Pb2063: appulse-pnh: a phase iiib trial to evaluate the efficacy and safety of switching to iptacopan in patients with paroxysmal nocturnal hemoglobinuria (pnh) on anti-c5 therapy with hemoglobin >10g/dl

Topic: 12. Bone marrow failure syndromes incl. PNH - Clinical Background: The anti-C5 monoclonal antibodies eculizumab (ECU) and ravulizumab (RAV) are standard of care (SoC) for PNH patients (pts), but several unmet needs exist. PNH pts who have a complete (transfusion independence and no anemia [hemoglobin (Hb) >12 g/dL]) or good (transfusion independence and mild anemia [Hb 10–12 g/dL]) response to ECU, according to criteria proposed by Risitano et al (Front Immunol 2019) and Debureaux et al (Bone Marrow Transplant 2021), can still have ongoing low-level extravascular hemolysis (EVH) and are at risk of breakthrough hemolysis (BTH). EVH and BTH can lead to PNH symptoms and negatively affect survival and quality of life, which can also be impaired by the need for lifelong intravenous infusions. Regional availability also limits pt access. Hence oral therapy may be a convenient alternative treatment for PNH pts. Iptacopan (IPTA) is an oral, selective, reversible, small molecule inhibitor of complement factor B in the alternative complement pathway. In the randomized Phase III APPLY-PNH trial of PNH pts with Hb <10 g/dL despite treatment with ECU or RAV, IPTA monotherapy was superior to SoC at improving Hb levels without the need for transfusions and pt-reported fatigue by maintaining control of intravascular hemolysis (IVH) and resolving EVH (Peffault de Latour et al. Blood 2022). IPTA was also superior to SoC when comparing annualized clinical BTH rate. Aims: APPULSE-PNH (NCT05630001) will assess the efficacy and safety of switching to IPTA monotherapy in pts with PNH receiving ECU or RAV and Hb ≥10 g/dL. Methods: Approximately 50 adult PNH pts will be enrolled. Eligible pts must be on a stable regimen of SoC for ≥6 months prior to screening and have a mean Hb level ≥10 g/dL, with the aim of ≥60% of pts having Hb <12 g/dL and the remaining pts having Hb ≥12 g/dL. Exclusion criteria include red blood cell transfusion in the 6 months prior to or during screening, known or suspected hereditary complement deficiency and history of hematopoietic stem cell or any solid organ transplantation. Enrolled pts will receive IPTA monotherapy 200 mg twice daily for 24 weeks. Pts benefiting from IPTA treatment will have the opportunity to enter a post-study rollover extension program (NCT04747613). As pts enrolling in APPULSE-PNH had a stable SoC regimen for ≥6 months with Hb ≥10 g/dL and no transfusions in this period, the primary objective is to demonstrate non-inferiority of IPTA after switching from SoC when assessing Hb change from baseline (BL) between Days 126 and 168 (Table). Clinical data and experience suggest that a Hb change of −1 g/dL is within natural variability. Assuming pts have stable Hb within 6 months prior to study treatment, mean change from BL Hb level between Days 126 and 168 is expected to be unchanged if pts continue on SoC. Non-inferiority of IPTA will, therefore, be tested by comparing the mean change from BL in Hb between Days 126 and 168 and demonstrated if the lower boundary of the 95% confidence interval (CI) is >−1g/dL. If the primary objective is met, superiority of IPTA for Hb change from BL will be tested by comparing the lower boundary of the 95% CI of change from BL in Hb to 0 g/dL (secondary objective). Other secondary objectives include assessments of pt-reported treatment satisfaction, effectiveness and convenience and changes in fatigue (Table). Results: The first pts are expected to be enrolled in APPULSE in summer 2023. Summary/Conclusion: APPULSE will assess the efficacy and safety of switching to IPTA monotherapy from SoC anti-C5 therapy in PNH pts with Hb ≥10 g/dL, a population not included in the Phase III APPLY-PNH trial.Keywords: PNH, Paroxysmal nocturnal hemoglobinuria (PNH), Clinical trial