China National Medical Products Administration Research Articles

China enters CAR-T cell therapy era

The emerging individualized and living-cell-based genetic engineering chimeric antigen receptor T (CAR-T) therapy demonstrates great curative effects in some hematological tumor treatments, thus it is turning out to be a star immunotherapy method of the world.1 Recently, the China National Medical Products Administration (NMPA) approved launching applications of two CAR-T cell cancer products, Axicabtagene Ciloleucel (FKC876) and Relmacabtagene Autoleucel (Carteyva), which marked the beginning of the of CAR-T cell therapy era in China (Figure 1).

Morus alba L. (Sangzhi) alkaloids (SZ-A) exert anti-inflammatory effects via regulation of MAPK signaling in macrophages

Ethnopharmacological relevanceMorus alba L. (Sangzhi) alkaloids (SZ-A) tablets have been approved by the China National Medical Products Administration for T2DM treatment. Our previous study (Liu et al., 2021) revealed that SZ-A protected against diabetes and inflammation in KKAy mice. However, the mechanism and components in SZ-A exerting anti-inflammatory effects are unclear. Aim of the studyInvestigate the effects and molecular mechanisms of SZ-A on inflammation, and identify anti-inflammatory active components in SZ-A. Materials and methodsThe major ingredients in SZ-A were analyzed by HPLC and sulfuric acid - anthrone spectrophotometry. The inhibitory activities of SZ-A on lipopolysaccharide (LPS)-stimulated inflammation were determined in bone marrow-derived macrophage (BMDM) and RAW264.7 cells. The cytokine levels of IL-6 and TNF-α in cell culture supernatant were measured by enzyme-linked immunosorbent assay (ELISA). Gene expression levels of IL-6 and TNF-α were detected by qRT-PCR. The levels of protein phosphorylation of p38 MAPK, ERK, and JNK were analyzed by Western blot. ResultsThe main components in SZ-A were found to be 1-deoxynojirimycin (DNJ), 1,4-dideoxy-1,4-imino-D-arabinitol (DAB), fagomine (FAG), polysaccharide (APS), and arginine (ARG). SZ-A reduced the levels of IL-6 and TNF-α secreted by LPS-induced RAW264.7 and BMDM cells. Simultaneously, the mRNA expression levels of IL-6 and TNF-α were all significantly suppressed by SZ-A in a concentration-dependent manner. Furthermore, SZ-A inhibited the phosphorylation of p38 MAPK, ERK, and JNK in BMDM and the activation of ERK and JNK signaling in RAW264.7 cells. We also observed that DNJ, DAB, FAG, and ARG markedly downregulated IL-6 and TNF-α cytokine levels, while APS did not have an obvious effect. ConclusionsSZ-A attenuates inflammation at least partly by blocking the activation of p38 MAPK, ERK, and JNK signaling pathways. DNJ, FAG, DAB, and ARG are the main constituents in SZ-A that exert anti-inflammatory effects.

Icotinib Induces Mechanism-Based Inactivation of Recombinant Human CYP3A4/5 Possibly via Heme Destruction by Ketene Intermediate.

Icotinib (ICT) is an antitumor drug approved by China National Medical Products Administration and is found to be effective against non-small cell lung cancer. The present study aimed at the interaction of ICT with CYP3A. ICT exhibited time-, concentration-, and NADPH-dependent inhibitory effect on recombinant human CYP3A4/5. About 60% of CYP3A activity was suppressed by ICT at 50 μM after 30 minutes. The observed enzyme inhibition could not be recovered by dialysis. Nifedipine protected CYP3A from the inactivation by ICT. The inhibitory effects of ICT on CYP3A were influenced neither by glutathione/N-acetyl lysine nor by superoxide dismutase/catalase. Incubation of ICT with human hepatic microsomes produced a ketene reactive intermediate trapped by 4-bromobenzylamine. CYP3A4 dominated the metabolic activation of ICT to the ketene intermediate. Ethyl and vinyl analogs of ICT did not induce inactivation of recombinant human CYP3A4/5, which indicates that acetylenic bioactivation of ICT contributed to the enzyme inactivation. Moreover, the metabolic activation of ICT resulted in heme destruction. In conclusion, this study demonstrated that ICT was a mechanism-based inactivator of recombinant human CYP3A4/5, and heme destruction by the ketene metabolite may be responsible for the observed CYP3A inactivation. SIGNIFICANCE STATEMENT: Cytochrome P450 enzymes play an important role in drug-drug interactions. The present study demonstrated that icotinib, an inhibitor of epidermal growth factor receptor used to treat non-small cell lung cancer, is a mechanism-based inactivator of recombinant human CYP3A4/5. The study provided solid evidence for the involvement of acetylene moiety in the metabolic activation as well as the inactivation of the enzyme. Furthermore, the resulting ketene intermediate was found to destroy heme, which is possibly responsible for the observed enzyme inactivation.

ESCORT-1st: A randomized, double-blind, placebo-controlled, phase 3 trial of camrelizumab plus chemotherapy versus chemotherapy in patients with untreated advanced or metastatic esophageal squamous cell carcinoma (ESCC).

4000 Background: The current standard first-line therapy for advanced or metastatic ESCC is doublet chemotherapy, and prognosis remains poor. Camrelizumab, a humanized anti-PD-1 monoclonal antibody, has shown promising antitumor activity in previously treated advanced or metastatic ESCC (Huang et al. Lancet Oncol 2019). Immunotherapy may work synergistically with chemotherapy, but lacking clinical evidences in ESCC. Here, we report the findings of the phase 3 ESCORT-1st study which evaluated the efficacy and safety of camrelizumab plus chemotherapy vs chemotherapy in patients with untreated advanced or metastatic ESCC. Methods: Eligible patients were randomized 1:1 to receive camrelizumab 200 mg or placebo, both combined with up to 6 cycles of paclitaxel (175 mg/m2) and cisplatin (75 mg/m2). All were given intravenously Q3W. Tumor response was assessed every 6 weeks according to RECIST v1.1. Co-primary endpoints were OS and independent review committee (IRC)-assessed PFS. Efficacy was assessed in all randomized patients and safety was assessed in all treated patients. Data cutoff date for the prespecified interim OS and final PFS analysis was Oct 30, 2020. Results: From Dec 3, 2018 to May 12, 2020, 596 patients were randomized. 298 patients were treated with camrelizumb-chemotherapy and 297 patients with placebo-chemotherapy. With a median follow-up of 10.8 months, camrelizumab plus chemotherapy significantly improved OS compared with placebo plus chemotherapy (median, 15.3 month [95% CI 12.8-17.3] vs 12.0 months [11.0-13.3]; HR, 0.70 [95% CI, 0.56-0.88]; one-sided P = 0.0010). Camrelizumab plus chemotherapy was also superior for PFS (per IRC) vs placebo plus chemotherapy (median, 6.9 months [95% CI, 5.8-7.4] vs 5.6 months [95% CI, 5.5-5.7]; HR, 0.56 [95% CI, 0.46-0.68]; one-sided P < 0.0001). ORR per investigator was 72.1% in camrelizumab-chemotherapy group vs 62.1% in placebo-chemotherapy group, and median DoR was 7.0 vs 4.6 months. Incidences of grade ≥3 treatment-related AEs were comparable between the two groups (63.4% vs 67.7%), with decreased neutrophil count (39.9% vs 43.4%) as the most common one. Serious treatment-related AEs occurred in 30.2% vs 23.2% of patients, and treatment-related deaths occurred in 3.0% vs 3.7% of patients, respectively. Conclusions: Addition of camrelizumab to chemotherapy provided superior OS and PFS vs placebo plus chemotherapy, with a manageable safety profile. Camrelizumab in combination with paclitaxel and cisplatin has the potential to become a new standard first-line therapy in patients with advanced or metastatic ESCC. Based on this trial, we are submitting NDA to seek the approval from China National Medical Products Administration for camrelizumab plus chemotherapy in the treatment of untreated advanced or metastatic ESCC. Clinical trial information: NCT03691090.

A Study to Decipher the Potential Effects of Butylphthalide against Central Nervous System Diseases Based on Network Pharmacology and Molecular Docking Integration Strategy.

Background Butylphthalide (NBP), approved by the China National Medical Products Administration (NMPA) for the treatment of ischemic stroke (IS), showed pleiotropic potentials against central nervous system (CNS) diseases, including neuroprotection and cognitive deficits improvement. However, the effects and corresponding modes of action were not fully explored. This study was designed to investigate the potential of NBP against IS-associated CNS diseases based on network pharmacology (NP) and molecular docking (MD). Methods IS was inputted as the index disease to retrieve the “associated diseases” in DisGeNET. Three-database-based IS genes were obtained and integrated (DisGeNET, Malacards, and OMIM). Then, IS-associated genes were identified by combining these genes. Meanwhile, PubMed references and online databases were applied to identify NBP target genes. The IS-related disease-disease association (DDA) network and NBP-disease regulation network were constructed and analyzed in Cytoscape. In silico MD and references were used to validate the binding affinity of NBP with critical targets and the potential of NBP against certain IS-related CNS disease regulation. Results 175 NBP target genes were obtained, while 312 IS-related disease genes were identified. 36 NBP target genes were predicted to be associated with IS-related CNS diseases, including Alzheimer's disease (AD), epilepsy, major depressive disorder (MDD), amyotrophic lateral sclerosis (ALS), and dementia. Six target genes (i.e., GRIN1, PTGIS, PTGES, ADRA1A, CDK5, and SULT1E1) indicating disease specificity index (DSI) >0.5 showed certain to good degree binding affinity with NBP, ranging from −9.2 to −6.7 kcal/mol. And the binding modes may be mainly related to hydrogen bonds and hydrophobic “bonds.” Further literature validations inferred that these critical NBP targets had a tight association with AD, epilepsy, ALS, and depression. Conclusions Our study proposed a drug-target-disease integrated method to predict the drug repurposing potentials to associated diseases by application of NP and MD, which could be an attractive alternative to facilitate the development of CNS disease therapies. NBP may be promising and showed potentials to be repurposed for treatments for AD, epilepsy, ALS, and depression, and further investigations are warranted to be carefully designed and conducted.

The changing landscape of anti-lung cancer drug clinical trials in mainland China from 2005 to 2020

BackgroundIn recent years, new drug development on lung cancer is in full swing in China. The aim of this study was to overview the changing landscape of anti-lung cancer drug clinical trials in mainland China from 2005 to 2020. MethodsWe analysed anti-lung cancer drug clinical trials registered on three websites including the China National Medical Products Administration Centre for Drug Evaluation platform, the Chinese Clinical Trial Registry and ClinicalTrials.gov. FindingsA total of 1595 anti-lung cancer drug clinical trials from Jan 1st, 2005 to Dec 31st, 2020 were extracted, which included 630 (39•5%) investigator-initiated trials (IITs), 698 (43•8%) domestic industry-sponsored trials (ISTs), and 267 (16•7%) international ISTs. During the past 16 years, the number of anti-lung cancer clinical trials including IITs and domestic ISTs had a remarkable growth, however, the number of international ISTs increased slowly. The number of principal clinical trial units also increased significantly over time. Of the 1595 trials, the largest growth was observed in phase I trials during 2013–2020, with an average annual growth rate of 38•6%. 278 trials were led by principal investigators (PI) from Guangdong, followed by Beijing (n=273) and Shanghai (n=257). Among the 965 ISTs, clinical trials involving targeted drugs (588, 60•9%) accounted for the largest proportion, followed by immunotherapeutic drugs (284, 29•4%), cytotoxic drugs (75, 7•8%), and traditional Chinese medicine (18, 1•9%). In terms of targeted drugs, EGFR-TKIs remained the most studied drugs (225/588, 38•27%). As for immunotherapy, 125 out of 284 (44•01%) trials involved PD-1 inhibitors, 60 (21•13%) trials involved PD-L1 inhibitors, and seven (2•46%) trials involved CTLA-4 inhibitors. InterpretationIn the past 16 years, the development of anti-lung cancer drug clinical trials has achieved much progress in mainland China. The most progress lied in targeted therapy and immunotherapy. FundingThis work was financially supported in part by China National Major Project for New Drug Innovation (2017ZX09304015) and Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-001).

Ramulus Mori (Sangzhi) Alkaloids (SZ-A) Ameliorate Glucose Metabolism Accompanied by the Modulation of Gut Microbiota and Ileal Inflammatory Damage in Type 2 Diabetic KKAy Mice

The novel Traditional Chinese Medicine Ramulus Mori (Sangzhi) alkaloid tablets (SZ-A) are approved by The China National Medical Products Administration for the treatment of type 2 diabetes mellitus (T2DM). However, the extensive pharmacological characteristics and the underlying mechanism are unknown. This study investigated the mechanisms by which SZ-A ameliorates glucose metabolism in KKAy mice, an animal model of T2DM. Diabetic KKAy mice were treated intragastrically with SZ-A once daily for 8 weeks, after which glucose levels, lipid metabolism, gut microbiome, systemic inflammatory factors, luminal concentrations of short-chain fatty acids (fecal samples), and ileal proteomic changes were evaluated. The ileum tissues were collected, and the effects of SZ-A on pathological inflammatory damage were evaluated by hematoxylin and eosin staining, immunofluorescence, and immunohistochemistry. The mRNA and protein expression levels of various inflammatory markers, including monocyte chemoattractant protein-1 and phosphorylated nuclear factor kappa B p65, were detected in the ileum tissues. SZ-A improved glucose metabolism with enhanced insulin response and elevated glucagon-like peptide 1 (GLP-1) nearly 2.7-fold during the glucose tolerance test in diabetic KKAy mice. Gut microbiota analysis demonstrated that SZ-A administration elevated the abundance of Bacteroidaceae and Verrucomicrobia, reduced the levels of Rikenellaceae and Desulfovibrionaceae; and increased the concentrations of fecal acetic and propionic acids compared to the diabetic model group. Additionally, SZ-A markedly improved ileal inflammatory injury and pro-inflammatory macrophage infiltration and improved intestinal mucosal barrier function in diabetic KKAy mice. SZ-A also attenuated the levels of circulating endotoxin, pro-inflammatory cytokines, and chemokines in the mice sera. Collectively, SZ-A ameliorated the overall metabolic profile including glucose and lipid metabolism in KKAy mice, which may be associated with an improvement in GLP-1 and insulin secretion, at least in part by modulating the gut microbiome and relieving the degree of ileal and systemic inflammation.

Clinical applications and pharmacological research progress of Lianhua Qingwen capsules/granules

Lianhua Qingwen capsule/granule is an innovative Chinese medicine developed under the guidance of the traditional Chinese medicine (TCM) collateral disease theory. It has the effect of “clearing heat and removing toxin, ventilating the lungs and discharging heat”. In 2003, it was approved as a new drug by the China National Medical Products Administration, through expedited approval during severe acute respiratory syndrome, and now, it has become a representative proprietary Chinese medicine for the treatment of infectious diseases of the respiratory system. Pharmacodynamic studies have revealed that Lianhua Qingwen has broad-spectrum antiviral, antibacterial and anti-inflammatory, antipyretic, cough-relieving, and immunoregulation effects. Clinically it has been used in the treatment of communicable and infectious respiratory diseases such as Coronavirus Disease 2019, influenza, colds, pulmonary infections, etc. and has achieved remarkable curative effects, showing the important clinical guidance of the TCM collateral disease theory.

P48.09 Anlotinib Plus Etoposide and Carboplatin as First-Line Treatment for Extensive-Stage Small Cell Lung Cancer: A Single Arm Phase II Trial

Anlotinib is a novel multi-target tyrosine kinase inhibitor approved by NMPA (China National Medical Products Administration) and its anti-tumor vascular targets include VEGFR, PDGFR, c-Kit and FGFR. This phase II study aims to further evaluate the efficacy and safety of anlotinib plus etoposide and carboplatin in treatment-naïve patients with extensive-stage small cell lung cancer (ES-SCLC).

Enterovirus A71 Vaccines.

Enterovirus A71 (EV-A71) is a major causative agent of hand, foot, and mouth disease (HFMD) and herpangina. Moreover, EV-A71 infection can lead to neurological complications and death. Vaccination is the most efficient way to control virus infection. There are currently three inactivated, whole EV-A71 vaccines licensed by the China NMPA (National Medical Products Administration). Several other types of vaccines, such as virus-like particles and recombinant VP1 (capsid protein), are also under development. In this review, we discuss recent advances in the development of EV-A71 vaccines.

The changing landscape of anti-lymphoma drug clinical trials in mainland China in the past 15 years (2005–2020): A systematic review

BackgroundTo depict a comprehensive changing landscape of anti-lymphoma drug clinical trials in mainland China from 2005 to 2020. MethodsA systematic review was conducted on the China National Medical Products Administration Center for Drug Evaluation platform, the Chinese Clinical Trial Registry and ClinicalTrials.gov websites. FindingsA total of 797 anti-lymphoma drug clinical trials registered from Jan 1st, 2005 to Aug 1st, 2020 were identified. The number of trials increased gradually over time, and a notable increase was observed in 2016, with the number growing from 29 in 2015 to 72 in 2016. Trials in phase I (26•1%) and phase II (26•6%) represented the majority, followed by phase III (12•5%) and phase IV (7•4%). Regarding sponsorship, industry-sponsored trials (53•2%) accounted for a slightly larger proportion than investigator-initiated trials (IITs) (46•8%). A dramatic growth for IITs was seen during 2017–2020, with the number increasing from 36 in 2017 to 96 in 2020. Additionally, the proportion of trials involving targeted agents (50•2%) accounted for the largest, followed by trials involving immunotherapy agents (41•0%), and cytotoxic agents (8•0%). Besides, a sustainable growth was observed in the number of leading anti-lymphoma drug clinical trial units in mainland China over the past 15 years. The majority of leading principal units (60•8%) were from Beijing, Shanghai, Guangdong and Jiangsu. InterpretationIn the past 15 years, the research and development of drugs and clinical trials for lymphoma in mainland China has achieved much progression. Future efforts are needed for improving innovation and sustainability of pharmaceutical research and development. FundingChina National Major Project for New Drug Innovation (2017ZX09304015); Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-001).

China NMPA perspective on clinical evaluation of SARS-CoV-2 antibody test reagents in the process of emergency approval.

Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 antibody testing an important supplement to nucleic acid testing. In the process of emergency approval, the Center for Medical Device Evaluation of the China National Medical Products Administration released The Key Points of Technical Review for the Registration of SARS-CoV-2 Antigen/Antibody Detection Reagents. The Clinical Study Requirement section of the Key Point has put forward requirements in terms of reference methods and subject enrolment among others, which can ensure that the test results can meet the clinical needs. This article draws on the experience of the China NMPA in evaluating diagnostic reagents used to supplement the gold standard test method in the early stage of an epidemic of an infectious disease, as well as to serve as reference for clinicians and regulators.

The Changing Landscape of Anti-Lymphoma Drug Clinical Trials in Mainland China in the Past 15 Years (2005-2020): A Systematic Review

Background: To depict a comprehensive changing landscape of anti-lymphoma drug clinical trials in mainland China from 2005 to 2020. Method: A systematic review was conducted on the China National Medical Products Administration Center for Drug Evaluation platform, the Chinese Clinical Trial Registry and ClinicalTrials.gov websites. Findings: A total of 797 anti-lymphoma drug clinical trials registered from 2005 to 2020 were identified. The number of trials increased gradually over time, and a notable increase was observed in 2016, with the number growing from 29 in 2015 to 72 in 2016. Trials in phase Ⅰ (26.1%) and phase Ⅱ (26.6%) represented the majority, followed by phase Ⅲ (12.5%) and phase IV (7.4%). Regarding sponsorship, industry-sponsored trials (5 3.2%) accounted for a slightly larger proportion than investigator-initiated trials (IITs) (46.8%). A dramatic growth for IITs was seen during 2017-2020, with the number increasing from 36 in 2017 to 96 in 2020. Additionally, the proportion of trials involving targeted agents (50.2%) accounted for the largest, followed by trials involving immunotherapy agents (41.0%), and cytotoxic agents (8.0%). The majority of leading principle unit (60.8%) were from Beijing, Shanghai, Guangdong and Jiangsu, reflecting a severe uneven geographical distribution. Besides, a sustainable growth was observed in the number of leading clinical trial units for lymphoma in China over the last decade. Interpretation: In the past 15 years, the research and development of drugs and clinical trials for lymphoma has achieved much progression. Future efforts are needed for improving innovation and sustainability of pharmaceutical research and development. Funding Statement: China National Major Project for New Drug Innovation (2017ZX09304015) ; Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-001). Declaration of Interests: All authors declare no competing interests.

267 Poster - HLX02, a China-manufactured trastuzumab biosimilar versus EU-sourced trastuzumab: Results of a global phase 3, randomized, double-blind efficacy and safety comparative study in metastatic breast cancer

Background: Trastuzumab (TZB) is a fully-humanised monoclonal antibody biologic and antagonist of the human epidermal growth factor receptor-type 2 (HER2) receptor. It has significantly prolonged time to progression and survival of patients with HER2 positive metastatic breast cancer, as both a monotherapy or in combination with other agents. HLX02, the first China (CN)-manufactured TRZ biosimilar being investigated in a global setting, was developed to provide more cost-effective and readily available alternatives to TRZ. The clinical program followed the biosimilar guideline of China National Medical Products Administration (NMPA) and European Medicines Agency (EMA), which aims to increase global patient accessibility. We have reported the establishment of clinical PK bioequivalence between HLX02 and reference TZBs, later released Week 24 efficacy data. Here, we announce 1-year efficacy result and updated safety profile of the Phase 3 trial comparing HLX02 and European Union (EU)-sourced TRZ in metastatic breast cancer patients.

Molecular diagnosis of COVID-19: Current situation and trend in China (Review).

COVID-19 is caused by a novel coronavirus (2019-nCoV or SARS-CoV-2) and has become a global public health emergency. Rapid and accurate molecular diagnostic technologies are crucial for the screening, isolation, treatment, prevention and control of COVID-19. Currently, nucleic acid detection-based techniques and rapid diagnostic tests that detect antigens or antibodies specific to 2019-nCoV infections are the primary diagnostic tools. China National Medical Products Administration has opened a special channel for approval of new pharmaceuticals owing to urgent clinical needs, with 18 nucleic acid detection kits, 11 protein detection kits and 1 sequencing-related equipment and supporting software having been approved until April 23, 2020. The current review summarizes the application situation, advantages, disadvantages and associated technology improvement trends of molecular diagnostics for COVID-19 in China, identifies knowledge gaps and indicates future priorities for research in this field. The most effective way to prevent and control COVID-19 is early detection, diagnosis, isolation and treatment. In the clinical application of molecular diagnosis technology, it is necessary to combine pathogenic microbiology, immunology and other associated detection technologies, advocate the combination of multiple technologies, determine how they complement each other, enhance practicability and improve the ability of rapid and accurate diagnosis and differential diagnosis of COVID-19.

Predicting Interactions between Rifampin and Antihypertensive Drugs Using the Biopharmaceutics Drug Disposition Classification System.

Lack of blood pressure control is often seen in hypertensive patients concomitantly taking antituberculosis medications due to the complex drug-drug interactions between rifampin and antihypertensive drugs. Therefore, it is of clinical importance to understand the underlying mechanisms of these interactions to help formulate recommendations on the use of antihypertensive drugs in patients taking these medications concomitantly. Our objective was to assess the reliability of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to predict potential interactions between rifampin and antihypertensive drugs and thus provide recommendations on the choice of antihypertensive drugs in patients receiving rifampin. Evidence-based in vitro and in vivo predictions of drug-drug interactions. We systematically evaluated interactions between rifampin and antihypertensive drugs using the theory of the BDDCS, taking into consideration the role of drug transporters and metabolic enzymes involved in these interactions. We provide recommendations on the selection of antihypertensive drugs for patients with tuberculosis. Antihypertensive drugs approved by the U.S. Food and Drug Administration and the China National Medical Products Administration were included in this study. The drugs were classified into four categories under the BDDCS classification. Detailed information on cytochrome P450 (CYP) enzymes and drug transporters for each antihypertensive drug was searched in PubMed and other electronic databases. This information was combined with the effects of rifampin on CYP enzymes and drug transporters, and the direction and relative extent of the potential interactions between rifampin and antihypertensive drugs were predicted. Recommendations were then made using the theory of BDDCS. A thorough systematic literature review was performed, and data from all published human studies and case reports were summarized for the validation of our predictions. Interventional and observational studies published in PubMed and two Chinese databases (CNKI and WanFang) through December 16, 2019, were included, and data were extracted for validation of the predictions. Using the BDDCS theory, class 3 active drugs were predicted to exhibit minimal interactions with rifampin. On reviewing case reports and pre-post studies, the predictions we made were found to be reliable. When antituberculosis medications that include rifampin are started in patients with hypertension, it is recommended that the use of calcium channel blockers and classes 1 and 2 β-blockers be avoided. Angiotensin-converting enzyme inhibitors, olmesartan, class 3 β-blockers, spironolactone, and hydrochlorothiazide would be preferable because clinically relevant interactions would not be expected. Application of the BDDCS to predict interactions between rifampin and antihypertensive drugs for patients with both tuberculosis and hypertension was found to be reliable. It should be noted, however, that based on the CYP enzyme and drug transporter information we reviewed, the mechanisms of all of the interactions could not be elucidated, and the predictions are only based on theory. The real effects of rifampin on antihypertensive drugs need to be further observed. More studies in both animals and humans are needed in the future.

LBA6 - First China-manufactured trastuzumab biosimilar HLX02 global phase III trial met primary endpoint in breast cancer

BackgroundHLX02, a fully-humanised anti-HER2 monoclonal antibody, was developed as trastuzumab (TZB) biosimilar to potentially increase treatment accessibility. The clinical program was developed in consultation with China National Medical Products Administration (NMPA) and European Medicines Agency (EMA) for global development. Previously, we reported clinical PK equivalence of HLX02 and TZBs at the ESMO-ASIA 2018 meeting. Here, we report the phase III study results. MethodsWe conducted a randomised, double-blind, parallel-controlled phase III study of HLX02 and EU-TZB at 89 centres in China, Philippines, Poland and Ukraine. Eligible adult women with HER2+ breast cancer were randomised to 8 mg/kg of either HLX02 or EUTZB with docetaxel on Day 1 Cycle 1 followed by a dose of 6 mg/kg in 3weekly cycles for up to 12 months. Primary endpoint was best overall response rate at Week 24 (ORRwk24). Secondary endpoints included ORR at weeks 6, 12, 18 and 24, clinical benefit rate (CBR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety profiles up to 12 months. ResultsOf the 649 patients being randomised (HLX02=324; EUTZB=325), the ORRwk24 (HLX02=71.0%; EU-TZB =71.4%; p = 0.952) and risk difference in ORRs (-0.4%; 95% CI: -7.4, 6.6) between the two groups were within the pre-defined margin (±13.5%). All secondary efficacy analyses at Week 24 concluded the therapeutic equivalence. Both groups in all populations (overall, Asian vs. non-Asian, and Chinese vs. non-Chinese) had similar range values of CBR (HLX02: 78.6% - 86.8%; EU-TZB: 79.3% - 82.4%) and DCR (HLX02: 80.6% - 95.4%; EU-TZB: 86.9% - 89.2%). 641 (98.8%) reported at least 1 AE (HLX02 and EU-TZB were 98.8%). Similar incidences of AEs (HLX02: 6610; EU-TZB: 6788), TEAEs (HLX02: 6464; EU-TZB: 6638) and immunogenicity were reported at Week 24. ConclusionsThe use of HLX02 compared with EUTZB resulted in an equivalent ORR at Week 24. All secondary efficacy and safety analyses of HLX02 at Week 24 supported the conclusion of biosimilarity without clinical meaningful differences with EUTZB. This interim analysis has been submitted to NMPA and EMA to support marketing approval of HLX02 in China and Europe. Clinical trial identificationNCT03084237; EudraCT: 2016-000206-10; Chinese Clinical Trial Register: 2015L01326. Legal entity responsible for the studyShanghai Henlius Biotech, Inc. FundingShanghai Henlius Biotech, Inc. DisclosureT. Sun: Research grant / Funding (institution): Shanghai Henlius Biotech, Inc. W. Li: Research grant / Funding (institution): Shanghai Henlius Biotech, Inc. Y. Teng: Research grant / Funding (institution): Shanghai Henlius Biotech, Inc. I. Bondarenko: Research grant / Funding (institution): Shanghai Henlius Biotech, Inc. H. Adamchuk: Research grant / Funding (institution): Shanghai Henlius Biotech, Inc. Y. Li: Full / Part-time employment: Shanghai Henlius Biotech, Inc. B. Shan: Full / Part-time employment: Shanghai Henlius Biotech, Inc. J. Cheng: Full / Part-time employment: Shanghai Henlius Biotech, Inc. T. Peng: Full / Part-time employment: Shanghai Henlius Biotech, Inc. X. Wang: Full / Part-time employment: Shanghai Henlius Biotech, Inc. Y. Chen: Full / Part-time employment: Shanghai Henlius Biotech, Inc. W. Jiang: Full / Part-time employment: Shanghai Henlius Biotech, Inc. S. Liu: Full / Part-time employment: Shanghai Henlius Biotech, Inc. X. Zhang: Full / Part-time employment: Shanghai Henlius Biotech, Inc. E. Liu: Full / Part-time employment: Shanghai Henlius Biotech, Inc. A. LUK: Full / Part-time employment: Shanghai Henlius Biotech, Inc. Q. Wang: Full / Part-time employment: Shanghai Henlius Biotech, Inc.

Marketing of drugs for rare diseases is speeding up in China: Looking at the example of drugs for mucopolysaccharidosis.

In May 2019, China National Medical Products Administration approved the marketing of an elosulfase alfa injection (brand name: Vimizim) from BioMarin Pharmaceutical for the treatment of patients with mucopolysaccharidosis (MPS) type IVA. This is the first drug to treat MPS in China, and it has ended the "dearth of medicines" to treat MPS in China, a situation that has persisted for many years. One can reasonably say that the drug has benefited from the continuous reform of the drug review and approval system in China and the increasing attention paid to rare diseases. At present, China has implemented a series of preferential policies for the review and approval of drugs for rare diseases, mainly including priority review and approval, accelerated review and approval, special review and approval (mainly simplified review and approval), data protection, and communication. Moreover, China now has a specific reference for the review and approval of drugs for rare diseases with the creation of China's First List of Rare Diseases and the publication of two batches of the List of Overseas New Drugs Urgently Needed in Clinical Settings. Drug review and approval has been significantly accelerated, as has marketing. The two batches of lists of new drugs, issued in November 2018 and May 2019, include 43 drugs for rare diseases (58.1% of all drugs in the lists), 37 of which were included in China's First List of Rare Diseases. The lists also include three other drugs for MPS. As of July 1, 2019, four drugs for rare diseases from the first batch of new drugs have been approved for marketing. In order to further improve the review and approval of drugs for rare diseases in China, a special department should be established for the evaluation of drugs for rare diseases, research on and management of drugs in the post-approval phase should be enhanced, international cooperation in research on use of drugs to treat rare diseases should be enhanced, and the incentive policy for marketing drugs for rare diseases should be improved.

Safety, Pharmacokinetics, and Pharmacogenetics of Single-Dose Teriflunomide Sodium and Leflunomide in Healthy Chinese Subjects.

Teriflunomide sodium, a novel derivative of leflunomide, was developed to treat systemic lupus erythematosus. The objectives of this trial were to study the safety, pharmacokinetics, and pharmacogenetics of teriflunomide sodium in healthy Chinese subjects in order to support its accelerated development. A clinical study was designed as a single-dose, randomized, parallel, open-label study. Healthy volunteers were randomly assigned to take teriflunomide sodium 10mg or leflunomide 10mg. Eligible healthy volunteers were monitored over a 98-day observation period. Blood and urine samples were collected and analyzed for teriflunomide and its metabolite concentrations, and ABCG2 and CYP2C9 genotypes were detected. The safety profile was also collected. All adverse events were mild in intensity, and all subjects completed this trial without any other treatment. After a single administration of teriflunomide sodium and leflunomide, teriflunomide maximal concentrations were 1.32 ± 0.341mg/L and 0.718 ± 0.169mg/L, and area under the concentration-time curve from time zero to infinity (AUC∞) was 423 ± 229mg·h/L and 303 ± 159 mg·h/L, respectively. Overall, teriflunomide AUC∞ in ABCG2 34A/A mutants was 70.4% lower than in wild-type ABCG2 34G/G after administration of teriflunomide sodium. In addition, after administration of leflunomide, teriflunomide AUC∞ in ABCG2 34A/A mutants was 30.0% lower than in subjects carrying ABCG2 34G/G. Teriflunomide sodium was generally safe and well tolerated in healthy Chinese subjects. The relative bioavailability of teriflunomide between teriflunomide sodium and leflunomide after a single dose administration was approximately 150%. Additionally, ABCG2 34G>A was found to significantly affect teriflunomide pharmacokinetics, which suggested ABCG2 34G>A may be a significant influencing factor. This study was registered at the China National Medical Products Administration ( http://www.nmpa.gov.cn ; registration number 2014L01935), and also at the China platform for registry and publicity of drug clinical trials ( http://www.chinadrugtrials.org.cn ; registration number CTR20150314).