Researchers demonstrated that iptacopan was well tolerated at a chronic dose of 200 mg twice daily in patients with paroxysmal nocturnal hemoglobinuria (PNH), according to a proof-of-concept phase II trial published in The Lancet Haematology.
The goal of the proof-of-concept trial was to “assess the safety, tolerability, pharmacokinetics and pharmacodynamics, and activity of the new complement factor B inhibitor, iptacopan, in patients with paroxysmal nocturnal haemoglobinuria who have active haemolysis despite anti-C5 therapy,” according to the authors, led by Antonio M Risitano, MD, PhD, of the University of Naples Federico II in Italy.
Between May 2018 and April 2019, the trial enrolled ten adult patients with PNH who exhibited signs of active hemolysis despite ongoing therapy with eculizumab. Eligible participants had LDH levels 1.5-times above the upper limit of normal and PNH type 3 erythrocyte or granulocyte clone sizes of 10% or greater.
Open-label iptacopan 200 mg was administered orally twice daily, and the primary endpoint was the reduction of chronic residual intravascular hemolysis, assessed via change in mean LDH levels from baseline to week 13. After 13 weeks, patients could opt into an ongoing long-term extension study that examined modifications of standard treatment.
Iptacopan Treatment Improves Hemolysis After Eculizumab Failure
Investigators reported iptacopan induced a “marked reduction” in LDH from a baseline mean of 539 ± 263 IU/L to a week 13 mean of 235 ± 44 IU/L, representing a change of -309.2 ± 265.5 IU/L (90% CI, -473.77 to -144.68; P=.0081). Iptacopan also yielded a “significant improvement” in hemoglobin concentrations from a baseline mean of 97.7 ± 10.5 g/L to a week 13 mean of 129.5 ± 18.3 g/L, for a change of 31.9 ± 14.5 g/L (90% CI, 23.42-40.28; P<.0001). The authors added all biomarkers of hemolysis improved during treatment.
Treatment benefits persisted throughout the long-term extension study, with seven patients ending previous standard-of-care treatment and continuing on iptacopan monotherapy. The report noted that two of the three nonrelated serious adverse events reported were in the same patient, including one that occurred before iptacopan exposure.
Overall, the researchers found that administering iptacopan 200 mg twice daily was well tolerated, reduced lactate dehydrogenase (LDH) levels, and normalized hemoglobin for most patients with PNH at 13 weeks and beyond, even when administered as a monotherapy.
“On the basis of these data, iptacopan will be tested as monotherapy in pivotal trials investigating its hematological benefit in a broader paroxysmal nocturnal hemoglobinuria population,” Dr. Risitano and colleagues concluded.
Reference
Risitano AM, Röth A, Soret J, et al. Addition of iptacopan, an oral factor B inhibitor, to eculizumab in patients with paroxysmal nocturnal haemoglobinuria and active haemolysis: an open-label, single-arm, phase 2, proof-of-concept trial. Lancet Haematol. 2021;8(5):e344-e354. doi:10.1016/S2352-3026(21)00028-4
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