Evaluation of Long-Term Safety and Tolerability of Iptacopan in Patients with Paroxysmal Nocturnal Hemoglobinuria Post-Phase II/III Studies

The primary objective of this study is to evaluate the **long-term safety** and tolerability of **iptacopan** monotherapy in participants with Paroxysmal Nocturnal Hemoglobinuria (PNH) who have completed the treatment extension period of previous Phase II and Phase III clinical studies. This is clinically relevant as it aims to ensure the continued safety of iptacopan, a treatment option for PNH, a rare and life-threatening blood disorder.

Secondary objectives include:

• Evaluating the clinical benefit of iptacopan in maintaining sustained hemoglobin levels ≥ 12 g/dL, in the absence of red blood cell transfusion.
• Assessing the clinical benefit of iptacopan in maintaining transfusion avoidance, defined as the proportion of participants who remain free from transfusions.
• Evaluating the clinical benefit of iptacopan by assessing the rates of breakthrough hemolysis and Major Adverse Vascular Events.

The clinical trial involves a total of **107 participants** diagnosed with **Paroxysmal Nocturnal Hemoglobinuria (PNH)**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their completion of the treatment extension period of previous Phase II and any Phase III clinical studies with iptacopan, without tapering down. The trial population is characterized by individuals who have been clinically stable on iptacopan monotherapy for at least three months and have up-to-date vaccinations against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae infections. The study includes a vulnerable population, and the selection criteria ensure that participants may benefit from continued treatment with iptacopan as per the investigator's clinical judgment.

The clinical trial is designed to evaluate the long-term safety and tolerability of **iptacopan** monotherapy in patients with **Paroxysmal Nocturnal Hemoglobinuria (PNH)** who have completed previous Phase II and Phase III studies with the investigational product. This trial is an open-label, multicenter roll-over extension program. Participants will be administered **iptacopan** in the form of hard gelatin capsules, with a maximum daily dose of 400 mg, taken orally. The trial is expected to run until October 2027, with participant involvement potentially lasting up to 36 months, depending on individual response and safety assessments.

The trial will include several key study visits. The initial inclusion visit will serve as a screening to confirm eligibility based on criteria such as age, prior completion of relevant studies, and up-to-date vaccinations against specific infections. Participants must have been clinically stable on **iptacopan** monotherapy for at least three months prior to enrollment. Follow-up visits will occur at regular intervals to monitor safety and efficacy, including assessments of adverse events, laboratory parameters, and vital signs. The primary endpoint focuses on safety evaluations, while secondary endpoints include maintaining hemoglobin levels, absence of transfusions, and monitoring for breakthrough hemolysis and major adverse vascular events.

The end-of-study visit will conclude the participant's involvement, with comprehensive evaluations to ensure safety and document any long-term effects. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it in their best interest. The trial's design ensures rigorous monitoring and data collection to support the assessment of **iptacopan**'s long-term safety profile in the treatment of PNH.

The clinical trial involves the administration of **Iptacopan**, also known by its sponsor product code **LNP023**. This experimental medication is provided in the form of **hard gelatin capsules**. The active substance, **Iptacopan**, is a chemical compound with the chemical name 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid. The medication is administered orally, with a maximum daily dose of 400 mg. The treatment period extends up to 36 months. The medication is not formulated for pediatric use and is designated as an orphan drug under the designation number EU/3/20/2281. The trial aims to evaluate the long-term safety and tolerability of **Iptacopan** in patients with **Paroxysmal Nocturnal Hemoglobinuria** (PNH) who have completed previous Phase II and Phase III studies.

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, as deemed necessary by the study protocol. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is designed to provide comprehensive data on the safety profile of **Iptacopan** when used as a monotherapy in the specified patient population.

Efficacy in this clinical trial will be assessed using several secondary endpoints. These include the maintenance of sustained **hemoglobin** levels of at least 12 g/dL in the absence of transfusions, evaluated over yearly follow-up intervals. Additionally, the absence of administration of packed-red blood cell transfusions will be monitored over the same intervals. The trial will also evaluate occurrences of breakthrough hemolysis and Major Adverse Vascular Events (MAVE), with MAVE occurrences being assessed annually. These parameters will provide a comprehensive evaluation of the efficacy of iptacopan in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) who have completed previous Phase II and Phase III studies.