Clinical Breakthrough Hemolysis (BTH) during Monotherapy with the Oral Factor B Inhibitor Iptacopan Is Generally Not Severe and Managed without Treatment Discontinuation: 48-Week Data from the Phase III Apply-PNH and Appoint-PNH Trials in Paroxysmal Nocturnal Hemoglobinuria (PNH)
Authors: Peffault De Latour Regis , Kulasekararaj Austin , Scheinberg Phillip , Ferber Philippe , Lawniczek Tomasz , Thorburn Christine , Dahlke Marion , Risitano Antonio M 
Published: December 2023

Background: In PNH, BTH is characterized by the re-emergence of intravascular hemolysis (IVH) despite ongoing complement inhibition and is recognized by the reappearance of IVH/PNH signs/symptoms, coupled with a marked increase in lactate dehydrogenase (LDH) and sharp decrease in hemoglobin (Hb). Iptacopan is the first oral proximal complement inhibitor targeting factor B in the alternative pathway and has shown efficacy and safety in complement inhibitor-naïve PNH patients (pts; APPOINT-PNH; NCT04820530) and pts with persistent anemia despite anti-C5 treatment (APPLY-PNH; NCT04558918). In the APPLY-PNH 24-week (wk) analysis, iptacopan monotherapy showed superiority in the adjusted annualized rate of clinical BTH vs C5 inhibitors.
Aim: We report the proportion of pts with clinical BTH, exposure-adjusted occurrence rates and BTH characteristics during iptacopan monotherapy in the Phase III APPLY-PNH and APPOINT-PNH trials (study completion [48-wk data]: 6 March and 18 April 2023, respectively).
Methods: The prespecified protocol criteria for clinical BTH were LDH &gt;1.5 × upper limit of normal (ULN) and increased vs the last 2 assessments, plus a ≥2 g/dL Hb decrease (vs the last assessment or within 15 days) or significant PNH signs/symptoms. All BTH was classed as an adverse event and evaluated for severity (investigator assessment) and seriousness (per protocol). In APPLY-PNH, adults who had received anti-C5 therapy for ≥6 months and had mean Hb &lt;10 g/dL were randomized to receive oral iptacopan 200 mg twice daily or continue their anti-C5 regimen for 24 wks (randomized treatment period [RTP]). In APPOINT-PNH, adult complement inhibitor-naïve pts with mean Hb &lt;10 g/dL and mean LDH &gt;1.5 × ULN received iptacopan 200 mg twice daily for 24 wks. Both trials then had extension periods in which all pts could receive iptacopan monotherapy for another 24 wks.
Results: In APPLY-PNH, 61/62 pts in the iptacopan arm continued iptacopan in the extension period and 34/35 in the anti-C5 arm switched to iptacopan. All 40 pts in APPOINT-PNH entered the extension period. When these 48-wk trials completed, 136 pts had received iptacopan with varying exposure (total exposure ~111 pt-years), of whom 9 had clinical BTH (10 events, Table). Two pts were in APPOINT-PNH (2/40, 2 events) and 7 in APPLY-PNH (7/96, 8 events). Of the iptacopan-treated pts in APPLY-PNH, 2 had BTH in the RTP; 1 of these pts plus 5 others had BTH in the extension period (including 1 who switched from anti-C5 to iptacopan at Wk 24). The exposure-adjusted occurrence rate of clinical BTH on iptacopan was 11.0 events per 100 pt-years in APPLY-PNH (95% confidence interval [CI] 5.2‒23.3) and 5.2 events per 100 pt-years in APPOINT-PNH (95% CI 1.3‒20.5). In the 24-wk APPLY-PNH RTP, 6/35 pts in the anti-C5 arm had clinical BTH (11 events); the exposure-adjusted occurrence rate was 66.9 events per 100 pt-years (95% CI 25.0‒178.9), which is &gt;6 times higher than the rates on iptacopan.
Of the 10 clinical BTH events reported on iptacopan, all were mild or moderate except 1 severe (and serious) event despite large PNH RBC clone sizes of &gt;90% reported before 5/8 events with available clone size data. The impact of BTH on Hb was generally transient (Figure). Potential complement-amplifying conditions (CACs) were identified for 8 clinical BTH events during iptacopan treatment; the severe event was associated with COVID-19 and the temporal appearance of cold agglutinins. No pts discontinued iptacopan because of clinical BTH. RBC transfusions were the most common intervention; 1 pt received a 900 mg dose of eculizumab. In the anti-C5 arm in the APPLY-PNH RTP, 1/11 BTH events was severe and 2/11 were associated with potential CACs.
Conclusions: In Phase III trials, 136 PNH pts received iptacopan monotherapy and few pts had clinical BTH, with severity being comparable to that with anti-C5 despite PNH RBC clone sizes &gt;90%. Most clinical BTH events on iptacopan were associated with potential CACs; BTH was manageable with no intervention or RBC transfusion and without iptacopan discontinuation. The exposure-adjusted occurrence rates support our prior finding of a significantly lower adjusted annualized rate of clinical BTH with iptacopan vs anti-C5. BTH must be monitored with any complement inhibitor, but these data show that BTH was infrequent on iptacopan and support the positive safety profile of proximal complement inhibition with oral iptacopan monotherapy in hemolytic PNH.