2025 Cornelius A phase 1 safety study of evexomostat in patients with late-stage cancer
Cambridge, MA (USA) and Brisbane (Australia) – Queensland University of Technology (QUT) in Brisbane, Australia, together with SynDevRx, Inc., a leader in polymer-drug conjugates for cancer and for metabolic dysfunction are honored to announce the receipt of a $1.2 million grant from the US Department of Defense (DoD) for continued research on evexomostat, SynDevRx’s novel clinical drug candidate targeting late-stage, androgen receptor pathway inhibitor resistant prostate cancer. More specifically, the research grant will fund both a pilot clinical study and mechanistic research in the lethal form of late-stage prostate cancer referred to as ‘Aggressive Variant’ (AVPC), including the challenging neuroendocrine tumor phenotype. This award was based on evexomostat’s surprisingly potent pre-clinical activity in PDX prostate cancer models.EINPresswire-775270180-1-2m-grant-awarded-for-groundbreaking-prostate-cancer-research-on-syndevrx-metap2-inhibitor-evexomostat 08Jan 2025
Methionine aminopeptidase type 2 (MetAP2) is a ubiquitous, evolutionarily conserved metalloprotease fundamental to protein biosynthesis which catalyzes removal of the N-terminal methionine residue from nascent polypeptides. MetAP2 is an attractive target for cancer therapeutics based upon its over-expression in multiple human cancers, the importance of MetAP2-specific substrates whose biological activity may be altered following MetAP2 inhibition, and additionally, that MetAP2 was identified as the target for the anti-angiogenic natural product, fumagillin. Irreversible inhibition of MetAP2 using fumagillin analogs has established the anti-angiogenic and anti-tumor characteristics of these derivatives, however, their full clinical potential has not been realized due to a combination of poor drug-like properties and dose-limiting CNS toxicity. This report describes the physicochemical and pharmacological characterization of SDX-7320 (evexomostat), a polymer-drug conjugate of the novel MetAP2 inhibitor (MetAP2i) SDX-7539.
SynDevRx, Inc. today announced the opening of the Amelia-1 study and data from the first patient treated in its Phase 1b/2 clinical study testing the novel MetAP2 inhibitor evexomostat (aka SDX-7320) in combination with the PI3K inhibitor alpelisib (Piqray®) and the estrogen receptor degrader (SERD) drug fulvestrant (Faslodex®) in breast cancer patients with metastatic disease and the PIK3CA gene mutation (NCT05455619 – Phase 1b/2 Study of the Safety and Efficacy of Evexomostat Plus Alpelisib and Fulvestrant in Postmenopausal Women at Risk for Hyperglycemia With Advanced Breast Cancer and a PIK3CA Mutation Following Endocrine Therapy and a CDK4/6 Inhibitor).
Amelia™-1 Study is testing if evexomostat can improve patients’ safety and clinical response to a PI3K inhibitor plus an estrogen receptor degrader. Evexomostat, a novel MetAP2 inhibitor, controlled PI3K-induced hyperglycemia in the first study patient, consistent with pre-clinical data. Further, ctDNA data shows no evidence of residual PIK3CA mutation in blood after 6 weeks of treatment.
SDX AACR 2023 poster 05Apr 2023.pptx
PRESS RELEASE • APR 14, 2023 08:00 EDT
Evexomostat (SDX-7320) shows potent anti-tumor effects in pre-clinical models of prostate cancer, including castration-resistant. New research data to be presented at AACR 2023 in Orlando, FL
Aug. 31, 2022 – SynDevRx, Inc., a clinical-stage biotechnology company leading the development of treatments for obesity-accelerated cancers, today announced the presentation of new scientific data on its lead compound evexomostat (SDX-7320) in a series of fibrosis models demonstrating potent anti-fibrosis data monotherapy and in combination with the standard of care therapy nintedanib. Evexomostat significantly improved lung function following lung injury, reduced fibrotic foci, and reduced lung edema both alone and even more potently when combined with nintedanib. Poster Presentation: 2022 IPF Summit
What You Need To Know About Your Metabolic Health and Breast Cancer
Breast Cancer Conversations is a podcast that discusses all things breast cancer! We share stories of those who have been diagnosed. We interview medical professionals, doctors, radiologists, and oncologists. We speak with advocates and caregivers. We are your voice! If you have questions, we go out and seek answers! We break it down to understandable terms and build community for our thriving tribe.
Welcome to the conversation.
SynDevRx, Inc. today announced the opening of a first-of-its-kind Phase 1b/2 study for patients with triple-negative breast cancer and baseline insulin resistance, testing the novel drug evexomostat (SDX-7320) in combination with standard-of-care treatment Halaven (eribulin, Esai). Evexomostat is among the first anti-cancer therapeutics being developed specifically for cancer patients with baseline metabolic dysfunction (obesity, type 2 diabetes and pre-diabetes). The clinical research study is being conducted in collaboration with New York’s Memorial Sloan Kettering Cancer Center (MSK).
– First prospective study of its kind aims to demonstrate that restoring insulin sensitivity in breast cancer patients with baseline insulin resistance will improve clinical outcomes
– Supports lead investigator Dr. Neil Iyengar of Memorial Sloan Kettering, NY long-term research into the profound and negative influence of metabolic dysfunction (obesity, diabetes, insulin resistance) on breast cancer progression, spread and clinical outcomes
SynDevRx, Inc., a clinical-stage biotechnology company leading the development of treatments for obesity-accelerated cancers, today announced a research collaboration with Maine Medical Center Research Institute’s Michaela Reagan, PhD. The collaboration will study the role of MetAP2 in obesity-accelerated growth and metastatic potential of multiple myeloma – a form of cancer that develops in bone marrow.
Obesity and systemic metabolic dysfunction are known to make many solid tumors more aggressive, but the connection goes beyond that: multiple myeloma (MM) and several other cancers are also accelerated by systemic issues brought on by obesity, pre-diabetes and type 2 diabetes. MetAP2 inhibitors, such as SDX-7320, have been shown to improve systemic metabolic hormone dysregulation and they demonstrate anti-tumor and anti-angiogenic properties. It’s this combination of attributes that targets the link between obesity and cancer which may prove well-suited to treat MM in combination with standard-of-care therapies.
Leptin may be a primary mediator of exercise-induced improvements in breast cancer recurrence.
The opportunity to draw upon genetic data from large-scale, international consortia allows for triangulation of evidence using distinct methodological approaches that make orthogonal underlying assumptions and suffer from distinct sources of bias. The findings of our study
support a potential causal effect of genetically predicted T2DM and/or fasting insulin levels, rather than genetically predicted fasting glucose levels, on risk of breast, endometrial, pancreatic and kidney cancer. These findings are consistent with experimental and molecular epidemiological data which support a role for insulin signalling in the development of several cancers and may therefore represent an important pathway linking T2DM and cancer.
Jim Shanahan from SynDevRx explains why metabo-oncology treatment modalities could be the answer to a rise in metabolic disorders and cancers.
SynDevRx, Inc., a clinical-stage biopharmaceutical company specializing in metabo-oncology, has announced the formation of its Prostate Cancer Medical Advisory Board (PCMAB), comprised of key opinion leaders and industry experts in clinical oncology research and prostate cancer patient care. The board’s overarching goal is to inform the development of SynDevRx’s lead drug candidate, SDX-7320, to target the link between metabolic dysfunction and prostate cancer treatment outcomes.
Metabo-oncology is the emerging area of research and treatment dedicated to addressing systemic metabolic dysfunction and its impacts on tumor formation, disease progression and patient quality of life. Little attention has been paid to addressing the fundamental role that dysregulated glucose homeostasis and its sequelae (insulin resistance) play in tumor progression and aggressiveness.
With a global epidemic of obesity and diabetes and their known relationship to cancer, researchers and oncologists are turning their attention to metabolic hormones as promising new targets for cancer treatment.
Technology Networks recently spoke with Jim Shanahan, co-founder, chief business officer and director of SynDevRx, to explore the impact of metabolic dysfunction on treatment outcomes and learn more about the company’s lead compound SDX-7320.
SynDevRx, Inc., a clinical-stage oncology company, has submitted results of its Phase 1 dose escalation safety study in late-stage cancer patients with progressive, metastatic solid tumors to the United States Food and Drug Administration (FDA). The study’s primary
endpoint was to establish the maximum tolerated dose and dosing schedule and the recommended Phase 2 dose for SDX-7320, the company’s lead drug candidate for the treatment of metabolically sensitive cancers. Secondary and exploratory endpoints included analysis of anti-tumor efficacy and changes in key angiogenic and metabolic biomarkers.
CAMBRIDGE, Mass. – October 21, 2020 – SynDevRx, Inc., a clinical-stage oncology company, announces the completion of a series of preclinical studies demonstrating that its anti-cancer drug candidate, SDX-7320, inhibits PI3K/Akt inhibitor-induced hyperglycemia and subsequent hyperinsulinemia in normal mice and inhibits tumor growth in multiple models of HR+ breast cancer. The company’s ongoing research places them at the vanguard of metabo-oncology, an emerging field of cancer research that focuses on the role metabolic hormones play in the development and progression of many common cancers, as well as tumor resistance developed in response to certain treatment.
SDX-7320 inhibits MetAP2, a clinically validated target that plays a key role in tumor growth, metastasis, angiogenesis, and metabolic dysfunction. In a series of efficacy and safety studies in a variety of syngeneic cancer models (breast, melanoma), SDX-7320 displayed single agent anti-tumor activity while improving metabolic dysfunction (in particular, hyperglycemia, insulin resistance and leptin resistance)1. SDX-7320 prevented the hyperglycemia and hyperinsulinemia associated with Piqray® (Novartis’ PI3Kα inhibitor)2 administration in normal mice – serious side effects of drugs from these classes that have been reported to lead to treatment resistance3. Furthermore, in a xenograft model of ER+/Her2- breast cancer, SDX-7320 and Piqray® (alpelisib),2 administered together at low doses, showed synergy at inhibiting tumor growth.
“Piqray is an important new therapy for patients with HR+/Her2-, metastatic breast cancer whose tumors have a mutation in the PIK3CA gene. However, drugs that target the PI3K/Akt pathway frequently cause hyperglycemia in patients, especially those with high baseline fasting glucose, HbA1c, insulin resistance, pre-diabetes, type 2 diabetes or obesity4. Treatment-induced hyperglycemia has been reported as a safety concern that can lead to dose interruptions and/or drug holidays. In addition, the treatment-induced hyperglycemia leads to hyperinsulinemia which in pre-clinical studies has been shown to cause resistance to these drug classes5.” said Jim Shanahan, Co-Founder and Chief Business Officer of SynDevRx. “Baseline systemic metabolic complications, such as obesity, pre-diabetes or type 2 diabetes were reported to correlate with and predict worse outcomes for many breast cancer patients taking Piqray”3.
Preclinical studies of SDX-7320 with another drug from the PI3k/Akt class, the Akt/mTOR inhibitor, capivasertib (AstraZeneca) showed that SDX-7320 also attenuated treatment-induced hyperglycemia (in normal mice), and inhibited tumor growth in a xenograft model of HR+/Her2+ breast cancer. “Our preclinical data with alpelisib (Piqray®) and capivasertib suggests that SDX-7320 may make drugs targeting the PI3k/Akt/mTOR pathway safer and more effective by controlling blood glucose and insulin levels in combination with tumor growth inhibition,” he continued.
“Companies developing drugs targeting the PI3K/Akt/mTOR pathway may experience toxicity issues related to drug-induced hyperglycemia followed by hyperinsulinemia, eventually resulting in resistance to therapy5. SDX-7320 has demonstrated that it can help to address this problem in vivo,” said Brad Carver, Co-Founder, President and CEO of SynDevRx. “Our data suggests that drugs targeting the PI3K/Akt/mTOR pathway should see better safety and better anti-tumor activity by administering SDX-7320 in combination with those agents.”
To test this hypothesis, SynDevRx intends to commence Phase 2 studies in late-stage ER+, Her2- breast cancer patients. To learn more about SynDevRx clinical trials, visit: www.syndevrx.com/
1. Abstract 4919: Preclinical activity of SDX-7320 in mouse models of obesity and obesity-driven cancer. Cornelius P, Petersen JS, Mayes B, Turnquist D, Sullivan K, Anderson-Villaluz A, Lutz R, Little S, Slee A, Carver BJ, Shanahan J. Cancer Res July 1 2018 (78) (13 Supplement) 4919; DOI: 10.1158/1538- 7445.AM2018-4919
2. Abstract 2147: Synergistic inhibition of MCF-7 mammary gland tumor growth with Piqray®(alpelisib) plus SDX-7320, a novel polymer-conjugated methionine aminopeptidase 2 (MetAP2) inhibitor. Cornelius P, Mayes B, Little S, Slee A, Nir R, Nir A, Carver B, Shanahan J. Cancer Res February 14 2020 80 (4 Supplement) P3-11-13-P3-11-13; DOI:10.1158/1538-7445.SABCS19-P3-11-13
3. André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor- Positive Advanced Breast Cancer. N Engl J Med. 2019;380(20):1929-1940. doi:10.1056/NEJMoa1813904: Fox et al., Breast Cancer Research volume 15, Article number: R55 (2013)
4. Rugo et al, 2020, Annals of Oncology: https://doi.org/10.1016/j.annonc.2020.05.001
5. Hopkins, B.D., Pauli, C., Du, X. et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560, 499–503 (2018). https://doi.org/10.1038/s41586-018-0343-4
SynDevRx is a privately held clinical stage biopharmaceutical company based in Cambridge, Massachusetts focused on the research and development of treatments that address the unique and underserved needs of cancer patients with systemic metabolic dysfunction – i.e., metabo-oncology. Obesity, pre-diabetes and type 2 diabetes are known to worsen cancer patients’ prognosis, but oncologists have no specific tools to deal with systemic metabolic complications except for changes in diet and exercise. SynDevRx intends to initiate a series of Phase 2 clinical studies of its drug candidate SDX-7320 to address this major, unmet medical need. Preclinical studies have shown that SDX-7320 reduces tumor growth and angiogenesis, helps to control aberrant metabolic hormone signaling, and reduces treatment resistance to certain standard cancer therapies in metabolically sensitive cancers. SDX-7320 is being developed for use in combination with standard of care therapies for a variety of solid tumors.
Kate Proudfoot
kproudfoot@cglife.com
(708) 717-6570