A Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of ARGX-113 in Patients With Myasthenia Gravis Who Have Generalized Muscle Weakness
Condition: Myasthenia Gravis
MeSH terms: Myasthenia Gravis; Muscle Weakness; Paresis
Intervention: ARGX-113; Placebo
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 24.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a randomized, double-blind, placebo-controlled, multicenter Phase II study to
      evaluate the safety, efficacy, and pharmacokinetics of ARGX-113 for the treatment of
      autoimmune Myasthenia Gravis (MG) with generalized muscle weakness.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Have the ability to understand the requirements of the study, provide written informed
             consent (including consent for the use and disclosure of research-related health
             information), and comply with the study protocol procedures (including required study
             visits).

          2. Male or female patients aged ≥18 years.

          3. Diagnosis of autoimmune MG 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 IVa, and likely not in need of a
             respirator for the duration of the study as judged by the Investigator.

             The confirmation of the diagnosis should be documented and supported by:

               -  Positive serologic test for anti-AChR antibodies before Screening and

               -  at least 1 of the following 3 tests: (i) History of abnormal neuromuscular
                  transmission test demonstrated by single-fiber electromyography or repetitive
                  nerve stimulation or (ii) History of positive edrophonium chloride test, or (iii)
                  Patient has demonstrated improvement in MG signs on oral cholinesterase
                  inhibitors as assessed by the treating physician.

          4. A total score of ≥ 5 on the MG ADL at Screening and Baseline with more than 50% of
             this score attributed to non ocular items.

          5. Patients are required to be on a stable dose of their MG treatment prior to
             randomization. For patients receiving AZA, other NSIDs, steroids, and/or
             cholinesterase inhibitors as concomitant medications the following conditions will
             apply:

               -  AZA: treatment initiated at least 12 months ago and no dose changes in the last 6
                  months before screening.

               -  Other NSIDs (e.g., methotrexate, cyclosporine, tacrolimus, mycophenolate mofetil,
                  and cyclophosphamide) treatment initiated at least 6 months ago and no dose
                  changes in the last 3 months before Screening.

               -  Steroids treatment initiated at least 3 months prior to and no dose changes in
                  the last month before Screening.

               -  Cholinesterase inhibitors: to be on a stable dose for >2 weeks before Screening.

             Note: cholinesterase inhibitors must be held for at least 12 hours consistent with the
             revised manual for the QMG test as recommended by the Myasthenia Gravis Foundation of
             America Inc (MGFA), before the MGQoL15r, MG-ADL, QMG, and MGC assessments.

          6. Females of childbearing potential must have a negative serum pregnancy test at
             Screening and a negative urine pregnancy test at Visit 1 prior to administration of
             IMP. Female of childbearing potential are defined as all female participants unless
             they are postmenopausal (defined by continuous amenorrhea) for at least 2 years with a
             Follicle stimulating hormone (FSH) > 40 IU/L or are surgically sterile (i.e., who had
             a hysterectomy, bilateral oophorectomy, or have current documented tubal ligation or
             any other permanent female sterilization procedure). Determination of FSH levels can
             be used to confirm postmenopausal status in amenorrheic patients not on hormonal
             replacement therapy if the test result is within the postmenopausal range per the
             central laboratory.

          7. Female participants of childbearing potential must agree to use a highly effective
             method of contraception (i.e., pregnancy rate of less than 1% per year) during the
             study and for 90 days after the discontinuation of the IMP. Adequate contraceptive
             methods include combined hormonal contraception associated with inhibition of
             ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception
             associated with inhibition of ovulation (oral, injectable, implantable), intrauterine
             devices (IUDs), intrauterine hormone-releasing system (IUS), true sexual abstinence
             (when this is in line with the preferred and usual lifestyle of the participant),
             bilateral tubal occlusion, or a female participant who is not of childbearing
             potential. Female participants and female partners of male study participants using a
             hormonal contraceptive must also use a barrier method (i.e., condom or occlusive cap
             [diaphragm or cervical/vault caps]) and should have been stable on their hormonal
             contraceptive treatment for at least 4 weeks before Screening.

          8. Sterilized male patients who have had vasectomy with documented aspermia post
             procedure can be included. In addition, male patients must be advised not to donate
             sperm during this period from signing of Informed Consent Form (ICF), throughout the
             duration of the study, and for 90 days after the last administration of IMP.
             Non-sterilized male patients who are sexually active with a female partner of
             childbearing potential must use effective method of double barrier contraception
             (e.g., condom with spermicidal cream or jelly, 1 hormonal plus 1 barrier method or 2
             simultaneous barrier methods). Male patients practicing true sexual abstinence (when
             this is in line with the preferred and usual lifestyle of the participant) can be
             included.

        Exclusion Criteria:

          1. Females who are pregnant or lactating.

          2. MGFA Class I, IVb, and V.

          3. Have an active infection, a recent serious infection (i.e., requiring injectable
             antimicrobial therapy or hospitalization) within the 8 weeks prior to Screening; or
             history of or known infection with human immunodeficiency virus (HIV), hepatitis B
             virus (HBV), hepatitis C virus (HCV), or Mycobacterium tuberculosis. Patients must
             have negative test results for HBV surface antigen, HBV core antibody, HCV antibody,
             HIV 1 and 2 antibodies, and a negative QuantiFERON®-TB Gold test at Screening.
             Patients with an indeterminate QuantiFERON®-TB Gold test result will be allowed one
             retest; if not negative on retesting, the patient will be excluded.

          4. At Screening, have clinically significant laboratory abnormalities or as below:

               -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 2 x upper
                  limit of normal (ULN).

               -  Total serum bilirubin of > 1.5 x ULN (except for Grade 1 hyperbilirubinemia
                  solely due to a medical diagnosis of Gilbert's syndrome).

               -  Serum creatinine > 1.5 mg/dL and creatinine clearance < 50 ml/min (using the
                  Chronic Kidney Disease Epidemiology [CKD-EPI]-Creatinine formula).

               -  Clinically Significant proteinuria (i.e., > 3 x ULN).

               -  Hemoglobin ≤ 9 g/L.

               -  Thyroid stimulating hormone or thyroglobulin outside of the central laboratory
                  normal range.

               -  International normalized ratio (INR) or activated partial thromboplastin time
                  (aPTT) > 1.2 x ULN.

               -  Total immunoglobulin G level < 6 g/L.

          5. Body Mass Index (BMI) at Screening ≥ 35 kg/m2.

          6. Use of rituximab, belimumab, eculizumab or any monoclonal antibody for
             immunomodulation within 6 months prior to first dosing. Patients with prior exposure
             to rituximab must have CD19 counts within the normal range per the central laboratory
             at Screening.

          7. Use of any biological therapy or investigational drug within 3 months or 5 half-lives
             of the drug (whichever is longer) before Screening.

          8. Immunoglobulins given by IV (IVIg), or intramuscular route, or plasmapheresis/plasma
             exchange (PE) within 4 weeks before Screening.

          9. Have known autoimmune disease other than MG that would interfere with the course and
             conduct of the study (such as uncontrolled thyroid disease or severe RA).

         10. Have received vaccinations within 4 weeks before Screening or have any vaccinations
             planned during the study.

         11. Have a history of malignancy, including malignant thymoma, or myeloproliferative or
             lymphoproliferative disorders at any time, unless deemed cured by adequate treatment
             with no evidence of recurrence for ≥5 years before Screening. Patients with completely
             excised nonmelanoma skin cancers (such as basal cell carcinoma or squamous cell
             carcinoma) or cervical carcinoma in situ would be permitted at any time.

         12. Have a history of cerebrovascular accident or myocardial infarction within the last 12
             months before Screening, or current severe/unstable angina, arrhythmia, symptomatic
             congestive heart failure New York Heart Association (NYHA) class III or IV, or
             uncontrolled hypertension.

         13. Have clinical evidence of significant unstable or uncontrolled acute or chronic
             diseases (i.e., cardiovascular, pulmonary, hematologic, gastrointestinal,
             endocrinologic, hepatic, renal, neurologic, malignancy, or infectious diseases) which,
             in the opinion of the Investigator, could confound the results of the study or put the
             patient at undue risk.

         14. Major past surgery (e.g., heart valve replacement, hip replacement) that, in the
             opinion of the Investigator, poses a risk to patient's safety or interferes with the
             study evaluation, procedures or completion.

         15. Thymectomy when performed < 3 months prior to Screening.

         16. History or presence of alcoholism or drug/chemical/substance abuse within 2 years
             before Screening per Investigator's opinion.