Study of Efficacy and Safety of Twice Daily Oral LNP023 in Adult PNH Patients With Residual Anemia Despite Anti-C5 Antibody Treatment

This study was a multi-center, randomized, open-label, active comparator-controlled, parallel group study.

The purpose of this Phase 3 study in PNH patients presenting with residual anemia despite treatment with anti-C5 antibody, was to determine whether iptacopan is efficacious and safe for the treatment of PNH through demonstration of superiority of iptacopan compared to anti-C5 antibody treatment.

The study comprised three periods:

* A screening period lasting up to 8 weeks (unless there was a need to extend it for vaccinations required for inclusion, vaccinations were started as early as possible to avoid extension of the screening period)
* A 24-week randomized, open-label, active controlled, treatment period for the primary efficacy and safety analyses. Patients who met the eligibility criteria at screening were stratified based on the type of prior anti-C5 antibody treatment (eculizumab or ravulizumab) and based on the transfusion history as reported during the last 6 months prior to randomization (i.e. transfusion received/not received). Patients were randomized to one of the two treatment groups in an 8:5 ratio to either iptacopan monotherapy at a dose of 200 mg orally b.i.d. or i.v. anti-C5 antibody treatment (patients continued with the same regimen during the randomized treatment period as they were prior to randomization), respectively.
* A 24-week open-label, iptacopan treatment extension period. The patients randomized to the active comparator group were offered to switch to iptacopan on Day 168 (Week 24 visit) and entered the treatment extension period, after receiving a last dose of anti-C5 antibody treatment (eculizumab or ravulizumab). For patients in the comparator group not agreeing to switch treatment, Week 24 visit was the End of Study visit for the trial with no participation in the treatment extension period. For patients agreeing to switch to oral iptacopan, the Extension treatment started on the day after completion of the Week 24 visit. The patients in the iptacopan group who, in the opinion of investigator, benefitted from treatment and were taking iptacopan at Week 24 visit (i.e. did not permanently discontinue study medication), were offered the opportunity to continue oral iptacopan treatment during the treatment extension period.
* Data cut-off date used for the primary results submission was 26- Sep-2022

Eligibility Criteria:
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%
* Stable regimen of anti-C5 antibody treatment (either eculizumab or ravulizumab) for at least 6 months prior to randomization
* Mean hemoglobin level \<10 g/dL
* Vaccination against Neisseria meningitidis infection is required prior to the start of treatment.
* If not received previously, vaccination against Streptococcus pneumoniae and Haemophilus influenzae infections should be given

Exclusion Criteria:

* Participants on a stable eculizumab dose but with a dosing interval of 11 days or less or patients on stable ravulizumab dose but with a dosing interval of less than 8 weeks.
* Known or suspected hereditary complement deficiency at screening
* History of hematopoietic stem cell transplantation
* Patients with laboratory evidence of bone marrow failure (reticulocytes \<100x10E9/L; platelets \<30x10E9/L; neutrophils \<500x10E6/L).
* Active systemic bacterial, viral (incl. COVID-19), or fungal infection within 14 days prior to study drug administration
* A 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., eGFR \< 30 mL/min/1.73 m2, dialysis), advanced cardiac disease (e.g., NYHA class IV), 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.