Pharmacokinetics, Safety, and Tolerability of Iptacopan Hydrochloride in Pediatric Patients with Paroxysmal Nocturnal Hemoglobinuria: A Phase 3 Study

The primary objective of this study is to evaluate the **safety** and tolerability of iptacopan during a 26-week treatment period in pediatric patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). This is clinically relevant as it aims to ensure that iptacopan is a safe therapeutic option for this patient population, potentially improving their quality of life and managing the symptoms associated with PNH.

Secondary objectives include:

• Evaluating the proportion of patients who achieve an increase in **hemoglobin** levels from baseline of ≥ 1 g/dL and ≥ 2 g/dL at 26 weeks and 52 weeks, without receiving red blood cell (RBC) transfusions from Day 14 until the end of these treatment periods.
• Assessing the proportion of participants achieving hemoglobin normalization at 26 weeks and 52 weeks, in the absence of RBC transfusions from Day 14 until the end of the treatment periods.
• Evaluating transfusion avoidance, defined as the proportion of participants who remain free from transfusions and do not meet transfusion criteria from Day 14 until the end of the 26-week and 52-week treatment periods.
• Assessing mean changes from baseline in hemoglobin and lactate dehydrogenase (LDH) at 26 weeks and 52 weeks, with separate evaluations for naive patients and those previously treated with anti-C5.
• Evaluating the safety and tolerability of iptacopan during the 52-week treatment period.

The clinical trial involves a total of **7 participants** diagnosed with **Paroxysmal Nocturnal Hemoglobinuria (PNH)**. The study population comprises both male and female subjects aged between 2 to less than 18 years. Participants were selected based on a confirmed diagnosis of PNH through high-sensitivity flow cytometry, with specific criteria regarding red and white blood cell clone sizes. The trial includes individuals who are either currently receiving anti-C5 therapy or are treatment-naive, with specific hemoglobin and lactate dehydrogenase levels required for inclusion. Participants must have a minimum body weight of 35 kg for certain cohorts. Vaccination against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae is mandated prior to the commencement of the study treatment, following local guidelines. The trial population is considered vulnerable due to the age range and health condition of the participants. The sponsor has not provided additional information regarding lifestyle considerations such as diet or physical activity.

The clinical trial is designed as an **open-label**, single-arm, multicenter, phase 3 study to evaluate the pharmacokinetics, safety, and tolerability of **iptacopan hydrochloride** in pediatric patients diagnosed with **Paroxysmal Nocturnal Hemoglobinuria (PNH)**. The trial will involve participants aged 2 to less than 18 years, with a confirmed diagnosis of PNH through high-sensitivity flow cytometry. The study will span a total duration of 52 weeks, with a primary focus on a 26-week treatment period. Participants will receive the investigational product in the form of hard gelatin capsules, administered orally, with a maximum daily dose of 400 mg.

The trial will commence with a screening visit to confirm eligibility based on inclusion criteria, such as age, diagnosis, and prior treatment history. Participants must have been on a stable anti-C5 therapy regimen for at least six months or meet specific laboratory criteria if treatment-naive. Vaccination against **Neisseria meningitidis**, **Streptococcus pneumoniae**, and **Haemophilus influenzae** is required prior to the start of the study treatment. Following the screening, eligible participants will be enrolled and will undergo regular follow-up visits to monitor safety and efficacy parameters, including adverse events, laboratory parameters, and vital signs.

The primary endpoints of the study include safety evaluations and pharmacokinetic parameters such as Cmax, AUClast, and Ctrough concentrations. Secondary endpoints focus on changes in hemoglobin levels and the absence of red blood cell transfusions. The study will conclude with an end-of-study visit to assess the overall outcomes and gather final data. Participant involvement is expected to last for the entire 52-week period unless early termination is warranted due to adverse events, non-compliance, or withdrawal of consent. The trial is not categorized as low intervention and is conducted under the sponsorship of Novartis Pharma AG.

The clinical trial involves the administration of **Iptacopan Hydrochloride**, a chemical compound developed by Novartis Pharma AG. This investigational medication is provided in the form of hard gelatin capsules, specifically designed for pediatric use. The active substance, **Iptacopan Hydrochloride**, is administered orally. The maximum daily dose is set at 400 mg, with the total dose not exceeding 400 mg per day. The treatment period is planned for a maximum duration of 52 weeks. The study aims to evaluate the safety, tolerability, and pharmacokinetics of Iptacopan in pediatric patients diagnosed with paroxysmal nocturnal hemoglobinuria (PNH), aged between 2 and less than 18 years.

In this open-label, single-arm, multicenter, phase 3 study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus remains solely on the administration of Iptacopan Hydrochloride. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen. The trial is designed to gather comprehensive data on the pharmacokinetic profile of Iptacopan, alongside its safety and tolerability in the specified patient population.

The efficacy of iptacopan hydrochloride in pediatric patients with **Paroxysmal Nocturnal Hemoglobinuria (PNH)** will be assessed through a series of primary and secondary endpoints. Primary endpoints focus on safety evaluations, including adverse events (AEs), serious adverse events (SAEs), laboratory parameters, vital signs, and cardiovascular parameters. Pharmacokinetic (PK) parameters such as Cmax, AUClast, AUCtau, and Ctrough concentrations will also be measured to characterize the drug's behavior in plasma.

Secondary endpoints will evaluate changes in hemoglobin (Hb) levels from baseline. Specifically, the study will assess changes in Hb of ≥1 g/dL and ≥2 g/dL at Weeks 26 and 52, in the absence of red blood cell (RBC) transfusions from Day 14. The achievement of normal Hb levels at Weeks 26 and 52 without RBC transfusions will also be evaluated. Additionally, the absence of packed-RBC transfusions and the non-fulfillment of transfusion criteria from Day 14 at Weeks 26 and 52 will be considered. Changes from baseline in Hb and lactate dehydrogenase (LDH) at Weeks 26 and 52 will be analyzed. Safety evaluations, including AEs, SAEs, laboratory parameters, vital signs, and cardiovascular parameters, will be continuously monitored throughout the study.