Study of Safety, Efficacy, Tolerability, Pharmacokinetics and Pharmacodynamics of LNP023 in in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)
Condition: Paroxysmal Nocturnal Hemoglobinuria (PNH) With Signs of Active Hemolysis
MeSH terms: Hemoglobinuria; Hemoglobinuria, Paroxysmal; Hemolysis
Intervention: iptacopan; Standard of Care
Intervention description: iptacopan bid orally administered; Standard of Care (SoC) is defined as an antibody with anti C5 activity. At the time of study start, eculizumab was the only available SoC; eculizumab will be hereafter referred to as SoC.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: Open label, non-randomized study
Masking: None (Open Label)
Masking description: No masking used in the study
Enrollment: 16.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Complement; alternative pathway; paroxysmal nocturnal hemoglobinuria; hemolysis

Summary:

      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.
    

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).