Long-term Safety and Efficacy Evaluation of Danicopan as an Add-on to Complement Component 5 Inhibitors in Paroxysmal Nocturnal Hemoglobinuria Patients

The primary objective of this study is to **characterize** the long-term safety of treatment with **danicopan** as an add-on therapy to a complement component 5 inhibitor (C5i) in patients with **Paroxysmal Nocturnal Hemoglobinuria** (PNH). This is clinically relevant as it aims to ensure the safety of prolonged use of danicopan, which is crucial for patients requiring long-term management of PNH, a rare and life-threatening blood disorder.

Secondary objectives include:

• To characterize the long-term efficacy of danicopan as an add-on therapy to a C5i.
• To assess the long-term effect of danicopan on Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue scores and on European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire-Core 30 Scale (EORTC-QLQ-C30) scores.
• To further characterize the safety of danicopan as an add-on therapy to a C5i.

The clinical trial involves a total of **55 participants** diagnosed with **Paroxysmal Nocturnal Hemoglobinuria**. The study population includes both male and female subjects, with an age range that encompasses adults and adolescents. Participants were selected based on their completion of a previous Alexion-sponsored clinical study involving danicopan as an add-on therapy to a complement component 5 inhibitor (C5i). The trial population includes individuals who are considered vulnerable, and all participants are required to have documentation of vaccination for Neisseria meningitidis, with revaccination as per national guidelines or local practices for complement inhibitor use. The study does not specify particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the long-term safety and efficacy of **danicopan** as an add-on therapy to a complement component 5 inhibitor (C5i) in patients with **paroxysmal nocturnal hemoglobinuria** (PNH) who have previously been treated with danicopan in an Alexion-sponsored study. This is a phase III, randomized, double-blind, controlled trial. The trial is expected to last until May 2025, with recruitment having commenced in May 2022. The study involves multiple visits, starting with an inclusion (screening) visit to confirm eligibility based on criteria such as prior completion of a danicopan study and documentation of vaccination for Neisseria meningitidis. Participants will undergo regular follow-up visits to monitor safety and efficacy endpoints, including the incidence of treatment-emergent adverse events (TEAEs), changes in hemoglobin levels, and other hematological parameters. The end-of-study visit will conclude the participant's involvement, which is anticipated to last up to 152 weeks. Conditions that may lead to early termination from the study include the occurrence of serious TEAEs or non-compliance with study protocols. The trial aims to provide comprehensive data on the safety profile of danicopan when used in conjunction with C5 inhibitors, contributing valuable insights into the management of PNH. The study will utilize both oral and intravenous administration routes, with danicopan being administered as a film-coated tablet and the C5 inhibitors, Soliris and Ultomiris, as solutions for infusion. The primary endpoint focuses on the safety profile, while secondary endpoints assess various efficacy measures, including changes in hemoglobin and lactate dehydrogenase levels, transfusion avoidance, and quality of life scores. Participants are expected to adhere to the study schedule and protocol to ensure the integrity and reliability of the trial outcomes.

The clinical trial involves the administration of **danicopan**, marketed under the name ALXN 2040, as an experimental medication. Danicopan is provided in the form of a film-coated tablet and is intended for **oral use**. The maximum daily dose of danicopan is 600 mg, with a total maximum dose of 638,400 mg over a treatment period of 152 days. The active substance, danicopan, is of chemical origin and is also known by its synonyms ACH-0144471 and ACH-4471. The medication is not formulated for pediatric use and is designated as an orphan drug under the number EU/3/17/1946.

In addition to danicopan, the study includes the use of **eculizumab**, marketed as Soliris 300 mg concentrate for solution for infusion. Eculizumab is administered via **intravenous use**. The maximum daily dose is 900 mg, with a total maximum dose of 68,400 mg over the same treatment period of 152 days. Eculizumab is a protein-based substance, specifically categorized as "Protein - Other," and is not designated as an orphan drug in this study. The product is not intended for pediatric use.

Another non-experimental treatment used in the study is **ravulizumab**, marketed as Ultomiris 300 mg/30 mL concentrate for solution for infusion. Similar to eculizumab, ravulizumab is administered through **intravenous use**. The maximum daily dose for ravulizumab is 3,600 mg, with a total maximum dose of 68,400 mg over 152 days. Ravulizumab is also a protein-based substance, categorized as "Protein - Other," and is not designated as an orphan drug. This product is not formulated for pediatric use.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen. The trial aims to characterize the long-term safety and efficacy of danicopan as an add-on therapy to a complement component 5 inhibitor in patients with **paroxysmal nocturnal hemoglobinuria** who have previously been treated with danicopan in an Alexion-sponsored clinical study.

The efficacy of the clinical trial will be assessed using a range of secondary endpoints designed to evaluate the therapeutic impact of **danicopan** as an add-on therapy to a complement component 5 inhibitor (C5i) in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). Key parameters include the change in hemoglobin (Hgb) values over time, the proportion of patients achieving an Hgb increase of ≥ 2g/dL without transfusion, and the change in absolute reticulocyte count. Additionally, changes in lactate dehydrogenase (LDH) levels will be monitored, with a focus on the proportion of patients maintaining LDH levels ≤ 1.5 times the upper limit of normal (ULN). The trial will also assess the proportion of patients achieving transfusion avoidance, defined as remaining transfusion-free according to protocol guidelines.

Patient-reported outcomes will be evaluated through changes in FACIT Fatigue scores and EORTC-QLQ-C30 scores over time. Safety laboratory parameters will be monitored to ensure comprehensive safety profiling. The incidence of treatment-emergent adverse events (TEAEs) leading to discontinuation will also be recorded. These efficacy parameters will be collected and analyzed at specified intervals throughout the trial to provide a detailed understanding of the long-term efficacy of danicopan in this patient population.