Evexomostat

Innovative pro-drug delivers superior efficacy with improved drug-like properties and safety pro > CAMBRIDGE, MA / ACCESSWIRE / March 28, 2024 / SynDevRx, Inc., a pioneering clinical-stage biotechnology company based in Cambridge, Massachusetts, has achieved a significant milestone. The company is delighted to announce the publication of a peer-reviewed research paper describing its optimized MetAP2 inhibitor, evexomostat/SDX-7320, targeting tumors sensitive to systemic metabolic dysfunction resulting from obesity, insulin resistance or induced by other cancer treatments. Published in the respected Molecular Cancer Therapeutics (MCT), a journal of the American Association for Cancer Research, the paper details the physicochemical and pharmacological properties of evexomostat and describes how the company's insights into polymer conjugation led to this optimized MetAP2 inhibitor with improved activity, better drug-like properties and enhanced safety pro prior MetAP2 inhibitors [ ]. SynDevRx logo company logo The publication highlights evexomostat's precision in targeting the methionine aminopeptidase 2 (MetAP2) enzyme, a crucial player in angiogenesis, tumor growth and metabolic hormone regulation that cancer cells exploit for proliferation and metastatic spread. Importantly, with respect to the drug class, the Company's polymer conjugation approach minimized CNS exposure while still providing excellent drug-like properties plus potent anti-tumor and anti-metastatic activity in multiple preclinical models of cancer. Peter Cornelius, Ph.D., the company's Senior Director of Translational Research and lead author of the publication, expressed his enthusiasm: "The first publication of our findings represents an important milestone in the development of evexomostat/SDX-7320. Our novel polymer-drug conjugate addresses critical issues that halted development of prior fumagillin-class MetAP2 inhibitors and demonstrates anti-tumor activity in vivo at low doses of active small molecule, a feature not seen with other polymer-drug conjugates." The SynDevRx team has dedicated years advancing the science of MetAP2 inhibition in cancer, building on the extensive body of MetAP2 research stemming from the discovery by Donald Ingber, MD, Ph.D., in the lab of the esteemed Dr. Judah Folkman, as well as additional subsequent research from Craig Crews, Ph.D., Tyler Jacks, Ph.D., and many others. Dr. Ingber expressed his hopes for evexomostat's clinical success: "Since my original discovery of this MetAP2 class of cancer therapeutics, I've long wanted to see its potential realized in patients. I'm excited at the progress SynDevRx has made with evexomostat, its advancement into multiple clinical trials and, hopefully, its eventual clinical approval." SynDevRx's CEO, Bradley Carver, reflected upon the impact of this achievement: "The recognition of our work by the scientific community underscores the game-changing nature of our approach to polymer-drug conjugation. MetAP2 inhibitors have consistently and repeatedly demonstrated clinical activity in studies for both cancer and obesity/diabetes. However, toxicities associated with small molecules from the class have prevented that clinical promise from being fulfilled. Our optimized MetAP2 inhibitor drug conjugate advances the work of other scientists culminating with a greatly improved drug candidate. As we pursue ongoing clinical trials, our focus remains on transforming the lives of patients battling cancer while simultaneously enhancing their quality of life through improvements to their metabolic health." In addition to the preclinical work described in the current research paper, SynDevRx has completed a Phase I dose-escalation safety trial of evexomostat in late-stage cancer patients, and currently has two open/enrolling clinical trials: the Amelia™-1 trial ( ) in HR+/Her2- metastatic breast cancer in combination with a PI3K/Akt pathway inhibitor plus fulvestrant; and the Aretha trial ( ), a first-of-its-kind Phase 1b/2 study for patients with triple-negative breast cancer (mTNBC) and baseline insulin resistance in combination with standard-of-care therapy eribulin/Halaven®. The Aretha clinical research study is being conducted in collaboration with New York's Memorial Sloan Kettering Cancer Center (MSK) and is being led by Dr. Neil Iyengar. SynDevRx is committed to leveraging its scientific leadership and expertise in the emerging field of metabo-oncology - the intersection of cancer and metabolic dysfunction. For more details about the paper and its content, please contact Peter Cornelius, Ph.D. For all other questions relating to evexomostat development, please contact: James Shanahan, Chief Business Officer, SynDevRx, Inc. Phone: (617) 401-3110 Website: About SynDevRx SynDevRx, a clinical-stage company located in the biotech hub of Cambridge, MA, is at the forefront of biotechnological innovation, focusing on developing novel therapies that target the intersection of cancer and metabolic dysfunction - i.e., metabo-oncology. With a commitment to creativity and a passion for life-changing scientific breakthroughs, SynDevRx is dedicated to addressing not just a patient's cancer, but also the pernicious effects of systemic dysregulated metabolic hormones. Our aim is to empower patients and their healthcare providers with new options that allow them not just to survive but to thrive, during and after treatment. About Evexomostat (SDX-7320) Evexomostat (SDX-7320) is a polymer drug-conjugate that is among the first drugs being developed specifically for cancer patients with metabolic complications, such as insulin resistance, obesity, diabetes, or pre-diabetes either intrinsic to the cancer patient or resulting from treatment. For patients with certain solid tumors, dysregulated metabolic hormone signaling can promote tumor growth and/or metastasis via known oncogenic pathways, making the cancer more aggressive and deadlier. Evexomostat acts by inhibition of its target enzyme MetAP2, simultaneously impacting downstream oncogenic and metabolic pathways. Evexomostat is intended to work with standard-of-care anti-cancer therapies to improve clinical outcomes. Contact Information James Shanahan CBO jshanahan@syndevrx.com (617)4013110 SOURCE: SynDevRx, Inc. View the original press release on newswire.com.

APL-1202 (nitroxoline) is a reversible and orally available MetAP2 inhibitor with anti-angiogenic and anti-tumor activities. Single-agent neoadjuvant programmed death 1 (PD-1) antibodies achieve pathological complete responses in a subset of patients (pts) with muscle-invasive bladder cancer (MIBC). APL-1202 and PD-1 antibody combination therapy demonstrates synergistic effects in several model systems of cancer, including bladder cancer. Recently, the clinical results of Nitroxoline, in combination with tislelizumab, a humanized IgG4 anti-PD-1 antibody, were presented in 2024 ASCO_GU, demonstrating an effective neoadjuvant therapy in MIBC. Nitroxoline's R&D ProgressNitroxoline is a small molecule drug that is being developed to target METAP2. It is primarily being investigated for its potential therapeutic applications in neoplasms and urogenital diseases. The active indications for Nitroxoline include non-muscle invasive bladder neoplasms, bladder cancer, and muscle invasive bladder carcinoma.  According to the Patsnap Synapse, Nitroxolin has reached the highest phase of clinical development, which is Phase 3 globally. And the clinical trial distributions for Nitroxoline are primarily in the United States, China and Australia. The key indication is Non-Muscle Invasive Bladder Neoplasms.  Detailed Clinical Result of NitroxolineThis randomized, parallel assignment, open-labeled clinical trial (NCT04813107) was aimed to assess the efficacy and safety of APL-1202 plus tislelizumab as an effective neoadjuvant therapy in MIBC.   In this study, eligible pts are randomly assigned to group 1 (APL-1202 plus tislelizumab) or group 2 (tislelizumab), with randomization stratified by PD-L1 expression. Neoadjuvant treatment is administered every 3 weeks for 3 cycles. The primary endpoint is pathological complete response (pCR, pT0N0) rate. A Simon’s 2-stage design is employed with planned interim analyses after 18 evaluable pts in group 1 and 14 evaluable pts in group 2. The result showed that 42 pts have enrolled and results for 32 evaluable pts for stage 1 of the 2-stage design are reported. Radical cystectomy was completed in 18/18 pts in group 1 and 13/14 pts in group 2; 1 patient who could not undergo surgery due to disease progression and 10 pts refused RC. The 32 evaluable pts consisted of 11/18 (61%) and 10/14 (72%) cT2, and 6/18 (33%) and 2/14 (14%) cT3, and 1/18 (6%) and 2/14 (14%) cT4a in group 1 and 2, respectively. PD-L1 expression was assessed using the VENTANA PD-L1 (SP263) Assay; 8/18 (44%) pts in group 1 and 7/14 (50%) in group 2 was positive. The pathological response was shown in the table. Treatment emergent adverse events (TEAEs) were reported in 17 (94.4%) pts in group 1 and 11 (78.6%) in group 2; most common (≥ 10%) TEAE of CTCAE grade ≥ 3 were anaemia (4, 22.2%), lymphocyte count decreased (3, 16.7%) in group 1 and intestinal obstruction (3, 21.4%) in group 2. AEs led to drug discontinuation in 3 (16.7%) pts in group 1 (acute kidney injury, anaemia, hepatic function abnormal) and 2 (14.3%) in group 2 (immune hyperthyroidism, COVID-19), and no treatment-related AEs led to death. It can be concluded that the pCR rates in both group 1 (APL-1202 plus tislelizumab) and group 2 (tislelizumab) exceeded thresholds to trigger expansion to stage 2 of the 2-stage design. The activity and safety of neoadjuvant APL-1202 plus tislelizumab support further evaluation of this novel regimen (NCT04813107). 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