Long-Term Data Support Use of Eculizumab Biosimilar as Soliris Alternative in PNH

Eculizumab biosimilar Elizaria showed long-term safety and efficacy comparable with the reference agent in patients with paroxysmal nocturnal hemoglobinuria (PNH), according to a recent study.¹

If left untreated, the disease can lead to hemolytic anemia, chronic kidney disease, or thrombosis, with approximately 38 patients in every 1 million people estimated to have PNH. | Image credit: olegganko - stock.adobe.com

The open-label, prospective, multicenter ECU-PNH-III-X study (NCT04679103) published in Acta Haematologica, was conducted as part of the clinical development process for Elizaria, with the cohort being recruited from a previous phase 3 clinical trial (NCT04463056) what demonstrated noninferiority of the biosimilar vs the originator (Soliris).

PNH is a rare blood condition in which a portion of the immune system attacks and damages red blood cells and platelets.² If left untreated, the disease can lead to hemolytic anemia, chronic kidney disease, or thrombosis. Approximately 38 patients for every 1 million people are estimated to have PNH, with the incidence of the condition ranging from 0.08 to 0.57 per 100,000 person-years.³

Elizaria is a biosimilar developed by Russia-based company Generium and was approved by the Russian Ministry of Health (Minzdrav) in 2019 for the treatment of PNH and atypical hemolytic uremic syndrome.¹ Although it was also developed in accordance with regulatory requirements of the Eurasian Economic Union and the European Medicines Agency, long-term data on eculizumab biosimilars remain limited.

The present study was conducted at 8 study sites. For inclusion, patients had to have completed the ECU-PNH-II and ECU-PNH-1b studies and be aged 23 to 75 years. After signing a consent form, 30 patients were enrolled. Prior to the study, 25 patients received Elizaria (Group A) and 5 patients had been administered Soliris (Group B). The study was broken up into 3 periods: the end of the study visit from the previous trial (first visit of the present study), the treatment period (up to 104 weeks), and the follow-up period (2 weeks).

Patients received a 900-mg maintenance dose of the biosimilar every 2 weeks, receiving from 18 to 44 injections overall (average [SD], 32.33 [6.74]). The median age of patients was 37 years (Group A median, 39 years; Group B median, 33 years), and the cohort mostly identified as women and Caucasian. Vascular diseases (50%) and cardiac diseases (36.7%) were the most common comorbidities.

Regarding pharmacokinetics and pharmacodynamics (PD), in group B, mean serum eculizumab concentrations showed variability but consistently exceeded 35 μg/mL, the level needed for complete inhibition of intravascular hemolysis. PD analysis revealed stable membrane attack complex levels across visits, ranging from 70.25 (34.86) ng/mL to 63.24 (31.44) ng/mL (P = .66), indicating effective biosimilar performance.

In the efficacy assessment, the median lactate dehydrogenase (LDH) activity remained stable throughout the study, ranging from 226 to 320 U/L, with median changes from baseline varying between −3.5 and −98.5 U/L (P = .21). Minor increases in LDH activity at weeks 64 and 68 were attributed to acute respiratory infection and chronic hepatitis exacerbation in 2 patients. No significant intergroup differences or changes from baseline were observed (P > .05). Both groups showed comparable mean hemoglobin level improvements by the study's end (3.7 [13.6] g/L in group A, 1.0 [2.5] g/L in group B; P = .36), with no significant changes at any visit compared with baseline.

The reticulocyte count remained stable throughout the study with no significant changes compared with baseline (P = .06), and both groups showed insignificant changes at the study's end. Both groups exhibited similar decreases in PNH type II and III red blood cells and granulocytes, with no significant differences (P > .05). Breakthrough hemolysis occurred in 4 patients in group A, 2 of whom experienced respiratory infections. Eight patients (27%) required red blood cell transfusions, with no significant difference between groups. No new thrombotic events were observed.

No cases of meningococcal or other complement-related infections were reported, and no severe adverse events related to hemolysis occurred. Two adverse reactions (alopecia in group A and elevated aspartate aminotransferase in group B) were mild or moderate and did not require treatment adjustment.

Binding antidrug antibodies (ADAs) were detected in 7 patients (23.3%), with no significant differences between groups. ADAs in group A showed no neutralizing activity or impact on efficacy or safety. One patient in group B had neutralizing antibodies, but these did not affect the study outcomes.

The study's main limitations were the small sample size due to the orphan status of eculizumab and reduced use of the originator, the absence of newly proposed response criteria for complement inhibitor therapy, and the lack of evaluation for extravascular C3-mediated hemolysis impacting erythroid response.

References

1. Kulagin AD, Putshkin VV, Lukina EA, et al. Results of long-term therapy with a biosimilar of eculizumab in patients with paroxysmal nocturnal hemoglobinuria. Acta Haematol. Published online November 25, 2024. doi:10.1159/000542294

2. Paroxysmal nocturnal hemoglobinuria. Cleveland Clinic. Updated April 25, 2022. Accessed January 28, 2025. https://my.clevelandclinic.org/health/diseases/22871-paroxysmal-nocturnal-hemoglobinuria

3. Dingli D, Maciejewski JP, Larratt L, et al. Relationship of paroxysmal nocturnal hemoglobinuria (PNH) granulocyte clone size to disease burden and risk of major vascular events in untreated patients: results from the International PNH Registry. Ann Hematol. 2023;102(7):1637-1644. doi:10.1007/s00277-023-05269-4