Evaluation of Pozelimab and Cemdisiran Combination Therapy Versus Ravulizumab and Eculizumab in Complement Inhibitor-Naive Paroxysmal Nocturnal Hemoglobinuria Patients

The primary objective of this study is to evaluate the effect of **pozelimab** and **cemdisiran** combination therapy compared to **ravulizumab** and **eculizumab** treatments on hemolysis in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) who are complement inhibitor treatment-naive or have not recently received such therapy. For Cohort A, the focus is on assessing hemolysis through lactate dehydrogenase (LDH) levels over a 26-week period. For Cohort B, the objective extends to evaluating sustained suppression of LDH and transfusion avoidance over the same duration. This is clinically relevant as it aims to determine the efficacy of the combination therapy in managing hemolysis, a critical aspect of PNH treatment.

Secondary objectives include: - Cohort A: Describing the effect of the combination treatment versus ravulizumab on measures of hemolysis, transfusion parameters, hemoglobin levels, fatigue, health-related quality of life (HRQoL), safety and tolerability, and complement activation. Additionally, assessing the concentrations of total pozelimab and ravulizumab in serum, cemdisiran, and total C5 protein in plasma, as well as the immunogenicity of pozelimab and cemdisiran. - Cohort B: Evaluating the effect of the combination treatment versus eculizumab on similar parameters as Cohort A, assessing the concentrations of total pozelimab and eculizumab in serum, cemdisiran, and total C5 protein in plasma, and evaluating the immunogenicity of pozelimab and cemdisiran.

The clinical trial involves a total of **173 participants** diagnosed with **paroxysmal nocturnal haemoglobinuria (PNH)**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a confirmed diagnosis of PNH through high-sensitivity flow cytometry testing and active disease characterized by PNH-related signs or symptoms. The trial includes individuals who are complement inhibitor treatment-naive or have not recently received such therapy. Participants are required to have an LDH level of at least two times the upper limit of normal at the screening visit. The study population is considered vulnerable, and participants must be willing and able to comply with study-related procedures, including the completion of a full series of meningococcal vaccinations as required by the protocol. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **randomized**, open-label, C5 inhibitor-controlled study to evaluate the efficacy and safety of a combination therapy involving **pozelimab** and **cemdisiran** in patients with **paroxysmal nocturnal hemoglobinuria** (PNH). The trial is structured into two cohorts: Cohort A and Cohort B. Cohort A will compare the combination treatment to **ravulizumab**, while Cohort B will compare it to **eculizumab**. The primary objective is to assess the effect on hemolysis, as measured by lactate dehydrogenase (LDH) levels, over a 26-week treatment period. The trial will also evaluate transfusion avoidance and other secondary endpoints such as changes in fatigue and physical function.

The trial will span approximately 26 weeks, with participant involvement expected to last the entire duration unless early termination criteria are met. Conditions for early termination include the occurrence of treatment-emergent serious adverse events (SAEs) or adverse events (AEs) of special interest that necessitate discontinuation. Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed diagnosis of PNH and an LDH level of at least twice the upper limit of normal (ULN).

Following the screening, participants will attend regular follow-up visits to monitor treatment effects and safety. These visits will include assessments of LDH levels, hemoglobin stabilization, and the incidence of breakthrough hemolysis. The end-of-study visit will conclude the trial, where final evaluations will be conducted to assess the overall impact of the treatment. The trial is expected to conclude by April 2027, with recruitment having commenced in September 2022.

The clinical trial involves the administration of several treatments to evaluate their efficacy and safety in patients with **Paroxysmal Nocturnal Hemoglobinuria** (PNH). The experimental medication **Pozelimab** is provided as a solution for injection. It is administered via intravenous, subcutaneous, or intramuscular routes. The active substance, pozelimab, is a protein-based compound developed by Regeneron Pharmaceuticals, Inc. The treatment period for pozelimab is set at 26 weeks, with no specified maximum daily or total dose amount.

Another experimental treatment, **Cemdisiran**, is also a solution for injection, administered subcutaneously. Cemdisiran is a nucleic acid-based compound, specifically a small interfering RNA (siRNA), developed by Regeneron Pharmaceuticals, Inc. The treatment duration for cemdisiran is 26 weeks, with no specified maximum daily or total dose amount. It is used in combination with pozelimab in the study.

The comparator treatment **Ravulizumab**, marketed as Ultomiris, is a concentrate for solution for infusion. It is administered intravenously. The active substance, ravulizumab, is a protein-based monoclonal antibody developed by Alexion Europe SAS. The maximum daily and total dose amounts are 3600 mg, with a treatment period of 26 weeks.

Another comparator treatment, **Eculizumab**, marketed as Soliris, is also a concentrate for solution for infusion, administered intravenously. The active substance, eculizumab, is a protein-based monoclonal antibody developed by Alexion Europe SAS. The maximum daily and total dose amounts are 900 mg, with a treatment period of 28 weeks.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints focused on evaluating the treatment effects on patients with **Paroxysmal Nocturnal Hemoglobinuria (PNH)**. The primary endpoints include the percent change in lactate dehydrogenase (LDH) levels for Cohort A, and for Cohort B, the maintenance of adequate control of hemolysis, defined as LDH ≤1.5 times the upper limit of normal (ULN), along with transfusion avoidance. Secondary endpoints encompass a range of measures such as the maintenance of adequate control of hemolysis, breakthrough hemolysis, hemoglobin stabilization, normalization of LDH, and transfusion avoidance. Additional assessments include changes in fatigue as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT)-Fatigue Scale, changes in physical function scores on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30), and changes in global health status/quality of life scale scores on the EORTC-QLQ-C30.

These efficacy parameters will be measured and collected at various timepoints throughout the 26-week treatment period. The analysis will involve comparing the effects of the combination therapy of pozelimab and cemdisiran against the treatments with ravulizumab and eculizumab. The trial will also monitor the incidence and severity of treatment-emergent serious adverse events (SAEs) and adverse events (AEs) of special interest, as well as the incidence of treatment-emergent anti-drug antibodies (ADAs) to pozelimab and cemdisiran. The concentration levels of total C5, pozelimab, cemdisiran, ravulizumab, and eculizumab in plasma or serum will also be evaluated to provide further insights into the treatment's efficacy and safety profile.