BCR

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.

[30-January-2024] MARKHAM, ON, Jan. 30, 2024 /CNW/ - Today, Astellas Pharma Canada, Inc. announced that Health Canada has approved a supplemental New Drug Application for XTANDI® (enzalutamide) in a new prostate cancer treatment setting. With this approval, XTANDI becomes the first and only androgen receptor pathway inhibitor (ARPI) approved for use with or without a GnRH analog therapy in patients with nmCSPC with biochemical recurrence at high risk for metastasis (high-risk BCR).i Health Canada granted a priority review of XTANDI in nmCSPC, which was further expedited as a result of XTANDI's inclusion in Project Orbis, an initiative of regulatory bodies, including Health Canada, with an aim to give patients faster access to promising cancer treatments around the world. Prostate cancer develops when abnormal cells form and grow in the prostate gland.ii Prostate cancer is considered nmCSPC if there is no detectable evidence of the cancer spreading to distant parts of the body (metastases) with conventional radiological methods (CT/MRI) and the cancer still responds to medical or surgical treatment to lower testosterone levels.iii Of men who have undergone definitive prostate cancer treatment, including radical prostatectomy, radiotherapy, or both, an estimated 20-40% will experience a biochemical recurrence (BCR) within 10 years.iv About 9 out of 10 men with high-risk BCR will develop metastatic disease, and 1 in 3 will die as a result of their metastatic prostate cancer.v "BCR is usually the first manifestation of recurrence following treatment for prostate cancer and some of these patients are at high risk of early metastases and eventual death from prostate cancer," said Dr. Fred Saad, Professor and Chairman, Department of Surgery, University of Montreal. "I welcome the approval of XTANDI as a promising earlier treatment option for eligible patients. This marks a significant step forward in addressing unmet needs for prostate cancer treatment." As the most common cancer among Canadian men, prostate cancer accounts for an average of 71 new diagnosis every day.vi It is estimated that about 1 in 8 Canadian men will develop prostate cancer during their lifetime and 1 in 30 will die from it.vii Approximately 98% of cases occur in men above the age of 50.viii This indication is based on the results of the EMBARK trial, the first Phase 3 registrational study to demonstrate a statistically significant improvement in metastasis-free survival (MFS) using the combination of XTANDI plus ADT and XTANDI as monotherapy in men with nmCSPC with high-risk BCR.ix Canadian patients contributed approximately 10% of enrollment in the EMBARK trial. "Astellas puts patients at the centre of our work. For more than 12 years, we have been advancing innovative treatments in hard-to-treat cancers with few or no current therapeutic options," said Frank Stramaglia, General Manager, Astellas Pharma Canada, Inc. "The latest indication for XTANDI is a clear demonstration of our ongoing commitment to patients and the physicians who treat them. With our recent acquisition of Propella Therapeutics, Inc., we strive to achieve even more in the investigation of targeted prostate cancer treatments for patients of the future." About XTANDI (enzalutamide) XTANDI is an - Androgen Receptor (AR) inhibitor that overcomes resistance to conventional antiandrogens by inhibiting AR signalling at multiple steps in the pathway.x Patients with nmCSPC with high-risk BCR may be treated with XTANDI with or without a gonadotropin-releasing hormone (GnRH) analog therapy.xi XTANDI has been prescribed to more than one million patients globally since 2012 including 33,200 to patients in Canada.xii XTANDI is a standard of care that has received regulatory approvals in more than 90 countries, including the United States, the European Union and Japan. In Canada, XTANDI is now approved for use in men in four prostate cancer disease states across five indications: Metastatic castration-resistant prostate cancer (mCRPC): chemotherapy naïve and post-docetaxel Non-metastatic castration-resistant prostate cancer (nmCRPC) Metastatic castration-sensitive prostate cancer (mCSPC) Non-metastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR). About EMBARK The approval is based on results from the Phase 3 EMBARK trial of XTANDI (enzalutamide) plus ADT (n=355), placebo plus ADT (n=358), and XTANDI as monotherapy (n=355) in men with nmCSPC with high-risk BCR. The EMBARK trial focused on men with high-risk BCR. Per the EMBARK protocol, patients with nmCSPC with high-risk BCR are those initially treated by radical prostatectomy or radiotherapy, or both, with a prostate-specific antigen (PSA) doubling time (PSA-DT) ≤ 9 months. High-risk BCR patients with a PSA-DT of ≤ 9 months have a higher risk of metastases and death. The study showed that treatment with XTANDI plus ADT reduced the risk of metastasis or death by 58% versus placebo plus ADT (Hazard Ratio [HR]: 0.42; 95% Confidence Interval [CI], 0.30–0.61; p<.0001) as assessed by the primary endpoint of metastasis-free survival (MFS). Detailed results from the primary analysis of EMBARK were presented as a plenary session during the 2023 American Urological Association (AUA) Annual Meeting and published in the New England Journal of Medicine. An analysis of health-related quality of life (HRQoL) in patients from the EMBARK trial were recently presented at the European Society of Medical Oncology (ESMO) Congress 2023 and subsequently published in NEJM Evidence. About Astellas Canada Astellas Pharma Canada, Inc. is a Canadian affiliate of Tokyo-based Astellas Pharma Inc., a pharmaceutical company conducting business in more than 70 countries around the world. At Astellas, we strive to become a cutting-edge, value-driven life science innovator. This means working at the forefront of healthcare change to turn innovative science into VALUE for patients. What sets us apart is our focus on patients, our pioneering innovation, our collaborative culture, and the passion of our talented people. Learn more: SOURCE Astellas Pharma Canada, Inc.

This was following FDA expedited development and review programs (Priority Review designation, Fast Track designation, Real-time Oncology Review), based on results from the phase 3 Embark trial ​. With this approval, Xtandi becomes the first and only androgen receptor signaling inhibitor approved by the FDA for the treatment of patients with nonmetastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR). Patients with nmCSPC with high-risk BCR may be treated with Xtandi with or without a gonadotropin-releasing hormone (GnRH) analog therapy. In their research, the companies found that those men who have undergone definitive prostate cancer treatment, including radical prostatectomy, radiotherapy or both, an estimated 20-40% will experience biochemical recurrence (BCR) within ten years. About nine out of ten men with high-risk BCR will develop metastatic disease and one in three will die as a result of their metastatic prostrate cancer. Previously treated prostate cancer “For patients who were previously treated for prostate cancer and had achieved remission, only to later receive the distressing news of disease recurrence with a risk of metastasis, the emotional toll can be profound,” said Courtney Bugler, president, and CEO of ZERO Prostate Cancer. “This approval of Xtandi is a promising treatment option for the community, offering a ray of hope to patients and their caregivers during these challenging times.” Neal Shore is chief medical officer of strategic innovation and pharmacy at GenesisCare, USA, and director of the Carolina Research Center and primary investigator for the trial. googletag.cmd.push(function () { googletag.display('text-ad1'); }); He said: “Having had the privilege of taking care of patients with prostate cancer for nearly 40 years, I have been fortunate to have participated in many of the prostate cancer landscape-changing trials; notably, we have not progressed our evidenced-based care for patients with biochemical recurrence (BCR), also known as nmCSPC, until the completion of the Embark trial. Important advancement “Previously, treatment options for these BCR patients, especially those who have a high likelihood of developing metastases were limited. The FDA approval of Xtandi for patients with nmCSPC with BCR at high risk of metastasis represents an important advancement whereby an androgen deprivation signaling inhibitor, enzalutamide, has achieved a standard of care discussion for patient-physician decision-making.” The approval is based on results from the phase 3 Embark trial, which evaluated Xtandi plus leuprolide, placebo plus leuprolide, and Xtandi (single agent) in patients with nonmetastatic hormone- (or castration-) sensitive prostate cancer (nmHSPC or nmCSPC) with high-risk BCR. Detailed results from the trial were presented as a plenary session during the 2023 American Urological Association Annual Meeting and subsequently published in the New England Journal of Medicine ​. “Today’s FDA approval is the culmination of over a decade of research and development as we’ve worked to bring Xtandi forward for as many patients with prostate cancer as possible who may benefit,” said Ahsan Arozullah, senior VP and head of oncology development, Astellas. “With every milestone, our clinical development program has played an instrumental role in changing the course of patients’ lives. We are proud that Xtandi can now be offered to a subset of men with nonmetastatic castration-sensitive prostate cancer with biochemical recurrence and at high risk for metastases.” Exciting approval Chris Boshoff, chief oncology research and development officer and executive vice president at Pfizer, observed that more than 300,000 men in the US have been prescribed Xandi. He said the companies were excited to have this approval expanding the indication for the first time into an earlier setting of the disease. “This milestone is a testament to Xtandi’s legacy and robust clinical profile, with overall survival demonstrated for patients with metastatic castration-resistant prostate cancer, nonmetastatic castration-resistant prostate cancer, and metastatic castration-sensitive prostate cancer. “With today’s approval, we look forward to bringing this therapy to even more patients who have nonmetastatic castration-sensitive prostate cancer at high risk for their cancer metastasizing.” Xtandi is currently under review with other regulatory authorities around the world, including the European Medicines Agency, to support an expanded indication in nmHSPC (or nmCSPC) with high-risk BCR based on the results of EMBARK.