IKZF3

Nurix now plans to restart enrollment, prioritizing patients with aggressive forms of non-Hodgkin lymphoma. Nurix is hoping to continue to surf the wave of interest in its BTK degraders now that the FDA has lifted a partial hold on a phase 1 trial of a B-cell malignancy drug. The agency placed the hold in November 2023 after Nurix alerted the FDA it was planning to improve the manufacturing process for NX-2127, a small molecule that drives targeted BTK and IKZF3 degradation. The change meant that screening and enrollment of new patients for the phase 1 study in relapsed or refractory B-cell malignancies was paused. “We are pleased with the timely resolution of the partial clinical hold, which allows us to reinitiate enrollment in the NX-2127 phase 1 study utilizing drug product from our new manufacturing process,” Nurix’s Head of Clinical Development Paula O’Connor, M.D., said in a statement this morning. “Following our clinical data disclosures at the American Society of Hematology Annual Meeting last year and the recent scientific publication in the journal Science, we are seeing an acceleration of interest in our BTK degrader programs.” Nurix now plans to restart enrollment, prioritizing patients with aggressive forms of non-Hodgkin lymphoma, including diffuse large B-cell lymphoma and mantle cell lymphoma where durable complete responses have been observed. “Patients currently enrolled in the clinical study who are deriving clinical benefit from NX-2127 manufactured with the prior process may continue to receive that treatment in accordance with the study protocol,” the biotech explained. Nurix has already seen some interest from Big Pharma. Gilead Sciences bought into the first licensing option stemming from a 2019 collaboration last year, snagging exclusive rights to Nurix’s IRAK4 degrader NX-0479 in exchange for $20 million in upfront cash and $425 million in biobucks. And in September 2023, Seagen paid $60 million to Nurix to collaborate on degrader-antibody conjugates—a new class of antibody therapies that are also being pursued by the likes of Merck & Co. Nurix’s shareholders seemed relatively unfazed by the FDA’s hold in the fall and responded to today’s news with an equally negligible 1% bump in the company’s share price to $15.01 in pre-market trading Monday. Since the hold was implemented, Nurix has read out phase 1a dose escalation and phase 1b dose expansion data for NX-2127 in chronic lymphocytic leukemia, mantle cell lymphoma and diffuse large B-cell lymphoma. The drug induced “robust and sustained degradation of BTK and biologically relevant degradation of IKZF1,” according to Nurix. The biotech’s other clinical-stage BTK degrader, called NX-5948, is being studied in a phase 1 trial of adults with relapsed or refractory B-cell malignancies. Nurix expects to expand the study into patients with chronic lymphocytic leukemia and non-Hodgkin lymphoma this year.

Data reveal oncogenic scaffold function of BTK mutations that lack kinase activity and show these mutations remain susceptible to degradation by NX-2127 NX-2127 degrades BTK in patients regardless of mutational status and shows proof-of-concept therapeutic benefit in chronic lymphocytic leukemia Nurix recently presented positive clinical data from ongoing Phase 1 clinical trial of NX-2127 in patients with relapsed/refractory B-cell malignancies at the 65th American Society of Hematology (ASH) Annual Meeting Feb. 01, 2024 -- Nurix Therapeutics, Inc. (Nasdaq: NRIX), a clinical stage biopharmaceutical company developing targeted protein modulation drugs designed to treat patients with cancer and inflammatory diseases, today announced the publication of a manuscript in the journal Science titled: “Kinase Impaired BTK Mutations Are Susceptible to Clinical Stage BTK and IKZF1/3 Degrader NX-2127” that elucidates a previously unappreciated oncogenic scaffold function of BTK responsible for clinical resistance to enzymatic inhibitors and shows that NX-2127, a potent targeted protein degrader with differentiated activity against BTK and IKZF1/3, can overcome this resistance across a broad range of acquired mutations. “While BTK inhibitors have positively changed clinical outcomes for patients with B-cell malignancies, the emergence of acquired resistance to these medicines is a growing clinical problem,” said Alexey Danilov, M.D., Ph.D. Professor and Co-Director, Toni Stephenson Lymphoma Center, City of Hope National Medical Center. “Identification of the different types of mutations has important implications for the therapeutic sequencing of currently used targeted BTK inhibitors and reinforces the need for the development of novel agents, such as Nurix’s NX-2127 and NX-5948, that have the potential to provide improved mutation-agnostic treatment options for patients.” The article describes studies designed to investigate and characterize acquired BTK mutations that confer resistance to BTK inhibitors commonly used in the treatment of B-cell malignancies. The research identified a new class of kinase impaired mutants that render BTK enzymatically inactive and revealed that these mutations create novel protein-protein interactions that can propagate biochemical signaling through a process known as scaffolding, a nonenzymatic function of the BTK protein that sustains B-cell receptor (BCR) signaling and promotes the growth of malignant B-cells. Importantly, the authors report data demonstrating efficient proteasomal degradation of BTK in the blood of all NX-2127-treated patients with chronic lymphocytic leukemia (CLL), resulting in reduction of BTK enzymatic activity and suppression of BCR signaling regardless of mutational status. The work was carried out by Nurix in collaboration with scientists and clinicians at several prominent cancer research centers, including Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine and the Sloan Kettering Institute at Memorial Sloan Kettering Cancer Center. A Drug Annotation manuscript published contemporaneously in The Journal of Medicinal Chemistry entitled “Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton’s Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies” reports data detailing the discovery and optimization of NX-2127, including characterization of NX-2127’s activity in preclinical tumor models, cross-species pharmacokinetics and in vitro safety which supported the advancement of this molecule into clinical testing. “These publications represent the first compendium of biochemical, cellular, and clinical evidence that NX-2127 degrades both previously described and newly discovered BTK inhibitor resistance mutations, a novel mechanism of action in the treatment of B-cell malignancies that is associated with meaningful clinical responses,” said Gwenn M. Hansen, Ph.D., chief scientific officer of Nurix. “The data described in this publication in Science reinforce the broad utility of the targeted protein degradation mechanism compared to inhibition approaches to more completely block BTK function and potentially other important enzymatic disease targets where development of acquired resistance is an issue.” “The first-in-human trial of NX-2127 is ongoing in patients with relapsed and refractory B-cell malignancies, including CLL. Based on our clinic data, which were recently presented at the 2023 ASH Annual Meeting, we have also initiated expansion cohorts in patients with diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL),” said Paula O’Connor, M.D., senior vice president of clinical development at Nurix. “With the ability to target BTK inhibitor resistance mutations and achieve clinical responses, we believe that BTK degraders have the potential to become the next dominant class of agents in the significant BTK-targeted therapy field. We look forward to presenting additional clinical data from this program, and from our NX-5948 BTK degrader program, which is also being evaluated in patients with CLL, at future medical meetings.” NX-2127 is a novel bifunctional, orally bioavailable, investigational new drug that degrades BTK and cereblon neosubstrates Ikaros (IKZF1) and Aiolos (IKZF3). NX-2127 is currently being evaluated in a Phase 1 clinical trial in patients with relapsed or refractory B cell malignancies. Additional information on the ongoing clinical trial can be accessed at www.clinicaltrials.gov (NCT04830137). NX-5948 is an investigational, orally bioavailable, small molecule degrader of BTK that, unlike NX-2127, has been designed to lack cereblon immunomodulatory activity. NX-5948 is currently being evaluated in a Phase 1 clinical trial in patients with relapsed or refractory B cell malignancies. Additional information on the ongoing clinical trial can be accessed at clinicaltrials.gov (NCT05131022). Nurix Therapeutics is a clinical stage biopharmaceutical company focused on the discovery, development and commercialization of innovative medicines based on the modulation of cellular protein levels as a novel treatment approach for cancer, inflammatory conditions and other challenging diseases. Leveraging extensive expertise in E3 ligases together with proprietary DNA-encoded libraries, Nurix has built DELigase, an integrated discovery platform, to identify and advance novel drug candidates targeting E3 ligases, a broad class of enzymes that can modulate proteins within the cell. Nurix’s drug discovery approach is to either harness or inhibit the natural function of E3 ligases within the ubiquitin-proteasome system to selectively decrease or increase cellular protein levels. Nurix’s wholly owned, clinical stage pipeline includes targeted protein degraders of Bruton’s tyrosine kinase, a B-cell signaling protein, and inhibitors of Casitas B-lineage lymphoma proto-oncogene B, an E3 ligase that regulates activation of multiple immune cell types including T cell and NK cells. Nurix is headquartered in San Francisco, California. For additional information visit http://www.nurixtx.com. The content above comes from the network. if any infringement, please contact us to modify.

In a scientific breakthrough that aids our understanding of the internal wiring of immune cells, researchers have cracked the code behind IKAROS, an essential protein for immune cell development and protection against pathogens and cancer. This disruptive research is poised to reshape our comprehension of gene control networks and its impact on everything from eye color to cancer susceptibility and design of novel therapies. In a scientific breakthrough that aids our understanding of the internal wiring of immune cells, researchers at Monash University in Australia have cracked the code behind IKAROS, an essential protein for immune cell development and protection against pathogens and cancer. This disruptive research, led by the eminent Professor Nicholas Huntington of Monash University’s Biomedicine Discovery Institute, is poised to reshape our comprehension of gene control networks and its impact on everything from eye colour to cancer susceptibility and design of novel therapies. The study, published in Nature Immunology, promises pivotal insights into the mechanisms safeguarding us against infections and cancers. When the transcription factor Ikaros/Ikzf1 was deliberately obstructed, be it in preclinical models or humans, the once-mighty activity of Natural Killer (NK) cells, our immune system's frontline warriors, plummeted. Loss of this transcription factor in NK cells resulted in wide-spread dysregulation of NK cell development and function, preventing their ability to recognize and kill virus-infected cells and clear metastatic tumour cells from circulation. Aiolos/Ikzf3 and Helios/Ikzf2, related family member were found to partial compensate for the loss of Ikaros, as such when multiple IKZF-family members were inhibited, NK cells underwent rapidly death. Mechanistically, Aiolos and Ikaros were found to directly bind and activate most members of the JUN/FOS family, transcription factors known for their essential roles in human embryo development and tissue function. This discovery opens the door to the prospect of potential novel cancer therapeutics. NK cells, our first line of defence against pathogens and internal threats like cancers, could be fortified by therapies enhancing their killing prowess by targeting IKAROS and JUN/FOS biology. Professor Huntington notes that drugs targeting IKAROS/AIOLOS have already received approval from the US Food and Drug Administration (FDA) and local Therapeutic Goods Administration (TGA) for the treatment of B cell malignancy “but until now we haven’t understood how these drugs work, armed with this new information it could be possible to develop novel drugs targeting these complexes which may offer differentiated pharmacology and therapeutic index for treating disease,” he said. Importantly on this front, Professor Huntington’s team were able to show that IKAROS had a conserved role in healthy B cells and thus potentially B cell cancers.