Factor B Inhibition with Oral Iptacopan Monotherapy Demonstrates Sustained Long-Term Efficacy and Safety in Anti-C5-Treated Patients (pts) with Paroxysmal Nocturnal Hemoglobinuria (PNH) and Persistent Anemia: Final 48-Week Results from the Multicenter, Phase III APPLY-PNH Trial
Authors: Risitano Antonio M , Kulasekararaj Austin , Roeth Alexander , Scheinberg Phillip , Ueda Yasutaka , de Castro Carlos , Di Bona Eros , Griffin Morag , Langemeijer Saskia MC , Schrezenmeier Hubert , Barcellini Wilma , Mauad Vitor AQ , Panse Jens , Schafhausen Philippe , Tavitian Suzanne , Beggiato Eloise , Gaya Anna , Huang Wei-Han , Kitawaki Toshio , Kutlar Abdullah , Maciejewski Jaroslaw P. , Notaro Rosario , Pullarkat Vinod , Schubert Jörg , Terriou Louis , Uchiyama Michihiro , Sicre De Fontbrune Flore , Frieri Camilla , Alashkar Ferras , Gandhi Shreyans , Kumar Rakesh , Thorburn Christine , Maitra Samopriyo , Solar-Yohay Susan , Lawniczek Tomasz , Dahlke Marion , Peffault De Latour Régis 
Published: December 2023

Drs Roeth and Kulasekararaj contributed equally as authors.
Background: Iptacopan is the first oral complement inhibitor that acts proximally in the complement system to target factor B in the alternative pathway. Iptacopan has shown efficacy/safety in PNH pts with persistent anemia despite anti-C5 therapy and complement inhibitor-naive pts. In the Phase III APPLY-PNH trial (NCT04558918), iptacopan monotherapy led to clinically meaningful hemoglobin (Hb) increases and normal/near-normal Hb levels in a majority of pts, transfusion avoidance and improved pt-reported fatigue, showing superiority vs C5 inhibitors at Week (Wk) 24.
Aim: We report the final APPLY-PNH data after a 24-wk extension period in which all pts received iptacopan monotherapy (study completion: 6 March 2023).
Methods: Adult PNH pts (mean Hb &lt;10 g/dL, receiving anti-C5 therapy for ≥6 months) were randomized to receive iptacopan 200 mg twice daily or continue their anti-C5 regimen for 24 wks. Pts could then opt to enter an extension period; pts in the iptacopan arm received iptacopan for another 24 wks and pts who had been receiving anti-C5 switched to iptacopan monotherapy.
Results: In the extension period, 95 pts received iptacopan: 61/62 in the iptacopan arm (1 discontinued iptacopan in the randomized period because of pregnancy) and 34/35 in the anti-C5-to-iptacopan arm (1 did not enter the extension period [investigator's decision]). In the iptacopan arm, the improvements at 24 wks were sustained at 48 wks, with maintenance of increased Hb, normal/near-normal mean Hb levels (Figure), improved Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) scores, decreased absolute reticulocyte counts (ARCs) and transfusion avoidance (Table). Pts who switched from anti-C5 to iptacopan had rapid changes in Hb, FACIT-F and ARC, achieving comparable improvements to the iptacopan arm. Mean Hb levels at Wk 48 were 12.2 and 12.1 g/dL in the iptacopan and anti-C5-to-iptacopan arms, respectively (standard deviations 1.6 and 1.4). At Wk 48, the adjusted mean change from baseline in the iptacopan arm was +3.35 g/dL for Hb, +9.80 FACIT-F points and −106.26 × 10 9/L for ARC. In the anti-C5-to-iptacopan arm, the adjusted mean change from baseline at Wk 48 was +3.36 g/dL for Hb, +10.96 FACIT-F points and −107.95 × 10 9/L for ARC (adjusted mean difference in change from baseline at Wk 48 vs Wk 24: +3.02 g/dL, +10.79 points and −102.29 × 10 9/L, respectively). Transfusion avoidance was achieved by 93.5% of pts in the iptacopan arm (Wks 2 to 48) and 94.1% in the anti-C5-to-iptacopan arm (Wks 26 to 48). Mean lactate dehydrogenase levels were generally maintained &lt;1.5 × upper limit of normal in both arms.
In the trial, 6/62 pts in the iptacopan arm had clinical breakthrough hemolysis (BTH). One pt in the anti-C5-to-iptacopan arm had clinical BTH after switching to iptacopan. BTH resolved without changing iptacopan dosing. Three pts had major adverse vascular events (MAVEs; randomized period: 1 serious transient ischemic attack [TIA]; extension period: 1 non-serious TIA, 1 serious portal vein thrombosis [PVT]). The pt with PVT had a history of PVT and discontinued heparin prior to the MAVE. All MAVEs were considered unrelated to iptacopan and resolved without changing iptacopan dosing. After 48 wks in the iptacopan arm, the most frequently reported treatment-emergent adverse events (TEAEs) were COVID-19 (29.0% of pts), headache (19.4%), diarrhea (16.1%) and nasopharyngitis (14.5%). There were no deaths, no serious hemolysis TEAEs on iptacopan, no serious infections caused by N. meningitidis, S. pneumoniae or H. influenzae and no pts discontinued treatment because of TEAEs.
Conclusions: Long-term data from the Phase III APPLY-PNH trial show a durable response to iptacopan monotherapy in anti-C5-treated PNH pts with persistent anemia. Pts who received iptacopan for 48 wks had sustained improvements in multiple hematological and clinical outcomes, including maintenance of increased Hb, mean normal/near-normal Hb levels, transfusion avoidance and decreased pt-reported fatigue; these benefits quickly emerged in the anti-C5-to-iptacopan arm, supporting the benefit of switching from C5 inhibitors to iptacopan monotherapy. The data indicate good control of hemolysis by iptacopan and a similar safety profile at Wk 48 vs Wk 24. Our findings continue to support oral iptacopan monotherapy as a potentially practice-changing treatment for hemolytic PNH.