Proof of Concept Study to Assess the Efficacy, Safety and Pharmacokinetics of LFG316 in Patients With Paroxysmal Nocturnal Hemoglobinuria

Inclusion criteria

• Written informed consent obtained before any assessment were performed.
• Male and female patients >= 18 years old with a diagnosis of PNH prior to screening. Based on local requirements (applicable in Czech Republic) only patients between the age of 18 to 65 (inclusive) with a diagnosis of PNH prior to screening were eligible for inclusion in this study.
• A documented PNH clone size of >= 10% by RBCs and/or granulocytes, measured by GPI deficiency on flow cytometry.
• Serum LDH levels at least 1.5-fold above the ULN at screening.
• Patients receiving treatment with corticosteroids and/or other immunosuppressive regimens could continue treatment throughout the study, if indicated for treatment of autoimmune disease (e.g., aplastic anemia). It was strongly recommended, at the investigator's discretion, that patients receive appropriate prophylactic antibiotics (e.g., ciprofloxacin, penicillin, erythromycin) while on treatment with any type of concomitant immunosuppressive agent other than LFG316 (including corticosteroids).
• Negative pregnancy test for women of child-bearing potential at screening.
• Previous vaccination against Neisseria meningitidis types A, C, Y and W-135 at least 2 weeks prior to first dosing, and vaccination against meningitidis type B if available and acceptable by local regulations, at least 2 weeks prior to first dosing.
• Able to communicate well with the investigator, to understand and comply with the requirements of the study.

Patients included in this study after protocol amendment 6 were also to fulfill the following:

• To be carriers of the C5 gene minor variants as defined by nucleic acid changes that lead to amino acid exchanges in position p.Arg885.

Additional inclusion criteria for period 4

• Patients who participated in period 3 of the current study who wanted to join the long-term extension study with LNP023 (CLNP023C12001B).
• Previous vaccination for the prevention of Streptococcus pneumoniae and Haemophilus influenzae at least 2 weeks prior to first dosing with LNP023 if locally available. If LNP023 treatment had to start earlier than 2 weeks post vaccination, prophylactic antibiotic treatment was required.

Exclusion criteria

• Known or suspected hereditary complement deficiency.
• History of hematopoietic stem cell transplantation.
• Participation in any other investigational drug trial or exposure to other investigational agent, device, or procedure within 30 days or 5-times the half-life prior to screening. Note: clinical trials solely involving over-the-counter vitamins, off label use of drugs within published standard of care guidelines, supplements, or diet did not exclude an otherwise eligible patient.
• Female patients who were pregnant, breastfeeding, or intended to conceive during the course of the study.
• History of recurrent meningitis, history of meningococcal meningitis despite vaccination.
• Presence or suspicion (based on judgment of the investigator) of severe active bacterial infection within 2 weeks prior to first dose of LFG316, or severe recurrent bacterial infections.
• A positive HIV test result.
• Under active therapy with other agents interfering with the complement system (e.g., eculizumab) Wash-out time was at least 5 half-lives, approximately 8 weeks for eculizumab.
• 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.
• Either one of the following laboratory abnormalities at screening:
• Neutrophils < 0.5 × 10^9/L
• Platelets < 30 × 10^9/L
• Co-morbidities that were likely caused by underlying autoimmune diseases other than PNH, e.g., kidney disease in the context of lupus nephritis, ANCA-associated vasculitis.
• Any medical condition deemed likely to interfere with the patient's pa