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 ≥60% by week 12 compared with 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 (Hb) levels, and all but 1 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 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 Hb levels in most patients. This trial was registered at www.clinicaltrials.gov as #NCT03896152.

Graphical abstract

Figure 1

Study design and iptacopan treatment duration. *Following period 3, patients will also have the possibility to transition directly to a long-term rollover extension program without a need for taper-down. †Week 13 for nonresponders or week 109 for responders. ‡Week 16 for nonresponders or week 112 for responders. bid, twice daily; EOS, end of study; qd, once daily; R, randomization.

Figure 2

Effect of Iptacopan on LDH and Hb levels. (A) Change in LDH levels over time for iptacopan 25/100 mg and 50/200 mg cohorts (pharmacodynamic analysis set). (B) Change in Hb levels over time for iptacopan 25/100 mg and 50/200 mg cohorts (pharmacodynamic analysis set). Note: 1 patient in cohort 2 (patient 10) was excluded from the Hb analysis due to a protocol deviation, whereby an RBC transfusion was given between screening and baseline, raising the Hb level to above the protocol-defined upper limit of 105 g/L at baseline. bid, twice daily; BL, baseline; LLN, lower limit of normal.

Figure 2

Effect of Iptacopan on LDH and Hb levels. (A) Change in LDH levels over time for iptacopan 25/100 mg and 50/200 mg cohorts (pharmacodynamic analysis set). (B) Change in Hb levels over time for iptacopan 25/100 mg and 50/200 mg cohorts (pharmacodynamic analysis set). Note: 1 patient in cohort 2 (patient 10) was excluded from the Hb analysis due to a protocol deviation, whereby an RBC transfusion was given between screening and baseline, raising the Hb level to above the protocol-defined upper limit of 105 g/L at baseline. bid, twice daily; BL, baseline; LLN, lower limit of normal.

Figure 3

Number of transfusions and packed RBC units transfused before entry and during study, normalized per year (pharmacodynamic analysis set). Blue bars represent the number of transfusions (normalized, per year) for each patient, and the associated red bars denote the number of packed RBC units transfused (normalized, per year). *Number of packed RBC units transfused was not available for 2 patients.

Figure 4

Effect of iptacopan on C3d deposition and PNH clones (type II+III) (pharmacodynamic analysis set). bid, twice daily.

Figure 5

Pharmacokinetic profiles of iptacopan at steady state (days 29 and 57) (pharmacokinetic analysis). Data are represented as arithmetic means with standard deviation. bid, twice daily.