作者: Christensen, James G. ; Haling, Jacob ; Calinisan, Andrew ; Marx, Matthew A. ; Sudhakar, Niranjan ; Rahbaek, Lisa ; Hover, Laura D. ; Parker, Cody ; Saechao, Barbara ; He, Leo ; Briere, David M. ; Yan, Larry ; Clarine, Jeffrey ; Vanderpool, Darin ; Moya, Krystal ; Coma, Silvia ; Laguer, Jade ; Hallin, Jill ; Pachter, Jonathan A. ; Ivetac, Anthony ; Engstrom, Lars D. ; Vegar, Laura ; Khare, Shilpi ; Ketcham, John M. ; Nguyen, Natalie ; Elliott, Adam J. ; Olson, Peter ; Bowcut, Vickie ; Waters, Laura ; Qiryaqos, Fadia ; Fernandez-Banet, Julio ; Smith, Christopher R. ; Lawson, J. David ; Hebbert, Allan

AbstractKRAS is the most frequently mutated oncogene in human cancer and facilitates uncontrolled growth through hyperactivation of the receptor tyrosine kinase (RTK)/mitogen-activated protein kinase (MAPK) pathway. The Son of Sevenless homolog 1 (SOS1) protein functions as a guanine nucleotide exchange factor (GEF) for the RAS subfamily of small GTPases and represents a druggable target in the pathway. Using a structure-based drug discovery approach, MRTX0902 was identified as a selective and potent SOS1 inhibitor that disrupts the KRAS:SOS1 protein–protein interaction to prevent SOS1-mediated nucleotide exchange on KRAS and translates into an anti-proliferative effect in cancer cell lines with genetic alterations of the KRAS–MAPK pathway. MRTX0902 augmented the antitumor activity of the KRAS G12C inhibitor adagrasib when dosed in combination in eight out of 12 KRAS G12C–mutant human non–small cell lung cancer and colorectal cancer xenograft models. Pharmacogenomic profiling in preclinical models identified cell cycle genes and the SOS2 homolog as genetic co-dependencies and implicated tumor suppressor genes (NF1 and PTEN) in resistance following combination treatment. Lastly, combined vertical inhibition of RTK/MAPK pathway signaling by MRTX0902 with inhibitors of EGFR or RAF/MEK led to greater downregulation of pathway signaling and improved antitumor responses in KRAS–MAPK pathway–mutant models. These studies demonstrate the potential clinical application of dual inhibition of SOS1 and KRAS G12C and additional SOS1 combination strategies that will aide in the understanding of SOS1 and RTK/MAPK biology in targeted cancer therapy.

2024-09-04·Cancer Discovery

D3S-001, a KRAS G12C Inhibitor with Rapid Target Engagement Kinetics, Overcomes Nucleotide Cycling, and Demonstrates Robust Preclinical and Clinical Activities

Article

作者: Chen, Cheng ; Cho, Byoung Chul ; Mok, Tony ; Rui, Haopeng ; Wang, Wenqian ; Zhang, Jing ; Lim, Sun Min ; Lu, Shun ; Chen, Zhi Jian ; Lu, Jingtao ; Wang, Jia ; Yu, Mi Ra

AbstractFirst-generation KRAS G12C inhibitors, such as sotorasib and adagrasib, are limited by the depth and duration of clinical responses. One potential explanation for their modest clinical activity is the dynamic “cycling” of KRAS between its guanosine diphosphate (GDP)– and guanosine triphosphate (GTP)–bound states, raising controversy about whether targeting the GDP-bound form can fully block this oncogenic driver. We herein report that D3S-001, a next-generation GDP-bound G12C inhibitor with faster target engagement (TE) kinetics, depletes cellular active KRAS G12C at nanomolar concentrations. In the presence of growth factors, such as epithelial growth factor and hepatocyte growth factor, the ability of sotorasib and adagrasib to inhibit KRAS was compromised whereas the TE kinetics of D3S-001 was nearly unaffected, a unique feature differentiating D3S-001 from other GDP-bound G12C inhibitors. Furthermore, the high covalent potency and cellular TE efficiency of D3S-001 contributed to robust antitumor activity preclinically and translated into promising clinical efficacy in an ongoing phase 1 trial (NCT05410145).Significance: The kinetic study presented in this work unveils, for the first time, that a GDP-bound conformation-selective KRAS G12C inhibitor can potentially deplete cellular active KRAS in the presence of growth factors and offers new insights into the critical features that drive preclinical and clinical efficacy for this class of drugs.

2024-09-03·Clinical Cancer Research

Circulating Tumor DNA Dynamics Reveal KRAS G12C Mutation Heterogeneity and Response to Treatment with the KRAS G12C Inhibitor Divarasib in Solid Tumors

Article

作者: Chang, Julie ; Royer-Joo, Stephanie ; Choi, Yoonha ; LoRusso, Patricia ; Sacher, Adrian ; Desai, Jayesh ; Assaf, Zoe J. ; Shi, Zhen ; Jun, Tomi ; Yau, Kenneth K. ; Aimi, Junko ; Schutzman, Jennifer L. ; Sivakumar, Smruthy ; Montesion, Meagan ; Dharia, Neekesh V.

AbstractPurpose:To inform prognosis, treatment response, disease biology, and KRAS G12C mutation heterogeneity, we conducted exploratory circulating tumor DNA (ctDNA) profiling on 134 patients with solid tumors harboring a KRAS G12C mutation treated with single-agent divarasib (GDC-6036) in a phase 1 study.Experimental Design:Plasma samples were collected for serial ctDNA profiling at baseline (cycle 1 day 1 prior to treatment) and multiple on-treatment time points (cycle 1 day 15 and cycle 3 day 1).Results:KRAS G12C ctDNA was detectable from plasma samples in 72.9% (43/59) and 92.6% (50/54) of patients with non–small cell lung cancer and colorectal cancer, respectively, the majority of whom were eligible for study participation based on a local test detecting the KRAS G12C mutation in tumor tissue. Baseline ctDNA tumor fraction was associated with tumor type, disease burden, and metastatic sites. A decline in ctDNA level was observed as early as cycle 1 day 15. Serial assessment showed a decline in ctDNA tumor fraction associated with response and progression-free survival. Except for a few cases of KRAS G12C sub-clonality, on-treatment changes in KRAS G12C variant allele frequency mirrored changes in the overall ctDNA tumor fraction.Conclusions:Across tumor types, the KRAS G12C mutation likely represents a truncal mutation in the majority of patients. Rapid and deep decline in ctDNA tumor fraction was observed in patients responding to divarasib treatment. Early on-treatment dynamics of ctDNA were associated with patient outcomes and tumor response to divarasib treatment.

项与 KRAS G12C Inhibitor(BioArdis) 相关的新闻（医药）

2024-09-27

·echemi

Jacobio Pharma Secures €172 Million: Concerns Over Collaboration Behind Ailis’ Massive Investment Exposed!

On September 27, 2024, Jacobio Pharma (stock code: 1167.HK) attracted a lot of attention in the industry when it officially announced a major cooperation development - the successful acquisition of Shanghai Ellis Pharmaceutical Technology Co., LTD. (stock code: 688578.SH) received up to 172 million yuan in cooperation funds. This payment not only marks the depth and stability of the cooperation between the two parties, but also demonstrates the excellent strength and extensive influence of Gax in the field of innovative drug research and development. The composition of this cooperation is quite remarkable, including a down payment of 150 million yuan, which is a direct reflection of Ellis' high recognition and value of Gax's research and development results. In addition, there is also 22.79 million RMB as research and development cost compensation and other related payments, which will strongly support Gax's continued investment and innovation exploration in subsequent research and development projects. Looking back at the history of cooperation between the two parties, it all began with the signing of a landmark cooperation agreement on August 30, 2024.This initiative not only shows CAx's trust and respect for its partners, but also reflects its firm determination to promote the development of China and even the global medical and health cause. KRAS G12C inhibitor Golelexel, as a star drug in the field of tumor therapy in recent years, has won widespread praise worldwide for its unique mechanism of action and remarkable efficacy. The SHP2 inhibitor JAB-3312 is another effort of GaX in the field of precision medicine, and its precision strike ability for specific targets has brought new hope to many patients with refractory diseases. The introduction of these two drugs will undoubtedly inject new vitality into Ellis' product line and further consolidate its leading position in the pharmaceutical market. It is worth noting that this cooperation not only reflects the depth of cooperation between the two sides in the field of drug research and development, but also indicates that China's pharmaceutical industry is gradually moving toward a new stage of internationalization and high-end. As the global pharmaceutical market continues to integrate and competition intensifies, Chinese pharmaceutical companies are enhancing their core competitiveness by strengthening international cooperation, introducing advanced technology and management experience. The cooperation between Gax and Ellis has undoubtedly set a new benchmark for the internationalization of China's pharmaceutical industry.

并购引进/卖出

2024-09-04

·Pharmaceutical Technology

FDA grants fast track status to Innovent’s IBI363 for melanoma

The fast track designation will expedite the clinical development of the asset for melanoma treatment. Credit: yanishevska/Shutterstock. The US Food and Drug Administration (FDA) has granted its fast track designation to Innovent Biologics ‘ IBI363, a PD-1/IL-2 α-bias bispecific antibody fusion protein to treat advanced unresectable locally advanced or metastatic melanoma. The designation will expedite the clinical development and review process for IBI363, which is currently undergoing Phase I/II clinical trials in China, the US and Australia. The product blocks the PD-1/PD-L1 pathway and activates the IL-2 pathway, targeting melanoma patients who have progressed after systemic therapy, including a PD-1/L1 inhibitor. However, it is not aimed at treating choroidal melanoma. Promising results from ongoing clinical studies have shown that of 37 melanoma patients who had previously received immunotherapy, 11 achieved objective responses after being treated with 1mg/kg of IBI363. See Also: A guide to host-cell protein analysis services for biomanufacturers Chime looks to expand manufacturing capacity and establish European presence This includes one complete response and ten partial responses, with an objective response rate of 29.7% and a disease control rate (DCR) of 73%. Fast track status is a process that facilitates the development of assets addressing serious conditions with unmet medical needs. It allows for more frequent interactions with the FDA, which can lead to earlier approval for medicines. Innovent Biologics senior vice-president Dr Hui Zhou stated: “As a first in-class PD-1/IL-2 α-bias bispecific antibody fusion protein, IBI363 monotherapy has shown encouraging efficacy and a favourable safety profile in melanoma subjects who have previously received immunotherapy. “We will continue to explore the efficacy and safety of IBI363 in melanoma to provide more effective clinical treatment for patients with immune-resistant melanoma.” Innovent recently received approval from China’s National Medical Products Administration for its KRAS G12C inhibitor, Dupert (fulzerasib), for treating advanced non-small cell lung cancer in adults. This content was updated on 25 January 2024

快速通道免疫疗法临床结果临床1期临床申请

2024-08-30

·FierceBiotech

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.