Phase 2 Randomized, Blinded, Placebo-Controlled Study of DNTH103 in Adults with Generalized Myasthenia Gravis

The primary objective of this study is to evaluate the **safety** and **tolerability** of DNTH103 in patients with Generalized Myasthenia Gravis (gMG) up to Week 13. This is clinically relevant as it aims to ensure that DNTH103 can be administered safely to patients, minimizing adverse effects while maintaining patient comfort and compliance.

Secondary objectives include: - Evaluating the clinical efficacy of DNTH103 in patients with gMG up to Week 13, which is crucial for determining the therapeutic potential of the treatment. - Assessing the **pharmacokinetics** (PK) and **pharmacodynamics** (PD) of DNTH103 in patients with gMG, providing insights into the drug's absorption, distribution, metabolism, and excretion, as well as its biological effects. - Evaluating the **immunogenicity** of DNTH103, which is important for understanding the potential for immune response against the drug. - Assessing the safety and tolerability of DNTH103 in patients with gMG over 52 weeks in the open-label extension (OLE), which will provide long-term safety data.

The clinical trial involves a total of **30 participants** diagnosed with **generalized myasthenia gravis** (gMG). The study population comprises adult males and females aged between 18 to 75 years, with a weight range of 40-120 kg. Participants were selected based on their diagnosis of gMG confirmed by specific tests, including acetylcholine receptor antibody positivity and a history of abnormal neuromuscular transmission tests. The trial includes individuals who are currently receiving immunosuppressant medications, provided they have maintained a stable dose for a specified period before randomization. Both male and female participants are required to adhere to specific contraceptive measures if of childbearing potential. The trial population is characterized by a generally stable health status, with no clinically significant abnormalities in screening tests, including serum chemistry and electrocardiograms. Participants are required to have documented vaccinations against certain bacterial pathogens within three years of enrollment or be vaccinated at least two weeks prior to randomization. The study does not exclude vulnerable populations, and participants must be willing and able to comply with all study assessments and protocol requirements.

The clinical trial is a **randomized**, **double-blind**, placebo-controlled study designed to evaluate the safety, tolerability, pharmacometrics, and efficacy of DNTH103 in adults with **generalized myasthenia gravis**. The trial is structured to include a primary treatment period of 13 weeks, followed by an open-label extension (OLE) period lasting up to 52 weeks. Participants will be randomly assigned to receive either DNTH103 or a placebo, with the administration route being either **intravenous (IV)** or **subcutaneous (SC)**. The study aims to assess the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) as primary endpoints, alongside secondary endpoints such as changes in Myasthenia Gravis Activities of Daily Living (MG-ADL) scale scores and pharmacokinetic parameters.

The sequence of study visits begins with a screening visit to confirm eligibility based on inclusion criteria, such as age, weight, and diagnosis of generalized myasthenia gravis. Participants must have a stable dose of immunosuppressant medications and meet specific health criteria. Following successful screening, participants will undergo randomization and commence the treatment phase. Regular follow-up visits will be scheduled to monitor safety, efficacy, and pharmacokinetic parameters, with assessments including serum chemistry, hematology, and electrocardiograms. The end-of-study visit will occur at the conclusion of the 13-week treatment period, with an option to continue into the OLE phase for further evaluation of long-term safety and tolerability.

Participant involvement is expected to last up to 65 weeks, encompassing both the initial treatment and OLE phases. Conditions that may lead to early termination from the study include the occurrence of significant adverse events, non-compliance with study protocols, or withdrawal of consent. The trial is anticipated to conclude by November 2026, with recruitment starting in June 2024. This study is pivotal in advancing the understanding of DNTH103's role in managing generalized myasthenia gravis, providing valuable insights into its safety and therapeutic potential.

The clinical trial involves the administration of **DNTH103**, a monoclonal antibody, formulated as a solution for injection. The pharmaceutical form is a solution for injection, and it is administered either intravenously (IV) or subcutaneously (SC). The maximum daily dose is 2400 mg, with a total maximum dose of 21600 mg over a treatment period of up to 65 weeks. Participant compliance is monitored through scheduled dosing and follow-up visits.

**Bexsero** is a suspension for injection in a pre-filled syringe, containing the Meningococcal group B Vaccine (rDNA, component, adsorbed). The active substances include recombinant Neisseria meningitidis group B NHBA fusion protein, NADA protein, FHBP fusion protein, and outer membrane vesicles (OMV) from Neisseria meningitidis group B strain NZ98/254, all adsorbed on aluminum hydroxide. The vaccine is administered via intramuscular injection, with a maximum daily dose of 0.5 ml and a total maximum dose of 1.0 ml over a 24-week period.

The **Nimenrix** vaccine is a powder and solvent for solution for injection in a pre-filled syringe, targeting Meningococcal groups A, C, W-135, and Y. The active substances are polysaccharides from Neisseria meningitidis groups A, C, W-135, and Y, each conjugated to tetanus toxoid carrier protein. The vaccine is administered intramuscularly, with a maximum daily dose of 0.5 ml and a total maximum dose of 1.0 ml over a 12-week period.

A **placebo** is used to match DNTH103, ensuring blinding in the study. The placebo is administered in a manner consistent with the experimental treatment to maintain the integrity of the trial design.

The efficacy of DNTH103 in the treatment of **generalized myasthenia gravis** (gMG) will be assessed through several secondary endpoints. These include changes from baseline to Week 13 in the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale score, the Quantitative Myasthenia Gravis (QMG) scale score, and the Myasthenia Gravis Composite (MGC) scale score. These scales are validated tools used to measure symptom severity and functional impairment in patients with gMG.

Data collection for these efficacy parameters will occur at baseline and at Week 13. The analysis will focus on the change in scores from baseline, providing a quantitative measure of the treatment's impact on disease symptoms and patient functionality. The trial will also monitor pharmacokinetic and pharmacodynamic parameters, including serum concentrations and PK parameters such as Cmax and Cmin, as well as PD parameters like CH50 (complement hemolysis 50%) in serum ex vivo. Additionally, the incidence and titer of antidrug antibodies against DNTH103 will be evaluated to assess immunogenicity.