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Iptacopan resolves anaemia in patients with paroxysmal nocturnal haemoglobinuria

In the phase III APPLY-PNH trial in patients with paroxysmal nocturnal haemoglobinuria (PNH) with residual anaemia on intravenous anti‑C5 standard of care therapy with eculizumab or ravulizumab, single-agent, oral iptacopan resulted in a significant majority of patients achieving clinically meaningful haemoglobin (Hb) increases and Hb ≥12 g/dL.

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, chronic haematological disorder characterised by intravascular haemolysis, thrombophilia and bone marrow failure. PNH is caused by a somatic mutation in the PIGA gene, resulting in a lack of the GPI-anchored complement-regulating proteins CD55 and CD59, leading to intravascular haemolysis. Targeting the terminal complement pathway at C5 with standard-of-care (SoC) eculizumab and ravulizumab controls intravascular haemolysis, reduces thrombosis and improves overall survival. However, up to two thirds of patients have clinically meaningful residual anaemia, largely because of emerging extravascular haemolysis. As a consequence, some patients are transfusion dependent. Iptacopan is a first-in-class, oral, selective factor B inhibitor that targets the complement system proximally via the alternative pathway. It binds to the active site of factor B, inhibiting the activity of C3 convertase. The APPLY-PNH trial is an open-label, randomised, multicentre, phase III trial investigating iptacopan monotherapy in PNH patients with residual anaemia despite SoC therapy.

Study design

Adult PNH patients with mean haemoglobin (Hb) <10 g/dL on stable SoC therapy (eculizumab/ravulizumab) for at least 6 months were randomised 8:5 to receive iptacopan monotherapy 200 mg twice daily or to continue their SoC regimen for 24 weeks. Randomisation was stratified by prior SoC therapy and red blood cell transfusions (RBCTs) in the preceding 6 months. The two primary endpoints were the proportion of patients with a ≥2 g/dL Hb increase from baseline and the proportion of patients with Hb ≥12 g/dL, each in the absence of RBCTs. Secondary endpoints were transfusion avoidance, changes from baseline in Hb level, Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) score, absolute reticulocyte count (ARC) and lactate dehydrogenase (LDH) level, rates of clinical breakthrough haemolysis (BTH) and major adverse vascular events (MAVEs), and safety.


In total, 97 patients were randomised to the iptacopan arm (N=62) or the anti-C5 SoC arm (N= 35). Demographics and disease characteristics at baseline were generally balanced between arms. In total, 51/60 iptacopan-treated vs. 0/35 SoC-treated patients with evaluable/non-missing data had a ≥2 g/dL Hb increase from baseline.  In addition, two-thirds of patients taking iptacopan (68.8%) and zero patients in the control arm achieved a Hb level of 12 g/dL or higher without a blood transfusion (both p< 0.0001). The need for blood transfusions was also markedly lower among patients taking iptacopan, with just two patients in the iptacopan arm (2/62) and more than half of those in the control group (21/35) requiring transfusions (p< 0.0001). At 24 weeks, those taking iptacopan saw an average haemoglobin level increase of 3.59 g/dL, compared with an average decrease of 0.04 g/dL among those in the control arm. The mean haemoglobin levels at 24 weeks irrespective of transfusions were 12.6 g/dL in those taking iptacopan and 9.2 g/dL in those on standard of care. Patients taking iptacopan also experienced significantly less fatigue (p< 0.0001) and iptacopan monotherapy achieved resolution of extravascular haemolysis and maintenance of intravascular haemolysis control.

There were no deaths and no serious encapsulated bacteria infections. One iptacopan-treated patient had a MAVE (transient ischemic attack, considered to be unrelated to iptacopan). Headache (iptacopan: 16.1% vs. SoC: 2.9%) and diarrhoea (14.5% vs. 5.7%) were more commonly reported with iptacopan, whereas infections/infestations (38.7% vs. 48.6%) and BTH events (3.2% vs. 17.1%) were more commonly reported with SoC. Two SoC-treated patients had serious adverse events of haemolysis, compared with no iptacopan-treated patients. No patients discontinued iptacopan or SoC because of adverse events.


Oral iptacopan monotherapy led to a significant majority of patients achieving clinically meaningful Hb increase and Hb ≥12 g/dL, associated with a higher rate of transfusion independence and reduced patient-reported fatigue, compared with SoC. In addition, iptacopan was well tolerated, with a favourable safety profile and no serious breakthrough haemolysis. Therefore, single-agent iptacopan may represent a practice-changing, oral, outpatient treatment for PNH patients who have an inadequate response to IV anti-C5 SoC therapy, potentially becoming the preferred treatment option for patients with haemolytic PNH.


Peffault De Latour R, et al. Oral Monotherapy with Iptacopan, a Proximal Complement Inhibitor of Factor B, Has Superior Efficacy to Intravenous Terminal Complement Inhibition with Standard of Care Eculizumab or Ravulizumab and Favorable Safety in Patients with Paroxysmal Nocturnal Hemoglobinuria and Residual Anemia: Results from the Randomized, Active-Comparator-Controlled, Open-Label, Multicenter, Phase III APPLY-PNH Study. Presented at ASH 2022; Abstract LBA2.

Speaker Régis Peffault De Latour

Régis Peffault De Latour

Régis Peffault De Latour, MD, PhD, Université Paris Cité, Paris, France


See: Keyslides


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