The studies were conducted from March 2018 to October 2021 in the CARDINAL trial, from March 2018 to November 2021 in the CADENZA trial, and from November 2021 to November 2022 in the Japan OLE trial. The total median (range) observation period of this report (i.e., from the enrollment of CARDINAL/CADENZA to the end of the Japan OLE study) was 3.8 (3.2–4.2) years.

Seven Japanese patients completed the Part B of the CARDINAL/CADENZA study from five Japanese investigational sites (CARDINAL, n = 3; CADENZA, n = 4 [sutimlimab, n = 3; placebo, n = 1 in Part A]), and all entered the Japan OLE study. All of them received at least one dose of sutimlimab and were in the 6.5 g dose cohort. The median (range) age of patients at baseline in the CARDINAL/CADENZA studies was 70 (46–83) years and the majority were female (n = 5, 71.4%) (Table 1). One (14.3%) patient discontinued the study drug due to treatment-emergent serious AEs (TESAEs) associated with worsening of chronic kidney disease (CKD); thus, six patients completed the Japan OLE study.

In the CARDINAL/CADENZA study, the median (range) duration of study treatment was 140.9 (104.9–157.3) weeks with the actual median (range) study dose of 461.5 (344.5−513.5) g. The median (range) cessation period between the last dose in the CARDINAL/CADENZA and the first dose in the Japan OLE study was 70 (61–133) days. The median (range) cessation period was longer in the patients who participated in CARDINAL study than those who participated in CADENZA study, 127 (126–133) vs 65 (61–70) days, respectively. In the Japan OLE study, the median (range) duration of sutimlimab treatment was 47.1 (15.1–49.1) weeks with an actual median (range) study dose of 156.0 (52.0−162.5) g (Table 1). No patients completed the 9-week safety follow-up period of the Japan OLE study, six patients switched to commercially available sutimlimab, and one patient died due to chronic kidney disease during the safety follow-up period (26 days after the last dose of sutimlimab) following discontinuation of the study drug. Compliance with the planned dosing schedule was 100%.

All four patients who transitioned from CADENZA to the Japan OLE study were vaccinated against COVID-19 during CADENZA Part B. Two of the three patients who transitioned from CARDINAL to the Japan OLE study were vaccinated during CARDINAL Part B. Overall, five of seven patients received COVID-19 vaccination during the Japan OLE study, with three receiving elasomeran and three receiving tozinameran.

During the CARDINAL/CADENZA study, all seven (100%) patients experienced at least one TEAE, with a total of 106 TEAEs. Of these, the most frequently (> 2 patients) reported TEAEs were iron deficiency anemia, constipation, and nasopharyngitis, experienced by three patients each. Injection site erythema, cystitis bacterial, viral infection, and blood pressure increased were assessed as treatment-related TEAEs and experienced by a total of three patients (42.9%) (Table 2A). Three (42.9%) patients reported at least one TESAE with hemorrhoids, viral infection and Raynaud’s phenomenon experienced by one patient each, where viral infection was assessed as related to study drug by the investigator.

In the Japan OLE study, all seven (100%) patients experienced at least one TEAE, with a total of 46 TEAEs. One (14.3%) patient had at least one TEAE (urinary tract infection) assessed as related to sutimlimab by the investigator. The event was nonserious and mild in severity and resolved after medication. The most frequently (≥ 20% [i.e., ≥ 2 patients]) reported TEAEs (by preferred term) were back pain (3; 42.9%) and pyrexia (2; 28.6%).

In the Japan OLE study, TESAEs and TEAEs leading to treatment discontinuation were reported in the same patient aged 81 years old who died during the study (Table 2B). This patient had chronic kidney disease (CKD), renal anemia, liver damage, and fatty liver at the time of enrollment in the Japan OLE study. During the safety follow-up period, 26 days after the last dose of sutimlimab, the patient died of renal failure exacerbated by hepatorenal syndrome due to liver cirrhosis, bacterial peritonitis in addition to CKD. This patient experienced three TESAEs which included: cholangitis acute on Day 17, spontaneous bacterial peritonitis on Day 81, and exacerbated CKD on Day 83. Two of these three TESAEs (spontaneous bacterial peritonitis and CKD) led to discontinuation of the study intervention and/or the study. The investigator did not consider any of these TESAEs as related to sutimlimab; cholangitis acute was attributed to gallstones, spontaneous bacterial peritonitis to transudative ascites in association with hepatic cirrhosis, and CKD to the underlying medical condition being exacerbated by transudative ascites, in association with hepatic cirrhosis, and spontaneous bacterial peritonitis, resulting in continuous hemodiafiltration.

No AESIs were reported throughout the observation period.

In the analysis population (n = 7), the median (range) hemoglobin level increased from 8.7 (6.2–12.7) g/dL at baseline to 12.0 (9.8–15.3) g/dL at the last dose of sutimlimab in the CARDINAL/CADENZA study (Fig. 2, Supplementary Fig. 1). The hemoglobin level decreased during the cessation period to 8.8 (6.3–11.3) g/dL at the baseline of the Japan OLE study; however, hemoglobin levels increased to 11.3 (7.6–14.6) g/dL at the end of the study.

Box–whisker plot for serum hemoglobin levels at each time point. The upper and lower limits of the box plot denote interquartile ranges; whiskers denote maximum and minimum ranges. The line and X in the box plot denote median and mean, respectively. The circle denotes outlier. The number below each timepoint denotes median (range) of the hemoglobin levels (N = 7). EOS, end of study; OLE, open-label extension

In the CARDINAL/CADENZA study, the median (range) total bilirubin level decreased from 2.0 (1.5–2.6) mg/dL at baseline to 1.0 (0.7–1.6) mg/dL at the last dose of sutimlimab (Fig. 3, Supplementary Fig. 2). The total bilirubin increased to 2.7 (1.4–4.6) mg/dL during the cessation period of the CARDINAL/CADENZA study to the baseline of the Japan OLE study; however, total bilirubin decreased again to 1.1 (0.8–2.5) mg/dL at the end of the Japan OLE study.

Box–whisker plot for serum bilirubin levels at each time point. The upper and lower limits of the box plot denote inter-quartile ranges, whiskers denote maximum and minimum ranges. The line and X in the box plot denote median and mean, respectively. The number below each timepoint denotes median (range) of the bilirubin levels (N = 7). EOS, end of study; OLE, open-label extension

In both studies, LDH levels varied widely among patients. In the CARDINAL/CADENZA study, the median (range) LDH level decreased from 304.0 (160.0–452.0) U/L at baseline to 266.0 (190.0–651.0) U/L at the last dose of sutimlimab in the CARDINAL/CADENZA study. The LDH level increased during the cessation period to 348.0 (254.0–800.0) U/L at the baseline of the Japan OLE study and increased to 534.0 (168.0–1284.0) U/L at the end of the study. Although the median LDH level increased during the Japan OLE study period, three out of seven patients showed a decrease in LDH levels from baseline in the Japan OLE study (Supplementary Figs. 3 and 4).

In general, all patients exhibited deterioration in the anemic and hemolytic markers after discontinuation of sutimlimab: decrease in hemoglobin level, increase in bilirubin level during the cessation period. However, these levels were restored during the Japan OLE study. The LDH level varied individually, and no improvement was observed in the median LDH level during the Japan OLE study.

One patient who participated in the CADENZA study and was assigned to the sutimlimab treatment group received blood transfusion during Part A (26-week treatment period). Two patients received blood transfusion during the cessation period (i.e., between the last dose of the CARDINAL/CADENZA study and the first dose of the Japan OLE study); however, none of the patients required blood transfusion after sutimlimab administration during the Japan OLE study.