Study of Efficacy and Safety of Twice Daily Oral Iptacopan (LNP023) in Adult PNH Patients Who Are Naive to Complement Inhibitor Therapy

Study Overview
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Brief Summary
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The purpose of this Phase 3 study was to determine whether iptacopan is efficacious and safe for the treatment of Paroxysmal nocturnal hemoglobinuria (PNH) patients who were naïve to complement inhibitor therapy.

Detailed Description
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This study was a multicenter, single-arm, open-label trial which was comprised of 8 weeks screening period, 24-week core treatment period and 24-week extension treatment period. Eligible PNH patients with hemolysis (LDH > 1.5 ULN) and anemia (hemoglobin <10 g/dL), who were naive to complement inhibitor therapy, including anti-C5 antibody treatment, received iptacopan monotherapy at a dose 200 mg orally b.i.d. Data cut-off date used for the primary results submission was 02-Nov-2022

Official Title
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A Multicenter, Single-arm, Open-label Trial to Evaluate Efficacy and Safety of Oral, Twice Daily Iptacopan in Adult PNH Patients Who Are Naive to Complement Inhibitor Therapy

Conditions
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Paroxysmal Nocturnal Hemoglobinuria (PNH)

Intervention / Treatment
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* Drug: Iptacopan (LNP023)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female participants ≥ 18 years of age with a diagnosis of PNH confirmed by high-sensitivity flow cytometry with clone size ≥ 10% Mean hemoglobin level <10 g/dL LDH > 1.5 x Upper Limit of Normal (ULN) Vaccination against Neisseria meningitidis infection is required prior to the start of study treatment If not received previously, vaccination against Streptococcus pneumoniae and Haemophilus influenzae infections should be given Exclusion Criteria: Prior treatment with a complement inhibitor, including anti-C5 antibody Known or suspected hereditary complement deficiency History of hematopoietic stem cell transplantation Patients with laboratory evidence of bone marrow failure (reticulocytes <100x109/L; platelets <30x109/L; neutrophils <0.5x109/L). Active systemic bacterial, viral (incl. COVID-19)or fungal infection within 14 days prior to study drug administration. History of recurrent invasive infections caused by encapsulated organisms, e.g. meningococcus or pneumococcus. Major concurrent comorbidities including but not limited to severe kidney disease (e.g., dialysis), advanced cardiac disease (e.g., NYHA class IV heart failure), severe pulmonary disease (e.g., severe pulmonary hypertension (WHO class IV)), or hepatic disease (e.g., active hepatitis) that in the opinion of the investigator precludes participant's participation in the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LNP023<br>Participants receive LNP023 at a dose of 200 mg orally b.i.d | Drug: Iptacopan (LNP023)<br>* Taken orally b.i.d. Dosage supplied: 200mg Dosage form: Hard gelatin capsule Route of Administration: oral<br>* Other names: Iptacopan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Marginal Proportion (Expressed as Percentage) of Participants With Sustained Increase in Hemoglobin Levels From Baseline of ≥ 2 g/dL in the Absence of Red Blood Cell Transfusions | Sustained increase in hemoglobin levels (responder) is defined as an increase from baseline in hemoglobin levels of ≥ 2 g/dL on three out of four measurements between Day 126 and 168 of the core treatment period, without requiring red blood cell (RBC) transfusions between Day 14 and Day 168. Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level of ≤9 g/dL (≤8 g/dL for Chinese population) with signs and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤7 g/dL (≤6 g/dL for Chinese population), regardless of presence of clinical signs and/or symptoms). The term 'marginal proportion' can be interpreted as the population average probability of being a responder for each treatment group. Results incorporated a method to handle missing data using multiple imputation. Hence, all 40 patients enrolled contributed to the primary analysis. | Baseline, hemoglobin between Day 126 and Day 168 and absence of transfusions between Day 14 and Day 168 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Marginal Proportion (Expressed as Percentage) With Sustained Hemoglobin Levels of ≥ 12 g/dL in the Absence of Red Blood Cell Transfusions | Sustained hemoglobin levels (responder) is defined as hemoglobin levels ≥ 12 g/dL on three out of four measurements between Day 126 and 168 of the core treatment period, without requiring red blood cell (RBC) transfusions between Day 14 and Day 168. Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level of ≤9 g/dL (≤8 g/dL for Chinese population) with signs and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤7 g/dL (≤6 g/dL for Chinese population), regardless of presence of clinical signs and/or symptoms). The term 'marginal proportion' can be interpreted as the population average probability of being a responder for each treatment group. Results incorporated a method to handle missing data using multiple imputation. Hence, all 40 patients enrolled contributed to the analysis. | Hemoglobin between Day 126 and Day 168 and absence of transfusions between Day 14 and Day 168 | 
| Marginal Proportion (Expressed as Percentage) of Participants Who Remain Free From Transfusions | Marginal proportion (expressed as percentage) of participants who did not require transfusions between Day 14 and Day 168. Requiring RBC transfusions refers to any patient receiving transfusions or meeting protocol defined criteria (Hemoglobin level of ≤9 g/dL (≤8 g/dL for Chinese population) with signs and or symptoms of sufficient severity to warrant a transfusion or Hemoglobin of ≤7 g/dL (≤6 g/dL for Chinese population), regardless of presence of clinical signs and/or symptoms). The term 'marginal proportion' can be interpreted as the population average probability of being a responder for each treatment group. The 95% CI was obtained using the bootstrap method | Between Day 14 and Day 168 | 
| Change From Baseline in Hemoglobin Levels | Change from baseline in hemoglobin levels as mean of visits between Day 126 and Day 168. In order to factor out the effect of transfusions in this analysis, if a patient had a transfusion during the core treatment period, the hemoglobin (Hb) values during 30 days following the transfusion were excluded and Hb data were imputed. Change from baseline was analyzed using a mixed model of repeated measures which included age (indicator variable of age ≥ 45 years), sex, history of transfusion (yes/no) prior to study treatment, visit, and baseline hemoglobin as fixed effects and the interaction between visit and baseline hemoglobin levels. | Baseline, Day 126 to 168 | 
| Percent Change From Baseline in LDH | Percent change from baseline in lactate dehydrogenase (LDH) levels as mean of visits between Day 126 and Day 168. Percentage change from baseline was analyzed using a mixed model for repeated measures (MMRM) which includes age (indicator variable of age ≥ 45 years), sex, history of transfusion (yes/no) prior to study treatment, visit, baseline LDH as fixed effects and visit*baseline LDH as interaction. Results incorporated a method to handle missing data using multiple imputation. Hence, all 40 patients enrolled contributed to the analysis. | Baseline, Day 126 to 168 | 
| Adjusted Annualized Clinical BTH Rate | Adjusted annualized rate of clinical breakthrough hemolysis (BTH) events is carried out using the Wilson method. The breakthrough is defined clinical if either there is a decrease in hemoglobin levels equal to or more than 2 g/dL (compared to the latest assessment, or within 15 days) or if patients present signs or symptoms of gross hemoglobinuria, painful crisis, dysphagia or any other significant clinical PNH-related signs & symptoms, in presence of laboratory evidence of intravascular hemolysis. | Between Day 1 and Day 168 | 
| Change From Baseline in Absolute Reticulocyte Count | Change from baseline in absolute reticulocyte counts as mean of visits between Day 126 and Day 168. Change from baseline was analyzed using a MMRM which includes age (indicator variable of age ≥ 45 years), sex, history of transfusion (yes/no) prior to study treatment, visit, baseline reticulocyte counts as fixed effects and visit*baseline reticulocyte counts as interaction. | Baseline and mean of visits between Day 126 and 168 | 
| Change From Baseline in FACIT-Fatigue Questionnaire | Change from baseline in FACIT-Fatigue scores as mean of visits between Day 126 and Day 168. The FACIT-Fatigue is a 13-item questionnaire with support for its validity and reliability in PNH that assesses patient self-reported fatigue and its impact on daily activities and function. All FACIT scales are scored so that a high score is better. As each of the 13 items of the FACIT-F Scale ranges from 0-4, the range of possible scores is 0-52, with 0 being the worst possible score and 52 the best. Change from baseline was analyzed using a Mixed Model of Repeated Measures (MMRM) which includes age (indicator variable of age ≥ 45 years), sex, history of transfusion (yes/no) prior to study treatment, visit, baseline FACIT-Fatigue score as fixed effects and visit*baseline FACIT-Fatigue score as interaction. | Baseline and mean of visits between Day 126 and Day 168 | 
| Adjusted Annualized Major Adverse Vascular Events Rate | Adjusted annual rate is carried out using the Wilson method. A MAVE is defined as: acute peripheral vascular occlusion, amputation (non-traumatic; nondiabetic), cerebral arterial occlusion/cerebrovascular accident, cerebral venous occlusion, dermal thrombosis, gangrene (non-traumatic; nondiabetic), hepatic/portal vein thrombosis (Budd-Chiari syndrome), mesenteric/visceral arterial, thrombosis or infarction, mesenteric/visceral vein thrombosis or infarction, myocardial infarction, pulmonary embolus, renal arterial thrombosis, renal vein thrombosis, thrombophlebitis / deep vein thrombosis, transient ischemic attack, unstable angina or other. | Between Day 1 and Day 168 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Paroxysmal nocturnal hemoglobinuria, Hemoglobin, Anemia, LNP023, Iptacopan