NEW ORLEANS, La.—Oral iptacopan treatment may be superior to standard-of-care treatment among patients with paroxysmal nocturnal hemoglobinuria (PNH), according to a phase 3 trial.

Study data showed that, from baseline, none of the patients receiving standard-of-care who had evaluable/complete data and 85% of the patients treated with iptacopan had hemoglobin levels rise by 2 g/dL or more. None of the standard-of-care treated patients, and 70% of the iptacopan-treated patients reached hemoglobin levels of 12 g/dL (both P <0.0001), reported Regis Peffault De Latour, MD, PhD, of the Assistance Publique Hôpitaux de Paris and Université Paris Cité in France.

The findings were presented as a late-breaking abstract at the 64th ASH Annual Meeting and Exposition here.

PNH is a chronic, rare hematological condition characterized by thrombophilia, intravascular hemolysis, and bone marrow failure. Intravascular hemolysis is brought on by PNH, which is brought on by a somatic mutation in the PIGA gene that prevents the production of the GPI-anchored complement-regulating proteins CD59 and CD55, said Dr. De Latour and colleagues.

“Targeting the terminal complement pathway at C5 with the standard-of-care eculizumab and ravulizumab controls intravascular hemolysis, reduces thrombosis, and improves overall survival. Up to two-thirds of patients have clinically meaningful residual anemia, largely because of emerging extravascular hemolysis; consequently, some patients are transfusion-dependent,” he continued.

Read more about PNH treatment

Iptacopan, a first-in-class oral selective factor B inhibitor, works by directly attacking the complement system through a different mechanism. Iptacopan inhibits the activity of C3 convertase by attaching to the factor B active site, De Latour noted.

“Iptacopan controlled intra- and extravascular hemolysis in 10 patients with a suboptimal response to eculizumab, leading to transfusion independence and an improved quality of life,” he added.  

When managing patients with hemolytic PNH, intravenous anti-C5 monoclonal antibodies ravulizumab and eculizumab are the standard of care, the researchers noted.  However, up to 60% of patients exhibit clinically relevant “residual anemia with [standard of care], secondary to C3-mediated extravascular hemolysis,” the authors noted in an abstract.

Iptacopan demonstrated promising efficacy and safety in 2 phase 2 trials involving naïve and anti-C5-treated patients with PNH, the researchers noted.

Hence, the investigators set out to evaluate the safety data and primary efficacy from the 24-week randomized therapy period of the multicenter, phase 3 APPLY-PNH trial.

The study team randomly assigned 35 patients to the standard-of-care group and 62 patients to the iptacopan group. Mean age was 51 years. Males comprised 30.9% of the cohort.

The cohort consisted of adult patients with PNH with an average hemoglobin level of 10 g/dL or less. The patients had also been on standard-of-care treatment for at least 6 months. They were randomly assigned 5:8 to continue their standard of care treatment or to receive iptacopan monotherapy at 200 mg 2 times per day for 24 weeks.

Using prior red blood cell transfusions and standard-of-care treatment, the researchers stratified randomization in the preceding 6 months.  

More than half of the cohort received red blood cell transfusions in the 6 months prior to randomization. About 35% of patients had previously received ravulizumab, and about 65% had previously received eculizumab for an average of 4 years.

Notably, iptacopan monotherapy also demonstrated superiority when it came to changes from baseline in hemoglobin level, absolute reticulocyte count, Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) score, transfusion avoidance, and rate of clinical breakthrough hemolysis.

From baseline, the adjusted average hemoglobin change was −0.04 g/dL for standard-of-care treatment and +3.59 g/dL for iptacopan. Other data showed that at 24 weeks the average hemoglobin levels were 9.2 for standard-of-care treatment and 12.6 for iptacopan regardless of red blood cell transfusions.

The results also indicated that 40% of patients in the standard-of-care arm and 96.7% of the iptacopan arm stayed red blood cell transfusion-free at 24 weeks.

There were no encapsulated bacteria infections and no deaths, although 1 patient had a transient ischemic attack, but it was determined it was unrelated to iptacopan.

Breakthrough hemolysis (17.1% for the standard-of-care group vs 3.2% for the iptacopan group) events and infestations/infections (48.6% vs 38.7%) were more commonly reported in the standard-of-care group.

Diarrhea (5.7% for the standard-of-care group vs 14.5% for the iptacopan group) and headache (2.9% vs 16.1%) were more commonly reported in the iptacopan group.

Serious adverse events were reported in the standard-of-care patient group, but not in the iptacopan group.

“Single-agent iptacopan may represent a practice-changing, oral, outpatient treatment for PNH patients who have an inadequate response to intravenous anti-C5 standard of care therapy, potentially becoming a preferred treatment option for patients with hemolytic PNH,”  De Latour concluded.


De Latour RP, Roeth  A, Kulasekararaj  A, 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. Poster presented at: 64th ASH Annual Meeting and Exposition; December 10-13, 2022. New Orleans, Louisiana.