Fujovee (abivertinib)

This is the first study in which the risk of AC0010-induced cardiotoxicity was evaluated. In addition, novel multifunctional biosensors can comprehensively evaluate the antitumor efficacy and cardiotoxicity of drugs and candidate compounds.

P2, N=100, Suspended, Sorrento Therapeutics, Inc. | Recruiting --> Suspended

At present, only two drugs are approved by the FDA for the treatment of IPF, including the synthetic pyridinone drug, pirfenidone, and the tyrosine kinase inhibitor, nintedanib. The cellular experiments also indicated that avitinib improved alveolar epithelial cell injury in A549 cells. In conclusion, the present findings demonstrated that avitinib attenuates bleomycin-induced pulmonary fibrosis in mice by inhibiting alveolar epithelial cell injury and myofibroblast activation.

P2, N=100, Recruiting, Sorrento Therapeutics, Inc. | Not yet recruiting --> Recruiting

P2, N=100, Not yet recruiting, Sorrento Therapeutics, Inc. | Initiation date: Oct 2022 --> Mar 2023

However, patients treated with third-generation TKIs (osimertinib, avitinib and rociletinib) targeting the EGFR T790M mutation have shown emerging resistances and relapses. This will pave the way for designing novel and effective chemotherapies to improve patients' overall survival. In this review, we provide an overview of the multifaceted mechanism of resistances towards EGFR-TKIs, as well as the challenges and perspectives that should be addressed in strategising chemotherapeutic treatments to overcome the ever evolving and adaptive nature of NSCLC.

P2, N=100, Not yet recruiting, Sorrento Therapeutics, Inc.

We also demonstrated in vivo that abivertinib decreased the number of MKs in bone marrow and platelet counts in mice, which suggested that thrombopoiesis was also inhibited. Thus, these preclinical data collectively suggested that abivertinib could inhibit MK differentiation and platelet biogenesis and might be an agent for thrombocythemia.

Abivertinib of 300 mg BID demonstrated favorable clinical efficacy with manageable side-effects in patients with EGFR T790M+NSCLC.

Other 3rd‑generation EGFR‑TKIs, such as abivertinib, rociletinib, nazartinib, olmutinib and alflutinib, are also at various stages of development. The mechanisms of acquired resistance mainly include an altered EGFR signaling pathway (EGFR tertiary mutations and amplification), activation of aberrant bypassing pathways (hepatocyte growth factor receptor amplification, human epidermal growth factor receptor 2 amplification and aberrant insulin‑like growth factor 1 receptor activation), downstream pathway activation (RAS/RAF/MEK/ERK and PI3K/AKT/mTOR) and histological/phenotypic transformations (SCLC transformation and epithelial‑mesenchymal transition). The combination of targeted therapies is a promising strategy to treat osimertinib‑resistant patients, and multiple clinical studies on novel combined therapies are ongoing.

P1/2, N=368, Active, not recruiting, Hangzhou ACEA Pharmaceutical Research Co., Ltd. | Phase classification: P1 --> P1/2 | Trial completion date: Dec 2020 --> Mar 2023 | Trial primary completion date: Dec 2019 --> Dec 2022

For in vivo studies, rats were pretreated with 30 mg/kg avitinib once daily for 7 days (avitinib multiple-doses group), 30 mg/kg avitinib on day 7 (avitinib single-dose group), or an equivalent amount of CMC-Na once daily for 7 days (control group), followed by intragastrical administration of the probe substrates (1 mg/kg tolbutamide and 10 mg/kg phenacetin, bupropion, chlorzoxazone, dextromethorphan, and midazolam). Avitinib had inhibitory effects on CYP450 enzymes, especially cyp2b1, cyp1a2 in RLMs, CYP2C9 in HLMs, and cyp1a2, cyp2b1, cyp2d1, and cyp2e1 in vivo. Our data recommend caution when avitinib was taken simultaneously with drugs metabolized by CYP450 enzymes.

In this review, we profiled many of the third-generation EGFR TKIs in late stage clinical development (e.g. almonertinib, lazertinib, alflutinib, rezivertinib, ASK120069, SH-1028, D-0316 and abivertinib) of their interim results of phase 1-3 trials and their chemical structures when publicly available. Additionally, we summarized the results of clinical trials that previously reported third-generation EGFR TKIs (rociletinib, olmutinib, nazartinib, maverlertinib) including phase 3 results of rociletinib and naquotinib. We further profiled the next-generation combination clinical trial design of third-generation EGFR TKIs including FLAURA2 (NCT04035486), MARIPOSA (NCT04487080), ACROSS1 (NCT04500704) and ACROSS2 (NCT04500717).

Following a single oral administration, the unchanged abivertinib was the predominant drug-related material in plasma, urine and faeces. The drug-related materials were primarily eliminated via the faecal route. Direct GSH conjugation of abivertinib played a significant role in the metabolic clearance and metabolite exposure of abivertinib.

For the first time, we systematically investigated the effect of avitinib, one newly developed third-generation EGFR-TKI, on the pharmacokinetics of osimertinib both in vitro and in vivo using a rat model.

Moreover, our in vitro and in vivo results show that Apigenin can synergize with Abivertinib, a novel BTK inhibitor, in treating DLBCL visa synergistically inducing apoptosis and inhibiting the p-GS3K-β and its downstream targets. Collectively, our study suggests that Apigenin exerts improving anti-lymphoma effect of BTK inhibitors and provides hope to targeted therapy of those develop resistance.

Abivertinib is a novel third-generation EGFR TKI targeting the EGFR T790M mutation Abivertinib is well tolerated and efficacious in T790M-positive patients Abivertinib has a unique structure, efficacy, and resistance mechanism compared with osimertinib Osimertinib treatment after AC0010 showed a good response.