P789: efficacy and safety of switching to iptacopan (ipta) monotherapy in patients with paroxysmal nocturnal hemoglobinuria (pnh) treated with the anti-c5 monoclonal antibody (mab) tesidolumab (tesi)

Topic: 12. Bone marrow failure syndromes incl. PNH - Clinical Background: The anti-C5 mAbs eculizumab (ECU) and ravulizumab (RAV) are standard treatment for PNH patients (pts). TESI (LFG316) is an anti-C5 mAb that binds to a different C5 epitope than ECU/RAV and reduces lactate dehydrogenase (LDH) levels in PNH pts (Nishimura et al. Haematologica 2022). IPTA is a complement factor B inhibitor shown to control intravascular hemolysis (IVH) and resolve extravascular hemolysis (EVH) in PNH pts who had residual anemia despite anti-C5 treatment. Aims: To report efficacy and safety of TESI and the effect of switching to IPTA monotherapy in PNH pts enrolled in an open-label, single-arm, Phase II trial (NCT02534909). Methods: Adults with PNH clone size ≥10% by red blood cells (RBCs) and/or granulocytes, LDH ≥1.5× upper limit of normal and no current anticomplement therapies were enrolled. The study had 4 periods (P) (P1: 4 weeks [wks]; P2: optional 48-wk extension; P3: optional 260-wk extension; P4: ~20 wks). In P1–3, pts received intravenous TESI 20 mg/kg every 2 wks. In P4, pts received oral IPTA 200 mg twice a day (bid) and TESI for 4 wks; pts then discontinued TESI and continued with IPTA 200 mg bid. The primary endpoint was reduction of LDH levels after 4 wks and over the entire study. Other endpoints were safety assessments, number of blood transfusions and levels of Hb, reticulocytes, bilirubin and PNH type III RBCs. 6 pts had C5 variants precluding a response to ECU; 7 had received prior ECU. Results: 10 pts were enrolled; 9 entered P4. All pts achieved ≥60% reduction in LDH levels at the end of P1. LDH reductions were sustained through P3 (−81.7% [N=10] from baseline [BL]) and maintained in P4 even after ECU/RAV termination (−78.7% from the BL of 9 pts entering P4). Mean total Hb (g/L; standard deviation [SD]) of 9 pts entering P4 was 90.3 (27.8) at BL and 113.6 (28.7) in P3, increasing to 138.8 (25.3) at the end of P4 (Figure). Mean reticulocyte percentage was similar to BL (5.0%) in P1–3 (P1 4.9%, P2 4.8%, P3 4.9% [N=10]). At the end of P4, mean reticulocyte percentage was 2.2% (N=8), −3.3% from the BL of pts entering P4. Mean bilirubin concentration (µmol/L [SD]) was 20.6 (10.2) at BL and 19.3 (10.4) at P3 (N=10). At the end of P4, mean bilirubin concentration was 10.3 (5.2) µmol/L, −11.0 µmol/L from BL of pts entering P4. No blood transfusions occurred in P4; pts entering this part of the study had a mean of 11.4 transfusions in the year before entering P1 (SD 3.8). PNH type III RBCs increased by 7.3% from BL (33.3%) to P3 (40.6%; not assessed in P4). In P1–3, all pts reported ≥1 adverse event (AE), most commonly nasopharyngitis (n=8), headache (n=5) and cystitis (n=4). In P4, 6 pts experienced ≥1 AE (n=1 for headache, arthralgia, cellulitis, pain in extremity, proteinuria, pruritus, renal colic and shunt stenosis). Most AEs were mild; no pts experienced serious AEs in P4. Summary/Conclusion: TESI, a mAb targeting C5 in the terminal complement pathway, led to early, sustained LDH decreases in PNH pts with or without C5 variants, which were maintained when switching to IPTA, an inhibitor of factor B in the alternative pathway. TESI was effective in improving Hb and PNH type III RBCs, with further increases in Hb seen when switching to IPTA. Improvements in reticulocytes and bilirubin were seen when pts switched to IPTA, suggesting that IPTA controlled both IVH and EVH. Despite the small pt number, these data indicate IPTA is effective in PNH pts irrespective of C5 mutation status. The Phase IIIb APPULSE-PNH study (NCT05630001) will assess the effect of switching to IPTA monotherapy in PNH pts who have Hb ≥10 g/dL in response to ECU/RAV.Keywords: Complement, Clinical trial, Paroxysmal nocturnal hemoglobinuria (PNH), PNH