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Clinical Trial
. 2024 Mar 1;109(3):929-935.
doi: 10.3324/haematol.2022.281780.

Phase II trials of zilucoplan in paroxysmal nocturnal hemoglobinuria

Austin G Kulasekararaj  1 , Anna-Elina Lehtinen  2 , Cecily Forsyth  3 , Shreyans Gandhi  1 , Morag Griffin  4 , Sixten Körper  5 , Gabor Mikala  6 , Petra Muus  7 , Ulrik Overgaard  8 , Christopher J Patriquin  9 , Humphrey Pullon  10 , Yu-Min Shen  11 , Ruth Spearing  12 , Jeff Szer  13 , Guillemette De la Borderie  13 , Petra W Duda  14 , Ramin Farzaneh-Far  14 , Sharan Ragunathan  14 , Camil E Sayegh  14 , Douangsone D Vadysirisack  14 , Hubert Schrezenmeier  15
Affiliations
Clinical Trial

Phase II trials of zilucoplan in paroxysmal nocturnal hemoglobinuria

Austin G Kulasekararaj et al. Haematologica. .
No abstract available

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Figures

Figure 1.
Figure 1.
(A) Study designs for Studies 201 and 203 and (B) patients’ flow, illustrated in a CONSORT diagram. The two 12-week, single-arm studies (Study 201; conducted from April 2017 to January 2018, and Study 203; conducted from September 2017 to February 2018) enrolled 26 and three patients, respectively. The analysis includes ten patients from Study 201 who were eculizumab-naïve and 19 who had previously been treated with eculizumab (eculizumab switch cohort; 16 patients from Study 201 and 3 patients from Study 203). All ten patients in the eculizumab-naïve cohort and 11/19 patients in the switch cohort entered the open-label extension study. *The eculizumab-naïve cohort consisted of patients with no prior exposure to eculizumab. †The switch cohort included patients with prior exposure to eculizumab for ≥6 months before screening. On day 1, a single loading dose of 0.3 mg/kg zilucoplan was administered subcutaneously. Thereafter, patients self-injected subcutaneous zilucoplan at home daily for the subsequent 12 weeks. Dose escalation to 0.3 mg/kg daily could be initiated at week 2 if a lactate dehydrogenase level of <1.5 times the upper limit of normal was not achieved or an overt breakthrough episode of hemolysis occurred (assessed via investigator judgement). A dose increase to 0.3 mg/kg was made in ten patients in the eculizumab-naïve cohort and 16 patients in the switch cohort after a median time of 19 days (range, 15-669 days) and 19.5 days (range, 1-57 days), respectively. ‡Blood samples for pharmacodynamics were collected within 1 hour of the administration of the first dose and at 1, 3, and 6 hours after the dose on day 1. §For patients who had a zilucoplan dose increase to 0.3 mg/kg, samples for pharmacodynamics were collected before the new dose, on day 1 of the new dose, and thereafter at scheduled visits. No patients from either study were lost to follow-up. D: day; W: week; LDH: lactate dehydrogenase.
Figure 2.
Figure 2.
Effect of zilucoplan on patients with paroxysmal nocturnal hemoglobinuria in the eculizumab-naïve cohort. (A-C) Mean complement activity as measured by sheep red blood cell (sRBC) assay (classical complement pathway; left y-axis, orange circles) and Wieslab enzyme-linked immunosorbent assay (ELISA) (alternative complement pathway; right y-axis, blue triangles) (A), mean lactate dehydrogenase (LDH) levels (B), and transfusion requirements (C) before and after initiation of zilucoplan. Change in serum LDH, sRBC lysis, and Wieslab ELISA at each time point were analyzed using the two-sided Wilcoxon signed-rank test in each cohort. Missing data were not imputed. *Baseline is the average of the screening and day 1 LDH values per patient. sRBC: sheep red blood cell; CP: complement pathway; SD: standard deviation; ELISA: enzyme-linked immunosorbent assay; SEM: standard error of the mean; LDH: lactate dehydrogenase; ULN: upper limit of normal; ID: identity; W: week.
Figure 3.
Figure 3.
Effect of zilucoplan on patients with paroxysmal nocturnal hemoglobinuria in the eculizumab switch cohort. (A-C) Mean complement activity as measured by sheep red blood cell (sRBC) assay (classical complement pathway; left y-axis, orange circles) and Wieslab enzyme-linked immunosorbent assay (ELISA) (alternative complement pathway; right y-axis, blue triangles) (A), mean lactate dehydrogenase (LDH) reductions (B), transfusion requirements before and after initiation of zilucoplan (C), and mean counts at baseline in the switch cohort, stratified by switch success (N=8) versus switch failure (N=11; 282×109/L vs. 159×109/L; male upper limit of normal: 130×109/L; female upper limit of normal: 120×109/L) (D). Switch failure was defined as zilucoplan discontinuation during the first 12 weeks; patients could resume eculizumab treatment per individual investigator’s procedures. Changes in serum LDH, sRBC lysis, and Wieslab ELISA at each time point were analyzed using the two-sided Wilcoxon signed-rank test in each cohort. Missing data were not imputed. *Most recent non-missing value obtained immediately before administration of the first dose of zilucoplan; mean (standard deviation) baseline LDH values: transfusion-independent (N=7), 232.6 (22.6) U/L; transfusion-dependent (N=12), 320.8 (44.4) U/L (P=0.0296). sRBC: sheep red blood cell; CP: complement pathway; SD: standard deviation; ELISA: enzyme-linked immunosorbent assay; SEM: standard error of the mean; ULN: upper limit of normal; LDH: lactate dehydrogenase; ID: identity; W: week.
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References

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