Evaluation of Iptacopan (LNP023) Efficacy and Safety in Complement Inhibitor-Naïve Adult Patients with Atypical Hemolytic Uremic Syndrome

The primary objective of this study is to evaluate the proportion of participants with **atypical hemolytic uremic syndrome** (aHUS) treated with **iptacopan** who achieve a complete thrombotic microangiopathy (TMA) response during 26 weeks of treatment. This is clinically relevant as achieving a complete TMA response is crucial for improving patient outcomes and reducing the risk of long-term complications associated with aHUS.

Secondary objectives include:

• Assessing the effect of iptacopan on the time to complete TMA response.
• Evaluating the proportion of participants achieving an increase in hemoglobin levels of ≥ 2 g/dL from baseline.
• Assessing the effect of iptacopan on hematologic parameters, including platelets, lactate dehydrogenase (LDH), and hemoglobin.
• Evaluating the effect of iptacopan on dialysis requirement status.
• Assessing the effect on estimated glomerular filtration rate (eGFR).
• Evaluating the effect on chronic kidney disease (CKD) stage.
• Assessing the effect on patient-reported overall fatigue severity and health-related quality of life.
• Evaluating the safety and tolerability of iptacopan.

The clinical trial involves a total of **27 participants** diagnosed with **atypical hemolytic uremic syndrome**. The study population includes both male and female subjects aged **18 years and older**. Participants were selected based on the presence of active thrombotic microangiopathy (TMA), characterized by thrombocytopenia, hemolysis, and kidney injury. The trial population is required to have specific laboratory findings, such as a platelet count below 150x10^9/L, elevated LDH levels, and serum creatinine above the upper limit of normal, indicating acute kidney function deterioration. Vaccination against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae is mandated prior to the commencement of the study treatment. The trial also includes individuals with a history of kidney transplantation, provided there is no evidence of transplant rejection or other causes of TMA unrelated to atypical hemolytic uremic syndrome. The study does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **single-arm, open-label** study to evaluate the efficacy and safety of **iptacopan** in adult patients with **atypical hemolytic uremic syndrome** (aHUS) who are naive to complement inhibitor therapy. The trial aims to assess the proportion of participants achieving a complete thrombotic microangiopathy (TMA) response during 26 weeks of treatment. The study involves the administration of iptacopan in the form of **hard gelatin capsules**, taken orally twice daily, with a maximum daily dose of 400 mg. The trial is expected to last until December 2025, with participant involvement spanning up to 52 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as evidence of active TMA and appropriate vaccination status. Following the screening, participants will commence treatment and attend regular follow-up visits to monitor safety and efficacy outcomes. These visits will include assessments of hematologic parameters, kidney function, and patient-reported outcomes. The primary endpoint is the achievement of a complete TMA response without the use of plasma exchange/plasma infusion (PE/PI) and anti-C5 antibody during the 26-week treatment period. Secondary endpoints include time to TMA response, changes in hematologic parameters, and improvements in kidney function and quality of life measures.

The end-of-study visit will occur at the conclusion of the treatment period, where final assessments will be conducted to evaluate the overall response to the treatment. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it necessary for their safety. The trial is conducted under the sponsorship of Novartis Pharma AG, with adherence to regulatory and ethical standards to ensure the integrity and reliability of the study results.

The clinical trial involves the administration of **Iptacopan**, an experimental medication, to evaluate its efficacy and safety in adult patients with atypical hemolytic uremic syndrome (aHUS) who have not previously received complement inhibitor therapy. **Iptacopan** is provided in the form of hard gelatin capsules, with each capsule containing the active chemical substance. The medication is administered orally, with a maximum daily dose of 400 mg. The dosing schedule involves twice-daily administration, and the treatment period extends up to 52 weeks. The chemical composition of **Iptacopan** includes the active substance known as 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid, also referred to by its synonyms such as NVP-LNP023-NX and LNP-023.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The study is designed as a single-arm, open-label trial, focusing solely on the administration of **Iptacopan**. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the prescribed treatment protocol. The primary objective is to assess the proportion of participants achieving a complete thrombotic microangiopathy (TMA) response during the initial 26 weeks of treatment. The trial is conducted under the sponsorship of Novartis Pharma AG, with the product identified by the sponsor product code LNP023.

The efficacy of the clinical trial will be assessed by evaluating the proportion of participants achieving a complete **thrombotic microangiopathy (TMA)** response during 26 weeks of study treatment with iptacopan. The primary endpoint is defined as a complete TMA response without the use of plasma exchange/plasma infusion (PE/PI) and anti-C5 antibody. This response is characterized by hematological normalization, specifically a platelet count of ≥150 x 10⁹/L and lactate dehydrogenase (LDH) levels below the upper limit of normal (ULN), along with an improvement in kidney function, indicated by a ≥25% reduction in serum creatinine from baseline. These criteria must be maintained for two measurements obtained at least four weeks apart, with any measurement in between.

Secondary endpoints include the time to achieve TMA response, changes from baseline in hematologic parameters (platelets, LDH, hemoglobin) at Week 26, and the proportion of participants who no longer require dialysis through 26 weeks of study treatment. Additional secondary endpoints involve changes from baseline in estimated glomerular filtration rate (eGFR) values and chronic kidney disease (CKD) stage at Week 26, as well as changes in patient-reported outcomes scores for FACIT-Fatigue, Patient Global Impression of Severity (PGIS), EuroQol 5-level EQ-5D version (EQ-5D-5L), and Short-form 36 health survey questionnaire version 2 (SF-36 v2) at Week 26. Efficacy assessments will be conducted using validated scales and laboratory tests at specified timepoints throughout the study duration.