A double-blind, randomised, placebo-controlled, first-in-human (FIH) Phase I/IIa, multi-centre trial to assess safety, tolerability, and immune response of single and multiple ascending doses of TOL2 (Immune Tolerising Agent) in patients with generalised myasthenia gravis

Prior treatment

• Any type of vaccination within 4 weeks prior to the first administration of IMP.
• Thymectomy within 12 months prior to the first administration of IMP or scheduled to occur during the study period.
• Any planned major surgery within the duration of the trial.
• History of plasmapheresis within 3 months prior to the first administration of IMP.
• Use of any prohibited medications as defined in Section 9.6.2. Stable treatment with standard of care such as corticosteroids, 1 immunosuppressive drug with or without concomitant use of corticosteroids, Rituximab and/or cholinesterase inhibitors is allowed as defined in Section 9.6.2.
• Planned treatment or treatment with another investigational drug unless 3 months, or 5 half-lives and/or PD activity of the investigational drug, whichever is longer have elapsed prior to Day 1.
• Plasma donation within 1 month of screening or blood donation (or corresponding blood loss) during the last 3 months prior to screening
• Patients with a history, or presence of, a primary or recurrent malignancy including malignant thymoma, or myeloproliferative or lymphoproliferative disorders, unless deemed cured by adequate treatment with no evidence of recurrence for at least 12 months before screening. Patients with completely excised non-melanoma skin cancer (such as basal cell carcinoma or squamous cell carcinoma) or cervical carcinoma in situ may be included in the trial.

Other illness

• Any confirmed or suspected immunosuppressive or immunodeficient condition not related to the treatment of MG including a family history of congenital or hereditary immunodeficiency.
• Patients with a history of MG crises where ventilator support was needed.
• Patients with any active infection, including clinically significant chronic or long-standing infections (e.g., stable and/or ongoing for more than 4 weeks), as judged by the Investigator.
• Patients with type 1 diabetes mellitus (T1D).
• History of Lambert-Eaton myasthenic syndrome, drug-induced MG, hereditary forms of myasthenic syndrome.
• Major congenital defects or history or presence of chronic degenerative, psychiatric, neurological disorder, other serious chronic illness other than MG, or any condition, which in the opinion of the Investigator, might interfere with the patient’s participation in the trial, poses any added risk for the patient, or confounds the assessment of the patient.
• History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to TOL2.
• Any clinically significant new or unstable illness, or significant worsening of ongoing condition, or medical/surgical procedure or trauma, within 4 weeks of the administration of IMP, as determined by the Investigator.

Lab values

• 11. Any positive result at the screening visit for serum hepatitis B surface antigen, (HBsAG), hepatitis B or C antibodies (anti-HBc or anti-HCV) and/or human immunodeficiency virus (HIV). NOTE: Participants who test positive only for hepatitis B surface antibody (anti-HBs+) are considered eligible.
• Severe hepatic, renal or cardiac insufficiency at screening defined as: • Liver: o Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level ≥2.5xupper limit of normal (ULN) o Total bilirubin ≥2.0xULN • Kidney: estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 • Heart: prolonged QTcF (>450 ms), cardiac arrhythmias or any clinically significant abnormalities in the resting ECG, as judged by the Investigator.
• Any out-of-range safety laboratory results considered as clinically significant according to the Investigator’s judgement.

Other

• Patients with clinically unstable MG, as determined by the Investigator. A >2 point worsening of the MG-ADL score since the last observation will warrant an assessment of the clinical relevance of the deterioration by the Investigator, who will take into consideration both the MG characteristics of the specific patient and the eligibility criteria. The Investigator can engage in a discussion with the medical monitor if deemed appropriate.
• Participants who are pregnant, currently breastfeeding, or intend to become pregnant during the course of the trial.
• Unwillingness to abstain from participation in any other interventional clinical trial from the screening visit until the end-of-trial visit.
• The Investigator considers the participant unlikely to comply with trial procedures, restrictions, and requirements.
• MG patients of Grade I, IVB or V based on MGFA Clinical Classification.

• Provision of signed and dated informed consent to participate in the trial.
• Diagnosis of autoimmune MG with generalised 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 ventilator for the duration of the trial as judged by the Investigator. The confirmation of the diagnosis should be documented and supported by: • A positive serologic test for anti-AChR antibodies before or at screening AND • At least 1 of the following 3 tests: o History of abnormal neuromuscular transmission test demonstrated by single fibre electromyography (SFEMG) or repetitive nerve stimulation OR o History of positive cholinesterase inhibitor test with unambiguous effects on ptosis and ocular motility OR o Patient has demonstrated improvement in MG signs on oral cholinesterase inhibitors as assessed by the treating physician.
• MG-ADL score ≥5.
• Between 18 and 80 years, inclusive, at screening.
• Blood pressure and heart rate (supine) within normal reference ranges or results within acceptable deviations that are judged as not clinically significant by the Investigator.
• Venous access sufficient to allow blood sampling as per the protocol.
• Women of childbearing potential (WOCBP) must practice abstinence from heterosexual intercourse (only allowed when this is the preferred and usual lifestyle of the participant) or must agree to use a highly effective method of contraception with a failure rate of <1 % to prevent pregnancy from at least 2 weeks prior to the (first) administration of IMP to 4 weeks after the last administration of IMP. In addition, any male partner of a female participant must, unless he has undergone vasectomy, agree to use a condom from the first administration of IMP until 4 weeks after the last administration of IMP. WOCBP must refrain from donating eggs from the first IMP administration until 3 months after the last IMP administration. Male participants must, unless they have undergone previous vasectomy, be willing to use condom or practice sexual abstinence from heterosexual intercourse (only allowed when this is the preferred and usual lifestyle of the participant) to prevent pregnancy and drug exposure of a partner and refrain from donating sperm from the first administration of IMP until 3 months after the last administration of IMP. Any female partner of a non-vasectomised male participant who is of childbearing potential must use contraceptive methods with a failure rate of < 1% to prevent pregnancy (see above) from at least 2 weeks prior to the first administration of IMP until 4 weeks after the last administration of IMP.
• Patients with clinically stable MG, and on stable treatment with standard-of-care according to local medical practice, with prior consideration of available options, as determined by the Investigator.