Iptacopan monotherapy in patients with paroxysmal nocturnal hemoglobinuria: a 2-cohort open-label proof-of-concept study

Abstract

Iptacopan (LNP023) is a novel, oral selective inhibitor of complement factor B under clinical development for paroxysmal nocturnal hemoglobinuria (PNH). In this ongoing open-label phase 2 study, PNH patients with active hemolysis were randomized to receive single-agent iptacopan twice-daily, at a dose of either 25 mg for 4 weeks followed by 100 mg for up to 2 years (cohort 1) or 50 mg for 4 weeks followed by 200 mg for up to 2 years (cohort 2). At the time of interim analysis, of 13 PNH patients enrolled, all 12 evaluable for efficacy achieved the primary endpoint of reduction in serum lactate dehydrogenase (LDH) levels by at least 60% by week 12 as compared to baseline; mean LDH levels dropped rapidly and durably, namely by 77% and 85% at week 2 and by 86% and 86% at week 12 in cohorts 1 and 2, respectively. Most patients achieved a clinically meaningful improvement in hemoglobin levels and all but one patient remained transfusion-free up to week 12. Other markers of hemolysis, including bilirubin, reticulocytes and haptoglobin, showed consistent improvements. No thromboembolic events were reported, and iptacopan was well tolerated, with no severe or serious adverse events reported up until the data cutoff. In addition to the previously reported beneficial effect of iptacopan add-on therapy to eculizumab, this study showed that iptacopan monotherapy in treatment-naïve PNH patients resulted in normalization of hemolytic markers and rapid transfusion-free improvement of hemoglobin levels in most patients. Registered at www.clinicaltrials.gov as NCT03896152.

The complement alternative pathway in paroxysmal nocturnal hemoglobinuria: From a pathogenic mechanism to a therapeutic target

“…Changes in other biomarkers of hemolysis such as bilirubine, reticulocyte count, haptoglobin were consistent with a remarkable control of MAC‐mediated intravascular hemolysis. Furthermore, the prevention of C3‐mediated intravascular hemolysis was documented by negligible C3d‐opsonization of PNH erythrocytes, and confirmed by the significant increase of PNH erythrocytes from mean 33.6% at baseline to mean 82.9% at week 12 102 . Iptacopan treatment was safe and well tolerated, since no death and no serious adverse event was observed during the study.…”

“…These data clearly confirm that iptacopan results in full inhibition of intravascular hemolysis in untreated PNH patients, and prevent the emergence of extravascular hemolysis. These effects were seen in a broad range of treatment doses, even if more sustained inhibition was seen at the dose of 200 mg twice a day (which showed a safety profile overlapping to that of lower doses) 102 …”

“…The second study investigated iptacopan in untreated hemolytic PNH randomizing patients with overt hemolysis to receive different schedules of iptacopan in monotherapy: in cohort 1 patients received iptacopan at 25 mg twice a day for 4 weeks, followed by dose escalation to 100 mg twice a day up to 2 years, while in cohort 2 the initial dose was 50 mg, then escalated to 200 mg. Thirteen patients were enrolled, and the interim analysis done on LDH change at week 12 was performed on 12 evaluable patients (one patient discontinued iptacopan after 2 days due to headache, and was not evaluable for efficacy). All the 12 evaluable patients achieved the 60% reduction in LDH levels which was set as primary endpoint of the study; more in detail, LDH reduction was achieved as rapidly as 2 weeks after treatment starting, irrespective of the dose cohort, with mean reduction by 76.5% (90% CI: 90.1, 63.0; P < 0.0001) and 85.0% (90% CI: 92.8, 77.2, P < 0.0001) in cohorts 1 and 2, respectively 102 . These results were sustained throughout the study, including long‐term extension; even if no patient exhibited LDH reduction <40% in any study cohort, patients in cohort 2 (the higher‐dose group) all showed sustained inhibition of intravascular hemolysis (defined as LDH <1.5 times the ULN), and less variability of LDH levels compared to lower‐dose cohort.…”

“…These effects were seen in a broad range of treatment doses, even if more sustained inhibition was seen at the dose of 200 mg twice a day (which showed a safety profile overlapping to that of lower doses). 102 The safety and the efficacy of iptacopan are now under investigation within large phase III trials in both PNH patients inadequately treated by C5 inhibitors (in a head-to-head randomization), as well as in untreated PNH patients. In both studies the selected dosing regimen was 200 mg orally, twice a day.…”

With complements: C3 inhibition in the clinic

“…Mechanistically, iptacopan binds to FB to selectively block the enzymatic activity of the AP convertases (see Table 2 and ref. 103). Danicopan (ALXN2040), an inhibitor of the AP‐specific serine protease FD, is in phase 3 development for treatment of patients with extravascular hemolysis in PNH.…”