CT-121: Phase 3 Study of the Efficacy and Safety of Iptacopan (LNP023), an Oral Factor B Inhibitor, in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Naïve to Complement Inhibitor Therapy

Context Standard of care in PNH is based on complement C5 inhibition with anti-C5 monoclonal antibodies (MAbs), which are generally effective at treating intravascular hemolysis (IVH), but unmet needs remain. Hematological responses to anti-C5 antibody treatment can be heterogeneous, and a substantial number of patients experience residual anemia associated with breakthrough hemolysis (BTH). Iptacopan, a first-in-class, oral, small-molecule, selective, and reversible complement factor B inhibitor, inhibits both IVH and extravascular hemolysis. In an ongoing Ph2 study (NCT03439839), iptacopan has demonstrated improvements in hematological response and biomarkers of disease activity in PNH adult patients who had active hemolysis, despite eculizumab treatment. Objective APPOINT-PNH study (NCT04820530) will assess iptacopan efficacy and safety in PNH adult patients naïve to complement inhibitors, including anti-C5 MAbs. Design The study comprises ≤8-wk screening; 24-wk, single-arm, open-label core treatment; and 24-wk, open-label treatment extension. On completion of week 24, patients who benefit from iptacopan treatment can enter extension. Eligible adult patients (N≈40) have confirmed PNH diagnosis (RBCs and WBCs [granulocyte/monocyte] clone size ≥10%); anemia (mean Hb <10g/dL), and active hemolysis (LDH >1.5× ULN). Key exclusion criteria: prior treatment with complement inhibitor; known or suspected hereditary complement deficiency; history of HSCT; laboratory evidence of bone marrow failure; active, systemic infection ≤14 days preceding study treatment; and history of recurrent, invasive infections caused by encapsulated microorganisms. Primary objective will assess hematologic response, defined as achieving sustained increase in Hb ≥2g/dL (in absence of RBC transfusions). Primary endpoint will evaluate proportion of patients achieving an increase from baseline in Hb ≥2g/dL between D126–D168 (in absence of RBC transfusions between D14–D168). Secondary endpoints include proportion of patients reaching Hb ≥12g/dL; absence of RBC transfusions; changes from baseline in Hb; changes in FACIT-Fatigue scores; changes from baseline in reticulocytes; % change from baseline in LDH; occurrence of BTH; and occurrence of major adverse vascular events (including thrombosis). Additional analyses include safety assessments; evolution of PNH clone size and C3d deposition on RBCs; and other PROs. Conclusions Ph3 studies to assess iptacopan efficacy in a wider population of PNH patients, including those naïve to anti-C5 MAbs treatment, are needed. Study sponsored by Novartis Pharmaceuticals Corporation. Standard of care in PNH is based on complement C5 inhibition with anti-C5 monoclonal antibodies (MAbs), which are generally effective at treating intravascular hemolysis (IVH), but unmet needs remain. Hematological responses to anti-C5 antibody treatment can be heterogeneous, and a substantial number of patients experience residual anemia associated with breakthrough hemolysis (BTH). Iptacopan, a first-in-class, oral, small-molecule, selective, and reversible complement factor B inhibitor, inhibits both IVH and extravascular hemolysis. In an ongoing Ph2 study (NCT03439839), iptacopan has demonstrated improvements in hematological response and biomarkers of disease activity in PNH adult patients who had active hemolysis, despite eculizumab treatment. APPOINT-PNH study (NCT04820530) will assess iptacopan efficacy and safety in PNH adult patients naïve to complement inhibitors, including anti-C5 MAbs. The study comprises ≤8-wk screening; 24-wk, single-arm, open-label core treatment; and 24-wk, open-label treatment extension. On completion of week 24, patients who benefit from iptacopan treatment can enter extension. Eligible adult patients (N≈40) have confirmed PNH diagnosis (RBCs and WBCs [granulocyte/monocyte] clone size ≥10%); anemia (mean Hb <10g/dL), and active hemolysis (LDH >1.5× ULN). Key exclusion criteria: prior treatment with complement inhibitor; known or suspected hereditary complement deficiency; history of HSCT; laboratory evidence of bone marrow failure; active, systemic infection ≤14 days preceding study treatment; and history of recurrent, invasive infections caused by encapsulated microorganisms. Primary objective will assess hematologic response, defined as achieving sustained increase in Hb ≥2g/dL (in absence of RBC transfusions). Primary endpoint will evaluate proportion of patients achieving an increase from baseline in Hb ≥2g/dL between D126–D168 (in absence of RBC transfusions between D14–D168). Secondary endpoints include proportion of patients reaching Hb ≥12g/dL; absence of RBC transfusions; changes from baseline in Hb; changes in FACIT-Fatigue scores; changes from baseline in reticulocytes; % change from baseline in LDH; occurrence of BTH; and occurrence of major adverse vascular events (including thrombosis). Additional analyses include safety assessments; evolution of PNH clone size and C3d deposition on RBCs; and other PROs. Ph3 studies to assess iptacopan efficacy in a wider population of PNH patients, including those naïve to anti-C5 MAbs treatment, are needed. Study sponsored by Novartis Pharmaceuticals Corporation.