Engineering the next generation of RNAi therapeutics

Unlocking the full potential of RNAi

City Therapeutics™ is a clinical-stage biotechnology company developing the next generation of RNAi therapeutics designed to silence the expression of disease-relevant proteins, with the aim of delivering meaningful and durable benefits for patients in need. Founded by pioneers in the field of RNAi, we are applying our deep expertise and breakthrough science to unlock the full potential of RNAi therapeutics.

Our strategy rests on four elements: advancing how RNAi therapeutics are designed and delivered; building a pipeline in diseases where RNAi offers a meaningful advantage; pursuing partnerships that extend the reach of our platform; and drawing on our team’s depth of experience to move programs faster. Together, we believe these support our goal of developing potentially best-in-class therapeutics and building a lasting, fully integrated RNAi company.

Our three lead product candidates are being developed for thromboembolic diseases, a leading cause of death worldwide; Stargardt disease, which renders many patients legally blind in their late twenties; and anemia of chronic disease, which can cause debilitating fatigue, weakness, and reduced physical function, and leaves many patients dependent on blood transfusions.

Our City Platform is the engine behind every therapeutic we develop. We engineer RNAi trigger molecules designed to improve potency and specificity and then pair them with tissue-targeting ligands for precise delivery to cell types in and beyond the liver, with the aim of reaching diseases that current RNAi approaches cannot.

Our leaders are pioneers and experts in the field of RNAi therapeutics, with extensive experience across research, development, and commercialization. That expertise extends throughout our organization, where scientists with decades of hands-on RNAi experience drive our programs forward with accuracy, insight, and speed.

A vast opportunity ahead

Expanding RNAi beyond the liver into the eye, CNS, and adipose tissues

RNAi is a specific, potent, and durable way to silence the expression of disease-relevant proteins, including intracellular targets that small molecules and antibodies cannot reach.

The first generation of RNAi therapeutics has transformed the treatment of certain diseases. However, these medicines have been limited to diseases that can be treated by delivering RNAi to the liver. Unlocking the full potential of RNAi therapeutics means reaching beyond the liver — expanding its reach to hundreds of distinct cell types and thousands of diseases that remain beyond the reach of current RNAi approaches.

This vision — to lead the next generation of RNAi therapeutics — is what drives us forward.

The City Platform

Novel Trigger Engineering

RNAi triggers are the molecules that initiate the gene-silencing process and are fundamental to the performance of every RNAi medicine. RNAi trigger engineering is the cornerstone of the City Platform, leveraging our deep expertise in canonical siRNA therapeutics, our next-generation cityRNA triggers, and our proprietary artificial intelligence and machine learning-enabled molecular-design capability.

While there continues to be substantial opportunity for liver-directed RNAi therapeutics, we believe the defining opportunity for the future of RNAi therapeutics lies beyond the liver. cityRNAs are a structurally distinct class of triggers engineered specifically to perform where conventional approaches fall short, potentially expanding the reach of RNAi to extrahepatic tissues.

We believe the next major advances in RNAi will come from innovations in RNAi trigger molecule design, tissue-selective delivery, and genetics-led target selection. The City Platform brings these three capabilities together, for liver-directed programs today, and to expand RNAi beyond the liver.

Tissue-selective delivery

Our conjugate chemistry is designed to direct RNAi triggers to the right tissue and enable efficient uptake into the right cells. For delivery to the liver, we use GalNAc, a well-established ligand. Beyond the liver, we are developing proprietary delivery ligands, starting with our proprietary LRP1 ligand, which is designed to enable delivery to ocular, CNS, and adipose tissues. We are also developing additional novel delivery technologies to reach other tissues.

Genetics-led target selection

Since RNAi can silence almost any gene, the choice of target is as consequential as the molecule that silences it, and we begin every program with a target supported by human genetics. Using genetic data linked to clinical information from more than 1 million participants, we seek to build confidence in a target's biological role and its potential clinical activity and tolerability before a therapeutic candidate enters the clinic.

Together, these capabilities let us pursue targets supported by human genetics, engineer for potency, and deliver to the tissues where it matters.

Our pipeline & programs

We are advancing a pipeline of RNAi therapeutics designed to achieve potent, specific, and durable suppression of disease-relevant hepatic and extrahepatic targets to treat diseases with significant unmet medical needs. The following table summarizes our current development-stage and partnered programs:

CITY-FXI

Thrombosis, the formation of harmful blood clots inside a blood vessel, is responsible for approximately one in four deaths worldwide. An estimated 40 to 50 million people are at risk for thromboembolic diseases.

Current anticoagulants, commonly known as blood thinners, can help lower that risk, but many people remain untreated or undertreated because of the bleeding risks, contraindications, treatment burden, and adherence challenges associated with available therapies, underscoring the need for new treatment options.

Factor XI is a clotting protein that plays an important role in the formation of harmful blood clots but a more limited role in the body’s normal response to bleeding. CITY-FXI targets Factor XI and is being developed for the prevention of thromboembolic diseases, based on its potential to reduce Factor XI activity while mitigating the bleeding risk associated with current anticoagulants.

CITY-RBP4

Stargardt disease is the most common inherited form of macular degenerative disease in children and young adults, affecting more than 30,000 people in the United States. Patients face decades of progressive loss of central vision, with many becoming legally blind in their late twenties. There are currently no approved treatments for the disease.

Stargardt disease is caused by mutations in the ABCA4 gene, which lead to the toxic accumulation of vitamin A byproducts in the eye. By targeting RBP4, the primary carrier of vitamin A from the liver to the eye, CITY-RBP4 is designed to reduce vitamin A delivery to the eye and decrease the formation of toxic vitamin A byproducts, with the goal of slowing the progression of vision loss associated with Stargardt disease.

We are also exploring CITY-RBP4 as a potential treatment for geographic atrophy, an advanced form of age-related macular degeneration that shares a common underlying mechanism with Stargardt disease.

CITY-TFR2

Anemia of chronic disease accounts for up to 40 percent of all cases of anemia and affects more than five million people in the United States. It can cause debilitating fatigue, weakness, and reduced physical function, significantly affecting quality of life. Current therapies come with significant safety and efficacy limitations, and many patients become dependent on blood transfusions.

Unlike people with anemia caused by iron deficiency, people with anemia of chronic disease have adequate iron stores, but their bodies cannot use that iron effectively. Elevated levels of a hormone called hepcidin restrict the availability of iron for red blood cell production. By targeting a protein known as TFR2, CITY-TFR2 is designed to lower hepcidin levels, restore iron availability, and address a central driver of anemia of chronic disease.

We are initially focused on the development of CITY-TFR2 for anemia associated with myelofibrosis, with potential to expand to other inflammatory chronic conditions, such as chronic kidney disease and inflammatory bowel disease.

Where curiosity meets commitment

From the very beginning of City Therapeutics, we knew building the right culture mattered. Our employees defined City’s core values to showcase what drives us, what we expect from one another, and the kind of company we want to create. The result is distinctly our own — a reflection of who we are and how we work together.

Courage

We explore the unknown in service of patients.

Innovation

We push the boundaries of what is possible.

Tempo

We move decisively — fast, focused and with purpose... but not frantic.

Yes

We embrace optimism and celebrate our team and journey.

How we work

We’re building a company in the heart of Kendall Square where we come together every day to collaborate, ideate and inspire one another. Our choice to be an in-person company is intentional – for us, being together fuels creativity, deepens connection and accelerates scientific discovery. We believe working side by side not only benefits our people but also propels our momentum, driving faster decisions and meaningful discoveries.

At the same time, we recognize that life doesn’t always follow a plan. When flexibility is needed, we make it possible because we believe the best work happens when people are supported, connected and inspired.

WFC (Work from City)