Shanghai, China, Apr 6th, 2023-Shanghai Henlius Biotech, Inc. (2696.HK) announced that the Center for Drug Evaluation (CDE) of China National Medical Products Administration (NMPA) has granted a Breakthrough Therapy Designation (BTD) to HLX208 for the treatment of adult Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) with BRAF V600E mutation. HLX208 is a small-molecule inhibitor that targets the human BRAF protein V600E mutation. Currently, HLX208 is now testing in Phase 2 clinical trial against BRAF V600E mutation LCH and ECD.
As per the NMPA’s Working Procedures for Review of Breakthrough Therapy Drugs (Interim) (2020 No.82), the BTD process is designed to expedite the development and review of therapies that are intended for treatment of a seriously debilitating or life-threatening condition for which there is no existing treatment and where preliminary evidence indicates advantages of the therapy over available treatment options. According to the CDE, BTD would grant benefits such as close communication with and intensive guidance from CDE regarding clinical trials and development strategy. When submitting a New Drug Application (NDA), drug candidates with BTD may be eligible for conditional approval and priority review.
ECD and LCH are currently regarded as myeloid neoplasias with inflammatory properties, affecting patients’ quality of life significantly. The National Health Commission (NHC) has placed them on the "First National List of Rare Diseases"[1]. According to the 2019 edition of the Clinical Practice Guidelines for Rare Diseases issued by the National Health Commission of China[2], LCH and ECD are driven by constitutive activation of the MAPK/ERK signalling pathway with more than 50% incidence of BRAF V600E mutation. Currently, except for a BRAF V600E inhibitor approved for ECD in the United States, no similar therapy is approved for the treatment of LCH globally, implying that many patients with BRAF V600E mutant have unmet medical needs.
BRAF is a member of the RAF kinase family and a critical upstream regulator in the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) cell signalling pathway. Its mutation can activate the downstream MEK and ERK protein, which induces the proliferation and invasion of tumour cells [3]. The BRAF mutation frequently occurs in colorectal cancer, thyroid cancer, melanoma and other types of cancers. Among all BRAF mutation types, BRAF V600E mutation is the most common one. Currently, targeted combination therapy represented by BRAF inhibitors has become one of the main treatments in different kinds of BRAF mutation-positive solid tumours [4-5], and a number of studies have shown that BRAF inhibitors combined with immunotherapy antibodies demonstrating a synergistic effect in inhibiting tumour growth [6-7].
HLX208 is a potential “best-in-class” BRAF inhibitor introduced from NeuPharma with a proprietary novel chemical structure that differs from other marketed BRAF inhibitors. It exhibited a single crystal morph, high bioavailability, and excellent anti-tumour efficacy in preclinical studies. Subsequent early clinical data also demonstrated preliminary efficacy and good safety and tolerability in patients with cancer, warranting further clinical development. In November 2022, the investigational new drug (IND) application of Phase 1b/2 clinical trials of HLX208 in combination with HANSIZHUANG for the treatment of BARF V600 mutation-positive solid tumours was approved by the NMPA. In February 2023, the first patient has been dosed in a phase 1b/2 clinical trial of HLX208 in combination with HANSIZHUANG for the treatment of non-small cell lung cancer (NSCLC) in Chinese mainland. And the combination of immuno-oncology therapy HANSIZHUANG and targeted therapy will enable Henlius to explore more effective treatment options for patients with BRAF V600 mutation-positive solid tumours.
Underpinned by the patient-centric strategy, Henlius has built an innovative product pipeline with many emerging targets, including PD-1/L1, LAG-3, OX40, GARP, and BRAF. Regarding antibody technology as a core, Henlius will continue conducting clinical studies for more innovative products in bispecific antibodies, antibody-drug conjugates (ADC), and fusion proteins and exploring combination therapies with improved efficacy to provide patients with quality and affordable biologics.
References
[1] 国家卫生健康委员会《关于公布第一批罕见病目录的通知》（国卫医发〔2018〕10号）http://www.gov.cn/zhengce/zhengceku/2018-12/31/content_5435167.htm
[2] 国家卫生健康委办公厅《罕见病诊疗指南（2019年版）》（国卫办医函〔2019〕198号）http://www.nhc.gov.cn/yzygj/s7659/201902/61d06b4916c348e0810ce1fceb844333/files/e2113203d0bf45d181168d855426ca7c.pdf
[3] Huang Z, Wu Y. Huang Z, Wu Y. Mutation of the BRAF genes in non-small cell lung cancer. Zhongguo Fei Ai Za Zhi. 2012;15(3):183-186.
[4] 国家卫生健康委办公厅《黑色素瘤治疗指南（2022年版）》（国卫办医函〔2022〕104号）http://www.nhc.gov.cn/yzygj/s7659/202204/a0e67177df1f439898683e1333957c74/files/58f7070620874d608e72a3f737330777.pdf
[5]《中国临床肿瘤学会（CSCO）结直肠癌诊疗指南2022》[M]. 人民卫生出版社.
[6] Sanlorenzo M, Vujic I, Floris A, et al. BRAF and MEK Inhibitors Increase PD-1-Positive Melanoma Cells Leading to a Potential Lymphocyte-Independent Synergism with Anti–PD-1 AntibodyBRAF and MEK Inhibitors Increase PD-1–Positive Melanoma[J]. Clinical Cancer Research, 2018, 24(14): 3377-3385.
[7] Trojaniello C, Vitale M G, Ascierto P A. Triplet combination of BRAF, MEK and PD-1/PD-L1 blockade in melanoma: the more the better?[J]. Current Opinion in Oncology, 2021, 33(2): 133-138.