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

NCT07875972 | Not Yet Recruiting Phase 1 DMC

• 1 other identifier: I-26PJ2099
• Study Type: interventional
• Target: 12
• Locations: 0 countries
• Sites: N/A

Brief Summary

This is a single-center, open-label, dose-escalation, investigator-initiated pilot study to evaluate the safety, tolerability, dose-limiting toxicity (DLT), and pharmacodynamic signals of orelabrutinib in patients with amyotrophic lateral sclerosis (ALS). A 12-week run-in observation period will be used to establish each participant's historical ALSFRS-R decline slope. Participants will receive orelabrutinib 50 mg once daily (QD), 100 mg QD, or optional 150 mg QD using a 3+3 dose-escalation design for 24 weeks, followed by a 4-week safety follow-up.

Conditions

Amyotrophic Lateral Sclerosis (ALS)

Keywords

Amyotrophic Lateral Sclerosis; Orelabrutinib; BTK inhibitor; Neuroinflammation; Safety; Open-label

Outcome Measures

Primary Outcomes (6)

• Serious adverse event (SAE) incidence

  ICH-GCP definition

  Week 0, Week 1, Week 4, Week 8, Week 12, Week 16, Week 24, and Week 28

• Adverse event (AE) incidence and severity

  CTCAE v5.0 grading

  Week 0, Week 1, Week 4, Week 8, Week 12, Week 16, Week 24, and Week 28

• Dose-limiting toxicity (DLT)

  Week 4

• Number of subjects who discontinue treatment prematurely

  Week 0, Week 1, Week 4, Week 8, Week 12, Week 16, and Week 24

• Number of patients who discontinue treatment prematurely due to adverse events

  Week 0, Week 1, Week 4, Week 8, Week 12, Week 16, and Week 24

• Number of patients with clinically significant abnormal laboratory and ancillary examinations (including routine laboratory tests, cardiac safety, infection markers, bleeding markers, and new-onset tumor examinations)

  Week -12, Week -8, Week -4, Week 0, Week 1, Week 4, Week 8, Week 12, Week 16, and Week 24; tumor markers and echocardiography at Week 0, Week 4, Week 12, and Week 24; CT of the chest, abdomen, and pelvis at Week 0 and Week 24

Secondary Outcomes (15)

• Plasma Orelabrutinib concentration

  Week 0 (pre-dose, 2 h, and 8 h); trough concentrations at Week 1, Week 4, Week 12, and Week 24

• Cerebrospinal fluid (CSF) Orelabrutinib concentration

  Week 0 and Week 4 (optional; only if the subject consents and the procedure is considered safe)

• Peripheral blood PBMC BTK target occupancy (TOR %)

  Week 0, Week 1, Week 4, Week 12, and Week 24

• Peripheral blood PBMC p-BTK level

  Week 0, Week 4, Week 12, and Week 24

• Peripheral blood B-cell count

  Week 0, Week 1, Week 4, Week 12, and Week 24

Other Outcomes (17)

• Plasma NfL

  Week -12, Week -8, Week -4, Week 0, Week 4, Week 12, and Week 24

• Plasma GFAP

  Week 0, Week 4, Week 12, and Week 24

• Cerebrospinal fluid (CSF) NfL/pNfH

  Week 0 and Week 4 (optional)

Study Arms (3)

Cohort 1: Orelabrutinib 50 mg QD

EXPERIMENTAL

Participants receive orelabrutinib 50 mg orally once daily (QD) for 24 weeks.

Drug: Orelabrutinib

Cohort 2: Orelabrutinib 100 mg QD

EXPERIMENTAL

Participants receive orelabrutinib 100 mg orally once daily (QD) for 24 weeks.

Drug: Orelabrutinib

Cohort 3 (Optional): Orelabrutinib 150 mg QD

EXPERIMENTAL

Optional exploratory cohort. Participants receive orelabrutinib 150 mg orally once daily (QD) for 24 weeks.

Drug: Orelabrutinib

Interventions

Orelabrutinib DRUG

Cohort 1 planned enrollment: 3 participants; may expand to 6 if 1/3 participants experience a dose-limiting toxicity (DLT). Cohort 2 planned enrollment: 3 participants. This cohort will be initiated only after Cohort 1 completes the 28-day DLT observation period and the DSMB approves dose escalation. Cohort 3 (Optional) planned enrollment: 3 participants. This cohort will be initiated only if Cohorts 1 and 2 are safe and if BTK target occupancy / PD signals suggest insufficient target coverage, with written DSMB approval. A traditional 3+3 dose-escalation design is used,. Dose-escalation rules: If 0/3 patients experience a DLT, escalate to the next dose level; if 1/3 patients experience a DLT, expand that dose level to 6 patients; if 1/6 patients experience a DLT, escalation may proceed, whereas if ≥2/6 patients experience a DLT, the dose is deemed intolerable and escalation must stop; if ≥2/3 patients experience a DLT, escalation must stop immediately.

Cohort 1: Orelabrutinib 50 mg QD; Cohort 2: Orelabrutinib 100 mg QD; Cohort 3 (Optional): Orelabrutinib 150 mg QD

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• Tracheostomy or use of non-invasive ventilation (NIV) \> 23 h/day.
• 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.
• Unable to swallow or tolerate oral medication at screening.
• Prior or current malignancy.
• Known active HBV, HCV, or HIV infection, or any uncontrolled active systemic infection.
• Major surgery within 6 weeks before screening, or need for major surgery during the study period.
• 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.
• 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.
• 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).
• Substance abusers or alcohol abusers.
• 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.

Sponsors & Collaborators

• Liu Qing: lead

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis; Neuroinflammatory Diseases

Interventions

orelabrutinib

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Chief Physician

Study Record Dates

• First Submitted: September 28, 2026
• First Posted: October 15, 2026
• Study Start: October 1, 2026
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): October 1, 2028
• Last Updated: October 15, 2026

Record last verified: 2026-10

Data Sharing

• IPD Sharing: Will not share