Flank Pain

MALVERN, Pa. & PARSIPPANY, N.J.--( BUSINESS WIRE )--Venatorx Pharmaceuticals (Venatorx) and Melinta Therapeutics (Melinta) announced today that the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) regarding the New Drug Application (NDA) for cefepime-taniborbactam, a beta-lactam/beta-lactamase inhibitor (BL/BLI) combination antibiotic under review as a potential treatment for adult patients with complicated urinary tract infections (cUTI), including acute pyelonephritis caused by susceptible gram-negative microorganisms. The CRL did not identify clinical safety or efficacy issues in the NDA, and the FDA did not request any new clinical trials to support the approval of cefepime-taniborbactam. The FDA requested additional chemistry, manufacturing, and controls (CMC) and related data about the drug, testing methods, and manufacturing process. “While we are disappointed with this setback, we maintain utmost confidence in cefepime-taniborbactam. We are already hard at work generating the additional requested CMC data, and we will continue to work closely with the FDA so that we can make this important new medicine available to patients as quickly as possible,” said Christopher J. Burns, Ph.D., Chief Executive Officer of Venatorx. Melinta Chief Executive Officer and President, Christine Ann Miller added, “We are committed to our plans of supporting the US commercialization of this drug, which we believe when approved, will offer healthcare providers an important therapy for adult patients suffering from complicated urinary tract infections including acute pyelonephritis caused by susceptible gram-negative microorganisms.” About Cefepime-Taniborbactam Cefepime-taniborbactam is an investigational intravenous (IV) beta-lactam/beta-lactamase inhibitor (BL/BLI) antibiotic combination being developed for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis, and hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) in adults. Cefepime, a fourth-generation cephalosporin, is a widely used beta-lactam (BL) antibiotic with more than two decades of proven safety and clinical utility against susceptible gram-negative and gram-positive bacteria. Taniborbactam is a beta-lactamase inhibitor (BLI) that, in combination with cefepime, is being studied as a potential treatment option for patients with serious bacterial infections caused by antibiotic resistant gram-negative bacteria, most notably Extended Spectrum Beta-lactamase (ESBL)-expressing Enterobacterales, carbapenem-resistant Enterobacterales (CRE), and multidrug-resistant (MDR) Pseudomonas aeruginosa (MDR-PA), which can include carbapenem-resistant P. aeruginosa (CRPA). Cefepime-taniborbactam has been granted Qualified Infectious Disease Product (QIDP) and Fast Track designations by the U.S. Food and Drug Administration (FDA). Fast Track designation is designed to facilitate the development, and to expedite the review of drugs to treat serious conditions that do not have sufficient treatment options. QIDP designation provides certain incentives for the development of new antibiotics, including priority review, as well as a five-year regulatory exclusivity extension. QIDP was authorized under the Generating Antibiotic Incentives Now (GAIN) Act of 2012, as part of the FDA Safety and Innovation Act, to underscore the urgency in development of new antibiotics. About Gram-Negative Infections and Antimicrobial Resistance (AMR) In a recent report on AMR, the U.S. Centers for Disease Control and Prevention (CDC) reported rates of resistance have increased significantly in the U.S. among bacterial pathogens including those commonly causing cUTI, pyelonephritis, and bacteremia. The CDC also cited that there are more than 2.8 million AMR infections annually in the U.S., which are directly related to more than 35,000 deaths. [1] Between 2014 and 2019, an analysis of U.S. UTI patients determined that 4.4% of cases were carbapenem resistant (CR) and 24.5% of U.S. UTI patients were bacteremic with 1.7% of cases caused by a CR pathogen. Patients with CR infections had a significantly longer hospital length of stay (LOS), were less likely to be discharged home, had a higher readmission rate, and had greater LOS-associated charges than patients with carbapenem-susceptible infections. Additionally, patients with bacteremia (urosepsis) due to CR pathogens had a significantly higher rate of mortality than those with carbapenem susceptible pathogens. [2] Gram-negative bacteria have multiple AMR mechanisms that continue to adapt in response to increases in antibiotic usage. Carbapenems are broad-spectrum antibiotics that have been widely used to treat infections caused by multidrug-resistant gram-negative bacteria, including Enterobacterales. With the increased global use of carbapenems, CRE have emerged, which have limited treatment options and are associated with increased morbidity and mortality. Resistance to carbapenems among Enterobacterales is primarily achieved by production of carbapenemases, which are enzymes capable of hydrolyzing carbapenem antibiotics and most other beta-lactams and fall into two distinct families: serine beta-lactamases and metallo-beta-lactamases (MBLs). K lebsiella pneumoniae carbapenemase (KPC), a class-A serine beta-lactamase, is one of the most prevalent carbapenemases, and New Delhi MBL (NDM) and Verona Integron-encoded MBL (VIM) are common variants of MBLs identified in gram-negative infections due to Enterobacterales and P. aeruginosa. According to an IHMA surveillance study in 2018-2019 and a JMI U.S. Surveillance study from 2021, MBLs were the most commonly identified carbapenem resistance mechanism globally among Enterobacterales isolates, with ~16 to 18% of U.S. CRE isolates carrying MBLs. [3,4] While CRPA is also increasing in some geographies due to emergence of MBLs, MDR-PA, which may exhibit resistance to carbapenems, represents an increasing challenge for clinicians and their patients in the U.S. and globally due to the paucity of treatment options for this primarily hospital-associated pathogen. Especially outside the U.S., CRPA may carry carbapenemases including MBLs (i.e., VIM); however, non-carbapenemase resistance mechanisms (i.e., efflux pumps, porins) also contribute to the growing global resistance of MDR-PA and CRPA. [5] If AMR infections continue on this trajectory, it has been projected that an estimated 10 million people will die per year of resistant infections by 2050—a number that surpasses the projected annual number of deaths (8.2 million) caused by cancer—and the cumulative cost to the global economy could be as high as U.S. $100 trillion. [6] In the U.S., estimates have reached as high as U.S. $20 billion in excess direct healthcare costs, with an additional U.S. $35 billion associated with lost productivity. [7] By 2050, the world is at risk of losing up to 3.8% of its annual gross domestic product with an annual shortfall of up to U.S. $3.4 trillion by 2030, a figure on par with losses attributable to the 2008 global financial crisis. [8] The Infectious Disease Society of America (IDSA) maintains updated guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections online at https://www.idsociety.org/practice-guideline/amr-guidance/ . [9] For those patients who do not respond to current treatment, new antibiotic therapies are needed to combat AMR. About Complicated Urinary Tract Infections Complicated UTIs, which include pyelonephritis, are defined as urinary tract infections ascending from the bladder accompanied by local and systemic signs and symptoms, including fever, chills, malaise, flank pain, back pain, and/or costovertebral angle pain or tenderness, that usually occur in the presence of a functional or anatomical abnormality of the urinary tract or in the presence of catheterization. Bacteremia can arise secondary to infections like cUTI and can result in substantial morbidity and mortality. [1] Annually in U.S., it is estimated that more than 3 million cUTI patients will be diagnosed and require antibiotic therapy leading to over $6 billion in annualized 30-day costs. [10] About Venatorx Pharmaceuticals Venatorx is a private, late-stage clinical pharmaceutical company focused on improving health outcomes for patients with multidrug-resistant bacterial infections and hard-to-treat viral infections. Venatorx’s lead program, cefepime-taniborbactam, is a clinical-stage antibiotic that completed a Phase 3 study in adults with complicated urinary tract infections (cUTI), including pyelonephritis. In October 2022, BARDA awarded a contract of up to $318M for development and procurement of cefepime-taniborbactam for the treatment of melioidosis and multi-drug resistant infections. Cefepime-taniborbactam is currently under review by the FDA for the treatment of cUTI, including acute pyelonephritis. Venatorx is also developing an oral antibacterial, ceftibuten-ledaborbactam (formerly known as VNRX-7145), for the treatment of cUTI, including pyelonephritis, caused by certain bacteria in adult patients with limited treatment options; this product is completing Phase 1 and will advance directly to a global Phase 3 cUTI clinical trial. For more information about Venatorx and its anti-infectives portfolio, please visit www.venatorx.com . About Melinta Therapeutics LLC Melinta Therapeutics is a biopharmaceutical company dedicated to providing innovative therapies to people impacted by acute and life-threatening illnesses. We focus our expanding portfolio on serving patients with an unmet need because that’s how we make the most meaningful impact. At Melinta, we’re visionaries dedicated to innovation while staying grounded in what matters most: patients. Our portfolio currently includes seven commercial-stage products: BAXDELA ® (delafloxacin), KIMYRSA ® (oritavancin), MINOCIN ® (minocycline) for Injection, ORBACTIV ® (oritavancin), REZZAYO ® (rezafungin for injection), TOPROL-XL ® (metoprolol succinate) and VABOMERE ® (meropenem and vaborbactam). For more information about Melinta Therapeutics, our commitment to patients, and to learn about our portfolio of therapies, visit www.melinta.com . Funding Partners and Collaborators for Cefepime-Taniborbactam This project has been funded in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract number HHSN272201300019C, and Wellcome Trust under Award No. 360G-Wellcome-101999/Z/13/Z, and has continued with federal funds from the Department of Health and Human Services; Administration for Strategic Preparedness and Response, Biomedical Advanced Research and Development Authority, under contract numbers HHSO100201900007C and 75A50122C00080. In September 2018, Venatorx entered into an exclusive license agreement with Everest Medicines to support the development, registration, and commercialization of cefepime-taniborbactam in Greater China, South Korea, and select countries in Southeast Asia. Everest will be solely responsible for the commercialization of cefepime-taniborbactam in its territory and Venatorx will be eligible to receive royalties on net sales. In April 2020, Venatorx and the GARDP Foundation (GARDP) announced a collaboration to accelerate the development of, and access to, cefepime-taniborbactam for adult and pediatric populations. Venatorx has granted GARDP exclusive rights to distribute and sub-distribute cefepime-taniborbactam, once it is approved for clinical use, in low- and lower-middle-income countries. In November 2023, Venatorx and Melinta entered into an exclusive License Agreement to facilitate a strategic partnership in the U.S. to commercialize cefepime-taniborbactam, a beta-lactam / beta-lactamase inhibitor (BL/BLI) combination antibiotic being developed for the treatment of complicated urinary tract infections (cUTI) and hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) in adults. In December 2023, Venatorx entered into an agreement with Menarini Group, who acquired the exclusive rights to commercialize, upon approval of relevant health authorities, cefepime-taniborbactam in 96 countries in Europe, Latin America, Middle East, Turkey and North Africa and the Commonwealth of Independent States (CIS). References [1] Antibiotic Resistance Threats in the United States 2019, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. [2] Shields et al. Burden of illness in U.S. hospitals due to carbapenem-resistant gram-negative urinary tract infections in patients with or without bacteremia. BMC Infectious Diseases (2021) 21:572. [3] Estabrook et al. Epidemiology of Resistance Determinants Identified in Meropenem-Nonsusceptible Enterobacterales Collected as Part of a Global Surveillance Study, 2018 to 2019. Antimicrobial Agents and Chemotherapy; May 2023, Vol. 67, Issue 5 [4] Castanheira et al. Increase in the Occurrence of Carbapenem-Resistant Enterobacterales in United States Hospitals from 2019 to 2021 and Activity of Novel Beta-Lactams/Beta-Lactamase Inhibitor Combinations Against these Isolates, 2022 ID Week Abstract #664. Open Forum Infectious Diseases, Volume 9, Issue Supplement_2, December 2022, ofac492.716 [5] Jean S-S, Harnod D and Hsueh P-R (2022) Global Threat of Carbapenem Resistant Gram-Negative Bacteria. Front. Cell. Infect.Microbiol.12:823684. doi:10.3389/fcimb.2022.823684[6] O’Neill, J. ‘Tackling Drug-Resistant Infections Globally: Final Report and Recommendations’. Review on Antimicrobial Resistance. May 2016. [6] O’Neill, J. ‘Tackling Drug-Resistant Infections Globally: Final Report and Recommendations’. Review on Antimicrobial Resistance. May 2016. [7] Antibiotic Resistance Threats in the United States 2013, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. [8] World Bank. Final Report Drug Resistant Infections: A Threat to Our Economic Future. Mar 2017. [9] Infectious Disease Society of America maintains updated guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections posted online at https://www.idsociety.org/practice-guideline/amr-guidance/ accessed July 2023 [10] Carreno et al. Longitudinal, nationwide, cohort study to assess incidence, outcomes, and costs associated with complicated urinary tract infection. Open Forum Infectious Diseases. 8 October 2019

Cefepime-taniborbactam has also demonstrated in vitro activity against CDC Urgent and Serious Threat Pathogens carbapenem-resistant Enterobacterales, multidrug-resistant Pseudomonas aeruginosa and Extended Spectrum Beta-lactamase-producing Enterobacterales In the CERTAIN-1 cUTI Phase 3 study, cefepime-taniborbactam demonstrated clinical efficacy in patients with infections due to Extended Spectrum Beta-lactamase producing Enterobacterales and carbapenem-resistant Enterobacterales PDUFA action date set for February 22, 2024 MALVERN, Pa.--(BUSINESS WIRE)-- Venatorx Pharmaceuticals, a private, pre-commercial pharmaceutical company focused on improving health outcomes for patients with difficult-to-treat drug resistant gram-negative bacterial infections and viral infections, today announced that the U.S. Food and Drug Administration (FDA) has accepted the company’s New Drug Application (NDA) for cefepime-taniborbactam, an investigational beta-lactam/beta-lactamase inhibitor (BL/BLI) antibiotic for the potential treatment of adult patients with complicated urinary tract infections (cUTI), including pyelonephritis. The FDA previously granted Qualified Infectious Disease Product and Fast Track designations to cefepime-taniborbactam. The FDA has granted Priority Review of the NDA with a Prescription Drug User Fee Act (PDUFA) target action date of February 22, 2024. “The NDA acceptance represents the culmination of unwavering dedication, scientific excellence, and the collaborative efforts of our talented team, partners, and clinical investigators,” said Christopher J. Burns, Ph.D., Chief Executive Officer of Venatorx. “Cefepime-taniborbactam exemplifies our commitment to innovation and improving patient outcomes. By addressing the evolving and increasing challenges posed by antimicrobial resistance, we aim to make a meaningful impact on global public health.” The cefepime-taniborbactam NDA is supported by results from the pivotal Phase 3 study, CERTAIN-1, evaluating the efficacy and safety of cefepime-taniborbactam compared to meropenem in adults with cUTI, including acute pyelonephritis. Cefepime-taniborbactam was superior to meropenem for the primary efficacy endpoint of composite microbiologic and clinical success at the Test of Cure (TOC) visit (Day 19-23) in the microbiological intent-to-treat (microITT) population. Cefepime-taniborbactam was well-tolerated and no new safety findings were identified. “Due to its broad spectrum of in-vitro activity against established and rapidly increasing mechanisms of carbapenem resistance such as serine- and metallo-beta-lactamases and the positive results demonstrated in CERTAIN-1, cefepime-taniborbactam, if approved, will address a critical unmet need and be a potentially essential treatment option in the continuing fight against antimicrobial resistance in gram-negative bacterial infections,” said Paul McGovern, M.D., Senior Vice President, Medical Sciences at Venatorx. “Patients with cUTIs, including pyelonephritis, and their healthcare providers should have a new treatment option when confronted with infections due to these antibacterial resistant infections.” About the CERTAIN-1 Phase 3 Clinical Trial CERTAIN-1 (Cefepime Rescue with Taniborbactam in cUTI) was a global, randomized, double-blind, active-controlled non-inferiority Phase 3 study evaluating the efficacy, safety, and tolerability of cefepime-taniborbactam compared to meropenem in adults with cUTI, including acute pyelonephritis. The trial enrolled 661 adult patients who were randomized 2:1 to receive cefepime-taniborbactam 2.5g q8h or meropenem 1g q8h for 7 days (up to 14 days for patients with bacteremia). The primary efficacy endpoint evaluated the composite clinical and microbiologic response (i.e., bacterial eradication) at the Test of Cure (TOC) visit (Day 19-23) in the microbiological intent-to-treat (microITT) population. Cefepime-taniborbactam met the primary efficacy endpoint of statistical noninferiority (NI) to meropenem in the microITT population at TOC with composite microbiologic and clinical success occurring in 70.6% of cefepime-taniborbactam treated patients and 58.0% of meropenem treated patients (treatment difference 12.6; 95% CI, 3.1, 22.2). A prespecified superiority assessment was conducted following confirmation of NI. Superiority was concluded as the lower bound of the 95% CI for noninferiority was greater than zero. The pre-specified superiority test (two-sided p-value = 0.0088) demonstrated the strength of evidence associated with the superiority conclusion for the composite endpoint at TOC. The efficacy of cefepime-taniborbactam was sustained for the composite microbiologic and clinical response at the Late-Follow-Up (Day 28-35) visit. Rates of treatment-emergent adverse events (TEAEs) were 35.5% for cefepime-taniborbactam and 29.0% for meropenem. Serious TEAEs occurred in 2.0% and 1.8% of cefepime-taniborbactam and meropenem treated patients, respectively. Treatment discontinuations due to TEAEs occurred in 3.0% of cefepime-taniborbactam patients and 0.9% of meropenem treated patients. There was one death in the cefepime-taniborbactam treatment group, which was unrelated to study treatment as assessed by the investigator. About Cefepime-Taniborbactam Cefepime-taniborbactam is an investigational intravenous (IV) beta-lactam/beta-lactamase inhibitor (BL/BLI) antibiotic combination being developed for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis, and hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP). Cefepime-taniborbactam was accepted for review by the US FDA for cUTI, including pyelonephritis with a PDUFA date of February 22, 2024. Cefepime, a fourth-generation cephalosporin, is a widely used beta-lactam (BL) antibiotic with more than two decades of proven safety and clinical utility against susceptible gram-negative and gram-positive bacteria. Taniborbactam is a beta-lactamase inhibitor (BLI) that, in combination with cefepime, is being studied as a potential treatment option for patients with serious bacterial infections caused by antibiotic resistant gram-negative bacteria, most notably extended spectrum beta-lactamase (ESBL)-expressing Enterobacterales, carbapenem-resistant Enterobacterales (CRE), and multidrug-resistant (MDR) Pseudomonas aeruginosa (MDR-PA), which can include carbapenem-resistant P. aeruginosa (CRPA). About Gram-Negative Infections and Antimicrobial Resistance (AMR) In a recent report on AMR, the U.S. Centers for Disease Control and Prevention (CDC) reported rates of resistance have increased significantly in the U.S. among bacterial pathogens including those commonly causing cUTI, pyelonephritis, and bacteremia. The CDC also cited that there are more than 2.8 million AMR infections annually in the U.S., which are directly related to more than 35,000 deaths.[1] Between 2014 and 2019, an analysis of U.S. UTI patients determined that 4.4% of cases were carbapenem resistant (CR) and 24.5% of U.S. UTI patients were bacteremic with 1.7% of cases caused by a CR pathogen. Patients with CR infections had a significantly longer hospital length of stay (LOS), were less likely to be discharged home, had a higher readmission rate, and had greater LOS-associated charges than patients with carbapenem-susceptible infections. Additionally, patients with bacteremia (urosepsis) due to CR pathogens had a significantly higher rate of mortality than those with carbapenem susceptible pathogens.[2] Gram-negative bacteria have multiple AMR mechanisms that continue to adapt in response to increases in antibiotic usage. Carbapenems are broad-spectrum antibiotics that have been widely used to treat infections caused by multidrug-resistant gram-negative bacteria, including Enterobacterales. With the increased global use of carbapenems, CRE have emerged, which have limited treatment options and are associated with increased morbidity and mortality. Resistance to carbapenems among Enterobacterales is primarily achieved by production of carbapenemases, which are enzymes capable of hydrolyzing carbapenem antibiotics and most other beta-lactams and fall into two distinct families: serine beta-lactamases and metallo-beta-lactamases (MBLs). Common variants of MBLs include New Delhi MBL (NDM) and Verona Integron-encoded MBL (VIM). According to an IHMA surveillance study in 2018-2019 and JMI US Surveillance study from 2021, MBLs were the most commonly identified carbapenem resistance mechanism globally among Enterobacterales isolates, with ~16 to 18% of US CRE isolates carrying MBLs. [3,4] While CRPA is also increasing in some geographies due to emergence of MBLs, MDR-PA, which may exhibit resistance to carbapenems, represents an increasing challenge for clinicians and their patients in the US and globally due to the paucity of treatment options for this primarily hospital-associated pathogen. Especially outside the US, CRPA may carry carbapenemases including MBLs (i.e., VIM); however, non-carbapenemase resistance mechanisms (i.e., efflux pumps, porins) also contribute to the growing global resistance of MDR-PA and CRPA.[5] If AMR infections continue on this trajectory, it has been projected that an estimated 10 million people will die per year of resistant infections by 2050—a number that surpasses the projected annual number of deaths (8.2 million) caused by cancer—and the cumulative cost to the global economy could be as high as US$100 trillion.[6] In the U.S., estimates have reached as high as US$20 billion in excess direct healthcare costs, with an additional US$35 billion associated with lost productivity.[7] By 2050, the world is at risk of losing up to 3.8% of its annual gross domestic product with an annual shortfall of up to US$3.4 trillion by 2030, a figure on par with losses attributable to the 2008 global financial crisis.[8] The Infectious Disease Society of America (IDSA) maintains updated guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections online at [9] For those patients who do not respond to current treatment, new antibiotic therapies are needed to combat AMR. About Complicated Urinary Tract Infections Complicated UTIs, which include pyelonephritis, are defined as urinary tract infections ascending from the bladder accompanied by local and systemic signs and symptoms, including fever, chills, malaise, flank pain, back pain, and/or costovertebral angle pain or tenderness, that usually occur in the presence of a functional or anatomical abnormality of the urinary tract or in the presence of catheterization. Bacteremia can arise secondary to infections like cUTI and can result in substantial morbidity and mortality.[2] Annually in U.S., it is estimated that more than 3 million cUTI patients will be diagnosed and require antibiotic therapy leading to over $6 billion in annualized 30-day costs.[10] Funding Partners and Collaborators for Cefepime-Taniborbactam Development of cefepime-taniborbactam began with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services under contract number HHSN272201300019C, and Wellcome Trust under award number 360G-Wellcome-101999/Z/13/Z, and continues with federal funds from the Biomedical Advanced Research and Development Authority, Administration for Strategic Preparedness and Response, Department of Health and Human Services under contract number HHSO100201900007C. In September 2018, Venatorx entered into an exclusive license agreement with Everest Medicines to support the development, registration, and commercialization of cefepime-taniborbactam in People’s Republic of China, Macau, Hong Kong, Taiwan, South Korea, and select countries in Southeast Asia (the “Territory”). In April 2020, Venatorx and GARDP announced a collaboration to accelerate the development of, and access to, cefepime-taniborbactam for adult and pediatric populations. Venatorx has granted GARDP exclusive rights to distribute and sub-distribute cefepime-taniborbactam, once it is approved for clinical use, in low- and lower middle-income countries About Venatorx Pharmaceuticals, Inc. Venatorx is a private, pre-commercial pharmaceutical company focused on improving health outcomes for patients with difficult-to-treat drug resistant gram-negative bacterial infections and viral infections. Venatorx’s lead asset, cefepime-taniborbactam, is an investigational antibiotic that completed a Phase 3 study (NCT03840148) in adults with complicated urinary tract infections (cUTI), including pyelonephritis and is under FDA review with a PDUFA action date of February 22, 2024. In October 2022, BARDA awarded a contract of up to $318M to Venatorx for development and procurement of cefepime-taniborbactam for the treatment of melioidosis and multidrug-resistant infections. As part of its broader pipeline, Venatorx is also developing an oral antibacterial, ceftibuten-ledaborbactam etzadroxil, that is currently in Phase 1 clinical studies. For more information about Venatorx and its anti-infectives portfolio, please visit . Forward Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements regarding the potential, safety, efficacy, and regulatory and clinical development of Venatorx Pharmaceuticals’ product candidates. References [1] Antibiotic Resistance Threats in the United States 2019, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. [2] Shields et al. Burden of illness in U.S. hospitals due to carbapenem-resistant gram-negative urinary tract infections in patients with or without bacteremia. BMC Infectious Diseases (2021) 21:572. [3] Estabrook et al. Epidemiology of Resistance Determinants Identified in Meropenem-Nonsusceptible Enterobacterales Collected as Part of a Global Surveillance Study, 2018 to 2019. Antimicrobial Agents and Chemotherapy; May 2023, Vol. 67, Issue 5 [4] Castanheira et al. Increase in the Occurrence of Carbapenem-Resistant Enterobacterales in United States Hospitals from 2019 to 2021 and Activity of Novel Beta-Lactams/Beta-Lactamase Inhibitor Combinations Against these Isolates, 2022 ID Week Abstract #664. Open Forum Infectious Diseases, Volume 9, Issue Supplement_2, December 2022, ofac492.716 [5] Jean S-S, Harnod D and Hsueh P-R (2022) Global Threat of Carbapenem Resistant Gram-Negative Bacteria. Front.Cell. Infect.Microbiol.12:823684. doi:10.3389/fcimb.2022.823684[6] O’Neill, J. ‘Tackling Drug-Resistant Infections Globally: Final Report and Recommendations’. Review on Antimicrobial Resistance. May 2016. [6] O’Neill, J. ‘Tackling Drug-Resistant Infections Globally: Final Report and Recommendations’. Review on Antimicrobial Resistance. May 2016. [7] Antibiotic Resistance Threats in the United States 2013, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. [8] World Bank. Final Report Drug Resistant Infections: A Threat to Our Economic Future. Mar 2017. [9] Infectious Disease Society of America maintains updated guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections posted online at accessed July 2023 [10] Carreno et al. Longitudinal, nationwide, cohort study to assess incidence, outcomes, and costs associated with complicated urinary tract infection. Open Forum Infectious Diseases. 8 October 2019

32-patient, multi-center study showed 9% occurrence of ureteral stenosis and 10% discontinuation rate All three stenosis patients were treated without later recurrence or chronic stenosis PRINCETON, N.J.--(BUSINESS WIRE)-- UroGen Pharma Ltd. (Nasdaq: URGN), a biotech company dedicated to developing and commercializing innovative solutions that treat urothelial and specialty cancers, today highlights results from a retrospective multi-center study of 32 patients evaluating the safety of antegrade administration of JELMYTO (mitomycin) for pyelocalyceal solution via percutaneous nephrostomy tube for the treatment of patients with upper tract urothelial carcinoma (UTUC). The study titled, “Antegrade Administration of Mitomycin Gel for UTUC via Percutaneous Nephrostomy Tube: A Multi-Institutional Retrospective Cohort Study,” provides additional real-world evidence of a favorable safety and tolerability pro JELMYTO when administered via percutaneous nephrostomy tube and is published in The British Journal of Urology International, November Issue. This retrospective study assessed the safety and feasibility of antegrade administration of JELMYTO via a percutaneous nephrostomy tube (PCNT) in 32 patients from four institutions. Each patient received at least one dose of JELMYTO via PCNT for UTUC, 29 of whom completed induction (at least 5 of 6 doses) and underwent primary disease evaluation (PDE) at a median 17 weeks after the last dose of therapy. At a median follow-up of 15 months following initiation of induction therapy, ureteral stenosis (defined as a discrete narrowing of the ureter on direct visual ureteroscopy, or a constriction identified on retrograde pyelogram at the time of ureteroscopy that required dilation or stenting to pass a ureteroscope for upstream visualization) occurred in three (9%) of patients. None of these patients had recurrent stenosis at a median 16 months follow- up. Other adverse events included fatigue (27%), flank pain (19%), urinary tract infection (12%), sepsis (8%), and hematuria (8%). No patient had impaired renal function during follow-up and there were no treatment-related deaths. Seventeen patients (59%) had no evidence of disease at PDE and had not recurred at a median follow-up of 13 months post induction. “We found that antegrade administration of JELMYTO via a nephrostomy tube offered a low rate of ureteral stenosis and a favorable safety and tolerability pro ” said Kyle Rose, M.D., Urologic Oncology Fellow at Moffitt Cancer Center in Tampa, Fla., and study investigator. “This study adds to the evidence that this form of administration is beneficial in many ways, including the ability to treat the elderly without the use of anesthesia, which can have negative cumulative effects when used repetitively.” In both retrograde and antegrade approaches, JELMYTO can be administered as an outpatient procedure in the clinic. Retrograde administration requires administration by a physician via a ureteral catheter which requires fluoroscopic guidance. Antegrade administration may be performed by trained nursing professionals under clean rather than sterile conditions and does not require fluoroscopy once tube placement is confirmed via nephrostogram at the first instillation. “JELMYTO is approved for antegrade and retrograde administration in patients with LG-UTUC, which gives physicians the added convenience of choosing a method that works best for them and their patients,” said Mark Schoenberg, Chief Medical Officer, UroGen. “Retrograde administration was the only method used in the pivotal OLYMPUS trial. Therefore, UroGen is pleased that this study adds to the growing body of real-world evidence demonstrating that antegrade administration of JELMYTO is a feasible alternative for patients with LG-UTUC.” About the Retrospective Study In this multi-center study, patients undergoing antegrade administration of JELMYTO via PCNT were retrospectively included for analysis from four tertiary referral centers between 2020 and 2022. The primary outcome was safety pro by Common Terminology Criteria for Adverse Events (v5.0). Post-therapy disease burden was assessed by primary disease evaluation (PDE) via ureteroscopy. Thirty-two patients received at least one dose of JELMYTO via PCNT for UTUC, 29 of whom completed induction and underwent PDE. Thirteen (41%) patients had residual tumor present prior to induction therapy. At a median follow up of 15 months following first dose of induction therapy, ureteral stenosis occurred in 3 (9%) patients, all of which were treated without later recurrence or chronic stenosis. Other adverse events included fatigue (27%), flank pain (19%), UTI (12%), sepsis (8%), and hematuria (8%). No patients had impaired renal function during follow up and there were no treatment related deaths. Seventeen patients (59%) had no evidence of disease at PDE and had not recurred at a median follow up of 13 months post induction. Limitations of this study include the retrospective nature and sample size. Some complications and side effects of the antegrade approach were contingent on patient reporting, and thus may be under-reported. Ureteral stenoses were noted incidentally at the time of PDE, and no patients presented with obstructive symptoms. There is a need for larger studies with longer follow-up to study more conclusively any potential advantages of antegrade JELMYTO administration when compared to retrograde instillation. About the Pivotal OLYMPUS Study OLYMPUS (Optimized DeLiverY of Mitomycin for Primary UTUC Study) was an open-label, single-arm Phase 3 clinical study of UGN-101 JELMYTO (mitomycin) for pyelocalyceal solution, to evaluate the safety, tolerability and tumor ablative effect of JELMYTO in patients with low-grade Upper Tract Urothelial Cancer UTUC (LG UTUC). Seventy-one patients were treated at clinical sites across the United States and Israel. Study participants were treated with six weekly instillations of JELMYTO administered via a standard catheter. Four to six weeks following the last instillation, patients underwent a Primary Disease Evaluation (PDE) to determine Complete Response (CR), the primary endpoint of the study. PDE involved a ureteroscopy and wash cytology, a standard microscopic test of cells obtained from the urine to detect cancer and for cause biopsy. Patients who achieved a CR at the PDE timepoint were eligible for the maintenance phase of the trial, during which they could receive monthly maintenance instillations for up to 12 months and were assessed to determine the durability of response with JELMYTO. In the OLYMPUS study, data was generated for the retrograde administration of JELMYTO. In that study, population ureteric obstruction was reported in 58% (n=41) of patients receiving JELMYTO, including 17% (n=12) of patients who experienced Grade 3 obstruction. About LG UTUC LG UTUC is a rare disease managed by endoscopic methods and radical nephroureterectomy. Endoscopic resection and laser ablation attempt to preserve the kidney, though there is a high risk of recurrence that may eventually necessitate removal of the kidney. Although kidney removal is the gold standard for treatment of high-grade UTUC, it may be over-treatment in LG UTUC, as kidney removal offers similar five-year survival as kidney-sparing procedures but is associated with significant morbidity. JELMYTO is efficacious as a primary chemoablative therapy in patients with LG UTUC. About JELMYTO® JELMYTO® (mitomycin) for pyelocalyceal solution is a mitomycin-containing reverse thermal gel containing 4 mg mitomycin per mL gel indicated for primary chemoablative treatment of LG UTUC in adults. It is recommended for primary treatment of biopsy-proven LG UTUC in patients deemed appropriate candidates for renal-sparing therapy. JELMYTO is a viscous liquid when cooled and becomes a semi-solid gel at body temperature. The drug slowly dissolves over four to six hours after instillation and is removed from the urinary tract by normal urine flow and voiding. It is approved for administration in a retrograde manner via ureteral catheter or antegrade through nephrostomy tube. The delivery system allows the initial liquid to coat and conform to the upper urinary tract anatomy. The eventual semisolid gel allows for chemoablative therapy to remain in the collecting system for four to six hours without immediately being diluted or washed away by urine flow. APPROVED USE FOR JELMYTO JELMYTO® is a prescription medicine used to treat adults with a type of cancer of the lining of the upper urinary tract including the kidney called low-grade Upper Tract Urothelial Cancer (LG-UTUC). IMPORTANT SAFETY INFORMATION You should not receive JELMYTO if you have a hole or tear (perforation) of your bladder or upper urinary tract. Before receiving JELMYTO, tell your healthcare provider about all your medical conditions, including if you: are pregnant or plan to become pregnant. JELMYTO can harm your unborn baby. You should not become pregnant during treatment with JELMYTO. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with JELMYTO. Females who are able to become pregnant: You should use effective birth control (contraception) during treatment with JELMYTO and for 6 months after the last dose. Males being treated with JELMYTO: If you have a female partner who is able to become pregnant, you should use effective birth control (contraception) during treatment with JELMYTO and for 3 months after the last dose. are breastfeeding or plan to breastfeed. It is not known if JELMYTO passes into your breast milk. Do not breastfeed during treatment with JELMYTO and for 1 week after the last dose. Tell your healthcare provider if you take water pills (diuretic). How will I receive JELMYTO? Your healthcare provider will tell you to take a medicine called sodium bicarbonate before each JELMYTO treatment. You will receive your JELMYTO dose from your healthcare provider 1 time a week for 6 weeks. It is important that you receive all 6 doses of JELMYTO according to your healthcare provider’s instructions. If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment. Your healthcare provider may recommend up to an additional 11 monthly doses. JELMYTO is given to your kidney through a tube called a catheter. During treatment with JELMYTO, your healthcare provider may tell you to take additional medicines or change how you take your current medicines. After receiving JELMYTO: JELMYTO may cause your urine color to change to a violet to blue color. Avoid contact between your skin and urine for at least 6 hours. To urinate, males and females should sit on a toilet and flush the toilet several times after you use it. After going to the bathroom, wash your hands, your inner thighs, and genital area well with soap and water. Clothing that comes in contact with urine should be washed right away and washed separately from other clothing. JELMYTO may cause serious side effects, including: Swelling and narrowing of the tube that carries urine from the kidney to the bladder (ureteric obstruction). If you develop swelling and narrowing, and to protect your kidney from damage, your healthcare provider may recommend the placement of a small plastic tube (stent) in the ureter to help the kidney drain. Tell your healthcare provider right away if you develop side pain or fever during treatment with JELMYTO. Bone marrow problems. JELMYTO can affect your bone marrow and can cause a decrease in your white blood cell, red blood cell, and platelet counts. Your healthcare provider will do blood tests prior to each treatment to check your blood cell counts during treatment with JELMYTO. Your healthcare provider may need to temporarily or permanently stop JELMYTO if you develop bone marrow problems during treatment with JELMYTO. The most common side effects of JELMYTO include: urinary tract infection, blood in your urine, side pain, nausea, trouble with urination, kidney problems, vomiting, tiredness, stomach (abdomen) pain. You are encouraged to report negative side effects of prescription drugs to the U.S. Food and Drug Administration. Visit or call 1‑800‑FDA‑1088. You may also report side effects to UroGen Pharma at 1-855-987-6436. Please see JELMYTO Full Prescribing Information, including the Patient Information, for additional information. About UroGen Pharma Ltd. UroGen is biotech company dedicated to developing and commercializing innovative solutions that treat urothelial and specialty cancers because patients deserve better options. UroGen has developed RTGel™ reverse-thermal hydrogel, a proprietary sustained release, hydrogel-based platform technology that has the potential to improve therapeutic profiles of existing drugs. UroGen’s sustained release technology is designed to enable longer exposure of the urinary tract tissue to medications, making local therapy a potentially more effective treatment option. UroGen’s first commercial product JELMYTO (mitomycin) for pyelocalyceal solution, and investigational treatment UGN-102 (mitomycin) for intravesical solution for patients with low-grade non-muscle invasive bladder cancer, are designed to ablate tumors by non-surgical means. UroGen is headquartered in Princeton, NJ with operations in Israel. Visit to learn more or follow us on Twitter, @UroGenPharma. Forward-Looking Statements This press release contains forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, statements regarding the potential benefits of antegrade administration as compared to retrograde instillation, including the ability to treat without the use of anesthesia. These statements are subject to a number of risks, uncertainties and assumptions, including, but not limited to: results from initial reports of the antegrade administration of JELMYTO in the publication may not be indicative of results that may be observed in future clinical practice; and potential safety and other complications from the antegrade administration of JELMYTO. In light of these risks and uncertainties, and other risks and uncertainties that are described in the Risk Factors section of UroGen’s Form 10-Q filed with the SEC on November 10, 2022 and other filings that UroGen makes with the SEC from time to time (which are available at ), the events and circumstances discussed in such forward-looking statements may not occur, and UroGen’s actual results could differ materially and adversely from those anticipated or implied thereby. Any forward-looking statements speak only as of the date of this press release and are based on information available to UroGen as of the date of this release. View source version on businesswire.com: Contacts INVESTORS: Vincent Perrone Sr. Director, Investor Relations vincent.perrone@urogen.com 609-460-3588 ext. 1093 MEDIA: Cindy Romano Director, Corporate Communications cindy.romano@urogen.com 609-460-3583 ext. 1083 Source: UroGen Pharma Ltd. View this news release online at: