Introduction: Patients with paroxysmal nocturnal hemoglobinuria (PNH) often develop iron deficiency (ID) due to chronic intravascular hemolysis (IVH), which can lead to iron loss in the urine and, consequently, require iron supplementation. Conversely, when IVH is controlled by terminal complement component 5 (C5) inhibitors e.g. eculizumab, some patients remain anemic due to extravascular hemolysis (EVH), and they may accumulate iron from frequent blood transfusions and/or increased intestinal iron absorption, which may lead to iron overload (IO). Serum ferritin (SF) is a well-established indicator of ID (when low) and IO (when high). Several studies demonstrated increased levels of SF during anti-C5 therapy due to emerging EVH and ongoing blood transfusions (Röth. IJH. 2011, Risitano. BJH. 2012, Schaap. Hemasphere. 2023, Waheed & Kuter. AJH. 2021). Here, we report SF changes in patients with PNH treated with the factor B inhibitor iptacopan for 48 weeks in the Phase 3 APPLY-PNH (anti-C5 pretreated patients) and APPOINT-PNH (anti-C5 naïve patients) trials.

Methods: Iptacopan-treated patients with available SF values at baseline (Day 1) and at the end of treatment (Week 48) were included in the analysis and divided by baseline SF into three categories: low SF (below the lower limit of normal), normal SF, and high SF (above the upper limit of normal). Median (interquartile range [IQR]) SF was calculated for anti-C5-naïve patients and anti-C5-pretreated patients separately. The categorical distribution of patients at baseline and at Week 48 was assessed to evaluate how many patients moved to another SF category. The same SF analysis was repeated in patients with a hematological response, defined as a 2 g/dL hemoglobin (Hb) increase at Week 48 versus baseline in the absence of blood transfusion from Day 14 to Week 48. To minimize the confounding effect of factors known to impact SF levels, patients who were either iron-supplemented, iron-depleted, or with a C-reactive protein level >10 mg/L at the time of SF measurement were excluded from the analysis.

Results: Thirty anti-C5-naïve and 36 anti-C5-pretreated patients were included in the analysis. In anti-C5 naïve patients, median (IQR) SF was 21 (12–44) ng/mL at baseline; 40.0% of patients had low SF and 10.0% of patients had high SF. In anti-C5-pretreated patients, median (IQR) SF was 460 (204–788) ng/mL at baseline; none of the patients had low SF, whereas 61.1% of patients had high SF.

In 12 anti-C5-naïve patients with low SF at baseline, median (IQR) SF increased from 11 (10–15) ng/mL at baseline to 29 (13–63) ng/mL at Week 48; 7/12 (58.3%) patients achieved normal SF. In 3 anti-C5-naïve patients with high SF at baseline, median (IQR) SF decreased from 539 (399–2464) ng/mL at baseline to 294 (161–1693) ng/mL at Week 48; 2/3 (66.7%) achieved normal SF. In 15 anti-C5-naïve patients with normal SF at baseline, median (IQR) SF was 33 (22–54) ng/mL at baseline and 36 (21–73) ng/mL at Week 48; 12/15 (80.0%) patients maintained normal SF at Week 48, whereas 2/15 (13.3%) had low SF and 1/15 (6.7%) had high SF at Week 48.

There were no anti-C5-pretreated patients with low SF at baseline. In 22 anti-C5-pretreated patients with high SF at baseline, median (IQR) SF was 748 (508–866) ng/mL at baseline and 731 (352–956) ng/mL at Week 48; 4/22 (18.2%) achieved normal SF at Week 48. In 14 anti-C5-pretreated patients with normal SF at baseline, median (IQR) SF was 179 (106–260) ng/mL at baseline and 66 (48–164) ng/mL at Week 48; 13/14 (92.9%) of patients maintained normal SF, whereas 1 patient had low SF at Week 48.

The SF changes in patients who gained at least 2g/dL of Hb were consistent with those seen in the overall population. However, in 18 anti-C5-pretreated patients with high SF at baseline, the median SF showed a decreasing trend from 653 (490–822) ng/mL to 554 (338–891) ng/mL at Week 48.

Conclusions: Treatment with iptacopan normalizes SF in anti-C5-naïve PNH patients with low SF by blocking IVH. In contrast to anti-C5 therapies, SF does not increase during iptacopan treatment in anti-C5-pretreated PNH patients, indicating that these patients no longer demonstrate EVH-related, persistent anemia, or require blood transfusions. Thus, by targeting IVH and EVH, iptacopan restores iron homeostasis to a more physiological state, possibly preventing ID and IO in patients with PNH.

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2025
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