Delving into the Latest Updates on Glecirasib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

戈来雷塞, 枸橼酸格来雷塞, JAB-21000

+ [2]

Target

KRAS G12C

Mechanism

KRAS G12C inhibitors(GTPase KRas G12C inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease+ [1]

Active Indication

KRAS G12C mutant Non-small Cell Lung CancerKRAS G12C mutant non-squamous non-small cell lung cancerKRAS p.G12C mutant pancreatic cancer+ [11]

Inactive Indication-

Originator Organization

Jacobio Pharmaceuticals Group Co., Ltd.

Active Organization

Beijing Jiakesi New Drug Development Co. Ltd.StartupJacobio Pharmaceuticals Group Co., Ltd.

Inactive Organization-

Drug Highest PhaseNDA/BLA

First Approval Date-

RegulationOrphan Drug (US), Orphan Drug (EU), Priority Review (CN), Breakthrough Therapy (CN)

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Structure/Sequence

Molecular FormulaC31H26ClF4N7O2

InChIKeyQRRJEUIQLZNPIO-UHFFFAOYSA-N

CAS Registry2657613-87-9

This umbrella trial directed by next generation sequencing (NGS) includes patients with treatment-naive unresectable stage III non-small-cell lung cancer (NSCLC). The aim of the umbrella study is to evaluate the efficacy of induction NGS-directed targeted therapies followed by surgery for stage III NSCLC patients whose tumor harbors a rare mutation.

Start Date01 Nov 2024

Sponsor / Collaborator

Sun Yat-Sen University

NCT06416410

/ RecruitingPhase 3

An Open-label, Randomized, Positive Control, Multicenter Phase III Clinical Study. Evaluating JAB-21822 Combined With JAB-3312 Compared Tislelizumab Combined With Pemetrexed + Carboplatin in the First Line for Treatment of Advanced Non-squamous Non-small Cell Lung Cancer With KRAS p.G12C Mutation

This Phase 3 study will evaluate the efficacy of JAB-21822+JAB-3312 versus tislelizumab (PD-1 Ab) combined with pemetrexed+carboplatin as the first line treatment in subjects with KRAS G12C mutated locally advanced or metastatic non-small cell lung cancer (NSCLC).

Start Date07 Aug 2024

Sponsor / Collaborator

Beijing Jiakesi New Drug Development Co. Ltd.Startup

CTR20241931

/ RecruitingPhase 3

JAB-21822联合JAB-3312对比替雷利珠单抗联合培美曲塞+卡铂一线治疗KRAS p.G12C突变的晚期非鳞状非小细胞肺癌的随机、阳性对照、开放标签的多中心Ⅲ期临床试验

[Translation] A randomized, active-controlled, open-label, multicenter phase III clinical trial of JAB-21822 combined with JAB-3312 versus tislelizumab combined with pemetrexed and carboplatin as first-line treatment for advanced non-squamous non-small cell lung cancer with KRAS p.G12C mutation

评价JAB-21822联合JAB-3312对比一线治疗KRAS p.G12C突变的晚期非鳞状非小细胞肺癌受试者的PFS

[Translation]

To evaluate the PFS of JAB-21822 plus JAB-3312 compared with first-line treatment in patients with advanced non-squamous NSCLC with KRAS p.G12C mutation

Start Date18 Jul 2024

Sponsor / Collaborator

Beijing Jiakesi New Drug Development Co. Ltd.Startup

100 Clinical Results associated with Glecirasib

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100 Translational Medicine associated with Glecirasib

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100 Patents (Medical) associated with Glecirasib

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3

Literatures (Medical) associated with Glecirasib

01 Oct 2024·Nature Chemical Biology

Direct RAS inhibitors turn 10

Article

Author: Ostrem, Jonathan M L ; Peters, Ulf ; Shokat, Kevan M

RAS proteins, central drivers of cancer, appeared ′undruggable′ for almost 30 years.Here we provide a personal perspective on the effort leading to our initial report of KRAS^G12C inhibitors in 2013, and the decade of discoveries that followed.

Journal of Translational Medicine

KEAP1 mutations as key crucial prognostic biomarkers for resistance to KRAS-G12C inhibitors

Article

Author: Yin, Enzhi ; Tian, Linyan ; He, Jie ; Zheng, Sufei ; Wei, Fang ; Sun, Nan ; Dong, Yucheng ; Liu, Chengming ; Jiang, Wenxin ; Xu, Haiyan ; Shi, Huiyang ; Wang, Yan

BACKGROUND:

KRAS-G12C inhibitors mark a notable advancement in targeted cancer therapies, yet identifying predictive biomarkers for treatment efficacy and resistance remains essential for optimizing clinical outcomes.

METHODS:

This systematic meta-analysis synthesized studies available through September 2024 across PubMed, Cochrane Library, SpringerLink, and Embase. Using CRISPR/Cas9 technology, this study generated cells with KEAP1 and STK11 knockouts, and utilized lentiviral vectors to overexpress PD-L1. Cellular sensitivity to KRAS-G12C inhibitors-AMG510, MRTX849, and JAB-21822-was evaluated through CCK-8 assays. Comprehensive bioinformatics analyses on stably transfected cell lines were conducted to elucidate pathways mediating resistance.

RESULTS:

Analysis of 13 studies involving 1132 patients highlighted the significant efficacy of KRAS-G12C inhibitor monotherapy, particularly among elderly and female patients. Treatment response was notably affected by liver and brain metastases, with KEAP1 mutations identified as a primary negative prognostic factor, closely associated with early resistance to treatment. Validation studies in NCI-H358 cells showed a marked increase in IC50 values for AMG510, MRTX849, and JAB-21822 after KEAP1 knockout (P < 0.0001), with IC50 values rising from 27.78 nm, 116.9 nm, and 118.7 nm in controls, respectively. Comparative analysis of differentially expressed genes in KEAP1 knockout cells versus controls, utilizing GO, KEGG, and Reactome pathway analyses, revealed substantial enrichment in pathways linked to extracellular matrix organization and cell adhesion processes. Although STK11 mutations and heightened PD-L1 expression indicated a trend toward poorer outcomes, these correlations lacked statistical significance.

CONCLUSION:

This research affirms KRAS-G12C inhibitors as promising treatments, especially for certain patient subgroups, and underscores KEAP1 mutations as key biomarkers for resistance. The findings highlight the urgent need for alternative therapeutic approaches in KEAP1-mutant patients and emphasize the role of molecular profiling in tailored treatment strategies.

JOURNAL OF MEDICINAL CHEMISTRY

Design, Structure Optimization, and Preclinical Characterization of JAB-21822, a Covalent Inhibitor of KRAS^G12C

Article

Author: Liu, Huan ; Wang, Yanping ; Zhang, Wei ; Fan, Xinrui ; Wang, Yinxiang ; Li, Sujing ; Li, Fu ; Dang, Chaojie ; Chen, Mengran ; Wang, Peng ; Li, Amin ; Liu, Dan

KRAS is the most frequently mutated driver oncogene in human cancer, and KRAS^G12C mutation is commonly found in non-small-cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). Inhibitors that covalently modify the mutated codon 12 cysteine have completed proof-of-concept studies in the clinic. Here, we describe structure-based design and cocrystal-aided drug optimization of a series of compounds with the 1,8-naphthyridine-3-carbonitrile scaffold. Biopharmaceutical optimization of the resulting leads to improve the solubility of the compounds and block the possible metabolic hotspots led to the identification of JAB-21822, a covalent KRAS^G12C inhibitor with high potency and excellent cross-species pharmacokinetic properties. JAB-21822 has finished the pivotal Phase II clinical trials in NSCLC, and a new drug application was submitted to the National Medical Products Administration in 2024.

31

News (Medical) associated with Glecirasib

07 Jan 2025

·www.prnewswire.com

The Registrational Clinical Data of Glecirasib was Published in Nature Medicine

BEIJING, SHANGHAI and BOSTON, Jan. 6, 2025 /PRNewswire/ -- Jacobio Pharma (1167.HK), a clinical-stage oncology company focusing on undruggable targets announced today that the data from a registrational clinical trial of its independently developed KRAS G12C inhibitor glecirasib has been published in Nature Medicine (impact factor 58.7). In the article, Jaocbio disclosed, for the first time, the complete dataset of glecirasib in KRAS G12C mutant non-small cell lung cancer patients in the second line or above setting. The pivotal phase II trial of glecirasib monotherapy demonstrated impressive efficacy, including the confirmed objective response rate of 47.9% (56/117), a median progression-free survival of 8.2 months, and a median overall survival of 13.6 months. Glecirasib has a manageable safety profile. Gleciasib has a favorable gastrointestinal safety profile compared with other KRAS G12C inhibitors. The new drug application of glecirasib is currently under evaluation by the Center for Drug Evaluation of the National Medical Products Administration of China, and has been granted Priority Review Designation. Dr. Yinxiang Wang, Chairman and CEO of Jacobio, said: "It's our great honor to present the data from our pivotal trial in such as prestigious journal as Nature Medicine. The development of KRAS-related inhibitors is still in the early stages. We will continue to explore registration clinical trials with our partners of glecirasib in combo with SHP2 inhibitor JAB-3312 for the treatment of first-line NSCLC and accelerate the development of our other RAS programs such as Pan-KRAS inhibitor." About Glecirasib Glecirasib is a KRAS G12C inhibitor developed by Jacobio. A number of clinical trials of glecirasib are currently ongoing in China, the United States and Europe for patients with advanced solid tumors harboring KRAS G12C mutation. These include combination therapy trials with SHP2 inhibitor JAB-3312 in NSCLC and with cetuximab in colorectal cancer. The pancreatic cancer indication has obtained orphan drug designation in the United States and breakthrough therapy designation in China. About Jacobio Jacobio Pharma (1167.HK) is committed to developing and providing new and innovative products and solutions to improve people's health. Our pipeline revolves around novel molecular targets on six major signalling pathways: KRAS, immune checkpoints, tumor metabolism, P53, RB and MYC. We aim for our key projects to be among the top three in the world. Our vision is to become a global leader recognized for our impact in drug R&D together with our partners. Jacobio has R&D centers in Beijing, Shanghai and Boston with our Induced Allosteric Drug Discovery Platform (IADDP) and our iADC Platform. Please visit us at SOURCE Jacobio Pharma WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Orphan DrugPhase 2Breakthrough TherapyClinical ResultPriority Review

02 Sep 2024

·www.pharmaceutical-technology.com

Jacobio Pharma grants Allist rights to two assets in China

Jacobio Pharma chairman and CEO Dr Yinxiang Wang (right) and Jinxiang Du (left) at the agreement signing ceremony. Credit: JACOBIO PHARMACEUTICALS GROUP CO., LTD. Jacobio Pharma has out-licensed the China rights of its assets, glecirasib and JAB-3312, to Shanghai Allist Pharmaceuticals. Glecirasib is a Kirsten rat sarcoma glycine 12 to cysteine inhibitor. JAB-3312 is a Src homology-2 domain-containing protein tyrosine phosphatase 2 inhibitor. The agreement includes mainland China, Hong Kong, Macau and Taiwan rights. Jacobio is entitled to receive 200m yuan ($28m) in the near term, which includes 150m yuan in upfront payment and 50m yuan for research and development expenses and other payments The agreement also includes milestone payments of 700m yuan contingent upon meeting specific development, regulatory and commercial goals. See Also: RegenxBio touts positive data for rare disease drug RGX-121 Ocaliva approval in Europe withdrawn following data re-assessment Jacobio is entitled to receive tiered royalty payments on net product sales from Allist. Royalty payments for JAB-3312 could reach 20%. Allist will handle the commercialisation of the assets in China and cover subsequent expenditures for their clinical development. A new drug application for glecirasib monotherapy for second-line non-small cell lung cancer (NSCLC) with KRAS G12C mutation received priority review in May 2024 and breakthrough therapy designation in December 2022 in China. In April 2024, data from a Phase II study of glecirasib showed a confirmed objective response rate of 47.9% in second-line NSCLC patients. The disease control rate was 86.3%, with median progression-free survival of 8.2 months and median overall survival of 13.6 months. The first subject was recently dosed in a Phase III clinical trial of the glecirasib and JAB-3312 combination versus standard care. In addition to NSCLC, glecirasib is undergoing pivotal studies for second-line or above pancreatic cancer and in combination with cetuximab for colorectal cancer. Jacobio Pharma chairman and CEO Dr Wang Yinxiang stated: “Allist has strong commercialisation capabilities in the field of lung cancer, and the first indication for glecirasib submitted the new drug application is lung cancer. We believe that with the deep fit of the advantages of both parties, this collaboration will demonstrate great clinical and commercial value. “In addition to the co-operation with glecirasib, Allist also licensed-in the SHP2 inhibitor JAB-3312, the first SHP2 inhibitor entering a registrational trial globally. It is expected to become a first-line therapy in combo with glecirasib, which reflects Allist’s foresight into the future of pipelines.”

Phase 2Phase 3Breakthrough TherapyLicense out/inClinical Result

30 Aug 2024

·www.fiercebiotech.com

Allist pays Jacobio $21M for KRAS drug combo, landing leading role in Chinese cancer race

The deal establishes Allist as a front-runner in China’s emerging KRAS market. Shanghai Allist Pharmaceuticals has bought itself a starring role in China’s KRAS market, paying Jacobio Pharma 150 million Chinese yuan ($21 million) for rights to a near-approval inhibitor of the oncogene and a potentially complementary molecule.The deal covers the Chinese rights to the KRAS G12C inhibitor glecirasib and the SHP2 inhibitor JAB-3312. Jacobio filed for approval of glecirasib in non-small cell lung cancer in China in May, hot on the heels of a data drop that suggested the molecule’s efficacy is in the same ballpark as rival drugs. Jacobio identified safety and tolerability as an area it may have an edge over the competition.Allist secured Chinese rights to glecirasib as part of a deal that included JAB-3312, the drug candidate that AbbVie walked away from last year. AbbVie picked up global rights to the molecule in 2020 but axed the asset as part of a portfolio review.Jacobio bounced back by offloading the Chinese rights to JAB-3312 to Allist in a two-asset deal that could support combination therapy. Studies suggest inhibiting SHP2 could boost the effect of KRAS blockers by increasing the amount of the KRAS target and inhibiting reactivation of other RAS isoforms. Pharma interest has cooled on SHP2, with Bristol Myers Squibb, Genentech and Sanofi all pulling back in recent years. Yet, Allist has seen value including JAB-3312 in its glecirasib deal. As well as the upfront fee, Allist will pay 50 million yuan ($7 million) in near-term R&D expenses and potentially up to 700 million yuan ($99 million) in milestones. The deal establishes Allist as a front-runner in China’s emerging KRAS market. While Amgen’s Lumakras and Bristol Myers Squibb’s Krazati are competing for the U.S. market, Innovent Biologics is making the running in China. Innovent claimed a first when the Chinese regulator accepted its KRAS G12C inhibitor for priority review in November.

License out/inPriority ReviewDrug ApprovalPhase 1Patent Infringement

100 Deals associated with Glecirasib

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
KRAS G12C mutant Non-small Cell Lung Cancer	NDA/BLA	CN	Beijing Jiakesi New Drug Development Co. Ltd.Startup	06 May 2024
KRAS G12C mutant non-squamous non-small cell lung cancer	Phase 3	CN	Beijing Jiakesi New Drug Development Co. Ltd.Startup	18 Jul 2024
KRAS p.G12C mutant pancreatic cancer	Phase 2	CN	Beijing Jiakesi New Drug Development Co. Ltd.Startup	16 Oct 2023
metastatic non-small cell lung cancer	Phase 2	CN	Jacobio Pharmaceuticals Group Co., Ltd.	06 Sep 2022
Pancreatic Ductal Carcinoma	Phase 2	CN	Beijing Jiakesi New Drug Development Co. Ltd.Startup	14 Apr 2022
KRAS p.G12C mutant colorectal cancer	Phase 2	CN	Beijing Jiakesi New Drug Development Co. Ltd.Startup	17 Feb 2022
Small intestine carcinoma recurrent	Phase 2	CN	Beijing Jiakesi New Drug Development Co. Ltd.Startup	17 Feb 2022
Appendiceal Neoplasms	Phase 2	CN	Beijing Jiakesi New Drug Development Co. Ltd.Startup	07 Feb 2022
Small intestine carcinoma	Phase 2	CN	Beijing Jiakesi New Drug Development Co. Ltd.Startup	07 Feb 2022
Non-Small Cell Lung Cancer	Phase 2	US	Beijing Jiakesi New Drug Development Co. Ltd.Startup	03 Sep 2021

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05009329 \| NCT05194995 (ASCO_GI2025)	Phase 1/2	KRAS G12C mutant Colorectal Cancer KRAS G12C mutation	44	Glecirasib 800mg QD	pudxqcxlci(ddyokoirys) = axhxqilyha zwrrksnbse (asimiopzsg ) View more	Positive	23 Jan 2025
				Glecirasib 800mg QD + Cetuximab	pudxqcxlci(ddyokoirys) = fqdxufxwha zwrrksnbse (asimiopzsg ) View more
NCT05009329 (Pubmed) Manual	Phase 2	KRAS G12C mutant Non-small Cell Lung Cancer KRAS G12C	119	Glecirasib 800 mg daily	bylrnzebqy(jxcclyqsdc) = llgtvstbrp tggnjaxsjr (pkhpyaodod, 38.5 - 57.3) View more	Positive	06 Jan 2025
NCT05288205 (ESMO2024) Manual	Phase 1/2	KRAS G12C mutant Non-small Cell Lung Cancer First line KRAS G12C \| PD-L1	102	Glecirasib plus JAB-3312	pzepqzuuoa(zfejvwipcq) = xrpbkhmngx eujyvetief (hfvetamdtx ) View more	Positive	14 Sep 2024
				Glecirasib plus JAB-3312 (PD-L1 TPS≥50%)	pzepqzuuoa(zfejvwipcq) = givfgvxwqy eujyvetief (hfvetamdtx ) View more
NCT05288205 (PRNewswire) Manual	Phase 1/2	KRAS G12C mutant Non-small Cell Lung Cancer First line KRAS G12C	194	JAB-21822+JAB-3312	dbrumskqfs(blvpcflwid) = mtbcwlrfnt vjnripygnf (canzekhfbw )	Positive	01 Jun 2024
				JAB-21822+JAB-3312 (frontline)	crivhqrxfy(pddfytjroq) = ddcgffkopu cjrqpthpvl (rnmhswjgfk ) View more
NCT05288205 (ASCO2024) Manual	Phase 1/2	KRAS G12C mutation Solid Tumors KRAS G12C	179	Glecirasib 800 mg	hjmpddkpzv(plrsgbjwul) = rrqsvinvjh vgoftbfxzi (grcxcyblwl ) View more	Positive	24 May 2024
NCT05009329 (ASCO2024) Manual	Phase 2	Non-Small Cell Lung Cancer Second line KRAS G12C	119	Glecirasib 800mg daily	avcylrcxxi(qyhephokll) = xlwrsqgrqr kwvhmrfegr (xkislwteuu ) Met View more	Positive	30 Apr 2024
PRNewswire Manual	Not Applicable	KRAS G12C mutation Solid Tumors \| Pancreatic Cancer KRAS G12C	50	Glecirasib	bkrgbkltlf(oiiyhmvrve) = aayhvqxhda hvyndelkvg (igssqmextu ) View more	Positive	19 Jan 2024
NCT05009329 \| NCT05002270 (ASCO_GI2024) Manual	Phase 1/2	Solid tumor \| Pancreatic Cancer KRAS G12C	48	Glecirasib	biyzyjyzyd(tkebjkvsvb) = vtbxmdqjrw qatptvosat (zacjmelvmp ) View more	Positive	18 Jan 2024
NCT05288205 (ESMO 12023 \| ESMO 22023) Manual	Phase 1/2	KRAS G12C mutation Solid Tumors KRAS G12C	60	Glecirasib +JAB-3312	wnlygjbrzv(senspdzkaj) = sckxjlcwdv tncyxouvge (ndxewkvynr ) View more	Positive	22 Oct 2023
				Glecirasib +JAB-3312 (KRAS G12Ci naïve NSCLC)	ekymctmhjb(kiqduxzups) = ntgpdcmwri ixutlvokjz (tyknribngo ) View more
NCT05009329 \| CTR20211470 (Corporate Publications) Manual	Phase 1/2	Non-Small Cell Lung Cancer Second line KRAS G12C	70	JAB-21822 400MG QD	ezaqrvzptx(jannymvwvl) = esvvakbdur omfjizzyyp (egciaeyide ) View more	Positive	25 Sep 2023
				JAB-21822 800MG QD	ezaqrvzptx(jannymvwvl) = lxlqxduagg omfjizzyyp (egciaeyide ) View more