Efficacy, Safety, Pharmacokinetics and Pharmacodynamics Study, Assessing Multiple LNP023 Doses in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria

Inclusion Criteria

• Written informed consent must be obtained before any assessment is performed.
• Male and female patients at least 18 years old at baseline.
• Diagnosis of active 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).
• LDH values > 1.5 x upper limit of the normal range (ULN) for at least 3 measurements over a maximum of 8 weeks prior to Day 1 (Screening, baseline or medical history data acceptable).
• Hemoglobin level < 10.5 g/dL at Baseline.
• For Period 3 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.
• Vaccinations against N. meningitidis, S. pneumoniae and H. influenzae is required at least 4 weeks prior to first dosing with LNP023 (existing vaccinations should provide effective titers at time of LNP023 treatment start). 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. -

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.
• Patients treated with eculizumab or any other complement inhibitor less than 3 months prior to study Day 1
• Known or suspected hereditary or acquired complement deficiency.
• History of currently active primary or secondary immunodeficiency.
• History of splenectomy.
• History of bone marrow/ hematopoietic stem cell or solid organ transplants (e.g. heart, lung, kidney, liver).
• Evidence of malignant disease, or malignancies diagnosed within the previous 5 years.
• Patients with laboratory evidence of bone marrow failure (reticulocytes < 60x10E9/L, or platelets < 50x10E9/L or neutrophils < 1x10E9/L) verified both at screening and baseline.
• History of recurrent meningitis, history of meningococcal infections despite vaccination, as verified at both screening and baseline.
• 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.
• A positive HIV, Hepatitis B (HBV) or Hepatitis C (HCV) test result at screening.
• Patients on immunosuppressive agents such, as but not limited to, cyclosporine, tacrolimus, mycophenolate or mycophenolic acid, cyclophosphamide, methotrexate or IV immunoglobulins, 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 unless on a stable dose for at least 4 weeks before randomization.
• Severe concurrent co-morbidities not amenable to active treatment; e.g., patients with severe kidney disease (CKD stage 4, dialysis), advanced cardiac disease (NYHA class IV), severe pulmonary arterial hypertension (WHO class IV), or unstable thrombotic event, as judged by the investigator, both at screening and 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.
• History of hypersensitivity to the study treatment or its excipients or to drugs of similar chemical classes.
• 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 during dosing and for 1 week after stopping of investigational drug