Efficacy, Safety, Pharmacokinetics and Pharmacodynamics Study, Assessing Multiple LNP023 Doses in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria
Condition: Paroxysmal Nocturnal Hemoglobinuria
MeSH terms: Hemoglobinuria; Hemoglobinuria, Paroxysmal
Intervention: LNP023
Intervention description: approximately 2 year of Treatment with LNP023
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomized, open label study
Masking: None (Open Label)
Enrollment: 13.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Complement; alternative pathway; paroxysmal nocturnal hemoglobinuria; hemolysis; LNP023; PNH; LDH; hemoglobin; Iptacopan

Summary:

      This was a Phase II randomized, open-label, multicenter, efficacy, safety, pharmacokinetic
      and pharmacodynamic study assessing four iptacopan doses in adult Paroxysmal nocturnal
      hemoglobinuria (PNH) patients with active hemolysis who were not on eculizumab or any other
      complement inhibitor less than 3 months prior to first iptacopan dose. Active hemolysis was
      defined by a lactate dehydrogenase (LDH) value ≥ 1.5 × ULN.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Written informed consent must be obtained before any assessment is performed.

          2. Male and female patients at least 18 years old at baseline.

          3. 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).

          4. 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).

          5. Hemoglobin level < 10.5 g/dL at Baseline.

          6. 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.

          7. 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.

          8. Able to communicate well with the investigator, to understand and comply with the
             requirements of the study. -

        Exclusion Criteria:

          1. 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.

          2. Patients treated with eculizumab or any other complement inhibitor less than 3 months
             prior to study Day 1

          3. Known or suspected hereditary or acquired complement deficiency.

          4. History of currently active primary or secondary immunodeficiency.

          5. History of splenectomy.

          6. History of bone marrow/ hematopoietic stem cell or solid organ transplants (e.g.
             heart, lung, kidney, liver).

          7. Evidence of malignant disease, or malignancies diagnosed within the previous 5 years.

          8. 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.

          9. History of recurrent meningitis, history of meningococcal infections despite
             vaccination, as verified at both screening and baseline.

         10. 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.

         11. A positive HIV, Hepatitis B (HBV) or Hepatitis C (HCV) test result at screening.

         12. 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.

         13. Systemic corticosteroids unless on a stable dose for at least 4 weeks before
             randomization.

         14. 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).

         15. 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.

         16. History of hypersensitivity to the study treatment or its excipients or to drugs of
             similar chemical classes.

         17. Female patients who are pregnant or breastfeeding, or intending to conceive during the
             course of the study.

         18. 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