Phase III Multicenter Study on Safety, Pharmacokinetics, and Efficacy of Crovalimab vs. Eculizumab in Paroxysmal Nocturnal Hemoglobinuria Patients on Complement Inhibitors

The primary objective of this study is to evaluate the **safety** and tolerability of **crovalimab** compared with **eculizumab** in patients with **Paroxysmal Nocturnal Hemoglobinuria (PNH)**. This is clinically relevant as it aims to determine the potential of crovalimab as a safer alternative to eculizumab, which is a current standard treatment for PNH. Ensuring the safety and tolerability of new treatments is crucial for patient outcomes and the advancement of therapeutic options.

Secondary objectives include:

• Characterizing the pharmacokinetics profile of crovalimab, eculizumab, and ravulizumab, which is essential for understanding the absorption, distribution, metabolism, and excretion of these drugs.
• Evaluating the immune response to crovalimab, which is important for assessing the potential for immunogenicity and its implications on treatment efficacy and safety.
• Identifying and/or evaluating biomarkers that can potentially provide evidence of the activity of crovalimab, eculizumab, and ravulizumab, which could aid in understanding the mechanisms of action and predicting patient response.
• Evaluating the efficacy of crovalimab compared with eculizumab, which is vital for determining the therapeutic potential and comparative effectiveness of crovalimab as a treatment option for PNH.

The clinical trial involves a total of **84 participants** diagnosed with **Paroxysmal Nocturnal Hemoglobinuria (PNH)**. The study population includes both male and female subjects, with an age range that encompasses adults and adolescents. Participants were selected based on specific inclusion criteria, such as a body weight of at least 40 kg and a documented diagnosis of PNH confirmed by high sensitivity flow cytometry evaluation of white blood cells. The trial includes individuals who have been previously treated with eculizumab or ravulizumab, with specific conditions for those in randomized and non-randomized arms. The health status of participants is characterized by a platelet count of at least 30,000/mm³ without recent transfusion support and a lactate dehydrogenase level of up to 1.5 times the upper limit of normal at screening. The trial population is considered vulnerable, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase III**, randomized, open-label, active-controlled, multicenter study designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of **Crovalimab** versus **Eculizumab** in patients with **Paroxysmal Nocturnal Hemoglobinuria (PNH)** who are currently treated with complement inhibitors. The trial aims to assess the safety and tolerability of Crovalimab compared to Eculizumab. The study is expected to run from August 31, 2020, to January 31, 2030, with a maximum treatment period of 284 days for Crovalimab and 24 days for Eculizumab.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as body weight, documented diagnosis of PNH, and platelet count. Randomized participants will be assigned to either Arm A or B, with specific criteria for those in Arm C. Follow-up visits will be conducted to monitor safety, efficacy, and pharmacokinetic parameters, with assessments including vital signs, laboratory tests, and adverse event monitoring. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any ongoing safety concerns are addressed.

Participant involvement is expected to last up to 25 weeks, with conditions for early termination including the occurrence of severe adverse events, non-compliance with study procedures, or withdrawal of consent. Primary endpoints focus on the incidence and severity of adverse events, changes in vital signs and laboratory results, and the incidence of adverse events leading to study drug discontinuation. Secondary endpoints include serum concentrations of the study drugs, prevalence of anti-drug antibodies, and changes in pharmacodynamic biomarkers. The study will also evaluate patient-reported outcomes such as treatment satisfaction and quality of life.

The clinical trial involves the administration of **Crovalimab**, a **solution for injection/infusion**. This experimental medication is provided in two formulations, identified by sponsor product codes RO 711-2689/F03-01 and RO 711-2689/F03-10. Crovalimab is administered either **intravenously (IV)** or **subcutaneously (SC)**. The maximum daily dose is 1500 mg, with a total maximum dose of 74260 mg over a treatment period of 284 days. The active substance, crovalimab, is a protein of other origin, developed by F. Hoffmann-La Roche Ltd. Participant compliance with the dosing schedule will be monitored throughout the trial.

The comparator treatment in this study is **Eculizumab**, a **concentrate for solution for infusion**. Eculizumab is administered **intravenously** with a maximum daily dose of 900 mg and a total maximum dose of 11400 mg over a treatment period of 24 days. The active substance, eculizumab, is also a protein of other origin. This treatment serves as the active control to evaluate the safety and efficacy of Crovalimab in patients with **paroxysmal nocturnal hemoglobinuria (PNH)** currently treated with complement inhibitors.

The efficacy of **Crovalimab** versus **Eculizumab** in patients with **Paroxysmal Nocturnal Hemoglobinuria (PNH)** will be assessed through a series of primary and secondary endpoints. Primary endpoints include the incidence and severity of adverse events, changes from baseline in targeted vital signs and clinical laboratory test results, and the incidence and severity of injection-site reactions, infusion-related reactions, hypersensitivity, and infections. Additionally, the incidence of adverse events leading to study drug discontinuation and the incidence and severity of clinical manifestations of drug-target-drug complex formation in patients who switched to Crovalimab treatment from Eculizumab or Ravulizumab treatment will be evaluated.

Secondary endpoints will focus on pharmacokinetic and pharmacodynamic parameters, including serum concentrations of Crovalimab, Eculizumab, and Ravulizumab, as well as the prevalence and incidence of anti-drug antibodies (ADAs) to Crovalimab. Changes over time in pharmacodynamic biomarkers and free C5 concentration in Crovalimab-treated patients will be monitored. Hemolysis parameters, such as the percent change from baseline in lactate dehydrogenase (LDH) levels averaged over specific weeks, will be assessed. The proportion of patients achieving transfusion avoidance (TA), experiencing breakthrough hemolysis (BTH), and maintaining hemoglobin stability will be measured. Additional assessments include the total number of units of packed red blood cells (pRBCs) transfused, the proportion of patients experiencing major adverse vascular events (MAVE), and changes in fatigue and quality of life metrics using validated scales such as the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) and the EORTC QLQ-C30.

Patient preference for Crovalimab after switching from Eculizumab or Ravulizumab will be evaluated using a Patient Preference Questionnaire, and treatment satisfaction will be assessed with the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9). These efficacy parameters will be collected and analyzed at various timepoints, including baseline, Week 25, and other specified intervals, to provide a comprehensive evaluation of the treatment's impact on patients with PNH.