A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 3-Arm, 3-Period Study to Assess the Efficacy and Safety of a New Formulation of Oral Cladribine Compared with Placebo in Participants with Generalized Myasthenia Gravis (MyClad)

The primary objective of this study is to assess the clinical efficacy of cladribine capsules at high and low doses in the treatment of generalized myasthenia gravis compared to placebo. This evaluation is clinically relevant for determining whether cladribine can provide therapeutic benefit in patients with this autoimmune neuromuscular disorder characterized by fluctuating muscle weakness.

The secondary objectives include:

• To evaluate the efficacy of cladribine capsules in the treatment of generalized myasthenia gravis relative to placebo.

• To assess the duration of the effect of the initial cladribine full dose, which is important for understanding the sustained therapeutic benefit and potential treatment intervals.

• To assess the safety of cladribine capsules in generalized myasthenia gravis, providing critical information on the tolerability and adverse event profile in this patient population.

• To characterize the pharmacokinetics of the new oral cladribine formulation in generalized myasthenia gravis within a rich pharmacokinetic sampling group, which will provide essential data on drug absorption, distribution, and elimination in this specific disease context.

This clinical trial enrolled a total of **196 participants** diagnosed with **Generalized Myasthenia Gravis** presenting with generalized muscle weakness. The study population included both **male and female subjects** across **adult and elderly age groups**. Participants were required to meet clinical criteria for Myasthenia Gravis Foundation of America Class II to IVa classification and demonstrate a baseline MG-ADL score of 6 or higher, with at least 50% of the total score attributed to non-ocular symptoms. The trial population was selected to include individuals who tested positive for **acetylcholine receptor antibody** (anti-AChR) or **muscle-specific kinase antibody** (anti-MuSK), as well as autoantibody seronegative participants and those positive for anti-low-density lipoprotein receptor-related protein 4 antibodies (anti-LRP4). Participants treated with **oral corticosteroids** were required to maintain a stable daily dose not exceeding 20 mg/day for prednisone/prednisolone or 16 mg/day for methylprednisolone for at least 3 months prior to and during screening. Those receiving **acetylcholinesterase inhibitor** therapy were also required to be on a stable dose for at least 3 months before and during the screening period. A minimum body weight of 40 kilograms was required for enrollment. The study included a **vulnerable population**.

This is a Phase 3, randomized, double-blind, placebo-controlled, 3-arm, 3-period clinical trial designed to evaluate the efficacy and safety of a new formulation of oral cladribine compared with placebo in participants with generalized myasthenia gravis. The primary objective is to assess the clinical efficacy of cladribine capsules at high and low doses on generalized myasthenia gravis relative to placebo. The study employs a controlled design to minimize bias and ensure robust evaluation of the investigational medicinal product. The trial is estimated to commence recruitment in December 2024 and is projected to conclude in August 2030.

Eligible participants must have a diagnosis of myasthenia gravis with generalized muscle weakness, meeting clinical criteria for Myasthenia Gravis Foundation of America Class II to IVa classification. Participants must be positive for acetylcholine receptor antibody or muscle-specific kinase antibody, or be autoantibody seronegative or positive for anti-low-density lipoprotein receptor-related protein 4 antibodies. At screening and baseline, participants must demonstrate an MG-ADL score of 6 or greater, with at least 50 percent of the total score attributed to non-ocular symptoms. The screening and baseline MG-ADL scores must remain stable, with a difference not exceeding 2 points and no reported myasthenia gravis exacerbation during the screening period. Participants treated with oral corticosteroids must maintain a stable daily dose for at least 3 months prior to and during screening, not exceeding 20 milligrams per day for prednisone or prednisolone, or 16 milligrams per day for methylprednisolone. Those receiving acetylcholinesterase inhibitor therapy must also be on a stable daily dose for at least 3 months prior to and during screening. Additionally, participants must have a body weight of 40 kilograms or greater.

The investigational medicinal products include cladribine administered as hard capsules via the oral route, with a maximum treatment period of 144 weeks. A matching cladribine placebo is utilized in the control arm. An auxiliary medicinal product, Shingrix, a recombinant adjuvanted herpes zoster vaccine administered as a suspension for injection via intramuscular injection, is also included in the trial protocol. The maximum dose of Shingrix is 0.5 milliliters per administration, with a maximum treatment period of 2 weeks.

The primary endpoint is the change from baseline in Myasthenia Gravis - Activities of Daily Living scale score at Week 24 during the double-blind placebo-controlled period. Secondary endpoints include the change from baseline in Quantitative Myasthenia Gravis scale score at Week 24, the percentage of MG-ADL responders at Week 24, the change from baseline in Myasthenia Gravis Composite scale score at Week 24, the percentage of Quantitative Myasthenia Gravis scale responders at Week 24, and the change from baseline in the Revised Myasthenia Gravis Quality of Life – 15 Scale score at Week 24. Additional secondary endpoints assess the time from initial cladribine full dose treatment to first retreatment or rescue treatment up to the end of study, the number of participants with adverse events and adverse events of special interest, the number of participants with adverse events by severity as per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, the number of participants with abnormal laboratory variables including absolute lymphocyte count and vital signs, and pharmacokinetic plasma concentrations of cladribine.

Participant involvement spans multiple study periods with scheduled visits for efficacy and safety assessments. The screening visit serves to confirm eligibility based on inclusion and exclusion criteria, establish baseline measurements, and ensure stability of disease parameters. Follow-up visits during the double-blind placebo-controlled period occur at regular intervals to monitor treatment response, assess primary and secondary endpoints, collect safety data, and obtain pharmacokinetic samples. The end-of-study visit is conducted to perform final efficacy and safety evaluations. The overall duration of participant involvement extends up to the completion of all study periods, with the total trial duration estimated at approximately 6 years. Early termination from the study may occur due to adverse events, participant withdrawal of consent, protocol non-compliance, disease exacerbation requiring alternative therapy, or at the discretion of the investigator for safety reasons.

The experimental medication **cladribine** is administered as **hard capsules** via the **oral route**. The treatment period extends up to 144 weeks. The pharmaceutical form is a hard capsule formulation containing cladribine as the active substance. The sponsor product code for this investigational medicinal product is MS700568. Dosing information will be determined according to the study protocol, with high and low dose regimens being evaluated in this three-arm clinical trial design.

A **placebo** comparator matching the cladribine formulation is included in the study design. The placebo is administered to provide a control arm for comparison with the active treatment groups. The placebo formulation is designed to maintain blinding throughout the double-blind phase of the trial.

**Shingrix** is utilized as an auxiliary medication in this clinical trial. The product is a **recombinant varicella zoster virus glycoprotein E vaccine** (adjuvanted) supplied as powder and suspension for suspension for injection. The pharmaceutical form for administration is a **suspension for injection**. The vaccine is administered via **intramuscular injection** at a dose of **0.5 ml**. The maximum daily dose and maximum total dose per administration are both 0.5 ml. The treatment period for this auxiliary medication is 2 weeks. The product is manufactured by GlaxoSmithKline Biologicals S.A. and holds marketing authorization number EU/1/18/1272/001.

Efficacy will be assessed through multiple parameters evaluating **myasthenia gravis** disease activity and functional status. The primary efficacy endpoint is the change from baseline in **Myasthenia Gravis - Activities of Daily Living (MG-ADL) Scale** score at Week 24 during the double-blind placebo-controlled period. Secondary efficacy endpoints include the change from baseline in **Quantitative Myasthenia Gravis (QMG) Scale** score at Week 24 during the double-blind placebo-controlled period, the percentage of MG-ADL responders at Week 24 during the double-blind placebo-controlled period, the change from baseline in **Myasthenia Gravis Composite (MGC) Scale** score at Week 24 during the double-blind placebo-controlled period, the percentage of Quantitative Myasthenia Gravis (QMG) Scale responders at Week 24 during the double-blind placebo-controlled period, and the change from baseline in the **Revised Myasthenia Gravis Quality of Life – 15 Scale (MG-Qol15r)** score at Week 24 during the double-blind placebo-controlled period. Additional secondary endpoints include the time from initial cladribine full dose treatment to first retreatment or rescue treatment up to end of study.