A Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of AST2303 Tablets (ABK3376 Tablets) in Patients With Advanced or Metastatic Non-Small Cell Lung Cancer

This study is a multicenter, single arm, open label, phase I clinical trial, including dose escalation (phase IA) and dose expansion (phase IB). This study aimed to evaluate the safety, tolerability, PK characteristics and preliminary antitumor activity of ast2303 tablets (abk3376 tablets) in subjects with locally advanced or metastatic non-small cell lung cancer. A safety review committee (SRC) was established in this study, which will review the safety, efficacy, pharmacokinetics and other data obtained from the study, and make decisions on key issues such as dose escalation and dose expansion.

Start Date04 Mar 2025

Sponsor / Collaborator

Shanghai Allist Pharmaceuticals Co., Ltd.

100 Clinical Results associated with ABK-3376

100 Translational Medicine associated with ABK-3376

100 Patents (Medical) associated with ABK-3376

Literatures (Medical) associated with ABK-3376

01 Feb 2023·Chemical and Pharmaceutical Bulletin

Synthesis and Evaluation of 2-Amine-4-oxyphosaniline Pyrimidine Derivatives as EGFR L858R/T790M/C797S Mutant Inhibitors

Article

Author: Yang, Yang ; Zhang, Mingguang ; Wu, Hongyan ; Wang, Yunyun ; Zhu, Yongqiang ; Wang, Jia

Epidermal growth factor receptor (EGFR) C797S mutation leads to Osimertinib drug resistance by disturbing the covalent biding of Michael acceptor group to the Cys797 residue in the ATP biding cleft. In this manuscript, a class of 2-amine-4-oxyphosaniline pyrimidine derivatives were designed, synthesized and evaluated as new noncovalent reversible EGFR inhibitors against L858R/T790M/C797S (CTL) triple mutant. The kinases inhibitiory activity evaluation showed that four compounds exhibited significant inhibitory activities against CTL (IC₅₀ < 30 nM). In particularly, the most promising compound 7a showed excellent enzymatic inhibitory activity against CTL with IC₅₀ value of 9.9 nM, which was more potent than control compound Osimertinib. Moreover, cell proliferation assays indicated that 7a effectively inhibited H1975-EGFR L858R/T790M/C797S with IC₅₀ value of 0.33 µM. Furthermore, compound 7a displayed good metabolic stabilities in human, rat and mouse liver microsomes, and the putative biding mode of compound 7a with ATP was revealed by molecular docking study. These findings strongly indicated that compound 7a was a promising L858R/T790M/C797S mutant EGFR inhibitor.

03 May 2022·Journal of Biomolecular Structure and Dynamics

p38α MAP kinase inhibitors to overcome EGFR tertiary C797S point mutation associated with osimertinib in non-small cell lung cancer (NSCLC): emergence of fourth-generation EGFR inhibitor

Article

Author: Ahmad, Iqrar ; Shaikh, Matin ; Surana, Sanjay ; Patel, Harun ; Ghosh, Arabinda

The third-generation EGFR (epidermal growth factor receptor) inhibitors selectively and irreversibly target EGFR-T790M and other activating EGFR mutations. Osimertinib is the only FDA-approved third-generation inhibitor, which has a good potency against the EGFR-T790M mutant with minimal toxicities and excellent selectivity for wild-type EGFR. EGFR tertiary Cys797 to Ser797 (C797S) point mutation emanate rapidly after the treatment of osimertinib, which is an undruggable mutation to all three existing generation drugs. Recently, trisubstituted imidazoles were reported based on an off-target hit of a p38α MAPK (mitogen-activated protein kinase) inhibitor as the fourth-generation EGFR-TKIs to overcome the C797S resistance by inhibiting the clinically relevant triple mutant kinase L858R/T790M/C797 EGFR. Here, we are reporting the clinical trial p38α MAPK kinase inhibitors SD-06, Amgen 16, RWJ67657 and SCIO-323 as L858R/T790M/C797S EGFR TK inhibitors to overcome the problem of drug resistance in non-small cell lung cancer (NSCLC).Communicated by Ramaswamy H. Sarma.

01 Jun 2020·Journal of Clinical Pharmacy and TherapeuticsQ4 · MEDICINE

Recent advances in targeted small‐molecule inhibitor therapy for non–small‐cell lung cancer—An update

Q4 · MEDICINE

Article

Author: Jhaj, Ratinder ; Asokan, Pravin ; Atal, Shubham

WHAT IS KNOWN AND OBJECTIVETargeted small molecule EGFR Tyrosine Kinase Inhibitors (TKI's) and the Anaplastic Lymphoma Kinase (ALK) inhibitors have been promising tools for advanced non-small-cell lung cancers (NSCLCs). However, tumours tend to develop subsequent mutations, rendering them drug-resistant. Hence, alternative pathways of therapy need to be explored.COMMENTGefitinib, erlotinib and afatinib, once considered as alternatives to platinum-based cytotoxic chemotherapy, have been rendered ineffective in patients with NSCLCs harbouring T790M mutation. Osimertinib is effective in T790M-mutant cancers, but not against those exhibiting the subsequent C797S mutation. ALK gene alterations have rendered tumours insensitive to crizotinib. However, lorlatinib and brigatinib are effective in tumours showing ALK+ mutations. Drugs acting through alternative pathways like the PD-1 pathway, BRAF, VEGFR, EGFR antibodies and NTRK inhibition have been showing promising results.WHAT IS NEW AND CONCLUSIONSOsimertinib, brigatinib and allosteric C797S EGFR inhibitors like AI1045, BRAF inhibitors like LXH254 under trials and entrictinib, a recently approved NTRK inhibitor, have all shown improved progression-free survival compared with earlier generations of small molecule inhibitors for NSCLCs.

News (Medical) associated with ABK-3376

02 Mar 2023

·www.fiercebiotech.com

A duo of deals sees Avenue secure rare disease med while Allist lands cancer drug

Allist has fortified its EGFR-focused pipeline by licensing a candidate locally from Abbisko. Two biotechs are shoring up their pipelines and commercial aspirations, tacking on a clinical-stage rare disease drug and a preclinical cancer med, respectively. Fortress Biotech-founded Avenue Therapeutics is adding on a phase 1/2-stage asset from AnnJi Pharmaceutical for the treatment of spinal and bulbar muscular atrophy (SBMA). Financial details are sparse, but Avenue is paying AnnJi $3 million upfront for AJ201 in addition to an undisclosed amount of biobucks and royalties, according to an announcement Thursday. Avenue is also offering more than a million shares, some of which are tethered to milestones, totaling no more than 19.99% of the company's outstanding stock. In return, the Miami-based biotech gets access to commercialization rights in the U.S., Canada, EU, U.K. and Israel. SMBA, also known as Kennedy’s disease, is an inherited motor neuron disorder marked by disruptions in the nerve signals between the brain and spinal cord. It only affects men, and symptoms usually begin between ages 20 and 40. In a statement, Avenue CEO Alexandra MacLean, M.D., called AJ201 “the lead molecule in the clinic to treat Kennedy’s disease.” The asset immediately slots in as the runner-up candidate in Avenue’s pipeline behind a postoperative pain therapy. Elsewhere Thursday, Shanghai Allist Pharmaceuticals inked its own deal for Abbisko Therapeutics' preclinical, next-generation EGFR antagonist, ABK3376. In exchange for the rights to commercialize the asset in mainland China, Abbisko is receiving an undisclosed upfront payment with up to $187.9 million in biobucks available. Allist will also have a time-limited opportunity to expand the licensing deal worldwide. The license allows Allist to bolster its already-established EGFR pipeline led by furmonertinib, which has been approved in China as a first- and second-line treatment for patients with non-small cell lung cancer depending on the mutations. Abbisko touts ABK3376 as being able to block L858R and exon 19 deletion mutations, traits that compete against AstraZeneca’s FDA-approved Tagrisso.

License out/inDrug Approval

02 Mar 2023

·endpts.com

Shanghai's Abbisko out-licenses EGFR candidate in potentially nine-figure deal

A Shanghai-based biotech is handing off rights to one of its candidates to another Shanghai company. Qiming-backed Abbisko — headed by Eli Lilly and Novartis veteran Yao-Chang Xu — said Wednesday that it would be out-licensing its candidate ABK3376 to Allist Pharmaceuticals. The small molecule is a preclinical, brain-penetrant EGFR inhibitor which can inhibit different mutations such as L858R activating mutation or the exon 19 deletion mutation, Abbisko said. Abbisko wrote in a statement that it would be eligible for an upfront payment from Allist, the exact amount of which was undisclosed, along with $187.9 million in milestones and certain royalties. An Endpoints News query to Abbisko was not immediately returned. Preclinical studies for the molecule, according to the Shanghai biotech, showed “positive results” when used as a single drug or if used in combination with furmonertinib, Allist’s third-generation EGFR inhibitor. While furmonertinib is already approved in China, the drug was out-licensed to ArriVent Biopharma, which launched in 2021. The biotech is currently testing the drug in a Phase Ib trial in patients with advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR or HER2 mutations. The deal calls for Allist to develop, manufacture and sell ABK3376 in China, Hong Kong, Taiwan and Macau, though Allist has a “time-limited option” to expand its rights worldwide. The amount of time that Allist has to make that option is undisclosed. Founded in 2016, Abbisko attracted VC investment from Qiming Venture Partners in 2019, when the prominent firm led the biotech’s Series B for $42 million. The Shanghai biotech went public in Hong Kong back in 2021, raising $226 million after initially pricing on the Hong Kong Index for HK$12.46 a share. Several months later, Abbisko reached a deal with Eli Lilly, partnering up on co-developing candidates for cardiometabolic diseases in early 2022. The deal gave Abbisko the opportunity to secure up to $258 million in milestones.

Phase 1License out/inDrug Approval

100 Deals associated with ABK-3376

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Indication	Highest Phase	Country/Location	Organization	Date
Locally Advanced Lung Non-Small Cell Carcinoma	Phase 1	China	Shanghai Allist Pharmaceuticals Co., Ltd.	04 Mar 2025
metastatic non-small cell lung cancer	Phase 1	China	Shanghai Allist Pharmaceuticals Co., Ltd.	04 Mar 2025
EGFR C797S Mutation Non-small Cell Lung Cancer	Phase 1	China	Shanghai Allist Pharmaceuticals Co., Ltd.	17 Feb 2025

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