在6月12-15日於西班牙馬德里IFEMA展覽中心舉行的2019年歐洲風濕病學年會上，復宏漢霖分享了HLX01（利妥昔單抗注射液）、HLX03（阿達木單抗注射液）在自身免疫疾病領域的最新研究進展，HLX01-RA01 、HLX03-HV01兩項臨床數據發佈。
海報1
海報標題: A mutlicentre, randomised, double-blind, parallel active-controlled clinical trial comparing pharmacokinetics, pharmacodynamics, safety and exploratory efficacy between HLX01 and Europe-sourced rituximab as a new indication in Chinese moderate to severe patients with rheumatoid arthritis
海報 ID: SAT0139
演講者: 陳霞教授, 北京天壇醫院
HLX01-RA01結果顯示，HLX01與歐盟市售的原研利妥昔單抗在類風濕關節炎患者中呈現生物等效。2019年2月22日，HLX01（漢利康®，利妥昔單抗注射液）用於非霍奇金淋巴瘤的治療正式獲得中國國家藥品監督管理局批准，而原研利妥昔單抗作為一款在美國和歐盟地區上市多年，用於多種血液瘤和類風濕關節炎治療的CD20靶向藥物，目前在中國只獲批用於治療非霍奇金淋巴瘤。HLX01臨床研究數據發佈，顯示出HLX01在葯代/藥效動力學與安全性方面均與歐盟市售的利妥昔單抗高度相似。此項臨床試驗支持開展臨床3期試驗 (HLX01-RA03)，旨在進一步評估在中、重度活動性類風濕關節炎且對疾病緩解類抗風濕藥物(DMARSs)不敏感的患者中，HLX01與標準療法相比的安全性與有效性。
海報2
海報標題: China-manufactured adalimumab biosimilar, HLX03, demonstrated pharmacokinetic equivalence and comparable safety to reference adalimumab
海報 ID: FRI0086
演講者: 丁艷華教授，吉林大學第一醫院
同時，一項在健康人群中比較HLX03（阿達木單抗注射液）與中國市售原研阿達木單抗生物等效性的臨床研究數據也於此間發佈。原研阿達木單抗注射液是一款在美國獲批用於治療類風濕關節炎、銀屑病性關節炎、強直性脊柱炎、克羅恩病、中重度慢性銀屑病及幼年特發性關節炎治療的TNF靶向藥物。在HLX03-HV01臨床試驗中，臨床試驗終點（葯代動力學、安全性和免疫原性）在健康受試者中均達到預設標準。此臨床試驗進一步支持HLX03在斑塊性銀屑病患者中開展一項隨機、雙盲的3期試驗，用以評估HLX03對比中國市售阿達木單抗的有效性和安全性。
臨床數據
HLX01
臨床試驗HLX01-RA01 (註冊號NCT03355872) 為一項隨機、雙盲、多次給葯、平行對照的1/2期試驗，在中重度類風濕關節炎且對抗風濕葯 (DMARSs) 不敏感的患者中對比 HLX01 與 歐洲市售利妥昔單抗。該試驗方案分析組一共179人，為1:1隨機分配，其中HLX01組88人，歐洲市售利妥昔組91人，均完成了第1天和第15天的兩次注射以及為期24周的評估。不同受試組濃度-時間0到無窮的曲線下面積的數據相似 (AUC0-inf) [HLX01: 200753.72 ug*h/mL 對比 EU-rituximab: 192435.09 ug*h/mL]。HLX01 與 歐洲市售利妥昔AUC0-inf的幾何平均數比值為104.32%，90%的置信區間(CIs) 為 (96.49%, 112.80%)，在生物相似性等效區間內 (80-125%)。兩組試驗安全和免疫原性的數據相似，並且均未出現大於等於3級的不良事件。依據美國關節炎學會的標準，在第24周緩解度大於20%的患者在兩組中比例相似且沒有顯著差異 [(ACR20) p=0.5604, ACR50 (p=0.0704), ACR70 (p=0.1259)]。兩組患者基於C反應蛋白的28個關節疾病活動性評分 (DAS28-CRP) 均顯著下降，且無組間差異 (p=0.6181)。此臨床試驗支持HLX01在類風濕關節炎患者中開展3期試驗，用以探索HLX01與MTX合用對比標準療法的安全性和有效性。(3期試驗註冊號NCT03522415)
HLX03
臨床試驗HLX03-HV01 (註冊號NCT03357939) 為一項隨機、雙盲、單次給葯、平行對照的1期試驗，在18至45歲健康男性受試者（體重指數19-28 kg/m2，體重50-80 kg）中對比 HLX03 與 中國市售阿達木單抗。該葯代動力學試驗方案分析組一共210人，為1:1隨機分配，其中HLX03組104人，中國市售阿達木組106人。兩組間藥物血清峰濃度 (Cmax) [HLX03組: 3.421 ug/mL 對比 中國市售阿達木組: 3.345 ug/mL] 和 濃度-時間0到最後一次測量曲線下面積，濃度-時間0到無窮曲線下面積 (AUC0-t 和AUC0-inf) 的數據 [HLX03組: 1938.75 ug*h/mL, 2017.61 ug*h/mL 對比 中國市售阿達木組: 1847.85 ug*h/mL, 1936.47 ug*h/mL] 均相似。葯代動力學幾何平均數的雙側90%的置信區間 (CIs) 在生物相似性等效區間內 (80-125%)。兩組試驗安全和免疫原性的數據相似 (p>0.05)，且多數治療中不良事件為輕度和中度。此臨床試驗進一步支持HLX03在斑塊性銀屑病患者中開展3期試驗，用以評估HLX03對比中國市售阿達木單抗的有效性和安全性。 (3期試驗註冊號NCT03316781)
Henlius presented data of two anti-inflammatory candidates at EULAR 2019
Shanghai, China, June 17, 2019 – Shanghai Henlius Biotech, Inc. announced new data from the Phase 1 HLX01-RA01 study, which show that HLX01 is bioequivalent to European-Union (EU) sourced MabThera® in rheumatoid arthritis (RA). HLX01 (漢利康®; rituximab injection) was approved by China National Medical Products Administration (NMPA) on February 22, 2019, for the treatment of non-Hodgkin』s』 lymphomas (NHLs). MabThera® is a CD20 targeting antibody that is approved to treat various of hematological malignancies (such as NHLs) and rheumatoid arthritis (RA) in the USA and Europe. In China, MabThera® has been approved for NHL indication only. HLX01 demonstrated pharmacodynamic/ pharmacokinetic (PD/PK) and safety equivalence between HLX01 and EU-rituximab in HLX01-RA01 study. The results from the phase 1 study support the ongoing phase 3 study, evaluating efficacy and safety of HLX01 versus standard-of-care in patients with moderately- to severely- active RA who had inadequate response to disease-modifying anti-rheumatic drugs (DMARSs).
In addition to the HLX01, HLX03-HV01 phase 1 study, which demonstrates that HLX03, its adalimumab biosimilar candidate, is bioequivalent to the subcutaneous injection of the China-sourced Humira®. Humira® is a tumor necrosis factor (TNF) antibody that has been approved in the USA for the treatment of RA, psoriatic arthritis, ankylosing spondylitis, Crohn』s disease, moderate to severe chronic psoriasis and juvenile idiopathic arthritis. In the HLX03-HV01 study, HLX03 met all the pre-defined PK, safety and immunogenicity endpoints in healthy individuals.The results support the ongoing HLX03-PS03, which is a randomized, double-blind phase 3 study evaluating efficacy and safety of HLX03 versus Humira® in patients with plaque psoriasis (PS).
HLX01
HLX01-RA01 (NCT03355872) was a randomized, double-blind, multiple dose, parallel-controlled phase 1/2 clinical study of HLX01 compared to EU-rituximab in patients with moderately- to severely-active RA who had inadequate response to disease-modifying anti-rheumatic drugs (DMARSs). A total of 179 patients [HLX01: 88 vs. EU-rituximab: 91] who were randomised at 1:1 ratio to 2 doses (days 1 and 15) either HLX01 or EU-rituximab in the per-protocol analysis completed 24-week evaluation. The area under the concentration-time curve from time 0 to infinity (AUC0-inf) [HLX01: 200753.72 ug*h/mL versus EU-rituximab: 192435.09 ug*h/mL] were similar. The geometric mean ration of AUC0-inf for HLX01 and EU-rituximab was 104.32% and the two-sided 90% confidential intervals (CIs) was (96.49%, 112.80%) within the 80-125% bioequivalence margin. The safety and immunogenicity profiles were similar between HLX01 and EU-rituximab. There was no report on Grade >/= 3 adverse events. There were no significant differences in the proportions of patients with >20% changes in American College of Rheumatology (ACR20) with p=0.5604, ACR50 (p=0.0704) and ACR70 (p=0.1259) at week 24 between HLX01 and EU-rituximab. The changes in disease activity score 28 based on C-reactive protein (DAS28-CRP) scores significantly decreased from baseline in both HLX01 (p<0.0001) and EU-rituximab (p<0.0001) groups with no significant differences between two treatment arms (p=0.6181). The results support the development of HLX01 in an ongoing phase 3 study (HLX01-RA03; NCT03522415) investigating the efficacy and safety of HLX01 combined with methotrexate comparing with standard-of-care in RA.
HLX03
HLX03-HV01 (NCT03357939) was a randomized, double-blind, single-dose, parallel-controlled phase 1 clinical study of HLX03 compared to CN-adalimumab in healthy male individuals aged 18-45 years with a body mass index of 19-28 kg/m2 and a weight of 50-80 kg. A total of 210 individuals [HLX03: 104 vs. CN-adalimumab: 106] who were randomised at 1:1 ratio to either HLX03 or CN-adalimumab in the per-protocol analysis for PK, the drug maximum serum concentration (Cmax) [HLX03: 3.421 ug/mL vs. CN-adalimumab: 3.345 ug/mL], area under the concentration-time curve from time 0 to the last measurable concentration and to infinity (AUC0-t and AUC0-inf, respectively) [HLX03: 1938.75 ug*h/mL and 2017.61 ug*h/mL vs. CN-adalimumab: 1847.85 ug*h/mL and 1936.47 ug*h/mL] were similar. The two-sided 90% CIs for the geometric mean ratios for all PK parameters were contained within 80-125% bioequivalent margin. The safety and immunogenicity profiles were similar between two treatment groups (p>0.05) and most treatment-emergent adverse events were mild to moderate. The data further support an ongoing phase 3 study (HLX03-PS03; NCT03316781) evaluating the efficacy and safety of HLX03 and CN-adalimumab in the treatment of PS.