibitors or strong CYP3A inducers that cannot be safely discontinued or replaced before screening; moderate CYP3A4 inducers require evaluation by a pharmacist and the investigator.
• Receipt of a live vaccine within 2 weeks or planned receipt of a live vaccine during the study period (Note: inactivated vaccines may be administered according to local regulations, but the vaccination time and AEs must be recorded).

Other illness

• Known active HBV, HCV, or HIV infection, or any uncontrolled active systemic infection.
• Bleeding disorders or active bleeding events within 3 months, or current use of anticoagulant/antiplatelet drugs.
• Diseases significantly affecting gastrointestinal function, such as dysphagia, chronic diarrhea, intestinal obstruction, or gastrectomy.
• Any history of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonitis, or severe pulmonary function impairment.
• Any other relevant medically significant condition that may pose a risk to the participant, interfere with safety assessments, or increase the risk of death during the trial.

Lab values

• Abnormal liver function (ALT/AST ≥ 3×ULN), abnormal renal function (eGFR \< 60 mL/min/1.73 m²), absolute neutrophil count (ANC) ≤ 1.5×10⁹/L, platelet count ≤ 100×10⁹/L, or hemoglobin ≤ 100 g/L; international normalized ratio (INR) ≥ 1.5×ULN, activated partial thromboplastin time (APTT) ≥ 1.5×ULN.
• Current clinically significant cardiovascular disease, including: NYHA class 3 or 4 heart disease, such as arrhythmia, congestive heart failure, or myocardial infarction, or left ventricular ejection fraction (LVEF) \< 50%; primary cardiomyopathy; history of clinically significant QTc prolongation, or QTc \> 470 ms (women), QTc \> 450 ms (men); uncontrolled hypertension.

Age

• Breastfeeding or pregnant women, or women of childbearing age who are unwilling to use contraceptive measures during the trial and for 180 days after the last dose of study drug.

Other

• Tracheostomy or use of non-invasive ventilation (NIV) \> 23 h/day.
• Substance abusers or alcohol abusers.
• Unable to understand the informed consent form (ICF).

• Age 18-75 years, either sex.
• Confirmed diagnosis of ALS by a neurologist according to the Gold Coast criteria or the revised El Escorial (Airlie House) criteria, with other diseases excluded.
• Duration from disease onset to enrollment no more than 36 months.
• ALSFRS-R score ≥ 35 at screening.
• FVC% predicted ≥ 70% and SVC% predicted ≥ 70%; no resting dyspnea, orthopnea, or need for long-term non-invasive ventilation/oxygen therapy.
• Participants are able to take medication orally and are independent of enteral nutrition support (e.g., PEG, gastric tube) at screening, as judged by the principal investigator.
• Stable-dose riluzole (≥ 30 days) and/or edaravone (stable use for one course) is permitted.
• Assessed as having full capacity to provide informed consent.