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

This was a Phase 2, open label, single arm, multiple dose study to assess efficacy, safety, pharmacokinetics and pharmacodynamics of iptacopan when administered in addition to Standard of care (SoC) in patients with paroxysmal nocturnal hemoglobinuria (PNH) with signs of active hemolysis.

LNP023 is a novel oral small molecular weight compound that inhibits factor B (FB) of the alternative pathway (AP). Blockade of the AP with oral LNP023 has the potential to prevent both intra - and extravascular hemolysis.

This two-cohort study consisted of a screening period of up to 68 days, a baseline visit, and Treatment periods Part 1 and Part 2. The planned duration of Treatment Part 1 was 13 weeks; the planned duration of Treatment Part 2 (treatment extension for patients who benefit from LNP023 treatment in Part 1 of the study based on reduced hemolytic parameters) was between approximately 2 to 3 years.

Cohort 1: Orally administered iptacopan 200 mg b.i.d. in Part 1 and Part 2 in addition to SoC.

Cohort 2: Orally administered iptacopan 50 mg b.i.d. for a minimum of 2 weeks in addition to SoC; this could be increased to iptacopan 200 mg b.i.d. at study day 15 or at any time later in the study if LDH was not within limit of normal or reduced by at least 60% as compared to baseline values.

End of Study (EoS) visit happened 2 weeks after last LNP023 administration for patients not joining the roll over extension program (REP).

A safety follow-up call was conducted 30 days after last administration of study treatment (applicable only for patients not joining the REP).

Eligibility Criteria:
Inclusion Criteria:

1. 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 glycosylphosphatidylinositol (GPI)-deficiency on flow cytometry (screening or medical history data acceptable).
2. For Cohort 1 only: LDH values ≥1.5 × Upper limit of normal (ULN) 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 must be \>1 × ULN range (for pre-SoC samples collected at the same day as SoC administration).
3. For Cohort 2 only: LDH values ≥1.25 × ULN 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 must be \>1 × ULN range (for pre-SoC samples collected at the same day as SoC administration).
4. For Cohort 2 only: Hemoglobin level \<10.5 g/dL at Baseline.
5. PNH patients on stable regimen of SoC complement blockade (monoclonal antibody with anti C5 activity) for at least 3 months prior to first treatment with iptacopan.
6. Previous vaccination against N. meningitidis types A, C, Y and W-135 is required at least 4 weeks prior to first dosing with iptacopan. 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 iptacopan. If iptacopan treatment must start earlier than 4 weeks post vaccination, prophylactic antibiotic treatment must be initiated.
7. Previous vaccination for the prevention of S. pneumoniae and H. influenzae at least 4 weeks prior to first dosing with iptacopan. If iptacopan treatment must start earlier than 4 weeks post vaccination, prophylactic antibiotic treatment must be initiated.

Exclusion Criteria:

1. Known or suspected hereditary complement deficiency at Screening.
2. History of hematopoietic stem cell transplantation as verified both at Screening and at Baseline (unless baseline was skipped).
3. Patients with laboratory evidence of bone marrow failure.
4. A positive Human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C test result at Screening.
5. Presence or suspicion (based on judgment of the Investigator) of active infection within 2 weeks prior to first dose of iptacopan, or history of severe recurrent bacterial infections.
6. History of recurrent meningitis, history of meningococcal infections despite vaccination as verified both at Screening and at Baseline (unless Baseline was skipped).
7. Patients on immunosuppressive agents such as (but not limited to) cyclosporine, mycophenolate mofetil, tacrolimus, cyclophosphamide, methotrexate less than 8 weeks prior to first treatment with iptacopan unless on a stable regimen for at least 3 months prior to first iptacopan dose.
8. Systemic corticosteroids administered at the dose of ≥10 mg per day prednisone equivalent within less than 4 weeks prior to first treatment with iptacopan.
9. Severe concurrent co-morbidities; e.g., patients with severe kidney disease (dialysis), advanced cardiac disease (New York Heart disease Association (NYHA) class IV), severe pulmonary arterial hypertension (World Health Organization (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).