The Effect of Oral Iptacopan Monotherapy on Hematological Parameters in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Is Consistent Regardless of the Type of Prior Anti-C5 Treatment Received: A Post Hoc Analysis of 24-Week Data from the Randomized Phase III APPLY-PNH Trial
Authors: Peffault De Latour Regis , Kulasekararaj Austin G. , Scheinberg Phillip , Ueda Yasutaka , de Castro Carlos , Maitra Samopriyo , Ferber Philippe , Dahlke Marion , Risitano Antonio M 
Published: December 2024

Background: Iptacopan, an oral proximal complement inhibitor that targets factor B, is approved as a monotherapy for the treatment of adults with PNH based on the results of 2 Phase III trials (APPLY-PNH [NCT04558918] and APPOINT-PNH [NCT04820530]). APPLY-PNH enrolled patients with PNH that were receiving either intravenous eculizumab or ravulizumab. Both treatments inhibit C5; however, ravulizumab has an extended half-life, allowing dosing every 8 weeks compared with eculizumab, which is dosed every 2 weeks. In APPLY-PNH, 24 weeks of iptacopan monotherapy was superior to anti-C5 treatment across a range of outcomes, including clinically meaningful hemoglobin (Hb) increases, Hb ≥12 g/dL and changes from baseline in Hb and absolute reticulocyte count (ARC). We performed a post hoc analysis to explore whether the type of anti-C5 treatment received prior to randomization (eculizumab or ravulizumab) affected hematological parameters and response to iptacopan monotherapy in the randomized treatment period of APPLY-PNH.
Methods: Adult PNH patients with mean Hb &lt;10 g/dL receiving a stable regimen of eculizumab or ravulizumab for ≥6 months were enrolled in APPLY-PNH. Patients were randomized 8:5 to receive iptacopan monotherapy 200 mg twice daily or to continue their anti-C5 regimen for 24 weeks. We performed a post hoc analysis in which mean changes from baseline for Hb and ARC and geometric mean ratio to baseline for lactate dehydrogenase (LDH) at each visit were presented according to whether the patient received eculizumab (eculizumab subgroup) or ravulizumab (ravulizumab subgroup) prior to randomization.
Results: In APPLY-PNH, 62 patients were randomized to the iptacopan arm, 40 of whom had received eculizumab prior to randomization and 22 had received ravulizumab.
Mean Hb at baseline was 9.0 (standard deviation [SD] 0.7) and 8.8 (SD 0.7) g/dL in the eculizumab and ravulizumab subgroups, respectively. Increases from baseline in Hb were comparable in both subgroups of the iptacopan arm at each individual visit during the randomized treatment period, with a 3.8 (SD 1.3) g/dL increase from baseline to Week 24 in the eculizumab subgroup and a 3.5 (SD 1.3) g/dL increase in the ravulizumab subgroup.
At baseline, mean ARC was 198.9 (SD 87.4) × 109/L in the eculizumab subgroup and 183.0 (SD 77.2) × 109/L in the ravulizumab subgroup. Reductions in mean ARC were consistent between the subgroups in the iptacopan arm at each visit in the randomized treatment period; at Week 24, mean changes from baseline in ARC were −122.0 [SD 65.1] and −116.7 [SD 65.4] × 109/L in the eculizumab and ravulizumab subgroups, respectively, reaching mean levels in the normal range.
Mean LDH at baseline was 265.6 (SD 70.0) and 275.5 (SD 71.6) U/L in the eculizumab and ravulizumab subgroups, respectively. LDH in both subgroups remained low throughout the randomized treatment period of APPLY-PNH, and the geometric mean ratio to baseline in the 2 subgroups of the iptacopan arm were consistent at each visit. At Week 24, the geometric mean ratio to baseline in LDH (U/L) was 1.0 in the eculizumab subgroup and 1.0 in the ravulizumab subgroup.
When plotted graphically, mean changes from baseline in Hb and ARC and geometric mean ratio to baseline in LDH for the eculizumab and ravulizumab subgroups of iptacopan-treated patients were generally superimposable throughout the randomized treatment period.
Results for all 3 parameters in the 35 patients randomized to continue anti-C5 treatment in APPLY-PNH were also consistent regardless of whether they were receiving eculizumab (23 patients) or ravulizumab (12 patients).
Conclusions: This post hoc analysis found that the improvements achieved in Hb and ARC in the iptacopan arm of APPLY-PNH were consistent regardless of the anti-C5 regimen patients with PNH received prior to randomization. LDH also remained similar to baseline throughout the randomized treatment period for both subgroups of the iptacopan arm. These results show that, despite the different pharmacokinetic profiles of eculizumab and ravulizumab, there was no difference between the 2 subgroups in the time courses of change from baseline in Hb and ARC and geometric mean ratio to baseline in LDH with iptacopan monotherapy, indicating that iptacopan was effective regardless of which C5 inhibitor patients with PNH received before randomization in the APPLY-PNH trial.