Evaluation of TOL2 Safety, Tolerability, and Immune Response in Generalized Myasthenia Gravis Patients: A Phase I/IIa Randomized, Double-Blind, Placebo-Controlled Trial
- Trial ID
- 2024-515627-10-00
- Protocol
- TLZ-C-001
- Sponsor
- Bonsai Biotherapeutics AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and **tolerability** of TOL2 in patients with acetylcholine receptor (AChR) antibody seropositive **generalised myasthenia gravis**. This is clinically relevant as it aims to ensure that TOL2, an immune tolerising agent, can be safely administered to this patient population, potentially offering a new therapeutic option for managing this chronic autoimmune neuromuscular disorder.
Secondary objectives include:
- Determining the pharmacokinetic profile of TOL2 after single and multiple dosing, which is essential for understanding the drug's absorption, distribution, metabolism, and excretion.
- Evaluating the tolerance induction and immune modulation upon administration of TOL2, which could provide insights into the drug's mechanism of action and its potential to modulate the immune response.
- Assessing the preliminary efficacy of TOL2 treatment by evaluating myasthenia gravis scales, which could indicate the therapeutic potential of TOL2 in improving clinical outcomes for patients.
Participants
The clinical trial involves participants diagnosed with **generalised myasthenia gravis**, specifically those who are AChR antibody seropositive. The study population includes both male and female subjects, aged between 18 and 80 years. Participants are required to have clinically stable myasthenia gravis and be on stable treatment with standard-of-care therapies. The trial population was selected based on specific inclusion criteria, including a confirmed diagnosis of autoimmune myasthenia gravis with generalised muscle weakness, as defined by the Myasthenia Gravis Foundation of America Clinical Classification Class II, III, or IVA. Participants must have a positive serologic test for anti-AChR antibodies and meet additional clinical criteria. Lifestyle considerations include the requirement for women of childbearing potential and their partners, as well as male participants and their partners, to use highly effective contraception methods to prevent pregnancy during and after the trial. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the safety, tolerability, and immune response of TOL2, an immune tolerizing agent, in patients with **generalized myasthenia gravis**. This trial is a first-in-human (FIH) Phase I/IIa, multi-center study. The trial is expected to commence recruitment on January 2, 2025, and conclude by November 30, 2026. Participants will be involved in the study for a duration that includes multiple visits, starting with a screening visit, followed by several follow-up visits, and concluding with an end-of-study visit.
The sequence of study visits begins with the inclusion (screening) visit, where eligibility is assessed based on criteria such as a confirmed diagnosis of autoimmune myasthenia gravis, age between 18 and 80 years, and stable treatment with standard-of-care. Following successful screening, participants will be randomized to receive either TOL2 or a placebo. The trial involves single and multiple ascending doses of TOL2, administered intravenously. Follow-up visits will be scheduled to monitor the incidence and severity of adverse events, local tolerability reactions, and changes in vital signs, among other safety parameters. The primary endpoints focus on the incidence and severity of adverse events, while secondary endpoints include pharmacokinetic parameters and changes in anti-AChR antibody levels.
The expected length of participant involvement is determined by the dosing schedule and follow-up period, which may vary depending on the cohort assignment. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, non-compliance with study procedures, or withdrawal of consent by the participant. The study aims to provide valuable insights into the safety and efficacy of TOL2 in managing generalized myasthenia gravis, contributing to the development of new therapeutic strategies for this condition.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. The primary experimental medication is **TOL2**, a recombinant mutated extracellular domain of the human acetylcholine receptor subunit alpha1. This substance is administered as a **solution for infusion** via the **intravenous** route. TOL2 is designated as an orphan drug and is intended to assess its safety, tolerability, and immune response in patients with generalized myasthenia gravis. The dosing schedule and frequency of administration are determined based on the study protocol, and participant compliance is monitored throughout the trial.
In addition to TOL2, the trial includes the use of **Prednisolone** in various dosages as a non-experimental treatment. Prednisolone is provided in tablet form with dosages of 2.5 mg, 5 mg, and 10 mg, all administered orally. These tablets are manufactured by Pfizer AB and are classified under the ATC code H02AB06, indicating their role as glucocorticoids. The administration of Prednisolone follows a standard dosing schedule as per the trial protocol, and it serves as a standard-of-care therapy in the study.
Another non-experimental treatment used in the trial is **Glucose**, provided as a solution for infusion. This treatment is administered intravenously and is available in different formulations, including Glucos Fresenius Kabi and Glucos Fresenius Kabi 50 mg/ml. These solutions are produced by Fresenius Kabi AB and are classified under the ATC code B05BA03, representing carbohydrates. The glucose solutions are used as auxiliary treatments to support the primary objectives of the trial.
The trial also incorporates the use of **Human Albumin Solution** and **Human Normal Immunoglobulin (IV)** as auxiliary treatments. Human Albumin Solution is administered intravenously and is utilized in plasma exchange (PLEX) procedures. Human Normal Immunoglobulin (IV) is also administered intravenously and is used as an intravenous immunoglobulin (IVIg) therapy. Both substances are derived from blood and are included in the trial to provide additional therapeutic support.
Efficacy
The efficacy of the investigational product TOL2 in patients with **generalised myasthenia gravis** will be assessed through several secondary endpoints. These include changes from baseline in anti-AChR antibody levels and anti-drug antibodies (ADAs). Additionally, patient-reported outcomes will be evaluated using the Myasthenia Gravis-Activities of Daily Living (MG-ADL) score, Quantitative-Myasthenia Gravis (QMG) score, Myasthenia Gravis Composite score (MGC), and the Myasthenia Gravis Quality of Life Scale (MGQoL15r [revised version]) score. The potential for discontinuation or reduction in the dose of concomitant immunosuppressant therapy or symptomatic MG therapy will also be monitored.
Pharmacokinetic (PK) parameters will be measured in both the single ascending dose (SAD) and multiple ascending dose (MAD) parts of the trial. For the SAD part, parameters such as AUClast, Cmax, and Tmax will be assessed, with additional parameters like AUCinf, T1/2(z), CL, Vz, and Vss evaluated if possible. Dose proportionality will be determined based on AUC and Cmax. In the MAD part, parameters including AUClast, AUCtau, Cmax, Tmax, and Ctrough from Day 5 will be measured, with further parameters like T1/2(z), CL, Vz, Vss, and accumulation ratio for AUC and Cmax assessed if feasible. Dose proportionality after multiple doses will be based on AUC at steady state (AUCtau,ss) and Cmax.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
Exclusion Criteria
- Any type of vaccination within 4 weeks 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.
- 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.
- Unwillingness to abstain from participation in any other interventional clinical trial from the screening visit until the end-of-trial visit.
- Plasma donation within 1 month of screening or blood donation (or corresponding blood loss) during the last 3 months prior to screening
- 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.
- 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.
- 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.
- Any confirmed or suspected immunosuppressive or immunodeficient condition not related to the treatment of MG including a family history of congenital or hereditary immunodeficiency.
- 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.
- 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.
- 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.
- 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.
- 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.
- Participants who are pregnant, currently breastfeeding, or intend to become pregnant during the course of the trial.
- Any out-of-range safety laboratory results considered as clinically significant according to the Investigator’s judgement.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Not Yet Recruiting | 01 Jun 2026 | 14 |
 Germany | Not Yet Recruiting | 01 Jun 2026 | 21 |
 Sweden | Not Yet Recruiting | 01 Jun 2026 | 20 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Prednisolon Pfizer 10 mg tabletter | Other | TABLETTER | ORAL | — | — | PRD495058 |
Glucos Fresenius Kabi 50 mg/ml, infusionsvätska, lösning | Placebo | INFUSIONSVÄTSKA, LÖSNING | INTRAVENOUS ADMINISTRATION | — | — | PRD767189 |
ALBUMIN | Other | PHF00230MIG | INTRAVENOUS | — | — | SCP101121895 |
Prednisolon Pfizer 2,5 mg tabletter | Other | TABLETTER | ORAL | — | — | PRD467856 |
Glucose 5 % "Fresenius" - Infusionslösung | Placebo | INFUSIONSLÖSUNG | INTRAVENOUS ADMINISTRATION | — | — | PRD767209 |
IMMUNOGLOBULINS, NORMAL HUMAN, FOR INTRAVASCULAR ADM. | Other | PHF00230MIG | INTRAVENOUS | — | — | SCP11430138 |
Glucos Fresenius Kabi | Placebo | SOLUTION FOR INFUSION | INTRAVENOUS ADMINISTRATION | — | — | PRD767186 |
Prednisolon Pfizer 5 mg tabletter | Other | TABLETTER | ORAL | — | — | PRD495033 |