Study of Safety, Efficacy, Tolerability, Pharmacokinetics and Pharmacodynamics of LNP023 in in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the efficacy of LNP023 in patients with PNH, showing signs of active hemolysis despite treatment with SoC (defined as an antibody with anti C5 activity).

Detailed Description
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LNP023 is a novel oral small molecular weight compound, that inhibits alternative complement pathway (AP). Blockade of the AP with oral LNP023 has the potential to prevent both intra - and extravascular hemolysis. This study includes a screening period of up to 68 days, a baseline visit, up to approximately 3 years of treatment with LNP023 administered in addition to SoC, and an End of Study (EoS) visit 2 weeks after last LNP023 administration. The main purpose of this study is to evaluate the efficacy of LNP023 in patients with PNH, showing signs of active hemolysis despite treatment with SoC (defined as an antibody with anti C5 activity).

Official Title
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An Open Label, Single Arm, Multiple Dose Study to Assess Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of LNP023 When Administered in Addition to Standard of Care (SoC) in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) With Signs of Active Hemolysis

Conditions
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Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)

Intervention / Treatment
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* Drug: LNP023


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent must be obtained before any assessment is performed. Male and female patients between the age of 18-80 (inclusive) at baseline with a diagnosis of PNH based on documented clone size of ≥10% by RBCs and/or granulocytes, measured by GPI-deficiency on flow cytometry (screening or medical history data acceptable). For Cohort 1 only: LDH values ≥1.5x upper limit of the normal range for at least 3 pre-SoC dosing measurements taken in relation to 3 different SoC dosing dates over a maximum of 10 weeks prior to Day 1 (screening, baseline or medical history data acceptable). All other screening pre-SoC LDH values have to be > 1x upper limit of normal range (for pre-SoC samples collected at the same day as SoC administration). For Cohort 2: LDH values ≥1.25x upper limit of the normal range for at least 3 pre-SoC dosing measurements taken in relation to 3 different SoC dosing dates over a maximum of 10 weeks prior to Day 1 (screening, baseline or medical history data acceptable). All other screening pre-SoC LDH values have to be > 1x upper limit of normal range (for pre-SoC samples collected at the same day as SoC administration). For Cohort 2 only: Hemoglobin level <10.5 g/dL at Baseline. PNH patients on stable regimen of standard of care complement blockade (monoclonal antibody with anti C5 activity) for at least 3 months prior to first treatment with LNP023. Previous vaccination against Neisseria meningitidis types A, C, Y and W-135 is required at least 4 weeks prior to first dosing with LNP023.Vaccination against N. meningitidis type B should be conducted if available and acceptable by local regulations, at least 4 weeks prior to first dosing with LNP023. If LNP023 treatment has to start earlier than 4 weeks post vaccination, prophylactic antibiotic treatment must be initiated. Previous vaccination for the prevention of S. pneumoniae and H. influenzae at least 4 weeks prior to first dosing with LNP023. If LNP023 treatment has to start earlier than 4 weeks post vaccination, prophylactic antibiotic treatment must be initiated. Able to communicate well with the investigator, to understand and comply with the requirements of the study. For Part 2 of the study patients who as per judgment of Investigator benefit from LNP023 treatment based on reduced hemolytic parameters as compared to Screening and Baseline. - Exclusion Criteria: Participation in any other investigational drug trial or use of other investigational drugs at the time of enrollment, or within 5 elimination half-lives of enrollment, or within 30 days, whichever is longer; or longer if required by local regulations Known or suspected hereditary complement deficiency at screening History of hematopoietic stem cell transplantation as verified both at screening and at baseline (unless baseline was skipped) Patients with laboratory evidence of bone marrow failure (reticulocytes <60x109/l, or platelets <30x109/l, or neutrophils <1x109/l) as verified both at screening and at baseline (unless baseline was skipped) A positive HIV, Hepatitis B (HBV) or Hepatitis C (HCV) test result at screening Presence or suspicion (based on judgment of the investigator) of active infection within 2 weeks prior to first dose of LNP023, or history of severe recurrent bacterial infections History of recurrent meningitis, history of meningococcal infections despite vaccination as verified both at screening and at baseline (unless baseline was skipped) Patients on the immunosuppressive agents such as but not limited to cyclosporine, MMF, tacrolimus, cyclophosphamide, methotrexate less than 8 weeks prior to first treatment with LNP023 unless on a stable regimen for at least 3 months prior to first LNP023 dose. Systemic corticosteroids administered at the dose of ≥ 10 mg per day prednisone equivalent within less than 4 weeks prior to first treatment with LNP023 Severe concurrent co-morbidities, e.g. patients with severe kidney disease (dialysis), advanced cardiac disease (NYHA class IV), severe pulmonary arterial hypertension (WHO class IV), unstable thrombotic event not amenable to active treatment as judged by the investigator both at screening and at baseline (unless baseline was skipped) Any medical condition deemed likely to interfere with the patient's participation in the study, or likely to cause serious adverse events during the study Female patients who are pregnant or breastfeeding, or intending to conceive during the course of the study Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception from first dosing with LNP023 until EOS.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open label, non-randomized study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>10 patients receiving LNP023 high dose daily over up to approximately 3 years | Drug: LNP023<br>* LNP023 bid<br>|
| Experimental: Arm 2<br>5 patients receiving LNP023 low dose daily over up to approximately 3 years | Drug: LNP023<br>* LNP023 bid<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction of chronic hemolysis | Reduction of chronic hemolysis based on LDH level | 13 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| C3 deposition | Level of C3 deposition on red blood cells | Baseline; day 1, 8, 22, 29, 57, 92, 106, 113, 141, 169, 253, 337, 505, 673, 785, 953, 1121, 1233, 1240, 1247, 1261 | 
| Profile of Pharmacokinetics: Maximum plasma concentration (Cmax) | Profile of Pharmacokinetics: Maximum plasma concentration (Cmax) | day 1,2, 8,15,29,57,92, 169, 337, 505, 673, 785, 953, 1121, 1233, 1240, 1247, 1261 | 
| Measurement of total and free hemoglobin | total and free hemoglobin in blood | Screening, Baseline; day 1, 2, 8, 15 22, 29, 36,43, 57,71, 85, 92, 106, 113, 127, 141, 155, 169, 197, 225, 253, 281, 309, 337, 393, 449, 505, 561, 617, 673, 729, 785, 841, 897, 953, 1009, 1065, 1021, 1171, 1233, 1240, 1247, 1261 | 
| Profile of Pharmacokinetics (PK): Area Under the Curve (AUC) | Profile of Pharmacokinetics (PK): Area Under the Curve (AUC) | day 1,2, 8,15,29,57,92, 169, 337, 505, 673, 785, 953, 1121, 1233, 1240, 1247, 1261 | 
| Measurement of bilirubin | Blood bilirubin | Screening, Baseline; day 1, 2, 8, 15 22, 29, 36,43, 57,71, 85, 92, 106, 113, 127, 141, 155, 169, 197, 225, 253, 281, 309, 337, 393, 449, 505, 561, 617, 673, 729, 785, 841, 897, 953, 1009, 1065, 1021, 1171, 1233, 1240, 1247, 1261 | 
| Incidence of blood transfusion | Incidence of blood transfusion | anytime during the study (day -70 to day 1261) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Complement, alternative pathway, paroxysmal nocturnal hemoglobinuria,, hemolysis