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A PHASE III RANDOMIZED CLINICAL TRIAL COMPARING SB12 (PROPOSED ECULIZUMAB BIOSIMILAR) WITH REFERENCE ECULIZUMAB IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
Author(s): ,
Jun Ho Jang
Affiliations:
Hematology-Oncology,Samsung Medical Center,Seoul,Corée, République De;Hematology-Oncology,Samsung Medical Center,Seoul,Corea del Sud;Hematology-Oncology,Samsung Medical Center,Seoul,South Korea,Republic;Hematology-Oncology,Samsung Medical Center,Seoul,Zuid Korea;Hematology-Oncology,Samsung Medical Center,Seoul,República da Korea;Hematology-Oncology,Samsung Medical Center,Seoul,Корея, южная
,
Roberta Demichelis Gomez
Affiliations:
Hematology,Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran,Mexico City,Mexique;Hematology,Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran,Mexico City,Mexiko;Hematology,Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran,Mexico City,Messico;Hematology,Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran,Mexico City,墨西哥;Hematolog
,
Horia Bumbea
Affiliations:
Hematology,Bucharest Emergency University Hospital,Bucharest,Roumanie;Hematology,Bucharest Emergency University Hospital,Bucharest,Rumänien;Hematology,Bucharest Emergency University Hospital,Bucharest,Romania;Hematology,Bucharest Emergency University Hospital,Bucharest,罗马尼亚;Hematology,Bucharest Emergency University Hospital,Bucharest,Rumania;Hematology,Bucharest Emergency University Hospital,Bucha
,
Larysa Nogaieva
Affiliations:
Regional Treatment-Diagnostic Hematology Center,Communal Nonprofit Enterprise Cherkasy Regional Oncology Dispensary of Cherkasy Oblast Council,Cherkasy,Ukraine;Regional Treatment-Diagnostic Hematology Center,Communal Nonprofit Enterprise Cherkasy Regional Oncology Dispensary of Cherkasy Oblast Council,Cherkasy,Ukraine;Regional Treatment-Diagnostic Hematology Center,Communal Nonprofit Enterprise Ch
,
Lily Lee Lee Wong
Affiliations:
Hematology Unit,Hospital Queen Elizabeth,Kota Kinabalu,Malaisie;Hematology Unit,Hospital Queen Elizabeth,Kota Kinabalu,Malaysia;Hematology Unit,Hospital Queen Elizabeth,Kota Kinabalu,Malaysia;Hematology Unit,Hospital Queen Elizabeth,Kota Kinabalu,马来西亚;Hematology Unit,Hospital Queen Elizabeth,Kota Kinabalu,Malasia;Hematology Unit,Hospital Queen Elizabeth,Kota Kinabalu,Maleisië;Hematology Unit,Hospi
,
Soo Min Lim
Affiliations:
Department of Medicine,Hospital Sultanah Aminah,Johor Bahru,Malaisie;Department of Medicine,Hospital Sultanah Aminah,Johor Bahru,Malaysia;Department of Medicine,Hospital Sultanah Aminah,Johor Bahru,Malaysia;Department of Medicine,Hospital Sultanah Aminah,Johor Bahru,马来西亚;Department of Medicine,Hospital Sultanah Aminah,Johor Bahru,Malasia;Department of Medicine,Hospital Sultanah Aminah,Johor Bahru,
,
Jihye Park
Affiliations:
Clinical Development,Samsung Bioepis,Incheon,Corée, République De;Clinical Development,Samsung Bioepis,Incheon,Corea del Sud;Clinical Development,Samsung Bioepis,Incheon,South Korea,Republic;Clinical Development,Samsung Bioepis,Incheon,Zuid Korea;Clinical Development,Samsung Bioepis,Incheon,República da Korea;Clinical Development,Samsung Bioepis,Incheon,Корея, южная
,
Younsoo Kim
Affiliations:
Biometrics,Samsung Bioepis,Incheon,Corée, République De;Biometrics,Samsung Bioepis,Incheon,Corea del Sud;Biometrics,Samsung Bioepis,Incheon,South Korea,Republic;Biometrics,Samsung Bioepis,Incheon,Zuid Korea;Biometrics,Samsung Bioepis,Incheon,República da Korea;Biometrics,Samsung Bioepis,Incheon,Корея, южная
Sanghyun Cho
Affiliations:
Clinical Development,Samsung Bioepis,Incheon,Corée, République De;Clinical Development,Samsung Bioepis,Incheon,Corea del Sud;Clinical Development,Samsung Bioepis,Incheon,South Korea,Republic;Clinical Development,Samsung Bioepis,Incheon,Zuid Korea;Clinical Development,Samsung Bioepis,Incheon,República da Korea;Clinical Development,Samsung Bioepis,Incheon,Корея, южная
(Abstract release date: 05/12/22) EHA Library. Ho Jang J. 06/10/22; 357691; P829
Jun Ho Jang
Jun Ho Jang
Contributions
Abstract
Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P829

Type: Poster presentation

Session title: Bone marrow failure syndromes incl. PNH - Clinical

Background

SB12, a proposed eculizumab biosimilar, is a humanized monoclonal antibody that blocks complement C5 cleavage, thereby inhibits terminal complement-mediated intravascular hemolysis.

Aims

The randomized, double-blind, multicenter, cross-over study was aimed to demonstrate comparable clinical efficacy by evaluating the lactate dehydrogenase (LDH), safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of SB12 and reference eculizumab (ECU) in paroxysmal nocturnal hemoglobinuria (PNH) patients (NCT04058158).

Methods

A total of 50 patients aged ≥ 18 years with a confirmed diagnosis of PNH and ≥ 1.5 upper limit of normal range (ULN) of LDH without previous exposure to a complement inhibitor were included. All patients provided written informed consents and were randomized (1:1) to treatment sequence I (TS1: SB12 to ECU, n=25) or II (TS2: ECU to SB12, n=25). Patient received 600 mg of SB12 (TS1) or ECU (TS2) intravenously every week for first 4 weeks (initial phase) and 900 mg for the fifth week, followed by 900 mg every 2 weeks thereafter (maintenance phase). The treatment was switched to ECU (TS1) or SB12 (TS2) at Week 26, and switched treatment was provided until Week 50.

Primary endpoints were LDH level at Week 26 and time-adjusted area of under the effect curve (AUEC) of LDH from Week 14 to Week 26 and Week 40 to Week 52. Equivalence was declared for LDH level at Week 26 if the two-sided 95% confidence interval (CI) of the mean difference in between SB12 and ECU lied within the pre-defined equivalence margin of [−1.2 × ULN, 1.2 × ULN] = [−337.2, 337.2], where ULN = 281 U/L. Equivalence was declared for time-adjusted AUEC of LDH if the two-sided 90% CI of the ratio of geometric means between SB12 and ECU lied within the pre-defined equivalence margin of [0.77, 1.29]. Secondary endpoints were LDH profile over time and number of units of packed red blood cells (pRBCs) transfused throughout the study period, safety, PK, PD, and immunogenicity.

Results

Of the 50 randomized patients, 49 patients received the study treatment and 46 patients completed the study. Baseline demographic and disease characteristic were comparable between the two treatment sequences. The 95% CI of mean difference in LDH level at Week 26 between SB12 and ECU (SB12 − ECU: 34.48, 95% CI [−47.66, 116.62]) lied within the pre-defined equivalence margin. The 90% CI of ratio of time‑adjusted AUEC of LDH between SB12 and ECU (SB12/ECU: 1.08, 90% CI [0.95, 1.23]) lied within the pre‑defined equivalence margin. The overall LDH profile during the study period was also comparable. The mean number of units of pRBCs transfused during Period 1 (TS1: 1.1 U; TS2: 0.9 U, respectively) and Period 2 (TS1: 1.1 U; TS2: 1.0 U, respectively) was comparable.

Treatment-emergent adverse events (TEAEs) was reported in 72.3% for SB12 and 68.1% in ECU. Three patients in SB12 and 2 patients in ECU had serious TEAEs. None of three serious TEAEs reported in SB12 were related to the treatment. Two of three TEAEs (cellulitis; infusion site hypersensitivity) reported in ECU were treatment-related, and 1 death due to major adverse vascular event (portal vein thrombosis) not related to the treatment was reported in ECU. The mean eculizumab serum trough concentrations and the mean terminal complement activities in both treatment sequences were comparable. No patient developed anti-drug antibodies during the study period. 

Conclusion

SB12 showed clinical equivalence to ECU measured by LDH. SB12 and ECU were comparable in terms of safety, PK, PD, and immunogenicity.

Keyword(s): Clinical data, Monoclonal antibody, Phase III, PNH

Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P829

Type: Poster presentation

Session title: Bone marrow failure syndromes incl. PNH - Clinical

Background

SB12, a proposed eculizumab biosimilar, is a humanized monoclonal antibody that blocks complement C5 cleavage, thereby inhibits terminal complement-mediated intravascular hemolysis.

Aims

The randomized, double-blind, multicenter, cross-over study was aimed to demonstrate comparable clinical efficacy by evaluating the lactate dehydrogenase (LDH), safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of SB12 and reference eculizumab (ECU) in paroxysmal nocturnal hemoglobinuria (PNH) patients (NCT04058158).

Methods

A total of 50 patients aged ≥ 18 years with a confirmed diagnosis of PNH and ≥ 1.5 upper limit of normal range (ULN) of LDH without previous exposure to a complement inhibitor were included. All patients provided written informed consents and were randomized (1:1) to treatment sequence I (TS1: SB12 to ECU, n=25) or II (TS2: ECU to SB12, n=25). Patient received 600 mg of SB12 (TS1) or ECU (TS2) intravenously every week for first 4 weeks (initial phase) and 900 mg for the fifth week, followed by 900 mg every 2 weeks thereafter (maintenance phase). The treatment was switched to ECU (TS1) or SB12 (TS2) at Week 26, and switched treatment was provided until Week 50.

Primary endpoints were LDH level at Week 26 and time-adjusted area of under the effect curve (AUEC) of LDH from Week 14 to Week 26 and Week 40 to Week 52. Equivalence was declared for LDH level at Week 26 if the two-sided 95% confidence interval (CI) of the mean difference in between SB12 and ECU lied within the pre-defined equivalence margin of [−1.2 × ULN, 1.2 × ULN] = [−337.2, 337.2], where ULN = 281 U/L. Equivalence was declared for time-adjusted AUEC of LDH if the two-sided 90% CI of the ratio of geometric means between SB12 and ECU lied within the pre-defined equivalence margin of [0.77, 1.29]. Secondary endpoints were LDH profile over time and number of units of packed red blood cells (pRBCs) transfused throughout the study period, safety, PK, PD, and immunogenicity.

Results

Of the 50 randomized patients, 49 patients received the study treatment and 46 patients completed the study. Baseline demographic and disease characteristic were comparable between the two treatment sequences. The 95% CI of mean difference in LDH level at Week 26 between SB12 and ECU (SB12 − ECU: 34.48, 95% CI [−47.66, 116.62]) lied within the pre-defined equivalence margin. The 90% CI of ratio of time‑adjusted AUEC of LDH between SB12 and ECU (SB12/ECU: 1.08, 90% CI [0.95, 1.23]) lied within the pre‑defined equivalence margin. The overall LDH profile during the study period was also comparable. The mean number of units of pRBCs transfused during Period 1 (TS1: 1.1 U; TS2: 0.9 U, respectively) and Period 2 (TS1: 1.1 U; TS2: 1.0 U, respectively) was comparable.

Treatment-emergent adverse events (TEAEs) was reported in 72.3% for SB12 and 68.1% in ECU. Three patients in SB12 and 2 patients in ECU had serious TEAEs. None of three serious TEAEs reported in SB12 were related to the treatment. Two of three TEAEs (cellulitis; infusion site hypersensitivity) reported in ECU were treatment-related, and 1 death due to major adverse vascular event (portal vein thrombosis) not related to the treatment was reported in ECU. The mean eculizumab serum trough concentrations and the mean terminal complement activities in both treatment sequences were comparable. No patient developed anti-drug antibodies during the study period. 

Conclusion

SB12 showed clinical equivalence to ECU measured by LDH. SB12 and ECU were comparable in terms of safety, PK, PD, and immunogenicity.

Keyword(s): Clinical data, Monoclonal antibody, Phase III, PNH

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