Oral iptacopan for paroxysmal nocturnal haemoglobinuria—First real‐world experience

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, acquired disorder, with affected individuals experiencing intravascular haemolysis (IVH) and an increased risk of thrombosis.1 In PNH, glycophosphatidylinositol-anchored proteins are reduced or absent leading to dysregulation of complement. This results in haemolysis and activation of leucocytes and platelets.2 The C5 inhibitors (C5i) eculizumab and ravulizumab reduce mortality and morbidity in patients with PNH.3-7 However, patients may remain anaemic due to extravascular haemolysis (EVH), which occurs due to opsonization of PNH erythrocytes by the complement protein C3b.8 To overcome EVH, newer therapies target complement factors earlier in the cascade. Pegcetacoplan, a complement protein C3 inhibitor, prevents IVH and improves anaemia in patients with PNH previously treated with eculizumab.9 Iptacopan is the first approved oral factor B complement inhibitor for patients with PNH. Clinical trials demonstrated improved outcomes in patients with persistent anaemia on C5i with 82% of patients achieving a >20 g/L haemoglobin rise and 69% achieving a haemoglobin >120 g/L in the absence of transfusions.10 Breakthrough IVH (BTH) can occur in patients on any complement inhibitor with recurrence of PNH symptoms and the risk of complications. Lactate dehydrogenase (LDH) is an important marker of IVH with a reduction of LDH to below 1.5 × the upper limit of normal (ULN) considered a treatment response.3, 4, 11 The UK PNH service participated in a managed access programme (MAP) with iptacopan provided by Novartis Pharmaceuticals Ltd. Patients were eligible if they had exhausted all locally approved treatment options, including those who had EVH on C5i, were intolerant of/had a suboptimal response to pegcetacoplan or had contraindications for pegcetacoplan. We present our experience of 20 patients treated with iptacopan for a minimum of 12 weeks via the MAP. Previous complement inhibitory treatment is shown in Figure 1. Current first-line anti-complement therapy for patients with PNH in the UK is ravulizumab, and prior to this, it was eculizumab. Prior treatment consisted of eculizumab in 10/20, eculizumab followed by ravulizumab in 9/20 and just ravulizumab in 1/20 patients (Figure 1). The mean duration of C5i was 8.7 years (range: 8 months to 17 years 11 months). The indication for C5i treatment was IVH, although three patients also presented with thrombosis (Budd-Chiari). All 20 patients had symptomatic anaemia thought to be due to EVH while on C5i and were therefore treated with proximal complement inhibition. Eight of the 20 patients enrolled in a non-Factor B targeting proximal inhibitor clinical trial (with 1 subsequently treated with pegcetacoplan and C5i) with a median treatment on trial of 21.5 months (Figure 1). Ten of the 20 patients received pegcetacoplan; two of these 10 received both pegcetacoplan and C5i (one with eculizumab and one with ravulizumab). Two of the 20 patients were unsuitable to receive subcutaneous treatment due to thrombocytopenia and switched directly from C5i to iptacopan. The eight patients who entered the non-Factor B inhibiting trial were on trial therapy for 7–42 months (mean: 21.5 months). Six of these patients switched straight from the study medication to iptacopan; one received a single dose of eculizumab before starting iptacopan. The final patient was switched to pegcetacoplan monotherapy, but after 5 months, C5i was given in addition to pegcetacoplan due to recurrent BTH. She continued to experience BTH on the combination therapy and switched to iptacopan after 6 months. The eight pegcetacoplan-treated patients had a mean treatment duration of 24.5 months (range: 5–50). Reasons for change from pegcetacoplan to iptacopan included recurrent BTH (4/8), intolerant of drug administration (2/8), periorbital oedema and muscle pains (1/8) and muscle pains and cramps (1/8). Five patients switched directly from pegcetacoplan to iptacopan without any washout period. The other three switched back to C5i before commencing iptacopan. For the two patients who had been on dual pegcetacoplan and C5i, one started iptacopan in order to receive a monotherapy; the second switched due to recurrent BTH, initially remaining on eculizumab 1800 mg every 14 days. The dose had been reduced gradually and will be discontinued when on 900 mg every 2 weeks. The mean age on starting iptacopan was 53 years (range: 25–83) and the mean duration of iptacopan by August 2024 was 6.9 months (range: 3–13) (Table 1). The mean haemoglobin upon starting iptacopan was 109 g/L (range: 67–136) and at 3 months on treatment was 124 g/L (range: 100–142). The mean LDH level at 3 months was 0.9 × upper limit of normal (ULN), with only one patient having a level at 1.6 × ULN. Seven patients required transfusions in the 3 months before starting iptacopan and one patient has needed transfusions since receiving iptacopan due to aplasia. Twelve patients had a haemoglobin >100 g/L at the initiation of iptacopan. There were no meningococcal infections or thrombotic events on iptacopan. Patient 17 experienced BTH due to an Escherichia coli urinary tract infection. She developed abdominal pain, two episodes of vomiting and haemoglobinuria with an increase in LDH from 174 to 1298 IU/L (ULN 246) and a concurrent fall in haemoglobin from 130 to 92 g/L. She was compliant with iptacopan, and the vomiting was not within hours of iptacopan dosing. She has received two doses of eculizumab. For now, she remains on iptacopan. Patient 10 was diagnosed with prostate cancer and required hip surgery while on iptacopan. The surgery was performed without any missed or extra drug doses; no BTH occurred. This study is the first real-world experience of iptacopan use in patients with PNH and is consistent with the phase 3 trial data published.10 In our patients, the switch from other proximal complement inhibitors to iptacopan was without complications, and patients with haemoglobin levels >100 g/L appear to benefit from iptacopan as well. Platelet counts have remained stable, and no patient has required treatment for raised cholesterol levels. We have also observed that surgical scenarios can be managed on iptacopan. Our patients have reported no side effects from iptacopan, and other than one patient transfused due to aplasia, there have been no transfusions required. All patients are continuing iptacopan. However, the number of patients evaluated is small, and longer experience with iptacopan is needed to confirm these findings. RJK, AGK and MG designed the research study and performed the research. All authors analysed the data. RJK wrote the paper. All authors reviewed and revised the paper. RJK reports consultancy fees/honoraria/speaker's bureau fees from Alexion, AstraZeneca Rare Disease, F. Hoffmann-La Roche, Novartis, Omeros, Otsuka and Sobi and research funding (to Institute) from Sobi and Novartis. AGK reports consultancy fees/honoraria/speaker's bureau fees from Alexion, AstraZeneca Rare Disease, Amgen, Biocryst, Celgene, F. Hoffmann-La Roche, Novartis, Pfizer, NovoNordisk, Samsung, Silence Therapeutics, Sobi and Ra Pharma and research funding (to Institute) from Celgene/BMS and Novartis. LMA reports consultancy fees/honoraria/speaker's bureau fees from Alexion, AstraZeneca Rare Disease, Amgen, Novartis and Sobi. CB reports consultancy fees/honoraria/speaker's bureau fees from Alexion, AstraZeneca Rare Disease, Amgen, F. Hoffmann-La Roche, Novartis and Sobi. JL reports consultancy fees/honoraria/speaker's bureau fees from Alexion, AstraZeneca Rare Disease, Bristol Myers Squibb, F. Hoffmann-La Roche, Novartis, Pfizer and Sobi. SN reports honoraria/speaker's bureau fees from Alexion and Novartis. SG reports consultancy fees/honoraria/speaker's bureau fees from Alexion, AstraZeneca Rare Disease, Celgene, Gilead, Jazz Pharma, Novartis, Pfizer and Sobi and research funding (to Institute) from Alexion. RT reports consultancy fees/honoraria/speaker's bureau fees from Alexion, AstraZeneca Rare Disease, Novartis and Sobi. TM reports consultancy fees/honoraria/speaker's bureau fees from Alexion, AstraZeneca Rare Disease, Abbvie, Johnson and Johnson, F. Hoffmann-La Roche, Novartis, Pfizer, MorphoSys, Sunesis, Lilly, Beigene, Gilead, Pharmacyclics and Sobi and research funding (to Institute) from Johnson and Johnson, Pharmacyclics and Abbvie. PM reports consultancy fees/honoraria from Novartis and F. Hoffmann-La Roche. MG reports consultancy fees/honoraria/speaker's bureau fees from Alexion, AstraZeneca Rare Disease, Amgen, Biocryst, Novartis, Omeros, Pfizer, Regeneron and Sobi. There was no funding for this study. IS, JM, NLY, LM and AV have no conflict of interest to disclose. Patients consented to the MAP. This work was carried out as a clinical service review for patients treated by the National PNH service in the United Kingdom. The data are available upon request to the corresponding author.