Sirpiglenastat

Researchers have revamped an anti-cancer drug to better target cancer cells and leave healthy tissues unharmed. Johns Hopkins Medicine researchers have revamped an anti-cancer drug to better target cancer cells and leave healthy tissues unharmed. Scientists have dubbed this type of targeted approach a "prodrug" -- a medicine designed to release its payload in a particular area of the body and in no other areas. The Johns Hopkins-discovered prodrug, called DRP-104 (sirpiglenastat), is in early-stage clinical trials in people with advanced solid tumors. The newly published studies in mice show that the augmented drug preferentially eliminates cancer cells but does not harm healthy cells. A report of their experiments is published November 16 in Science Advances. "Our goal was to modify an old cancer drug that had shown robust efficacy but was too toxic, especially to the gut, to be developed clinically. To do this, we used a prodrug approach. What is unique about our approach is that we utilized a novel chemistry design to create a prodrug that was simultaneously bio-activated in cancer cells but bio-inactivated in healthy tissues such as the gut. This preferential targeting of the payload to cancer cells is now enabling this efficacious class of drugs to be reevaluated safely in people," says study author Barbara Slusher, Ph.D., M.A.S., director of the Johns Hopkins Drug Discovery Program and professor of neurology, pharmacology and molecular sciences, psychiatry, neuroscience, medicine and oncology at the Johns Hopkins University School of Medicine. The newly modified prodrug takes advantage of a common property of cancer cells: a voracious appetite for an amino acid called glutamine, which is a critical building block for proteins, lipids and nucleotides, as well as for energy formation. Rapidly growing cancer cells use a tremendous amount of glutamine, a phenomenon called "glutamine addiction," but other healthy cells with rapid turnover, like those lining the gut, also rely on glutamine. Co-author Rana Rais, Ph.D., an associate professor of neurology and pharmacology, says, "DRP-104 is a tumor-targeted prodrug of the glutamine mimic drug called DON (6-Diazo-5-Oxo-L-norleucine), which inhibits multiple glutamine-utilizing enzymes in cancer cells. Many early studies of DON showed it was robustly efficacious in people and mice, but its development was halted due to its toxicity to normal tissues, especially the gut." Development of this promising class of drugs did not resume until Slusher, Rais and team decided to make chemical modifications to DON. "We added chemical groups, called promoieties, to DON that rendered it inactive in the body until it reached the tumor, where the promoieties were clipped off by enzymes that are abundant in the tumor but not in the gut," says Slusher, who is a member of the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy. "This specific prodrug design made DON targeted to its intended destination (tumor) and have less of an impact on healthy cells elsewhere." For the new study, researchers gave the original DON drug and the souped-up DRP-104 drug to mice implanted with tumors. In mice that received DRP-104, the researchers found 11 times more active drug in the tumor compared with the gastrointestinal tract (gut). Both drugs completely wiped out the tumor, but DON caused more gut toxicity in the mice than DRP-104. Slusher and study co-authors Rana Rais, Pavel Majer and Jonathan Powell co-founded a biotechnology company, Dracen Pharmaceuticals Inc, which licensed this new prodrug for clinical development. DRP-104 is in phase I/II clinical trials at sites across the U.S., including the Johns Hopkins Kimmel Cancer Center, for people with advanced-stage solid tumors. Slusher says her Johns Hopkins Drug Discovery lab is also actively looking for other drugs that have failed clinical trials because of toxicity problems. They hope to apply this same prodrug design to medicines for other conditions. This research was funded by the National Institutes of Health's National Cancer Institute and National Institute of Neurological Disorders and Stroke R01CA193895, R01CA229451, R01NS103927, R01CA226765, Bloomberg Kimmel for Cancer Immunotherapy at Johns Hopkins and CureSearch for Children's Cancer. Additional Johns Hopkins authors of the study includeKathryn Lemberg, Lukáš Tenora, Matthew Arwood, Arindom Pal, Jesse Alt, Ying Wu, Jenny Lam, Joanna Marie Aguilar, Liang Zhao, Diane Peters, Carolyn Tallon, Rajeev Pandey, Ajit Thomas, Ranjeet Dash, Tanguy Seiwert, Robert Leone and Jonathan Powell. Pavel Majer is from the Academy of Sciences of the Czech Republic. Slusher, Rais, Tenora, Majer, Alt and Powell are inventors on Johns Hopkins University patents covering novel glutamine antagonist prodrugs described in this research. These patents have been licensed to Dracen Pharmaceuticals Inc. Slusher, Rais, Majer and Powell are founders and hold equity in Dracen Pharmaceuticals Inc. Slusher also serves as a scientific consultant to Dracen. Under a license agreement between Dracen Pharmaceuticals, Inc. and the Johns Hopkins University, the University is entitled to royalty distributions related to technology cited in the study and referenced in this story. This arrangement has been reviewed and approved by The Johns Hopkins University in accordance with its conflict of interest policies.

While the world has largely been focused on the development of vaccines and therapeutics for COVID-19, the U.S. FDA has remained busy lining up potential approvals of medications for other diseases and illnesses. While the world has largely been focused on the development of vaccines and therapeutics for COVID-19, the U.S. Food and Drug Administration (FDA) has remained busy lining up potential approvals of medications for other diseases and illnesses. Many of these drugs have been granted Fast Track designation over the past several weeks, which is intended to expedite the review of these treatments. BioSpace takes a look at some of the most recent medications to receive this designation. Astellas Pharma – The FDA granted Fast Track designation to Astellas Pharma’s ASP5354 , an imaging agent being investigated for intraoperative ureter visualization in patients undergoing minimally invasive and open abdominopelvic surgeries. ASP5354, a derivative of indocyanine green that fluoresces upon excitation with a particular wavelength of near-infrared light, is an optical imaging agent being developed by Astellas’ Rx+ business as a surgical adjunct to lessen the likelihood of iatrogenic ureteral injury (IUI) during complex abdominal and pelvic surgeries such as colorectal or gynecologic surgeries. A Phase II study is currently underway to evaluate the safety and efficacy of ASP5354 in patients undergoing colorectal surgery. One week before the FDA granted Fast Track to ASP5354 , the regulatory agency also awarded the designation to Astellas for the development of ASP0367/MA-0211 as a potential treatment for primary mitochondrial myopathies (PMM). ASP0367 will be entering a Phase II / III study to validate the efficacy and safety in PMM patients. Earlier data suggest ASP0367, an orally administered PPARδ modulator, could improve exercise intolerance and fatigue in PMM patients by increasing the number and enhancing the function of mitochondria in patient’s cells. There is no FDA-approved treatment for PMM, a rare disease with a high unmet medical need. BioMarin – California-based BioMarin was awarded Fast Track designation for BMN 307 , an investigational gene therapy for the treatment of patients with phenylketonuria (PKU). In September, BioMarin dosed the first patients in a Phase I/II study of BMN 307, an AV5-phenylalanine hydroxylase (PAH) gene therapy designed to normalize blood phenylalanine concentration levels in patients with PKU by inserting a correct copy of the PAH gene into liver cells. Both the FDA and European Medicines Agency granted BMN 307 Orphan Drug designation. If BMN 307 passes regulatory muster, it will be the third treatment for PKU in the company’s pipeline. LogicBio Therapeutics – Kentucky-based LogicBio announced this morning the FDA awarded Fast Track designation to its methylmalonic acidemia (MMA) candidate LB-001. Clinical trials for the gene editing treatment LB-001 are expected to begin in 2021. The trial will be a Phase I/II study designed to assess the safety and tolerability of a single intravenous infusion of LB-001 in pediatric patients with MMA. Inventiva —Last month, France’s Inventiva secured Fast Track designation for odiparcil, the company’s clinical-stage drug candidate for the treatment of MPS type VI (MPS VI), a rare and progressive genetic disorder. Odiparcil is an orally-available small molecule that acts on the underlying cause of the symptoms of mucopolysaccharidosis, a group of rare, progressive genetic disorders. Odiparcil has been granted Orphan Drug designation by both the FDA and the European Medicines Agency and also obtained Rare Pediatric Disease designation in the U.S. for the treatment of MPS VI. PMV Pharma – The FDA granted Fast Track designation to New Jersey’s PMV Pharma for its lead product candidate PC14586, for the treatment of cancer patients with locally advanced or metastatic solid tumors that have a p53 Y220C mutation. There are currently no FDA-approved medicines that target the p53 Y220C mutation. The p53 Y220C mutation is associated with many cancers including but not limited to breast, non-small cell lung cancer, colorectal, pancreatic and ovarian cancers. PC14586 is a first-in-class small molecule designed to structurally correct the p53 Y220C mutant protein. PMV Pharma plans to conduct a Phase I/II open-label, multicenter study to assess the safety, tolerability, pharmacokinetics, and anti-tumor activity of PC14586 in adult patients with a p53 Y220C mutation in locally advanced or metastatic solid tumors. Xeris Pharmaceuticals – Chicago’s Xeris Pharmaceuticals received the designation for XP-0863 (diazepam non-aqueous injection) for the treatment of acute repetitive seizures. Following an end of Phase Ib meeting with the FDA, the regulatory agency approved Xeris to launch a Phase III study in both pediatric and adult patients with epilepsy. Xeris’ XP-0863 was previously granted orphan designations both for the treatment of acute repetitive seizures and for the treatment of Dravet Syndrome. X4 Pharmaceuticals – In early October, the FDA granted Fast Track to Boston’s X4 Pharmaceuticals for its lead asset mavorixafor , for the treatment of adult patients with WHIM (Warts, Hypogammaglobulinemia, Infections and Myelokathexis) syndrome, a rare, inherited, primary immunodeficiency disease caused by genetic mutations in the CXCR4 receptor gene. Mavorixafor is a potential first-in-class, once-daily, oral, small molecule antagonist of chemokine receptor CXCR4, currently being investigated in a global pivotal Phase III clinical trial for the treatment of WHIM syndrome. Mavorixafor was previously granted Breakthrough Therapy designation by the FDA, as well as Orphan Drug status by the FDA and the European Commission for the treatment of WHIM syndrome. Dracen Pharmaceuticals – New York’s Dracen Pharmaceuticals secured Fast Track designation for the company’s novel glutamine antagonist DRP-104 for the treatment of advanced, previously treated non-small cell lung cancer (NSCLC) patients whose tumors express mutations in KEAP1, NFE2L2 and/or STK11. The asset is currently in early-stage clinical studies.