City Therapeutics Submits Clinical Trial Application for CITY-FXI, an Investigational RNAi Therapeutic Targeting Factor XI for the Treatment of Thromboembolic Diseases
City Therapeutics, Inc., a pioneering biopharmaceutical company focused on advancing the field of RNA interference (RNAi)-based medicine, today announced that it has submitted a Clinical Trial Application (CTA) to the UK Medicines and Healthcare Products Regulatory Agency (MHRA). The CTA seeks authorization to initiate a Phase 1 clinical study evaluating CITY-FXI, an investigational RNAi therapeutic designed to target Factor XI (FXI) — a validated and genetically supported target involved in blood coagulation and thrombus formation.
The submission of this CTA represents a significant corporate and scientific milestone for City Therapeutics, marking its transition from a preclinical-stage to a clinical-stage biotechnology company. The planned clinical study will be the first-in-human evaluation of CITY-FXI and will assess its safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy volunteers.
Advancing a New Paradigm in Anticoagulation Therapy
CITY-FXI is an investigational therapy developed using City Therapeutics’ proprietary RNAi platform technology. The therapeutic candidate is designed to silence the production of Factor XI, a key enzyme in the intrinsic coagulation pathway. FXI plays a critical role in the amplification of thrombin generation and clot formation; however, clinical and genetic studies have shown that individuals with naturally low FXI levels exhibit substantial protection from thromboembolic events—such as deep vein thrombosis (DVT), pulmonary embolism (PE), and ischemic stroke—without experiencing significant bleeding complications.
Traditional anticoagulant therapies, including heparins, vitamin K antagonists (such as warfarin), and direct oral anticoagulants (DOACs), have transformed the treatment of thrombotic disorders over the past several decades. However, these agents are still limited by a narrow therapeutic window, the risk of bleeding, and challenges related to patient adherence and long-term safety. CITY-FXI aims to address these limitations by providing a durable, once-infrequent dosing regimen that reduces clot formation while minimizing the risk of hemorrhage.
This CTA filing marks our transition to a clinical-stage company and underscores our team’s ability to move rapidly and effectively to bring our product candidates into the clinic,” said Andy Orth, Chief Executive Officer of City Therapeutics. “Our long-term vision is to leverage our differentiated RNAi platform to build a deep and diverse pipeline of high-value clinical programs. We believe we have the expertise, scientific insight, and innovative technology to lead the next wave of RNAi breakthroughs.”
Unmet Need in Thromboembolic Disease
Thromboembolic disorders represent one of the leading causes of morbidity and mortality worldwide, contributing to an estimated one in four deaths globally. These diseases encompass a range of conditions in which abnormal clot formation impedes blood flow, potentially resulting in life-threatening complications such as stroke, pulmonary embolism, or myocardial infarction.
Despite major advances in anticoagulant therapy, achieving safe and effective long-term anticoagulation remains an unmet medical challenge. Most available treatments, while effective in preventing clot formation, come at the expense of increased bleeding risk. For many patients, particularly those requiring chronic therapy, this trade-off can result in underdosing, discontinuation, or avoidance of therapy altogether—leaving a large proportion of at-risk individuals insufficiently protected from thrombotic events.
By specifically targeting Factor XI using RNA interference, CITY-FXI has the potential to deliver a novel therapeutic mechanism that separates antithrombotic efficacy from bleeding risk.
Low FXI levels are associated with protection from many thromboembolic diseases such as deep vein thrombosis, pulmonary embolism, and stroke,” said Baisong Mei, M.D., Ph.D., Chief Medical Officer of City Therapeutics. “A large and growing body of scientific evidence suggests that FXI knockdown via RNAi offers a highly direct and efficient means of reducing FXI production. This, in turn, could provide long-term protection against thrombosis while minimizing the bleeding risk that complicates existing anticoagulant therapies. CITY-FXI is designed to meet a critical unmet need for patients who require sustained, safe, and effective anticoagulation.”
Preclinical Data and Scientific Rationale
Preclinical studies conducted by City Therapeutics have demonstrated that CITY-FXI achieves robust and selective suppression of FXI expression in animal models. The compound exhibited strong potency, durable activity lasting several weeks after a single administration, and high specificity for the FXI target gene. Notably, no off-target or safety-related findings have been observed in nonclinical studies to date.
The company’s RNAi platform enables the precise delivery of small interfering RNAs (siRNAs) to hepatocytes, the cells responsible for producing most coagulation factors. This approach allows for sustained target suppression following a single subcutaneous dose, offering the potential for infrequent dosing schedules—perhaps once every few months—which could significantly improve patient adherence and quality of life compared to daily or twice-daily oral anticoagulants.
“From a pharmacological perspective, CITY-FXI’s preclinical data are among the most encouraging we’ve seen in the anticoagulation space,” noted Dr. Mei. “The drug has shown durable knockdown of FXI with a clean safety profile. We believe this validates both our target selection and the strength of our delivery technology.”
Next Steps: Advancing to the Clinic
Following clearance of the CTA by the MHRA, City Therapeutics plans to initiate a Phase 1 clinical trial in healthy adult volunteers. The study will be designed as a randomized, placebo-controlled, single- and multiple-ascending dose trial. Its primary objectives will be to evaluate the safety, tolerability, and pharmacokinetics of CITY-FXI, while secondary objectives will explore its pharmacodynamic effects, including changes in circulating FXI levels and coagulation biomarkers.
Successful completion of this Phase 1 study will pave the way for subsequent Phase 2 evaluations in patients with thromboembolic disorders at elevated risk of clot formation, including those with atrial fibrillation, deep vein thrombosis, or a history of ischemic stroke.
City Therapeutics anticipates generating initial topline results from the Phase 1 study within the first year after trial initiation.
The Promise of RNAi in Cardiovascular Medicine
RNA interference (RNAi) represents one of the most significant advances in molecular medicine over the past two decades. By selectively silencing gene expression, RNAi-based therapeutics can target diseases at their genetic root, enabling a precision-medicine approach that was previously unattainable with conventional small-molecule or antibody-based therapies.
Several RNAi therapies have already been approved for rare genetic and metabolic disorders, demonstrating the platform’s clinical viability, durability, and safety. City Therapeutics aims to extend this success into the cardiovascular and hematologic disease areas—fields where long-term therapy, consistent efficacy, and predictable safety are of paramount importance.
“Our mission is to harness RNAi to develop transformative medicines for prevalent and high-burden diseases,” said Orth. “The success of early RNAi therapeutics has proven that this approach is not only scientifically sound but also commercially viable. CITY-FXI is the first in what we expect to be a series of innovative programs applying RNAi to common yet underserved conditions.”
Company Vision and Pipeline Expansion
Founded by a team of leading scientists and biotech veterans, City Therapeutics is committed to building a pipeline of RNAi-based therapies addressing cardiovascular, metabolic, and hematologic disorders. The company’s proprietary RNAi platform integrates optimized siRNA chemistry, advanced conjugate design, and data-driven target selection to maximize both potency and safety.
Beyond CITY-FXI, the company is advancing multiple preclinical programs targeting key genes involved in lipid metabolism, inflammation, and coagulation pathways, with the goal of generating a robust portfolio of differentiated therapeutics. Each program is guided by strong genetic validation and a clear understanding of disease biology, ensuring a focused and strategic development approach.
“CITY-FXI represents not just a single product opportunity but a demonstration of our platform’s potential,” Orth added. “By efficiently silencing disease-causing genes in the liver, we have the opportunity to create a new generation of medicines with durable efficacy and favorable safety profiles. Our approach combines cutting-edge RNAi science with a clear translational strategy aimed at improving outcomes for millions of patients.”
About CITY-FXI
CITY-FXI is an investigational, subcutaneously administered RNAi therapeutic that selectively targets Factor XI (FXI) messenger RNA in hepatocytes. By reducing FXI protein synthesis, CITY-FXI aims to inhibit the intrinsic pathway of coagulation and prevent the formation of pathological blood clots. The therapeutic has demonstrated sustained FXI knockdown and potent antithrombotic activity in preclinical models, with no evidence of bleeding or other safety concerns.
CITY-FXI is currently under regulatory review by the MHRA as part of City Therapeutics’ CTA submission, seeking approval to begin human clinical trials.
About City Therapeutics, Inc.
City Therapeutics is a biopharmaceutical company dedicated to advancing the next generation of RNAi-based medicines for serious and prevalent diseases. Leveraging a proprietary RNAi platform, the company is developing a pipeline of novel therapeutic candidates targeting key pathways in thrombosis, cardiovascular disease, and metabolic disorders.
City Therapeutics’ mission is to transform the standard of care by delivering durable, precise, and safe gene-silencing therapies that address the root causes of disease. The company’s leadership team combines expertise in RNA biology, clinical development, and drug commercialization, positioning City Therapeutics to become a leading force in the RNAi therapeutic landscape.
This press release contains forward-looking statements regarding City Therapeutics’ research and development activities, the potential therapeutic benefits of CITY-FXI, the anticipated initiation and timing of clinical trials, and the company’s future plans and goals. These statements are based on current expectations and are subject to risks and uncertainties that could cause actual results to differ materially. City Therapeutics undertakes no obligation to update forward-looking statements as a result of new information, future events, or otherwise, except as required by law.
About City Therapeutics
City Therapeutics is a biopharmaceutical company harnessing its next-generation RNAi platform to improve and expand the reach of RNAi-based medicines. The company is building a pipeline of innovative RNAi therapeutics to make a significant impact for patients across multiple therapeutic areas. Co-founded by pioneering executives and scientists in RNAi, City Therapeutics is based in Cambridge, MA, and has raised $135 million from leading life sciences investors. For more information, please visit us at www.citytx.com and follow us on LinkedIn.
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