A 43-year-old female patient was diagnosed with PNH in 2006. She received ravulizumab in 2017. From November 2019 until June 2021 she participated in trials investigating BXC9930. After trial discontinuation, the patient received again ravulizumab 3300 mg every 8 weeks. Apart from PNH-targeting drugs, the patient has been treated with cabergoline for prolactinoma since 2006. The patient remained anemic despite ravulizumab therapy and also developed transfusion dependence.

Anemia, together with high reticulocyte counts, lactate dehydrogenase (LDH) < 1.5 × upper limit of normal (ULN, 250 U/L) and a Coombs test positive for C3d suggested EVH.

Pegcetacoplan, even though approved in Austria, was not refunded at our institution and therefore could not be used to treat EVH in our patient.

Iptacopan was supplied by Novartis within the framework of a Named Patient/Managed Access Program. After informed consent, the patient received iptacopan 200 mg orally twice daily beginning on day 41 after the last dose of ravulizumab. The patient had vaccine protection against infections with Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae.

Following the start of iptacopan, the hemoglobin increased from 9.1 g/dL to normal range (NR, 12.0–16.0 g/dL) at week 3 and remained within NR during follow-up (Fig. 1a; Table 1). The reticulocyte count decreased from 234.8 G/L at baseline to NR within 2 weeks (NR 32–110 G/L) (Fig. 1b; Table 1). Haptoglobin remained below the detection limit. The FACIT fatigue score showed results comparable to healthy subjects at baseline and during follow-up (Table 1). The erythrocyte clone size was equivalent to the granulocyte clone size and remained stable at 96–100% during follow-up (Table 1).

a Development of hemoglobin levels after the start of oral iptacopan. Following the initiation of iptacopan, the hemoglobin level increased rapidly from baseline and reached the normal range in week 3. Even though decreasing after a peak in week 4, hemoglobin remained within the normal range for the duration of follow-up. The thin grey line indicates the lower level of normal. b Development of reticulocyte counts after the start of oral iptacopan. Following the initiation of iptacopan, the reticulocyte counts decreased rapidly from baseline and reached the normal range in week 2. Even though increasing after a nadir in week 5, reticulocyte counts remained within the normal range for the duration of follow-up. The thin grey line indicates the upper level of normal

Due to red cell transfusions, the patient had developed moderate iron overload. The ferritin level amounted to 728.2 μg/mL before iptacopan therapy was started. Within 1 week of iptacopan, ferritin levels substantially decreased to 454.7 μg/L (Table 1).

After a peak in week 4, hemoglobin levels decreased slightly, and reticulocyte counts and LDH levels slightly increased, most probably indicating mild hemolysis (Fig. 1; Table 1).

Adverse events included chills without fever, mild muscle pain and minor flush symptoms with erythema, all of which subsided during follow-up.

After 17 weeks of iptacopan treatment, hemoglobin remained within NR and the FACIT fatigue score was stable. The reticulocyte counts, even though increasing from the trough values achieved, stayed within NR. No BTH or infections occurred.