A Study of TAK-079 in People With Generalized Myasthenia Gravis

Study Overview
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Brief Summary
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Myasthenia gravis is an autoimmune condition that causes muscle weakness. Autoimmune means the body makes antibodies that attack its own cells and tissues. These types of antibodies are also known as autoantibodies. People with generalized myasthenia gravis have a weakness in many muscles. TAK-079 is a medicine to help people with generalized myasthenia gravis. The main aim of this study is to check if people with generalized myasthenia gravis have side effects from 2 doses of TAK-079. Other aims are to learn if TAK-079 improves their clinical condition and lowers their autoantibody levels. At the first visit, the study doctor will check if each person can take part. For those who can take part, participants will continue with their standard medicines for this condition during the study. Each participant will have a check-up by the study doctor. Then, the participants will have 1 of 3 treatments: A low dose of TAK-079. A high dose of TAK-079. A placebo. In this study, a placebo looks like TAK-079 but does not have any medicine in it. Participants will not know which treatment they received, nor will their study doctors. This is to help make sure the results are more reliable. For each treatment, participants will receive injections just under the skin, once a week for 8 weeks. The study doctors will check for side effects from the study treatments. The study doctors can stop or delay the injections in each participant if needed. Then, the study doctors will continue to check for side effects for up to 24 weeks after treatment. They will also check the clinical condition of the participants, including their autoantibody levels.

Detailed Description
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Myasthenia gravis (MG) is an autoimmune disorder in which autoantibodies, such as those targeting the nicotinic acetylcholine receptor (AChR) or muscle specific kinase (MuSK), interfere with neuromuscular transmission, resulting in fatigue and weakness. The drug being tested in this study is called TAK-079. TAK-079 is being tested to treat people who have generalized myasthenia gravis.

Official Title
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A Phase 2, Randomized, Placebo-Controlled Study to Evaluate Safety, Tolerability, and Efficacy of TAK-079 in Patients With Generalized Myasthenia Gravis

Conditions
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Myasthenia Gravis

Intervention / Treatment
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* Drug: TAK-079
* Drug: TAK-079 Placebo


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Diagnosis of Myasthenia Gravis (MG) supported by a positive serologic test for anti-AChR or anti-MuSK antibodies at screening. Myasthenia Gravis Foundation of America (MGFA) clinical classification II to IV at screening. Myasthenia Gravis Activities of Daily Living (MG-ADL) total score of 6 or greater at screening, with at least 4 points attributed to nonocular items. If receiving immunosuppressive drugs (ie, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, cyclophosphamide), therapy must be ongoing for at least 6 months, with stable dosing ongoing for at least 3 months before screening. Participants receiving azathioprine must be on a stable dose for at least 6 months before screening. If receiving oral corticosteroids, therapy must be ongoing for at least 3 months, with a stable dose at least 1 month before screening. Corticosteroids, including dexamethasone, must be given as oral, daily or every-other-day therapy, as opposed to pulse therapy. If receiving cholinesterase inhibitors, therapy with a stable dose is required at least 2 weeks before screening. The doses of concomitant standard background therapy must be expected to remain stable throughout the study unless dose reduction is required due to toxicities. Allowed background therapy is defined as no more than a cholinesterase inhibitor ± corticosteroid ± 1 steroid-sparing immunosuppressive drug (limited to azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, or cyclophosphamide). Participants must be on at least one allowed background medication. Main Exclusion Criteria: Presence of a thymoma (previous history of a fully encapsulated thymoma removed ≥ 12 months before screening is allowed) or history of invasive thymic malignancy unless deemed cured by adequate treatment with no evidence of recurrence for ≥ 5 years before screening. History of thymectomy within 12 months before screening. MGFA class I or V. Received intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin (SCIg), or plasmapheresis/plasma exchange within 4 weeks before screening, or an expectation that any therapy besides the participants standard background therapies may be used for treatment of MG (eg, a rescue therapy) between screening and dosing. Chronic obstructive pulmonary disease (COPD) or asthma with a pre-bronchodilatory forced expiratory volume in 1 second (FEV1) <50% of predicted normal. Note: FEV1 testing is required for participants suspected of having COPD or asthma. Received rituximab, belimumab, eculizumab, or any monoclonal antibody for immunomodulation within 6 months before first dosing. Participants with prior exposure to rituximab must have CD19 counts within the normal range at screening. Known autoimmune disease other than MG that could interfere with the course and conduct of the study. Received a live vaccine within 4 weeks before screening or has any live vaccination planned during the study. Opportunistic infection ≤12 weeks before initial study dosing or currently receiving treatment for a chronic opportunistic infection, such as tuberculosis (TB), pneumocystis pneumonia, cytomegalovirus, herpes simplex virus, herpes zoster, or atypical mycobacteria. A mild, localized herpes simplex infection within 12 weeks of study dosing is allowed, as long as the lesion has resolved without systemic therapy prior to Day 1.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: TAK-079 Placebo-matching<br>TAK-079 placebo-matching injection, subcutaneously (SC), once weekly in combination with standard background therapy for 8 weeks. | Drug: TAK-079 Placebo<br>* TAK-079 placebo-matching subcutaneous injection<br>|
| Experimental: TAK-079 300 mg<br>TAK-079 300 mg injection, SC, once weekly in combination with standard background therapy for 8 weeks. | Drug: TAK-079<br>* TAK-079 subcutaneous injection<br>* Other names: Mezagitamab;|
| Experimental: TAK-079 600 mg<br>TAK-079 600 mg injection, SC, once weekly in combination with standard background therapy for 8 weeks. | Drug: TAK-079<br>* TAK-079 subcutaneous injection<br>* Other names: Mezagitamab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Grade 3 or Higher TEAEs, and Adverse Event (AE) Leading to TAK-079 Discontinuation | AE is defined as any untoward medical occurrence in clinical investigation participant administered drug; it does not necessarily have to have causal relationship with this treatment. TEAE is defined as AE with onset that occurs after receiving study drug. SAE is an adverse event resulting in any of following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Severity of TEAEs was graded using National cancer institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 definitions of Grade 1 through Grade 5 wherein Grade 1=mild symptoms, Grade 2=moderate symptoms, Grade 3=Severe or medically significant but not immediately life-threatening, Grade 4=life-threatening consequences and Grade 5=death related to AEs. Percentages are rounded off to whole number at single decimal. | From signing the informed consent form up to end of long-term follow-up (up to Week 32) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) Scale Score | Participant-reported scale to assess MG symptoms to evaluate capacity to perform activities of daily living. Each question is graded on a 4-point scale from 0=normal to 3=severe with a total score of 0 to 24; the higher score indicates greater functional impairment and disability. Negative change indicates improvement. Mixed-effects model for repeated measures (MMRM) was used for the analysis. | Baseline up to Week 32 | 
| Change From Baseline in Quantitative Myasthenia Gravis (QMG) Scale Score | Physician-reported scale to assess MG disease severity by quantifying several body functions by physical exam. Each question is graded on a 4-point scale from 0=normal to 3=severe with a total score of 0 to 39; the higher score indicates greater disease burden. Negative change indicates improvement. MMRM was used for the analysis. | Baseline up to Week 32 | 
| Change From Baseline in Myasthenia Gravis Composite (MGC) Scale Score | An assessment scale of MG disease activity based on a combination of participant- and physician-reported items. Items are scored based on 4 potential levels of impact: normal, mild, moderate, or severe with a total score of 0 to 50; the higher score indicates worse MG disease activity. Negative change indicates improvement. MMRM was used for the analysis. | Baseline up to Week 32 | 
| Change From Baseline in Revised 15-item Myasthenia Gravis Quality of Life Scale (MG-QoL15r) Scale Score | A participant-reported score that assesses the participant's perception of impairment and disability and the degree to which the participant tolerates disease manifestations. Each question is graded on a 3-point scale from 0=normal to 2=severe with a total score of 0 to 30; the higher score indicates worse MG disease activity. Negative change indicates improvement. MMRM was used for the analysis. | Baseline up to Week 32 | 
| Change From Baseline in Anti-acetylcholine Receptor (AChR) Antibody Levels | Clinical laboratory evaluations of anti-AChR antibodies were tested to monitor disease activity. MMRM was used for the analysis. | Baseline up to Week 32 | 
| Change From Baseline in Anti- Muscle-specific Tyrosine Kinase (MuSK) Titer Levels | Clinical laboratory evaluations of anti-MuSK antibodies were tested to monitor disease activity. Data is reported for participants who were positive for anti-MuSK antibodies at baseline. | Baseline up to Week 32 | 
| Percentage of Participants With 2-point Reduction in MG-ADL Total Score | The percentage of responders with at least a 2-point reduction in MG-ADL total score from baseline is reported. MG-ADL is a participant-reported scale to assess MG symptoms to evaluate capacity to perform activities of daily living. Each question is graded on a 4-point scale from 0=normal to 3=severe with a total score of 0 to 24; the higher score indicates greater functional impairment and disability. Percentages are rounded off to whole number at the nearest decimal. | At Weeks 4, 6, 8, 10, 12, 14, 16, 20, 24, 28 and 32 | 
| Percentage of Participants With 3-point Reduction in QMG Total Score | The percentage of responders with at least a 3-point reduction in QMG total score from baseline is reported. QMG is a physician-reported scale to assess MG disease severity by quantifying several body functions by physical exam. Each question is graded on a 4-point scale from 0=normal to 3=severe with a total score of 0 to 39; the higher score indicates greater disease burden. Percentages are rounded off to whole number at the nearest decimal. | At Weeks 4, 6, 8, 10, 12, 14, 16, 20, 24, 28 and 32 | 
| Percentage of Participants With 3-point Reduction in MGC Total Score | The percentage of responders with at least a 3-point reduction in MGC total score from baseline is reported. MGC is an assessment scale of MG disease activity based on a combination of participant- and physician-reported items. Items are scored based on 4 potential levels of impact: normal, mild, moderate, or severe with a total score of 0 to 50; the higher score indicates worse MG disease activity. Percentages are rounded off to whole number at the nearest decimal. | At Weeks 4, 6, 8, 10, 12, 14, 16, 20, 24, 28 and 32 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy