Oral Iptacopan Monotherapy Leads to Long-Term Improvements in Patient (Pt)-Reported Health-Related Quality of Life (HRQoL) and Investigator-Assessed Signs and Symptoms of Paroxysmal Nocturnal Hemoglobinuria (PNH): 48-Week (Wk) Results from the Phase III APPLY-PNH and APPOINT-PNH Trials

Iptacopan, an oral factor B inhibitor approved as a monotherapy for treatment of adults with PNH, enabled sustained normalization of hemoglobin (Hb) levels, transfusion independence and decreased pt‑reported fatigue in PNH pts with persistent anemia despite anti-C5 treatment (APPLY‑PNH; NCT04558918) or who were complement inhibitor naïve (APPOINT‑PNH; NCT04820530). In this study, carried out by Dr. Antonio M. Risitano et al, the authors report changes in pt-reported HRQoL outcomes and investigator‑assessed PNH signs/symptoms with 48 wks of iptacopan monotherapy in APPLY‑PNH and APPOINT-PNH.

In APPLY-PNH, adult PNH pts receiving anti-C5 for ≥6 months with mean Hb <10 g/dL were randomized to receive iptacopan monotherapy 200 mg twice daily (bid) or continue anti-C5 for 24 wks. All pts could then enter a 24-wk extension period (EP) and receive iptacopan monotherapy. In APPOINT‑PNH, complement inhibitor-naïve adult PNH pts with mean Hb <10 g/dL received iptacopan monotherapy 200 mg bid for 48 wks (24‑wk treatment period and 24-wk EP). Changes in pt-reported HRQoL (assessed using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ-C30]) and investigator-assessed PNH signs/symptoms (reddish or cola-colored urine/hemoglobinuria, feeling weak or tired, shortness of breath/dyspnea, dysphagia, chest pain, abdominal pain and erectile dysfunction) were exploratory endpoints in both trials.

In APPLY-PNH, 62 and 35 pts were randomized into the iptacopan and anti-C5 arms, respectively, 61 and 34 of whom received iptacopan monotherapy in the EP, respectively. In APPOINT-PNH, 40 pts received iptacopan monotherapy for 48 wks. Pts in the iptacopan arm of APPLY-PNH reported improvements in mean change from baseline (CFBL) to Wk 48 in all functional domains of EORTC QLQ‑C30 (mean CFBL [standard deviation (SD)]: cognitive, 9.5 [15.8]; emotional, 11.7 [23.6]; physical, 14.7 [16.4]; role, 14.4 [23.8]; social, 13.2 [30.3]). Mean CFBL in global health status was 16.3 (SD 18.0) at Wk 48 in the iptacopan arm, with pt-reported improvements in dyspnea (mean CFBL: −28.8 [SD 29.5]) and fatigue (mean CFBL: −18.2 [SD 23.5]) observed at Wk 48. Pts who switched from anti-C5 to iptacopan reported improvements comparable with the iptacopan arm in all functional domains, global health status, dyspnea and fatigue at Wk 48 after 24 wks of iptacopan monotherapy. In APPOINT‑PNH, improvements in all functional domains, global health status, dyspnea and fatigue were reported by pts at Wk 48.

In APPLY-PNH, 62.9% of pts in the iptacopan arm and 68.6% in the anti-C5 arm had ≥1 PNH sign/symptom at baseline (BL; most common symptoms: feeling weak or tired and dyspnea). In the iptacopan arm, this decreased to 25.8% at Wk 48. In the anti-C5 arm, 57.1% of pts had ≥1 sign/symptom at Wk 24, decreasing to 26.5% at Wk 48 after 24 wks of iptacopan monotherapy. In the iptacopan arm, the proportion of pts not feeling weak or tired was 48.4% at BL and 75.8% at Wk 48. In the anti-C5 arm, the proportion of pts not feeling weak or tired was 31.4% at BL, 45.7% at Wk 24 and 82.4% at Wk 48 after 24 wks of iptacopan monotherapy. In the iptacopan arm, the proportion of pts who did not have dyspnea was 71.0% at BL and 87.1% at Wk 48. At BL, 62.9% of pts in the anti-C5 arm did not have dyspnea; 74.1% did not have dyspnea at Wk 24, which increased to 85.3% at Wk 48 after 24 wks of iptacopan monotherapy. Most pts did not have other signs/symptoms of PNH at BL.

In APPOINT-PNH, the proportion of pts with ≥1 PNH sign/symptom was 97.5% at BL (most common symptom: hemoglobinuria), decreasing to 27.5% at Wk 48. At BL, 22.5% of pts did not have hemoglobinuria, increasing to 95.0% at Wk 48; improvements in all other PNH signs/symptoms were also observed.

Improvements in pt-reported EORTC QLQ-C30 functional domains, global health status and symptom scores, and investigator-assessed PNH signs/symptoms were observed among pts receiving 48 wks of iptacopan monotherapy in APPLY‑PNH and APPOINT-PNH. Both pts and investigators reported improvements in debilitating symptoms of PNH, including fatigue and dyspnea, with iptacopan treatment. Pts in APPLY‑PNH who switched from anti-C5 to iptacopan experienced improvements in EORTC QLQ-C30 scores and PNH signs/symptoms comparable with those achieved by pts initially randomized to receive iptacopan. These results provide further evidence of the long-term positive impact of iptacopan on HRQoL and common signs/symptoms of PNH.

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

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).  A post hoc analysis, carried out by Dr. Regis Peffault De Latour et al, was performed 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.

Adult PNH patients with mean Hb <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.

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).

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.