Long-term safety and efficacy of iptacopan in patients with paroxysmal nocturnal hemoglobinuria: 4- and 5-year follow-up of patients from Phase 2 studies who entered the roll-over extension program

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease characterized by complement-mediated hemolysis and consequent anemia. Despite treatment with antiC5 therapy, many patients with PNH remain anemic and may continue to experience symptoms of PNH and extravascular hemolysis. Iptacopan is an oral proximal complement inhibitor that targets factor B to selectively inhibit the alternative pathway of the complement system. In Phase 2 and Phase 3 studies of patients with PNH, iptacopan has shown rapid and sustained hemolysis control, with improvements in hemolytic markers, and a well-tolerated safety profile, regardless of prior complement inhibitor treatment. Here, the authors report 4- and 5-year follow-up data on the long-term safety and efficacy of iptacopan in patients who entered the roll-over extension program (REP) from Phase 2 studies. PNH-REP (NCT04747613) is an ongoing, open-label, single-arm, multicenter, Phase 3 study of patients with PNH who completed the treatment extension periods (without tapering down) of Phase 2 or Phase 3 studies. This analysis reports long-term data from 26 patients who entered the PNH-REP study from two Phase 2 iptacopan studies (NCT03439839 and NCT03896152). Phase 2 studies included different treatment sequences and iptacopan dosing (25 mg, 50 mg, 100 mg, and 200 mg twice daily [BID]). Baseline for this analysis is first dose of iptacopan 200 mg BID. Efficacy assessments reported at 4 and 5 years of follow-up include mean hemoglobin (Hb) levels, Hb ≥12.0 g/dL (irrespective of red blood cell [RBC] transfusion), transfusion avoidance, mean lactate dehydrogenase (LDH) levels, LDH <1.5×upper limit of normal (ULN), absolute reticulocyte count (ARC), and ARC normalization. Safety assessments include frequency and occurrence rate (OccR, exposure-adjusted OccR expressed as total number of episodes per 100 patient-years) of breakthrough hemolysis (BTH) and major adverse vascular events (MAVEs), and frequency of adverse events (AEs) and serious AEs (SAEs).

Of 26 patients included in the Phase 2 studies, 22entered the PNH-REP study. Among the 26 patients, sixteen (61.5%) were exposed to iptacopan treatment for ≥4 years, while 8 (30.8%) were exposed for ≥5 years. Mean (standard deviation [SD]) Hb levels were 12.1 g/dL (2.0) and 12.9 g/dL (2.0) at 4 and 5 years, respectively; 63.6% and 66.7% of patients achieved a Hb level of ≥12.0 g/dL irrespective of RBC transfusion, respectively. Nearly all patients (96.2%) achieved transfusion independence during the 5-year follow-up. Mean (SD) LDH levels were 315.8 U/L (123.7) and 292.2 U/L (71.9) at 4 and 5 years, respectively; the proportion of patients achieving LDH <1.5×ULN levels were 81.8% and 83.3%, respectively. Mean (SD) ARC levels were 81.4×10⁹/L (31.3) and 84.6×10⁹/L (15.7) at 4 and 5 years, respectively; all patients achieved normalization of ARC. Four BTH events occurred in 3 patients (11.5%), with an OccR (95% confidence interval) of 3.7 (1.2, 11.6). MAVE (unstable angina) occurred in 1 patient, with an OccR of 0.9 (0.1, 6.6). Twenty-two patients (84.6%) reported ≥1 AE; the most frequently reported AEs were COVID-19 and pyrexia (30.8% each), and headache (15.4%). Ten patients (38.5%) reported SAEs.

No SAE occurred in more than 1 patient. Treatment-emergent infection SAEs occurred in 3 patients (11.5%) and included pneumonia (considered related to study drug by investigator), bacterial pneumonia, pneumococcal pneumonia, sepsis, and urinary tract infection. Three deaths (11.5%) occurred; none of which were considered related to study drug by investigator.

These long-term data show that initial improvement in Hb levels with iptacopan is retained over time, with most patients keeping normal Hb levels at their latest follow-up. This hematologic improvement was associated with transfusion independence, as well as with LDH <1.5×ULN, and ARC normalization in most patients, confirming the comprehensive, long-term control of intravascular and extravascular hemolysis with iptacopan. Despite the increased proportion of PNH erythrocytes, BTH and MAVEs remain rare. Iptacopan was well tolerated, with no new safety findings. These results support oral iptacopan as a potentially practice-changing treatment for patients with PNH.

Iptacopan monotherapy demonstrated improved clinical outcomes in a real-world cohort with paroxysmal nocturnal hemoglobinuria: Evidence from a managed access program

Iptacopan, the first-in-class oral complement factor B inhibitor that selectively inhibits the alternative pathway of the complement system, has been approved for the treatment (tx) of patients (pts) with paroxysmal nocturnal hemoglobinuria (PNH). In 2023, prior to launch, a managed access program (MAP) was initiated to provide iptacopan (200 mg, twice daily) to PNH pts with high unmet clinical need who had exhausted the available tx options in clinical practice. Here, the authors report updated efficacy and safety outcomes from the MAP. Adult pts with a confirmed diagnosis of PNH were eligible to be included in the MAP if they had received the required vaccinations. In addition, pts were required to fulfill the following eligibility criteria for participation: (i) an unsolicited request was submitted by a licensed physician; (ii) there was a lack of viable alternative therapy for serious/life-threatening conditions; (iii) they were ineligible for clinical trials or unable to participate; (iv) the risk of tx was justified by potential benefit; (v) they met additional medical criteria by experts or health authorities. At baseline (BL), most physicians requested 1 to 3 months of iptacopan tx. Retreatment requests (RRs) were permitted for pts benefiting from iptacopan tx. Categorical parameters collected at BL and RRs included: hemoglobin (Hb) range, reticulocyte count (RLC), lactate dehydrogenase (LDH) level, blood transfusion visits in the past 3 months, fatigue, tx satisfaction, and prior tx. Data were presented according to the prior tx status (complement inhibitor [Ci] –naïve and –experienced). Adverse events (AEs) were monitored continuously from the time of tx start by physicians

As of April 1, 2025, 212 pts across 27 countries received iptacopan tx as part of the MAP, with 50 discontinuing the program. The main reason for discontinuation was the transition to commercial supply of iptacopan in clinical practice (n=36) and 3 pts discontinued due to AEs. This analysis reports baseline characteristics and the outcomes at 2 successive retreatment visits (RR1 and RR2). Complete datasets were available for 95 pts at BL and RR1 (10 Ci-naïve, 85 Ci-experienced). Of these, 60 pts had complete datasets at BL and RR2 (6 Ci-naïve, 54 Ci-experienced). The proportion of pts previously treated with eculizumab, ravulizumab, pegcetacoplan, and danicopan was 71.6%, 37.9%, 13.7%, and 6.3%, respectively. The median age was 46.0 years (Interquartile range [IQR], 35-59 years), 57.9% were females, and 57.9% were Caucasians. The median exposure to iptacopan was 202 days (IQR, 119-307 days). The proportion of pts with Hb ≤9.9/≥10-11.9/≥12 g/dL changed from 69.5%/14.7%/15.8% at BL to 22.1%/32.6%/45.3% at RR1 and 6.7%/25%/68.3% at RR2. At RR1 and RR2, 68 (71.6%) and 55 (91.7%) pts, respectively, had LDH levels below 1.5 × upper limit of normal vs 53 (55.8%) at BL. The number of pts who achieved RLC within normal range was 62 (65.3%) and 41 (68.3%) at RR1 and RR2, respectively, vs 28 (29.5%) pts at BL. The number of pts with ≥1 transfusion visits within the past 3 months decreased to 24 (25.3%) and 5 (8.3%) pts at RR1 and RR2, respectively, compared with 45 pts (47.4%) at BL. Furthermore, only 5 (5.3%) and 1 (1.7%) pts reported experiencing severe fatigue at RR1 and RR2, respectively, vs 29 (30.5%) pts at BL. Overall, 54 (56.8%) and 25 (26.3%) pts at RR1 and 47 (78.3%) and 7 (11.7%) pts at RR2 expressed being very satisfied and satisfied with their current therapy, respectively, vs only 8 (8.4%) and 9 (9.5%) pts at BL. Results for reported parameters in the Ci-experienced and Ci-naive population were consistent. Among 212 pts, 147 AEs were reported in 39 cases until April 1, 2025. Of these, 43 serious AEs were reported in 13 cases, including 4 break-through hemolysis/hemolysis and 4 infections, with only 1 infection suspected to be related to iptacopan. Conclusions: The updated data from this MAP confirm hematological and clinical improvements with iptacopan in Ci-naive and Ci-experienced pts with PNH, with approximately 6 months of iptacopan therapy. Oral iptacopan monotherapy led to normalization of Hb and LDH level, and RLC, along with a higher proportion of pts achieving transfusion avoidance at retreatment visits compared to BL. Pts also reported notable improvements in fatigue and tx satisfaction. The safety profile of iptacopan in the PNH MAP population was consistent with the findings from clinical trials.

Real-world breakthrough hemolysis patterns across 1,723 patient-years of complement inhibition in paroxysmal nocturnal hemoglobinuria

Despite the introduction of specific treatment, some patients with paroxysmal nocturnal hemoglobinuria (PNH) will still experience various degrees of hemolysis. Specifically, breakthrough hemolysis (BTH) is the most common cause of treatment failure in PNH, yet contemporary incidence data, especially concerning proximal complement inhibitors (CI), are limited. The authors reviewed 1,723 patient-years (PY) on CI therapy from our center from 2004 (with the first FDA approval of a CI) to 2025 across 208 patients to understand features of BTH in a real word PNH patient cohort. BTH was defined as an acute hemoglobin fall ≥ 1.5 g/dL or LDH ≥ 1.5× upper limit of normal (ULN). “Continuous” BTH required LDH elevation for ≥ 2 weeks. Incidence was expressed per 100 PY. For the purpose of this study, 2 levels of granularity were applied: i) all available patients with available data (208 patients, 1723 PY); ii) granular, formal analysis with continuous longitudinal data from 117 patients with 721 PY total. Complete responders were defined of stable Hgb levels ≥10 g/dl. Across 721 PY we documented 153 BTH episodes with 16 continuous events. Exposure was 445 PY to eculizumab, 169 PY to ravulizumab, 46 PY to pegcetacoplan, and 62 PY to iptacopan, yielding BTH rates of 22.3, 24.8, 30.4, and 6.5 events/100 PY, respectively. Iptacopan had a 59% lower BTH rate than the three alternate CI comparators combined (rate ratio 0.41, p=0.046). Notably, there was a ubiquitous decrease in BTH in complete responders to CI (defined as Hgb ≥ 10 g/dL) compared to non-responders (8.1 vs. 26.7 events/100 PY; p=.04). Functionally, all 138 BTH episodes on terminal-CI were intravascular (IVH). Among the 15 proximal-CI events, 2 presented mixed extravascular features; neither patient carried complement-gene mutations on WES. There were 98/153 “clinical” BTH episodes with symptoms, transfusions, or medication changes needed. Clinical BTH episodes were more common in non-responders than responders in eculizumab (OR 2.32; p = .003), ravulizumab (OR 2.32; p = .a044), iptacopan (OR 10; p = 0.18) and pegcetacoplan (OR 2.5; p = 0.21). Six were “massive” (≥ 3 pRBC units): two in responders and four in non-responders.

Among 103 therapy switches, ravulizumab-to-iptacopan (25 patients, 19.6 PY) reduced BTH from 34.7 to 19.6 events/100 PY (43%, p=0.39). Pegcetacoplan-to-iptacopan (11 patients, 4.6 PY) dropped rates from 21.6 to 0 events/100 PY (p=0.16). Eculizumab-to-iptacopan (5 patients, 2.6 PY) rose from 61.7 to 79.4 events/100 PY, driven by one early event (p = 0.72). Among terminal-to-terminal moves, eculizumab-toravulizumab (34 patients) increased rates from 13.7 to 28.5 events/100 PY (p = 0.12), whereas ravulizumab-to-pegcetacoplan (13 patients) decreased them from 50.8 to 28.8 events/100 PY (p = 0.21). Pooled by mechanism, proximal inhibition (pegcetacoplan + iptacopan; 107 PY) showed 20.4 events/100 PY versus 23.0 events/100 PY with terminal C5 blockade (eculizumab + ravulizumab; 614 PY, p=0.48). Overall, terminal-to-proximal transitions, especially to iptacopan, consistently reduced BTH burden.

This two-decade, real-world analysis shows that proximal factor B blockade with iptacopan provided the lowest BTH incidence, outperforming terminal C5 inhibitors and C3 blockade. Importantly, in BTH and clinical BTH, non-responders were more prone for episodes and with no significant difference in massive BTH episodes. This suggests that maintained Hgb does not predispose to more BTH episodes or massive BTH episodes. Additionally, although switch cohorts were limited, terminal-to-proximal transitions consistently lowered BTH rates. These findings support prospective multicenter validation and that iptacopan could maintain long-term disease stability. Current complement sequencing analysis is ongoing to classify patients with hemolysis.

The 2-year efficacy and safety of iptacopan monotherapy in patients with paroxysmal nocturnal hemoglobinuria with a history of aplastic anemia on concomitant immunosuppressive therapy who entered the roll-over extension program

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease characterized by complement-mediated hemolysis, thrombosis, and potential concurrent bone marrow failure. A strong clinical relationship exists between PNH and aplastic anemia (AA); approximately 40-60% of patients have overlapping PNH and AA. While immunosuppressive therapy (IST) is generally effective in treating AA, recovery of blood cell count is often incomplete. For patients with overlapping disease, in which hemolysis is more dominant than bone marrow failure, treatment with complement inhibitors is required. Iptacopan is an oral proximal complement inhibitor approved for the treatment of PNH that targets factor B to inhibit the alternative complement pathway and provide comprehensive hemolysis control. The oral administration, unique mechanism of action, and safety profile of iptacopan present potential advantages over other complement inhibitors, supporting its long-term evaluation in patients with overlapping AA and PNH. Here, the authors present the subgroup analysis of PNH patients with history of AA and concomitant IST (AA+IST) during the Phase 3 trials of iptacopan (APPLY- and APPOINT-PNH) who entered the roll-over extension (PNH-REP) study.

PNH-REP (NCT04747613) is an ongoing, open-label, single-arm, multicenter, Phase 3 study of patients with PNH who completed the treatment extension periods (without tapering down) of Phase 2 or Phase 3 clinical studies. This subgroup analysis of patients from APPLY-PNH (NCT04558918) and APPOINT-PNH (NCT04820530) who entered PNH-REP included patients with a history of AA receiving concomitant IST (cyclosporine); patients with severe AA were excluded from the studies based on laboratory parameters. Outcomes were evaluated over 2 years by subgroup and included mean hemoglobin (Hb) levels, achievement of Hb level of ≥12 g/dL (irrespective of red blood cell [RBC] transfusion), transfusion avoidance, mean lactate dehydrogenase (LDH) levels, achievement of LDH <1.5×ULN, absolute reticulocyte count (ARC), and neutrophil and platelet counts, as well as the incidence of breakthrough hemolysis (BTH), major adverse vascular events (MAVEs), and serious treatment emergent adverse events (TEAEs), with a focus on infections.

Of the 136 patients (with AA+IST, n=11; without AA+IST, n=125) who successfully completed APPLY-PNH (n=96) and APPOINT-PNH (n=40), 132 entered the PNH-REP. At 2 years follow-up, mean (SD) Hb was 13.32 g/dL (2.037) and 12.63 g/dL (2.020) in patients with and without AA+IST, respectively (mean [SD] change from baseline, 5.65 g/dL [1.829] and 3.73 g/dL [2.454]). For patients with available data, 72.7% (8/11) and 71.7% (81/113) of patients with and without AA+IST achieved Hb ≥12 g/dL, irrespective of RBC transfusion; RBC transfusion avoidance through 2 years was achieved by 100% and 89.6% (112/125) of patients.

Mean (SD) LDH at 2 years follow-up was 375.55 U/L (148.902) and 293.05 U/L (199.609) in patients with and without AA+IST, respectively; LDH <1.5×ULN was achieved by 63.6% and 91.2% of patients. Mean (SD) ARC levels at 2 years follow-up were 77.78×10⁹/L (36.998) and 78.90×10⁹/L (47.525) for patients with and without AA+IST, respectively, with mean (SD) changes from baseline of −73.18×10⁹/L (50.757) and −103.36×10⁹/L (66.471). Mean (SD) neutrophil counts were 2.37×10⁹/L (0.500) and 2.71×10⁹/L (1.259) in patients with and without AA+IST, respectively, with mean (SD) changes from of 0.17×10⁹/L (1.366) and 0.42×10⁹/L (1.427). Mean (SD) platelet counts were 145.18×10⁹/L (61.437) and 135.47×10⁹/L (54.383) in patients with and without AA+IST, respectively, with mean (SD) changes from baseline of 5.00×10⁹/L (87.413) and −17.84×10⁹/L (40.348). BTH occurred in 1 patient (4.5 events per 100 patient-years) with and 13 patients (8.7 events per 100 patient-years) without AA+IST; MAVEs were reported in 0 patients with and 3 patients (1.7 events per 100 patient-years) without AA+IST. Serious infection-related TEAEs were reported in 18.2% (2/11) of patients with and 14.4% (18/125) without AA+IST.

In this subgroup analysis of PNH patients with AA+IST, long-term treatment with iptacopan maintained clinically meaningful improvements in Hb levels, reduced transfusion needs, and sustained control of hemolysis over 2 years, with safety outcomes comparable to patients without AA. These findings support the durable efficacy and safety of iptacopan in this population.

APPLY-PNH: Analysis of complement pathway biomarkers provides evidence for pharmacodynamic response in PNH patients who receive oral iptacopan monotherapy versus continuing anti-C5 therapy

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hemolytic disorder characterized by complement-mediated intravascular hemolysis (IVH), bone marrow failure, and severe thrombophilia. Anti-C5 therapies like eculizumab help control IVH but do not impact C3 fragment deposition on PNH erythrocytes, leaving them susceptible to extravascular hemolysis (EVH). Iptacopan, an oral Factor B (FB) inhibitor targeting the alternative pathway (AP) of the complement system, provides comprehensive control of hemolysis through inhibition of IVH and prevention of the emergence of EVH. Biomarkers of activation of the AP such as soluble C5b-9 (sC5b-9) and Factor Bb can help evaluate the inhibitory effect of iptacopan on AP-mediated complement activation.

The Phase 3 APPLY-PNH trial (NCT04558918) evaluated iptacopan in adults with PNH and residual anemia (Hb <10 g/dL) despite ≥6 months of stable anti-C5 therapy (either eculizumab or ravulizumab), which showed superior efficacy of receiving iptacopan monotherapy over continuing anti-C5 therapy. Here, we report the pharmacodynamic response of the complement pathway in patients who received iptacopan following previous anti-C5 therapy in the APPLY-PNH study

In this biomarker analysis, a set of complement pathway biomarkers (sC5b-9, FB, and Factor Bb) were measured using validated immunoassays. Data from APPLY-PNH was preprocessed and inspected. Measurements below the lower limit of quantification (LLoQ) were imputed as half the LLoQ value, whereas measurements exceeding the upper limit of quantification were imputed as the maximum observed value. Unmeasured values were excluded from the dataset for the relevant analysis, and concentration values were log10 transformed. Geometric mean baseline and end of treatment levels (Day 168), with 95% confidence intervals (CIs) are reported. Geometric mean ratios (GMRs) to baseline (95% CI) are reported for the change in biomarker levels for each treatment arm from baseline to end of treatment; a statistically significant difference is based on 95% CIs.

In APPLY-PNH, 97 patients were randomized to receive iptacopan (n=62) or continue anti-C5 therapy (n=35). Overall, 75 patients had complete data for sC5b-9 (iptacopan, n=46; anti-C5, n=29) and 87 patients had complete data for FB and Factor Bb (iptacopan, n=56; anti-C5, n=31). In patients who received iptacopan, geometric mean (95% CI) sC5b-9 decreased from baseline to end of treatment (540 ng/mL [410, 790] vs 230 ng/mL [190, 300]; GMR = 0.4 [0.26, 0.66]). In contrast, patients who continued anti-C5 therapy showed no significant change from baseline (420 ng/mL [300, 620] vs 330 ng/mL [240, 510]; GMR = 0.81 [0.50, 1.30]). In patients who received iptacopan, geometric mean (95% CI) FB increased from baseline to end of treatment (200 µg/mL [190, 210] vs 300 µg/mL [260, 400]; GMR = 1.5 [1.3, 2.1]). In patients who continued anti-C5 therapy, FB showed no significant change (210 µg/mL [180, 300] vs 190 µg/mL [170, 210]; GMR = 0.89 [0.59, 1.00]). Factor Bb decreased from baseline for both iptacopan (1600 ng/mL [1400, 1700] vs 1300 ng/mL [1200, 1400]; GMR = 0.86 [0.80, 0.92]) and anti-C5 (1700 ng/mL [1500, 2300] vs 1500 ng/mL [1300, 1700]; GMR = 0.87 [0.63, 1.00]). However, while a statistically significant reduction from baseline in Factor Bb was observed in the iptacopan treatment arm, the similarity of the geometric mean point estimates and overlapping 95% CIs suggests no difference between the two treatment arms. Analysis of complement pathway biomarkers provides evidence for pharmacodynamic response and supports the clinical benefits of switching from anti-C5 therapy to iptacopan. sC5b-9 decreased after receiving iptacopan, consistent with the observed clinical efficacy of iptacopan treatment in the study through inhibition of the terminal complex activation of the complement pathway. FB increase in the setting of iptacopan could be due to decreased consumption and/or increased production of FB. Despite a significant reduction of Factor Bb in the iptacopan treatment arm, the lack of a statistical difference compared to continued anti-C5 therapy suggests a similar effect between the two treatment arms. There was no statistically significant change in all three complement biomarkers in patients who continued anti-C5 therapy.

Oral iptacopan monotherapy demonstrates clinically meaningful hemoglobin increases in patients with paroxysmal nocturnal hemoglobinuria with baseline hemoglobin levels 10 to <12 g/dl on anti-C5 therapy: Subgroup analysis of the APPULSE-PNH Phase 3b trial

Despite achieving a 'good response' with anti-C5 therapy (defined as hemoglobin [Hb] levels 10 to <12 g/dL), some patients with paroxysmal nocturnal hemoglobinuria (PNH) remain anemic and continue to experience symptoms due to extravascular hemolysis. Iptacopan, the first oral selective factor B inhibitor, demonstrated superior efficacy vs anti-C5 therapy (eculizumab/ravulizumab) in patients with PNH and Hb <10 g/dL on anti-C5 in APPLY-PNH (NCT04558918). APPULSE-PNH (NCT05630001) was a Phase 3b trial evaluating iptacopan in patients with Hb ≥10 g/dL who had received anti-C5 therapy. The study met its primary and key secondary objectives: noninferiority and superiority in Hb change from baseline (BL) after switching to iptacopan. Here, the authors present subgroup analyses in patients with BL Hb 10 to <12 g/dL.

In APPULSE-PNH, adult patients with PNH and mean Hb ≥10 g/dL on stable anti-C5 therapy for ≥6 months, who had not received red blood cell (RBC) transfusions for 6 months, were switched to oral iptacopan monotherapy 200 mg twice daily for 24 weeks. The primary endpoint was change from BL in Hb, tested hierarchically for noninferiority (primary objective) and superiority (key secondary objective) compared with anti-C5 therapy using predefined thresholds (lower bound of 95% confidence interval [CI] greater than –1 and 0 g/dL, respectively). All endpoints reported as adjusted mean change from BL, or ratio vs BL, used the mean of four visits between Days 126 and 168, except Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-Fatigue) and Treatment Satisfaction Questionnaire for Medication – 9 items (TSQM-9), which used Day 168 only. Exploratory subgroup analyses of BL Hb levels 10 to <12 g/dL were performed for the primary and key secondary endpoints.

Of the 52 patients enrolled in APPULSE-PNH, 32 (61.5%) had BL Hb 10 to <12 g/dL. In this subgroup of patients, mean age was 47.0 years; 43.8% were female and mean (standard deviation [SD]) time since diagnosis was 9.4 (6.8) years; 93.8% switched from ravulizumab and 6.3% from eculizumab. The mean (SD) duration of anti-C5 treatment was 3.0 (2.2) years. Mean (SD) BL Hb and lactate dehydrogenase (LDH) were 11.1 (0.5) g/dL and 236.6 (75.5) U/L, respectively. Overall adjusted mean (95% CI) change from BL in Hb was +2.0 g/dL (1.7, 2.3; P<0.0001 for both noninferiority and superiority). In patients with BL Hb 10 to <12 g/dL, adjusted mean (95% CI) change from BL in Hb was +2.4 (2.0, 2.7) g/dL.

The lower bound of the 95% CI exceeded thresholds for noninferiority and superiority. No patients required RBC transfusions between Days 1 and 168. Adjusted mean (95% CI) change from BL in absolute reticulocyte count (ARC) was −101.9 10⁹/L (−107.9, −95.9) in these patients. Geometric adjusted mean ratio (95% CI) of LDH vs BL was 1.0 (0.9, 1.1) in patients with Hb 10 to <12 g/dL. FACIT-Fatigue improved by +6.4 (95% CI: 3.2, 9.5). TSQM-9 scores for effectiveness, convenience, and global satisfaction improved by +11.1 (95% CI: 0.7, 21.6), +25.1 (16.4, 33.9), and +20.6 (12.3, 28.8) in patients with 10 to <12 g/dL, respectively.

In the overall population of APPULSE-PNH (N=52), the most frequently occurring treatment-emergent adverse events were headache (17.3% of patients), diarrhea, nausea, and nasopharyngitis (11.5% each). No patients experienced clinical breakthrough hemolysis, major adverse vascular events, treatment related serious adverse events, or died. In APPULSE-PNH, switching from anti-C5 to oral iptacopan monotherapy led to clinically meaningful increases in Hb in patients with PNH and Hb ≥10 g/dL. Results in patients with BL Hb 10 to <12 g/dL were consistent with the overall study findings. Iptacopan was well tolerated. These results support iptacopan as a potentially practice-changing, outpatient treatment option for patients with PNH with BL Hb 10 to <12 g/Dl