A Study of Orelabrutinib in Patients With Secondary Progressive Multiple Sclerosis

A Phase 3, Randomized, Double-blind, Efficacy and Safety Study Comparing Orelabrutinib to Placebo in Patients With Non-active Secondary Progressive Multiple Sclerosis

Orelabrutinib is a CNS-penetrable BTK inhibitor. This is a phase 3, randomized, double-blind, parallel-group, multicenter study to evaluate the efficacy and safety of orelabrutinib compared with placebo in patients with non-active Secondary Progress MS. Patients will be treated for approximately 24 to 60 months, with a minimum treatment duration of 12 months. The study will enroll approximately 990 subjects in a 2:1 randomization (orelabrutinib: placebo), globally.

Study Overview

• Status: Recruiting
• Conditions: Secondary Progressive Multiple Sclerosis
• Intervention / Treatment: Drug: Orelabrutinib; Drug: Placebo

Detailed Description

This is a phase 3, randomized, double-blind, parallel-group, multicenter study to evaluate the efficacy and safety of orelabrutinib compared with placebo in patients with naSPMS. The study will enroll approximately 990 subjects in a 2:1 randomization (orelabrutinib: placebo), globally.

The study consists of the following periods:

• Screening Period: Up to 4 weeks.
• Treatment Period: The duration of treatment will vary for individual participants ranging from approximately 24 to 60 months, depending on the time of recruitment. A month is defined as a period of 28 days by convention.
• Double-blinded (DB) Treatment: All eligible participants will be randomized at 2:1 ratio to accept orelabrutinib QD or placebo during the DB treatment period. The study will be unblinded when all participants in the DB period have reached a minimum treatment duration of 12 months at the time of primary analysis timing cutoff.
• Open-label (OL) Treatment: Participants with 24-week CDP as assessed by EDSS are eligible for 2-year open-label orelabrutinib treatment.
• Safety Follow-Up Period: It will last 4 weeks. The safety follow-up period will begin when the participants discontinue from the treatment before the end of the trial for any reasons or complete the trial but do not enter the long-term safety study (LTS) (see below).

All active study participants will have a final end of study (EOS) visit within 4 weeks of the study end date. Participants who are receiving IMP in DB or OL but do not consent to or are not eligible for enrollment in the LTS study, must return for a final safety follow-up visit 4 weeks later. For participants who intend and are eligible to join the LTS, open-label treatment with orelabrutinib will continue and no safety follow-up will occur.

• Study Type: Interventional
• Enrollment (Estimated): 990
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Patient and Medical Information; Phone Number: 833-269-4696; Email: clinicaltrialsinfo@zenasbio.com
• Study Contact Backup: Name: Patient and Medical Information; Phone Number: 833-269-4696; Email: clinialtrialsinfo@zenasbio.com

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85253
      • Recruiting
      • Perseverance Research Center, LLC (PRC)
      • Principal Investigator: Barry Hendin
  • Florida
    • Maitland, Florida, United States, 32751
      • Recruiting
      • Neurology Associates
  • Massachusetts
    • Boston, Massachusetts, United States, 02131
      • Recruiting
      • Boston Clinical Trials
      • Principal Investigator: Deborah Green-LaRoche
      • Contact: Tara Strandwitz; Phone Number: 617-477-4868; Email: tara.strandwitz@bostontrials.com
      • Sub-Investigator: Tara Strandwitz
      • Sub-Investigator: Antonio Mendes
  • Texas
    • San Antonio, Texas, United States, 78258
      • Recruiting
      • Lone Star Neurology
      • Principal Investigator: Ann Bass
    • Sherman, Texas, United States, 75092
      • Recruiting
      • Texas Institute for Neurological Disorders - Sherman
      • Principal Investigator: Bharathy Sundaram
      • Contact: Laurie Jarvis; Phone Number: 903-891-4297; Email: ljarvis@texasneurologyinstitute.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 18 to 60 years of age, inclusive, at the time of signing the informed consent.
2. Participant must have a previous diagnosis of RRMS in accordance with 2024 McDonald criteria
3. Participant must have a current diagnosis of SPMS in accordance with the clinical course criteria revised in 2013
4. Participant must have documented evidence of disability progression independent of clinical relapse observed during the 24 months before screening. A written summary of the clinical evidence of disability progression must be discussed and aligned between the Investigator and the Sponsor's dedicated qualified person(s).
5. Absence of clinical relapses for at least 24 months.

Exclusion Criteria:

1. The patient has been diagnosed with primary progressive MS (PPMS) according to 2024 McDonald diagnostic criteria
2. Immunologic disorder other than MS or any other conditions requiring corticosteroid therapy.
3. History or current diagnosis of other neurological disorders that may mimic MS
4. History or current diagnosis of progressive multifocal leukoencephalopathy
5. Active, clinically significant viral, bacterial, or fungal infection
6. History of any other significant active medical condition
7. History of suicidal behavior within 6 months prior to Screening
8. Any prior history of malignancy
9. Patients on anticoagulation, or antiplatelet therapy
10. Patients took strong/moderate CYP3A inhibitors or strong/moderate CYP3A inducers within 14 days
11. Clinically significant laboratory abnormalities at Screening.
12. Vaccination with live or live-attenuated virus vaccine within 1 month prior to Screening
13. History of alcohol abuse or alcohol use disorder or other drug abuse within 12 months prior to screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Orelabrutinib Group; Orelabrutinib PO daily	Drug: Orelabrutinib; Orelabrutinib orally
Placebo Comparator: Placebo Group; Placebo PO daily	Drug: Placebo; Placebo orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to onset of confirmed disability progression (CDP) events, confirmed over at least 24 weeks	Expanded disability status scale (EDSS) score increase ≥ 1.0 point from baseline when the baseline score is ≤ 5.0, or ≥ 0.5 points from baseline when the baseline score is > 5.0	Up to approximately 120 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
12 Week CDP	Time to onset of CDP events on EDSS, confirmed over at least 12 weeks	Up to approximately 120 weeks
T2 lesions on MRI	The total number of new or enlarging T2 lesions on MRI scans of the brain	Up to approximately 120 weeks
24-week CDP-9-hole Peg Test	Time to onset of CDP events on 9-hole Peg Test (9HPT), defined as ≥ 20% increase on 9HPT from baseline, confirmed over at least 24 weeks	Up to approximately 120 weeks
24-week CDP-T25FWT	Time to onset of CDP events on Timed 25-Foot Walk Test (T25FWT), defined as ≥ 20% increase on T25FWT from baseline, confirmed over at least 24 weeks	Up to approximately 120 weeks
24-week CDI	Time to onset of confirmed disability improvement (CDI) events on EDSS, defined as ≥ 1.0-point decrease on the EDSS score from baseline when the baseline score is ≤ 5.0, or ≥ 0.5 points from baseline when the baseline score is > 5.0, confirmed over at least 24 weeks	Up to approximately 120 weeks
24-week CDI-9HPT	Time to onset of CDI events on 9HPT, defined as ≥ 20% decrease on the 9HPT score from baseline, confirmed over at least 24 weeks	Up to approximately 120 weeks
24-week CDI-T25FWT	Time to onset of CDI events on T25FWT, defined as ≥ 20% decrease on the T25FWT score from baseline, confirmed over at least 24 weeks	Up to approximately 120 weeks
Symbol Digit Modalities Test	The change in cognitive function as assessed by Symbol Digit Modalities Test (SDMT) from baseline to each scheduled visit	Up to approximately 120 weeks
Annualized relapse rate	Annualized relapse rate (ARR) during the study period assessed by protocol-defined adjudicated relapses	Up to approximately 120 weeks
To evaluate the safety and tolerability of orelabrutinib	Safety as assessed by the nature, severity, and incidence of adverse events (AEs) (graded according to National Cancer Institute-Common Terminology Criteria for AEs, NCI-CTCAE version 5.0);	Up to approximately 120 weeks

Collaborators and Investigators

• Sponsor: Zenas BioPharma (USA), LLC

Study record dates

Study Major Dates

• Study Start (Actual): March 23, 2026
• Primary Completion (Estimated): June 1, 2030
• Study Completion (Estimated): July 1, 2030

Study Registration Dates

• First Submitted: December 18, 2025
• First Submitted That Met QC Criteria: December 19, 2025
• First Posted (Actual): December 23, 2025

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: May 4, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Pathologic Processes; Chronic Disease; Disease Attributes; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Pathological Conditions, Signs and Symptoms; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; orelabrutinib
• Other Study ID Numbers: ZB020-03-002

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No