HLX01, the first China manufactured Rituximab biosimilar, was approved by the China National Medicinal Products Administration (NMPA) for the treatment of non-Hodgkin’s lymphoma (NHL) on February 22, 2019. We previously reported the establishment of PK, safety and efficacy equivalence between HLX01 and European-sourced Rituximab (EU-Rituximab) from a Phase 1/2 study (HLX01-RA01) in 195 rheumatoid arthritis (RA) patients at this year EULAR 72nd Annual Scientific 2019 Congress. We further reported the PopPK model validation of HLX01 and China-sourced Rituximab (CN-Rituximab) from a Phase 3 study (HLX01-NHL03) in 110 patients with CD20-positive diffuse large B-cell lymphoma (DLBCL) at ESMO 2019 Congress and ESMO-Asia 2019 Congress. Here at the ASH 61st Annual Meeting 2019, we present the primary endpoint of both HLX01-NHL03 and HLX01-RA01, the development of PopPK model, ethnicity comparison and all external validations.
Methods
In the multicentre, randomised, double-blind, parallel Phase 3 clinical study of HLX01-NHL03 (NCT02787239), 407 CD20-positive DLBCL patients were randomised 1:1 to receive chemotherapy in combination with either HLX01 or CN-Rituximab. The primary efficacy endpoint was the best overall response rate after 6 treatment cycles (“ORR6cycle”). The HLX01-RA01 study (NCT03355872) randomised 195 RA patients (HLX01: 97; EU- Rituximab: 98), and the primary endpoint was area under the curve zero to infinity (AUC0–inf). The PopPK model was developed with PK data from the HLX01-RA01 study (serum sample number=4289) using non-linear mixed-effect modelling (NONMEM®) and first-order estimation with interaction (FOCEI) method. PK-pharmacodynamic (PK-PD) relationship was characterised with various covariates (i.e., demographics, pathophysiologic and disease conditions etc.). A total of 1,000 simulations were tested using the observed covariates. The PopPK model was then externally validated with the PK data in DLBCL patients and compared to the published PK data of Caucasian RA patients.
Results
Based on the result of HLX01-NHL03, the best ORR6cycle of the HLX01 treatment group was 92.8% with a 95% Confidence Interval (CI) of (88.19%, 96.00%), and the best ORR6cycle of the CN-Rituximab treatment group was 94.1% (95%CI: 89.77%, 97.04%). The risk difference between the two ORR6cycles was 1.4% (95%CI: −3.59%, 6.32%), which falls within the pre-defined equivalence margin of (-12%, +12%). In the HLX01-RA01 study, the geometric mean ratio between HLX01 and EU-Rituximab of AUC0–inf was 104.32%, 90% CI (96.49%, 112.80%), which fell within the 80%–125% PK bioequivalence margin. The PopPK model was developed as a two-compartment model with first-order elimination. The external validation results showed PopPK model derived from RA patients adequately predicted the HLX01 and CN-Rituximab in patients with CD20-positve DLBCL, and Rituximab PK profiles were similar between HLX01 and two reference Rituximabs. The PK parameter of Chinese patients were also similar to the published data in Caucasian RA patients.
Conclusions
HLX01 demonstrated equivalence in safety and efficacy compared to CN-Rituximab for the treatment of CD20-positive DLBCL. HLX01 also established PK bioequivalence compared to EU-Rituximab for the treatment of RA. This PopPK model proved PK similarity between HLX01 and two reference Rituximabs sourced from different origins in RA patients and DLBCL patients, with no differences across races.
About Henlius
Henlius(2696.HK) is a leading biopharmaceutical company in China with the vision to offer high-quality, affordable and innovative biologics for patients worldwide with a focus on oncology and autoimmune diseases. Since its inception in 2010, Henlius has built an integrated and efficient global R&D platform with key facilities in Shanghai, Taipei and California. The three R&D centers closely collaborate with each other to ensure a highly productive and cost-efficient R&D process. Starting from biosimilar, Henlius presses forward with novel mAb products and immuno-oncology combination therapies with proprietary anti-PD-1 and PD-L1 mAbs as backbone. Henlius establishes a diversified product pipeline of biosimilars, bio-innovative drugs and combination therapies, and builds an integrated platform covering the whole product lifecycle including R&D, commercial-scale production and commercialization. On September 25, 2019, Henlius was listed on the Main Board of the Stock Exchange of Hong Kong Limited with the stock code: 2696.HK.
Until now, in addition to one product launched commercially, two products under New Drug Application (NDA) review and one product under Marketing Authorization Application (MAA) review, Henlius has conducted over 20 clinical studies for 14 products and 6 combination therapies worldwide. HLX01 (汉利康®, rituximab injection), the first product of Henlius, has been granted approval by the NMPA as the first approved biosimilar in China. HLX03 (adalimumab injection) and HLX02 (trastuzumab for injection) have their NDA under priority review by the NMPA. HLX02 is also the first China-manufactured biosimilar developed in a global setting. In June 2019, the MAA for HLX02 was accepted for review by EMA. Moreover, Henlius advances immuno-oncology combination therapies with proprietary mAbs including HLX10 (anti-PD-1 mAb) as backbone in combination with chemotherapy and other mAbs including HLX04 (bevacizumab biosimilar). The global multi-center clinical trials are ongoing in various countries and regions worldwide.