Adagrasib

SHANGHAI--( BUSINESS WIRE )--D3 Bio, a global clinical stage biotechnology company focusing on discovery, development, and registration of innovative cancer drugs, announced that its lead compound, a next-generation KRAS G12C inhibitor, D3S-001, demonstrated rapid target engagement, overcame the limiting factors of nucleotide cycling and RTK activation, and showed robust preclinical and clinical activities in KRAS G12C-mediated cancers, in a study published in Cancer Discovery. In a paper titled, “A KRAS G12C Inhibitor with Rapid Target Engagement Kinetics, Overcomes Nucleotide Cycling, and Demonstrates Robust Preclinical and Clinical Activities”, researchers from D3 Bio and its collaborators demonstrated that D3S-001 performed significantly better than other KRAS G12C inhibitors in multiple pre-clinical and clinical studies designed to profile the class of KRAS G12C small molecule inhibitors. Specifically, D3S-001 demonstrated substantially improved covalent potency and better and faster target engagement (TE) kinetics, compared to the approved drugs (sotorasib and adagrasib) in the class. This suggests that D3S-001 has the potential to “lock” KRAS G12C in its inactive (GDP-bound) state more efficiently, possibly resulting in cellular active KRAS depletion in clinically relevant doses. In addition, D3S-001's high potency and rapid kinetics allow it to block the GDP-to-GTP transition even in the presence of growth factors. In contrast, first-generation G12C inhibitors are less effective in these conditions, which may contribute to their limited clinical efficacy. In cell line and patient-derived tumor xenograft models across multiple cancer types, D3S-001 demonstrated significantly more robust anti-tumor responses than the other KRAS G12C inhibitors in the study. Importantly, these include a delay in disease progression in tumors that were resistant to an FDA-approved KRAS G12C inhibitor. D3S-001 also exhibited brain penetration properties, resulting in durable intracranial tumor regression in mouse models with brain metastases. Citing the ongoing D3S-001 Phase 1/2 trial in KRAS G12C-mediated solid tumors, the study noted that durable RECIST responses were observed across all dose cohorts, as well as systemic and intracranial anti-tumor activity in two highlighted patients with non-small cell lung cancer (NSCLC) enrolled in the first dose cohort of this trial. The researchers conclude that D3S-001 is a next-generation GDP-bound KRAS G12C inhibitor with robust antitumor preclinical activity and promising durable responses in the ongoing clinical trial, which could overcome the limitations of the first-generation drugs. Separately, in an oral presentation at the ESMO Congress 2024, dose-escalation data from the D3S-001 Phase 1 clinical trial in 42 patients of locally advanced or metastatic KRAS G12C-mutated cancers with prior systemic treatments was presented. The presenter and trial investigator, Byoung Chul Cho, MD, PhD, Professor in the Division of Medical Oncology at Yonsei Cancer Center, Yonsei University College of Medicine and Chief of Lung Cancer Center at Yonsei Cancer Center, Yonsei University College of Medicine, highlighted that D3S-001 functionally abolishes the KRAS G12C transition from GDP-bound (inactive) state to the GTP-bound (active) state, depleting cellular active KRAS, even in the presence of growth factor stimulation. Results from the Phase 1a dose-escalation study (42 patients in total) showed favorable tolerability across different dose levels, with no maximum-tolerated dose reached. In addition, D3S-001 demonstrated consistent and promising efficacy in the G12C-inhibitor naïve population, with a confirmed overall response rate (ORR) of 73.5% across tumor types. Researchers also observed brain tumor shrinkage in patients with brain metastases and a rapid, sustained reduction of mutant allele frequency (MAF), which measures mutated genes, in circulating tumor cell DNA (ctDNA) as early as Day 8 post-treatment. Expansion study cohorts are ongoing and focus on monotherapy and combination therapy regimens in non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). “While promising, the first generation of KRAS G12C inhibitor class has exhibited limited durability in the clinic, which could be addressed by a more efficient mode of action,” said Dr. Cho. “This paper, demonstrating that D3S-001 has a more robust covalent potency and rapid target engagement kinetics, unaffected by RTK activation, unveils a novel mode of action that correlates with pre-clinical anti-tumor activity and promising Phase 1 clinical results. Furthermore, the study shows, for the first time, that GDP-bound KRAS G12C inhibitors can deplete cellular-active KRAS as efficiently the GTP-bound inhibitor class, suggesting that D3S-001 could address the issues that have challenged this class of drugs.” “Believing that a next-generation KRAS-G12C inhibitor with significantly improved target inhibition efficiency could become the backbone of a new standard of care for cancers carrying KRAS G12C mutations and provide profound clinical advantages, we selected D3S-001 for its superior covalent potency and differentiated target engagement kinetics,” said George Chen, MD, Founder, Chairman and CEO, D3 Bio. “This study validates our strategy of discovering a next-generation and differentiated G12C inhibitor with rapid target engagement to deliver more efficacious clinical activity. At the ESMO 2024 Congress, we presented Phase 1 data from 42 patients, showing a consistent and clinically meaningful response across all cancer types. We are excited with the progress of D3S-001, a potential best-in-class compound, and expect to report topline Phase 2 data in 2025.” About D3S-001 D3S-001 is a next-generation KRAS G12C inhibitor designed to enhance KRAS G12C target engagement. In preclinical investigations, D3S-001 has demonstrated high covalent potency, the ability to rapidly and completely engage the KRAS G12C target at clinically relevant doses and CNS penetration properties. D3S-001 is currently in a Phase 2 global clinical trial in patients with advanced solid tumors harboring a KRAS G12C mutation, including non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and other tumor types. For detailed information about D3S-001, please refer to the highlighted Research Article published at the 2024 September issue of Cancer Discovery , titled “D3S-001, A KRAS G12C Inhibitor with Rapid Target Engagement Kinetics, Overcomes Nucleotide Cycling, and Demonstrates Robust Preclinical and Clinical Activities” (Cancer Discovery 1 September 2024; 14 (9): 1675–1698. https://doi.org/10.1158/2159-8290.CD-24-0006 ) . D3S-001 has received US FDA Orphan Drug Designation (ODD) for the treatment of pancreatic cancer and Fast Track Designation (FTD) for the treatment of late-line non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). For more on the D3S-001 clinical trial, please go to: https://clinicaltrials.gov/study/NCT05410145?intr=D3S-001&rank=1 About D3 Bio D3 Bio is a global biotechnology company that focuses on the discovery, development, and registration of new medicines in oncology and immunology. The D3 Bio discovery and development platform leverages our proprietary clinical insight and biomarker strategy to guide discovery and development for the creation of novel and clinically meaningful new therapies for patients in need. D3 Bio is funded by Boyu Capital, Matrix Partners China, HongShan China, Temasek, WuXi AppTec's Corporate Venture Fund, and Medicxi.

Alan Bash is joining Legend Biotech as its president of Carvykti , an unconventional, newly-created role to oversee the commercial future of the biotech’s sole marketed cell therapy, among other aspects. Legend is developing Carvykti in partnership with Johnson & Johnson , which reported $286 million in sales in the third quarter. The BCMA-targeted cell therapy is expected to grow into a blockbuster multiple myeloma treatment — in large part as a result of a label expansion to earlier-line patients in April. Legend said in its press release that Bash’s new role will be to oversee Carvykti’s “commercial, technical operations, and quality functions.” Despite impressive results reported from the drug’s clinical studies, Legend and J&J have struggled to meet the commercial demand for the cell therapy. Carvykti has pulled ahead in a field that includes Bristol Myers Squibb ’s Abecma . But it faces an up-and-coming challenger in Gilead and Arcellx : The two companies announced on Tuesday that they had dosed the first patient in a Phase 3 trial of their experimental cell therapy anito-cel , which they say does not come with certain neurotoxicities reported with Carvykti. Bash had joined targeted therapeutics biotech ZielBio as CEO in early 2023. Before that, he was briefly head of Checkmate Pharmaceuticals as the immuno-oncology biotech sold to Regeneron for $250 million in cash. — Lei Lei Wu → Novo Nordisk said in its Q3 report that North America head Doug Langa will step aside at the end of the year “in order to focus on personal priorities and take up a role as senior advisor to Novo Nordisk’s executive management.” Novo has installed corporate development chief Dave Moore as the head of US commercial operations, while CFO Karsten Munk Knudsen will orchestrate the Danish pharma’s corporate strategy. Two days after the FDA declared that Ozempic and Wegovy were available in all doses, Novo’s semaglutide was on the march again, generating positive results in patients with metabolic dysfunction-associated steatohepatitis (MASH) and setting up a possible showdown with Madrigal Pharmaceuticals in an indication also referred to as NASH. → Moderna CEO Stéphane Bancel had been in charge of commercial operations since last December, when the company parted ways with chief commercial officer Arpa Garay . Bancel is now handing over those duties to president Stephen Hoge at Moderna, which made several other changes to its leadership team. Rose Loughlin , the SVP of research and early development, has been elevated to EVP of research. She came to Moderna from Biogen in 2016 as director of business development. Elsewhere, longtime GSK vet Jacqueline Miller has been promoted to CMO at the Covid vaccine titan after she had been SVP and therapeutic area head for infectious diseases. Finally, HR chief Tracey Franklin has expanded the scope of her responsibilities, becoming chief people and digital technology officer. She was chief HR talent and strategy officer at the end of her 14-year career at Merck . Moderna’s late entry into the RSV race produced only $10 million in third-quarter sales for the vaccine, miles behind the market leaders GSK and Pfizer , who haven’t exactly been scorching the nets themselves. But Moderna did turn in a profit as its shares $MRNA received a momentary boost before falling 3% on Thursday. → Axel Sven Malkomes will be the next CFO of German mRNA vaccine maker CureVac on Nov. 11. He succeeds Pierre Kemula , who just started his new CFO gig at Agomab . Malkomes is the ex-finance chief at two other German companies: Cardior Pharmaceuticals , the heart disease biotech that Novo Nordisk bought in March for $1.1 billion; and BioNTech ’s TCR partner Medigene . He’s also a board member at Cellectis . In July, CureVac said it would lay off 30% of its employees as GSK shelled out $429 million upfront for full control of the pair’s flu and Covid vaccine candidates. “It’s never nice to have this kind of news, but I do believe we need to do it now out of a position of financial strength,” CureVac CEO Alexander Zehnder told Endpoints News when the job cuts were announced. → Another notable CFO hire comes from Seaport Therapeutics , the Endpoints 11 winner that followed up its $100 million launch round with a $225 million Series B haul a few weeks ago. Lauren White had held this role for nine months at Elahere developer ImmunoGen , which was purchased by AbbVie for $10.1 billion . She landed her first CFO job at C4 Therapeutics in June 2021 after nine years at the Novartis Institutes for BioMedical Research . Are IPO plans not far behind? Time will tell. “I’m enjoying my brief hiatus as a private CEO right now,” Seaport chief Daphne Zohar said in an interview with Endpoints. → Swedish rare disease specialist Sobi has nominated David Meek as chairman of the board. Not long after Meek’s departure as CEO of Mirati , Bristol Myers swooped in to buy the company and its KRAS drug Krazati to compete with Amgen ’s Lumakras in the space. Meek has also held the top spot at Ipsen and FerGene , and has board seats at uniQure and Cullinan Therapeutics . → Mene Pangalos is the newest board member at Quotient Therapeutics , a Flagship joint that debuted last year and teamed up with Pfizer in August. Since his retirement from AstraZeneca , Pangalos has picked up a board seat at Absci and will join the board of directors at Biogen in January. He’s also on the scientific advisory board at Demis Hassabis ’ Isomorphic Labs. (By the way, check out this week’s Q&A with Hassabis and Andrew Dunn from the Financial Times ’ Global Pharma and Biotech Summit.) → After losing its former CEO Raj Kannan back in July, I-Mab has now locked Sean Fu into the position. Fu has been serving in the interim since Kannan’s exit. Prior to I-Mab, Fu was operating partner of ABio-X and CEO of RVAC Medicines and GeneLeap . Earlier in his career, Fu was with Merck, where he helped lead the integration work of the company following its $42 billion merger with Schering-Plough . It’s been quite a year for I-Mab: Back in April, the company officially spun out its China operations into a new company, I-Mab Biopharma (Hangzhou) , in a bid to win over investors. → Verrica Pharmaceuticals CEO Ted White is out after data for its basal cell carcinoma candidate VP-315 failed to move the needle with investors and job cuts affected 47 staffers. Verrica also drastically reduced its sales presence for its molluscum contagiosum drug Ycanth , from 80 sales territories to 35. In walks Jayson Rieger as president and CEO, and John Kirby as interim finance chief to lead a “leaner and more efficient operating structure,” as chairman Paul Manning put it . Rieger has spent more than a decade with PBM Capital , while Kirby is the former CFO of Aceragen and Idera Pharmaceuticals . → London-based protein degradation biotech Kesmalea Therapeutics has recruited Robert Johnson to steer the Syncona -backed company as CEO. Johnson’s résumé includes stints as CEO of Adrestia Therapeutics (acquired by Insmed ) and co-founder and CBO of Boston-based gene therapy company Affinia Therapeutics . → ElevateBio ’s gene editing sub Life Edit has welcomed Amy Pooler as SVP of R&D. Pooler was VP of neuroscience and head of research in her tenure with Sangamo Therapeutics . While ElevateBio has made eye-popping financing rounds routine, Life Edit formed separate partnerships with Moderna and Novo Nordisk in quick succession last year. → Acumen Pharmaceuticals ’ regulatory affairs leader Janice Hitchcock will retire “at the end of the year,” and Amy Schacterle has been named chief regulatory officer & head of quality at the Alzheimer’s biotech. Schacterle and Acumen president/chief development officer Jim Doherty were colleagues at Sage Therapeutics — Schacterle recently left Sage as part of the latest wave of job cuts after the company said it would no longer develop zuranolone for major depressive disorder. Acumen is testing its monoclonal antibody sabirnetug in patients with early Alzheimer’s. → The latest hires at Dublin-headquartered SynOx Therapeutics are based in the US: Medical chief Elyse Seltzer held multiple roles at GSK and is the former chief development officer at UroGen Pharma , while chief commercial officer Robert Francomano was appointed to the same position at Stemline Therapeutics and Sellas Life Sciences . “We are thrilled to welcome Elyse and Robert to the SynOx leadership team as we continue to work to strategically build out our presence within the key US market,” CEO Ray Barlow said in a statement . SynOx’s $92 million Series B includes a $17 million extension from Gilde Healthcare . → MaaT Pharma has recruited Eric Soyer to succeed Siân Crouzet as finance chief. Crouzet spent the last eight years as CFO and will now be MaaT Pharma’s chief of staff. Soyer had been CFO and COO at another French biotech, Erytech Pharma . His new company’s lead program MaaT013 is in a Phase 3 study for acute graft-versus-host disease. → Frits van Alphen has replaced Gerald Parzmair as chief development officer of Memo Therapeutics , a Swiss biotech that pulled together a total of $49 million for its Series C. After eight years at Novartis , van Alphen would go on to be CMO of Vifor Pharma from 2008-13 and Swiss-based Inositec , the undercard in Vifor’s M&A spree that included Sanifit in late 2021. He also worked for Roche as global head of product development excellence in between these two CMO gigs. → Synthetic lethality player Tessellate BIO has selected Lara Boyd as CBO. Boyd had a six-year run with Takeda partner F-star Therapeutics and was elevated to VP, head of business development & corporate strategy in May 2023. Former F-star boss Eliot Forster chairs the board at Tessellate BIO, which raised $8 million in seed funding from BioGeneration Ventures and Forbion . → La Jolla, CA-based I&I biotech CalciMedica has tapped Stephen Bardin as CFO, replacing interim finance chief Daniel Geffken . Earlier this year, Peer Review covered Bardin’s departure as CFO of atai Life Sciences , a position now held by Anne Johnson . He’s also worked for Myovant Sciences as director of corporate development and BridgeBio as SVP of finance and operations. → Joe Truluck has turned in his resignation as CFO of Adial Pharmaceuticals , and Vinay Shah will replace him on Nov. 16. We told you about Shah’s last CFO appointment at Virpax Pharmaceuticals in June 2023 and he’s had the same title at Aravive . Truluck will stay with Adial as a consultant until March 31. → Claudia Lopez has joined Seattle-based breast cancer biotech Atossa Therapeutics as VP, clinical product development. Lopez led the clinical development team at another AbbVie M&A pickup , Landos Biopharma , and the 16-year Takeda vet also spent two years with Arena Pharmaceuticals . → Tony Gibney has been named chairman of the board at Clearside Biomedical , which unspooled positive Phase 2b data last month for its suprachoroidal injection of axitinib called CLS-AX in patients with wet AMD. Gibney tackled the role of chief business & strategy officer at Iveric Bio until it was sold to Astellas last year for $5.9 billion. → Radiotherapy specialist Actinium Pharmaceuticals has elected June Almenoff to the board of directors. Almenoff, a GSK alum and the ex-president/CMO at Furiex Pharmaceuticals , is also on the boards of Avalo Therapeutics and Tenax Therapeutics . → Heron Therapeutics has reserved a seat on its board of directors for Liquidia CFO and COO Michael Kaseta . Before his gig with Liquidia, Kaseta was CFO at Aerami Therapeutics and Aralez Pharmaceuticals , as well as North American CFO, global services over a decade with Sanofi .