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

Background: 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). We 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.

Methods: 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.

Results: 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.

Conclusions: 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.