Efficacy and Safety of Tolebrutinib (SAR442168) Tablets in Adult Participants With Generalized Myasthenia Gravis

NCT05132569 | Terminated Phase 3 Results DMC FDA Drug

• 3 other identifiers: EFC17262U1111-1265-63782021-003898-59
• Study Type: interventional
• Target: 6
• Locations: 9 countries
• Sites: 22

Brief Summary

This was a multicenter, randomized, double-blind, placebo-controlled, Phase 3 study to evaluate the efficacy and safety of tolebrutinib compared with placebo in adult participants aged 18 to 85 years old with moderate-to-severe generalized myasthenia gravis (gMG), who received Standard of Care (SoC). The double-blind (DB) treatment period of 26 weeks comprised of 7 site visits followed by a 2-year open label extension (OLE) period with quarterly visits. The efficacy of tolebrutinib versus placebo during the DB period was assessed by clinical evaluations, including scales based on physician examination or direct participant feedback i.e., patient reported outcomes (PROs). These evaluations continued during the OLE to measure long term efficacy and safety.

Conditions

Myasthenia Gravis

Outcome Measures

Primary Outcomes (6)

• DB Period: Change From Baseline in Myasthenia Gravis-activities of Daily Living (MG-ADL) Total Score at Week 26

  The MG-ADL is an 8-item patient-reported categorical scale that assesses MG symptoms and their effects on daily activities. The MG-ADL targeted symptoms and disability across ocular (2 items), bulbar (3 items), respiratory (1 items), and gross motor or limb impairment (2 items) symptoms. It evaluates a participant's capacity to perform different activities in their daily life. Each item is scored on a 4-point scale ranged from 0 (normal) to 3 (severe), where higher score represents the more severe symptoms or impaired performance. MG-ADL total score is the sum of each item score which ranged from 0 (normal) to 24 (severe). Higher score represents severe disability due to MG. DB period Baseline value was defined as last available value prior to the first dose of the study medication in the DB period.

  Baseline (Day 1), Week 26

• OLE Period: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Events Leading to Permanent Study Intervention Discontinuation and Adverse Events of Special Interests (AESIs)

  An AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. A SAE was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was a medically important event. An AESI was defined as one of scientific \& medical concern specific to the Sponsor's product or program, for which ongoing monitoring and immediate notification by the Investigator to the Sponsor was considered appropriate. Relatedness to study vaccine was based on Investigator's discretion.

  From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)

• OLE Period: Number of Participants With Hematological Abnormalities

  Hematological parameters assessed were: platelet count, red blood cell count, hemoglobin, hematocrit, white blood cell, neutrophils, lymphocytes, monocytes, eosinophils, and basophils. Only those categories in which at least 1 participant had data were reported.

  From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)

• OLE Period: Number of Participants With Clinical Chemistry Parameter Abnormalities

  Clinical chemistry parameters assessed were blood urea nitrogen, creatinine, glucose, total and direct bilirubin, potassium, sodium, chloride, bicarbonate, calcium, albumin, creatine phosphokinase, alkaline phosphatase, aspartate aminotransferase/serum glutamic-oxaloacetic transaminase, alanine aminotransferase/serum glutamic-pyruvic transaminase, lipase, and total protein. Only the category (Alkaline phosphatase) in which at least 1 participant had data were reported.

  From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)

• OLE Period: Number of Participants With Electrocardiogram (ECG) Abnormalities

  ECG parameters assessed were heart rate, pulse rate, QRS interval, QT interval and QT interval corrected using Fridericia's formula \[QTcF\]).

  From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)

• OLE Period: Number of Participants With Vital Signs Abnormalities

  Vital signs assessed were heart rate, systolic blood pressure, diastolic blood pressure, weight and temperature. Only those category (Weight \>=5% decrease from Baseline) in which at least 1 participant had data were reported.

  From Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61)

Secondary Outcomes (18)

• DB Period: Change From Baseline in Quantitative Myasthenia Gravis (QMG) Total Score at Week 26

  Baseline (Day 1), Week 26

• DB Period: Change From Baseline in Quantitative Myasthenia Gravis (QMG) Total Score at Week 12

  Baseline (Day 1), Week 12

• DB Period: Change From Baseline in Myasthenia Gravis Impairment Index (MGII) Total Score at Week 26

  Baseline (Day 1), Week 26

• DB Period: Change From Baseline in Myasthenia Gravis-quality of Life 15-item Scale (MG-QoL15) Total Score at Week 26

  Baseline (Day 1), Week 26

• DB Period: Percentage of Participants With Greater Than Equal to (>=) 2-point Improvement (Reduction) in Myasthenia Gravis-activities of Daily Living Total Score at Week 26

  Week 26

Study Arms (2)

Placebo/Tolebrutinib

PLACEBO COMPARATOR

Participants with moderate-to-severe gMG received placebo (matched to tolebrutinib) tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period. Participants who completed the DB period entered the OLE period and received tolebrutinib 60 milligrams (mg) orally daily along with SoC starting from Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61).

Drug: Tolebrutininb; Drug: Placebo

Tolebrutinib/Tolebrutinib

EXPERIMENTAL

Participants with moderate-to-severe gMG received tolebrutinib 60 mg tablet orally once daily as an add-on therapy to their SoC for 26 weeks in the DB treatment period. Participants who completed the DB period entered the OLE period and continued to receive tolebrutinib 60 mg orally daily along with SoC starting from Week 27 up to an additional 35 weeks in the OLE period until the study termination (i.e., up to Week 61).

Drug: Tolebrutininb

Interventions

Tolebrutininb DRUG

Pharmaceutical form: Film-coated tablet Route of administration: Oral

Placebo/Tolebrutinib; Tolebrutinib/Tolebrutinib

Placebo DRUG

Pharmaceutical form: Film-coated tablet Route of administration: Oral

Placebo/Tolebrutinib

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants were 18 years of age to 85 years of age inclusive, at the time of signing the informed consent.
• Participants with a diagnosis of gMG at screening with generalized muscle weakness meeting the clinical criteria for diagnosis of MG, as defined by the myasthenia gravis foundation of America (MGFA) Clinical Classification Class II, III, or IV, and likely not in need of a respirator for the duration of the study, as judged by the Investigator.
• Positive serologic testing for anti-acetylcholine receptor (anti-AChR) or anti-muscle-specific kinase (anti-MuSK) autoantibody at screening OR
• Seronegative for both anti-AChR and anti-MuSK autoantibodies and with prior diagnosis supported by greater than or equal to (\>=) 1 of the following 3 tests:
• History of abnormal neuromuscular transmission demonstrated by single-fiber electromyography or repetitive nerve stimulation.
• History of positive edrophonium chloride test.
• Participant had demonstrated improvement in gMG signs on oral acetylcholinesterase inhibitors as assessed by the treating physician.
• The participant had a total score \>=6 on myasthenia gravis-activities of daily living scale at screening and Day 1 with greater than half of the score attributed to non-ocular items.

You may not qualify if:

• MGFA Class I (ocular MG) or Class V.
• Participants had undergone thymectomy within 6 months of screening or having a planned thymectomy during the trial period.
• The participant had a history of infection or might be at risk for infection: A history of active or latent tuberculosis (TB); Participants at risk of developing or having reactivation of hepatitis; Persistent chronic or active recurring infection required treatment with antibiotics, antivirals, or antifungals; Fever within 4 weeks of the Screening Visit (\>=38 degree Celsius; however, if due to brief and mild ear, nose, throat viral infection participant might be included based on the Investigator's judgment); A history of infection with human immunodeficiency virus (HIV); A history of T-lymphocyte or T-lymphocyte-receptor vaccination, transplantation (including solid organ, stem cell, and bone marrow transplantation) and/or antirejection therapy.
• Conditions that might predispose the participant to excessive bleeding.
• Clinically significant laboratory abnormalities (including evidence of liver injury) or electrocardiogram abnormalities at Screening.
• The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Sponsors & Collaborators

• Sanofi: lead

Study Sites (22)

Georgetown University-Site Number:8400008

Washington D.C., District of Columbia, 20007, United States

Location

SFM Clinical Research, LLC-Site Number:8400006

Boca Raton, Florida, 33487, United States

Location

University of South Florida Health- Morsani Center for Advanced Healthcare-Site Number:8400001

Tampa, Florida, 33612-6601, United States

Location

Harvard Medical School - Brigham and Women's Hospital-Site Number:8400004

Boston, Massachusetts, 02115, United States

Location

Neurology Center of San Antonio, PA-Site Number:8400009

San Antonio, Texas, 00000, United States

Location

Investigational Site Number :1240004

Edmonton, Alberta, T6G 2B7, Canada

Location

Investigational Site Number :1240003

London, Ontario, N6A 5A5, Canada

Location

Investigational Site Number :1560003

Chengdu, 610041, China

Location

Investigational Site Number :1560001

Shanghai, 200040, China

Location

Investigational Site Number :1560002

Wuhan, 430030, China

Location

Investigational Site Number :3480002

Pécs, 7623, Hungary

Location

Investigational Site Number :3480001

Szeged, 6725, Hungary

Location

Investigational Site Number :3800002

Milan, Lombardy, 20133, Italy

Location

Investigational Site Number :3800001

Milan, 20132, Italy

Location

Investigational Site Number :3800004

Napoli, 80131, Italy

Location

Investigational Site Number :3800003

Roma, 00168, Italy

Location

Investigational Site Number :3920002

Sagamihara-shi, Kanagawa, 252-0392, Japan

Location

Investigational Site Number :6160001

Zabrze, 41-800, Poland

Location

Investigational Site Number :7240003

L'Hospitalet de Llobregat, Catalunya [Cataluña], 08907, Spain

Location

Investigational Site Number :7240005

Madrid, Madrid, Comunidad de, 28046, Spain

Location

Investigational Site Number :8260002

Exeter, Devon, EX2 5DW, United Kingdom

Location

Investigational Site Number :8260001

Liverpool, L9 7LJ, United Kingdom

Location

Related Links

• EFC17262 Plain Language Results Summary

MeSH Terms

Conditions

Myasthenia Gravis

Condition Hierarchy (Ancestors)

Paraneoplastic Syndromes, Nervous System; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Paraneoplastic Syndromes; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Neurodegenerative Diseases; Neuromuscular Junction Diseases; Neuromuscular Diseases; Autoimmune Diseases; Immune System Diseases

Limitations and Caveats

The study was prematurely terminated by the Sponsor due to strategic reasons and was not based on any safety issues. Hence, several planned efficacy analysis were not conducted for the study.

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi aventis recherche & développement

Contact-US@Sanofi.com

800-633-1610

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 12, 2021
• First Posted: November 24, 2021
• Study Start: December 3, 2021
• Primary Completion: February 21, 2023
• Study Completion: February 21, 2023
• Last Updated: September 9, 2025
• Results First Posted: April 8, 2024

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share

Locations

CN (3); US (5); HU (2); PL (1); GB (2); ES (2); CA (2); IT (4); JP (1)