The efficacy, safety, tolerability, and pharmacodynamics of the novel complement component 5 (C5) inhibitor zilucoplan—a potential treatment option for patients with paroxysmal nocturnal hemoglobinuria (PNH)—has undergone evaluation in 3 separate phase 2 studies, according to findings from a review published in the journal Haematologica.

Among patients with the chronic, clonal hematopoietic stem cell disorder PNH, uncontrolled complement activation is key to the pathogenesis of the disease. Known for their inhibition of the activity of C5, approved first-line treatments for PNH include eculizumab and ravulizumab. Zilucoplan is a small 15-amino acid macrocyclic peptide that has been shown to bind to C5 with high specificity and affinity.

The investigators of the current review evaluated 2 12-week studies of zilucoplan in adult patients with PNH, Study 201 and Study 203, as well as a long-term extension study.

In the 12-week studies, the primary endpoint was change from baseline in serum lactate dehydrogenase (LDH) concentrations. Ten eculizumab-naive participants and 19 patients who had received prior eculizumab treatment (ie, eculizumab-switch cohort) were enrolled. In the extension study, 20.0% (2 of 10) of the eculizumab-naive participants discontinued. In the switch cohort, 42.1% (8 of 19) of the participants discontinued, with 57.9% (11 of 19) entering the extension study. At data cutoff (November 2020), 10.5% (2 of 19) of the patients discontinued and 47.4% (9 of 19) of participants continued to receive zilucoplan therapy.

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Findings from the studies showed that the eculizumab-naive cohort exhibited higher baseline LDH levels and median free hemoglobin compared with the switch cohort. In fact, in the switch cohort, zilucoplan treatment was associated with complete, consistent, sustained inhibition of both the classical and the alternative complement pathways, which resulted in substantial, rapid, sustained reductions in LDH levels from baseline (median LDH, 378.0 U/L [1.6 × the upper limit of normal of 234 U/L]).

Among the participants who required more than 1 transfusion in the 6 months prior to study initiation, 40.0% (2 of 5) of them became transfusion-independent following the start of zilucoplan therapy. At all postbaseline time points, treatment with zilucoplan was associated with a consistent reduction in median-free hemoglobin (baseline, 7.10 mg/dL; range of median change, −3.90 to −5.95 mg/dL).

In the switch cohort, zilucoplan therapy was associated with complete, sustained inhibition of the classical and alternative pathways. During the primary evaluation, participants in the switch cohort experienced a 230.3 U/L median increase in LDH level from baseline.

Zilucoplan is a self-administered, at-home, subcutaneous, small volume injection that was well tolerated. Overall, more than 18.6 patient-years of exposure were reported, with a mean duration of exposure of 36.4 weeks.

In the initial 12-week study period, all 29 patients reported adverse events; however, no occurrences of thrombosis were reported. In the long-term extension study, all of the 19 participants experienced adverse events.

“In conclusion, in eculizumab-naive patients with PNH treated with zilucoplan, LDH reductions were similar to those previously reported with eculizumab, which agrees with the pharmacodynamic effect of zilucoplan,” the researchers noted. “Despite the cessation of clinical development of zilucoplan in PNH, the efficacy and safety profile of this novel C5 inhibitor in myasthenia gravis, along with the flexibility of once-daily at-home subcutaneous injections, has established zilucoplan as another potential option in the growing armamentarium of C5 inhibitors,” they concluded.


Kulasekararaj AG, Lehtinen A-E, Forsyth C, et al. Phase II trials of zilucoplan in paroxysmal nocturnal hemoglobinuria. Haematologica. Published online August 3, 2023. doi:10.3324/haematol.2022.281780