Divarasib

Funding will support BridgeBio Oncology Therapeutics and "significant clinical inflection points over the next 18-24 months." BridgeBio Pharma has spun its Rolodex to fund a subset of its sprawling list of opportunities. Busy with launch and late-phase activities, BridgeBio has secured $200 million to equip a cancer-focused offshoot to push a pipeline led by a KRAS inhibitor through early-phase tests. In 2017, TheRas, which is now doing business as BridgeBio Oncology Therapeutics (BBOT), struck a deal with Leidos Biomedical Research that led to the licensing of a KRAS G12C inhibitor and two other assets. TheRas was a wholly owned subsidiary of BridgeBio for years but required limited funding, with R&D expenses related to the Leidos agreements totaling $3.6 million in 2023.  Now, with one asset in the clinic and two approaching human testing, BridgeBio has decided to spin the molecules out to create BBOT and bring outside investors on board. The funding gives BBOT the “runway to achieve significant clinical inflection points over the next 18-24 months,” BridgeBio said.  BBOT began a phase 1 trial of KRAS G12C inhibitor BBO-8520 in non-small cell lung cancer last month. The start date of the study, which will test the molecule as a single agent and in combination with Keytruda, puts the program years behind approved KRAS drugs sold by Amgen and Bristol Myers Squibb. But BBOT and its backers contend a feature of BBO-8520 could lead to better efficacy.  KRAS cycles between an “on” and “off” state. Amgen’s Lumakras and BMS' Krazati target the off state, as does Roche’s challenger divarasib. BBOT believes molecules also need to inhibit KRAS in its on state to achieve optimal target coverage and prevent adaptive mechanisms of resistance. BBOT’s preclinical tests suggest BBO-8520 has advantages over Amgen, BMS and Roche’s molecules. And the biotech's researchers saw responses when the molecule was administered after the development of resistance to Lumakras.   The spinout is working to generate human data on BBO-8520 while preparing to move two other assets into the clinic. BBO-10203 is designed to block an interaction between RAS and PI3Ka. In doing so, the molecule may inhibit a tumor signaling pathway without causing the high blood sugar that affects people on PI3Kα inhibitors. BBOT is aiming to start enrolling patients in a clinical trial this year. A pan-KRAS inhibitor, BBO-11818, is following close behind. Like Lumakras and Krazati, BBOT’s lead drug candidate only targets a subset of patients with KRAS mutations. BBO-11818 is designed to target the on and off states of multiple forms of KRAS, potentially making it effective in more patients. BBOT is aiming to file to study the molecule in humans next year. Eli Wallace, Ph.D., and Pedro Beltran, Ph.D., will oversee the programs as BBOT’s CEO and chief scientific officer, respectively. Wallace joined BridgeBio as CSO in residence for oncology in 2019. Beltran arrived the following year to work with Wallace on programs targeting RAS biology.  The financing round was led by Cormorant Asset Management and co-led by Omega Funds. Affiliates of Deerfield Management, GV, EcoR1 Capital, Wellington Management, Enavate Sciences, Surveyor Capital, Aisling Capital, Casdin Capital and Longwood Fund also participated. Securing outside investment frees BridgeBio to spend its cash on launching acoramidis and enrolling patients in a clutch of phase 3 studies.

KRAS stands out as the most commonly altered among the trio of RAS genes, with NRAS and HRAS following suit. The human KRAS gene resides on chromosome 12p12.1 and comprises six exons, primarily positioned in exon 1 at sites 12 and 13, though occasionally found in codons 61, 63, 117, 119, and 146. The emergence of KRAS inhibitors marks a notable advancement in the rapidly progressing field of oncology, instilling hope in combating formidable solid tumors. The landscape of treatment for KRAS-mutant cancers is undergoing rapid evolution, marked by several promising advancements in recent years. Forecasts anticipate significant growth in the KRAS inhibitors market in the coming years, propelled by rising cancer incidence rates and the escalating demand for personalized cancer therapies. Ongoing research and clinical trials continue to unveil potential treatment strategies, fostering optimism for improved patient outcomes. According to DelveInsight’s analysis, the market size for KRAS inhibitors across the 7MM and is expected to grow with a tremendous 36% CAGR to reach USD 10 billion by 2032. As per the estimates, the US is set to be the largest market for KRAS inhibitors, with ~70% of the market share among the seven major markets. The KRAS inhibitor market is expected to grow significantly in the coming years, driven by the increasing incidence of cancer and the growing demand for personalized cancer treatments; ongoing research and clinical trials have identified potential treatment strategies. Key players, including Mirati, Novartis Pharmaceuticals, Amgen, Eli Lilly, Verastem, and others, are involved in developing drugs for KRAS mutation for various indications such as NSCLC, colorectal cancer, pancreatic cancer, and others. The treatment landscape for KRAS-mutant cancers has rapidly evolved, with several promising advancements in recent years. Keen to know how the KRAS inhibitors market will evolve by 2032? Find out @ KRAS Inhibitors Market Forecast Amgen and Mirati Therapeutics are at the forefront of the race to develop KRAS inhibitors for cancer treatment. However, their current candidates are focused solely on targeting G12C-mutant tumors, leaving a significant gap in addressing other KRAS variants. This represents a major unmet need in the field, as no approved treatments are currently available for other variants. Recognizing this challenge, numerous key players actively explore alternative KRAS variants and expand their research to include other types of cancers beyond NSCLC. This shift in focus holds promising potential for developing effective therapies that can address a wider range of KRAS mutations and target multiple cancer types. Many companies are focusing on developing their candidates in pan-KRAS, like Cardiff Oncology (onvansertib), Gritstone bio (SLATE KRAS), Hookipa Pharma (HB-700), and others. Now, let’s examine the emerging KRAS inhibitor therapies JDQ443: Novartis Pharmaceuticals Phase III JDQ443 represents an experimental KRASG12C inhibitor that is selective, covalent, and can be taken orally. Initial findings from the Phase Ib stage of the KontRASt-01 trial (NCT04699188) indicate a confirmed overall response rate (ORR) of 57% at the recommended dosage of 200 mg twice daily in individuals with advanced non-small cell lung cancer (NSCLC). Presently, JDQ443 is undergoing Phase III evaluation, aiming to compare its effectiveness as a standalone treatment against docetaxel in patients with advanced NSCLC carrying a KRASG12C mutation who have previously undergone platinum-based chemotherapy and immune checkpoint inhibitor therapy, either sequentially or in combination. Novartis intends to New Drug Application (NDA) for NSCLC by 2024 and for colorectal cancer (CRC) post-2026. Avutometinib (VS-6766): Verastem Oncology Phase II Avutometinib (VS-6766) functions as an RAF/MEK clamp, prompting the formation of inactive complexes involving MEK and ARAF, BRAF, and CRAF. This mechanism potentially enhances the anti-tumor response by thoroughly inhibiting the RAS pathway, possibly leading to more sustained effects. Currently, avutometinib is in advanced stages of development. Unlike other MEK inhibitors, it not only blocks MEK kinase activity but also prevents RAF from phosphorylating MEK. This distinctive mode of action enables avutometinib to inhibit MEK signaling effectively without triggering compensatory activation, a limitation observed in other inhibitors. The FDA has recognized the potential of avutometinib in combination with defactinib (a FAK inhibitor) by granting it Breakthrough Therapy designation for treating all patients with recurrent low-grade serous ovarian cancer (LGSOC), irrespective of their KRAS status, after one or more prior lines of therapy, including platinum-based chemotherapy. RAMP 201 is a trial aimed at registering avutometinib, either alone or combined with defactinib, in patients with recurrent LGSOC. RMC-4630 (SAR442720): Revolution Medicines Phase II RMC-4630 (also known as SAR442720) is a highly effective small compound intended for oral use, engineered to specifically hinder the function of SHP2. This essential cellular protein regulates cell survival and proliferation by transmitting signals from receptor tyrosine kinases to RAS. Currently, the company is in the Phase II trial stage, investigating the combination of RMC-4630 with sotorasib for individuals with non-small cell lung cancer harboring a KRAS G12C mutation. These patients have not responded to standard therapies and have not previously undergone treatment with an RAS inhibitor. Discover which therapies are expected to grab major KRAS inhibitors market share @ KRAS Inhibitors Market Report BI 1701963: Boehringer Ingelheim Phase I BI 1701963 is a compound designed to inhibit the activity of KRAS across various oncogenic variants, particularly targeting major G12 and G13 oncoproteins. Its mechanism involves binding to SOS1, a crucial component in activating KRAS by facilitating the exchange of RAS-bound GDP for GTP. This selective inhibition of SOS1 presents a promising therapeutic approach, enabling KRAS suppression regardless of mutation type. Preclinical studies demonstrate the efficacy of this pan-KRAS inhibitor in impeding tumor growth across numerous tested G12 and G13 KRAS mutations, which are commonly observed in the protein. Additionally, the compound exhibits selectivity towards cancer cell lines bearing mutations in the KRAS gene. Currently undergoing Phase I trials, BI 1701963 is being assessed both as a standalone treatment and in combination with trametinib for patients with advanced or metastatic solid tumors carrying KRAS mutations. Boehringer Ingelheim has initiated a clinical collaboration with Amgen to explore the potential of BI 1701963 in combination with LUMAKRAS. Divarasib/GDC-6036: Roche Phase I Divarasib/GDC-6036, an orally administered small molecule, exhibited strong and specific inhibition of the KRAS G12C protein in preclinical trials. Engineered to target the switch II pocket of the KRASG12C protein, it interacts specifically with the cysteine at position 12, effectively locking it in an inactive GDP-bound state irreversibly. Results from a Phase Ib study presented at AACR 2023 showed that combining GDC-6036 with cetuximab effectively treated colorectal cancer (CRC), displaying notable clinical efficacy and tolerable safety levels. LY353798: Eli Lilly Phase I LY353798 is a specific covalent blocker of KRASG12C, exhibiting efficacy both alone and when paired with other anti-cancer treatments in preliminary studies. Its pharmacokinetic pro well, prompting its progression to clinical trials. In laboratory settings, LY3537982 has displayed the ability to target the KRAS G12C mutation, hindering mutant KRAS-driven signaling. Phase I clinical trials are underway, focusing on patients with non-small cell lung cancer, colorectal cancer, or other advanced solid tumors. For further information on the most promising KRAS inhibitors, reach out @ KRAS Inhibitors Treatment Pipeline Related Reports PD-1 and PD-L1 Inhibitors Competitive Landscape PD-1 and PD-L1 Inhibitors Competitive Landscape – 2023 report provides comprehensive insights about the pipeline landscape, pipeline drug pro including clinical and non-clinical stage products, and the key PD-1 and PD-L1 inhibitors companies, including Merck, Laekna Therapeutics, Genentech, Tracon Pharmaceuticals Inc., Celgene, MedImmune, Hangzhou Sumgen Biotech, among others. 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