Using RNA to interfere with a disease-driving protein is a proven way to address disease targets in the liver. City Therapeutics is one of the companies developing the next-generation of these medicines for a wealth of targets in the rest of the body. With its lead drug candidate in clinical development for cardiovascular indications, the biotech now has $200 million in IPO cash to fund clinical development of that program and others in its pipeline.
Investor interest enabled City to increase the deal size to more than 11.1 million shares, up from the 9.7 million shares it initially planned. Late Thursday, City priced those shares at $18 each, which was the midpoint of the targeted price range. Those shares began trading on the Nasdaq Friday under the stock symbol “CTY.”
Cambridge, Massachusetts-based City is developing RNA interference (RNAi) drugs, which employ small interfering RNA (siRNA) to target and degrade messenger RNA before it can be translated into a protein that contributes to disease. This modality, also called gene silencing, was pioneered by Alnylam Pharmaceuticals, which sells four FDA-approved RNAi drugs — all for rare diseases stemming from liver proteins. City’s co-founder and executive chair is John Maraganore, who was the founding CEO of Alnylam.
The delivery systems for currently available RNAi therapies preferentially target the liver, but Alnylam and other biopharmaceutical companies are working on ways to reach other types of tissue to potentially treat more common diseases. For example, ADARx Pharmaceuticals last month raised $535 million in an IPO and private placement to support clinical development of its siRNA therapies that go beyond the liver. In City’s IPO filing, the company said the surge in RNAi research puts this modality on a path comparable to the explosive growth of monoclonal antibodies 30 years ago.
“With approximately 100 programs currently in clinical development, we believe RNAi therapeutics are poised to follow a growth trajectory analogous to that of monoclonal antibody therapeutics, a modality that was first approved by the FDA in the mid-1990s and has since expanded to more than 150 approved medicines,” City said in the filing.
City’s therapies come from a platform technology that engineers “triggers,” the RNA that silences the target mRNA. This platform also develops tissue-targeting ligands that enable delivery of the therapy to places other than the liver. Lead program CITY-FXI employs a ligand that targets low-density lipoprotein receptor-related protein 1 (LRP1) for potential applications in blood clot disorders, including secondary stroke prevention, atrial fibrillation in patients ineligible for oral blood thinners, extended secondary prophylaxis following venous thromboembolism, and cancer-associated thrombosis. The standard of care for all of them is anticoagulants.
CITY-FXI is a siRNA designed to suppress Factor FXI (FXI), a protein that circulates in the blood and contributes to harmful blood clots. Here, City faces potential competition from ADARx, which is preparing to advance its FXI-targeting siRNA to mid-stage testing in secondary stroke prevention. A Phase 1 study of CITY-FXI is ongoing; in preliminary data from healthy volunteers, City reported a single injection of the study drug led to FXI knockdown of 60% at the lowest dose and 85% at the highest dose. The City drug was generally well tolerated.
City expects to report more Phase 1 data later this year. The company also plans to evaluate CITY-FXI for efficacy in a Phase 2 test in total knee arthroplasty patients, which comes with a high risk of blood clots following surgery. City plans to start this study in mid-2027 and report data in early 2028.
Two preclinical City programs are on the path to human testing. CITY-RBP4 is a siRNA designed to target mRNA for a protein called RBP4. The lead indication is Stargardt disease, a rare inherited vision loss disorder. Later this year, City expects to begin a Phase 1 trial enrolling healthy volunteers and Stargardt patients; data are expected in early 2028. The company also plans to explore use of this siRNA in other eye diseases, such as geographic atrophy secondary to macular degeneration. A Phase 2 test in this indication is planned to start late next year.
CITY-TFR2 is a potential treatment for myelofibrosis-associated anemia. This siRNA is designed to reduce levels of TFR2 protein, lowering levels of hepcidin to restore the availability of iron for red blood cell production. City is also exploring use of this siRNA for anemia associated with chronic kidney disease and chronic inflammatory disorders, including inflammatory bowel disease. In these indications, elevated hepcidin and iron restriction contributes to the disease.
City’s research has attracted collaborators. Bausch + Lomb is working with the biotech to develop RNAi therapies for eye diseases, specifically geographic atrophy. Biogen’s alliance is focused on the central nervous system. In the first half of this year, City reported $6.3 million in collaboration revenue.
City formed in 2023. As a private company, City had raised nearly $239 million, according to the filing. The most recent financing was a $99.5 million Series B round in July. Arch Venture Partners is City’s largest shareholder with a 26.7% post-IPO stake, the filing shows.
As of the end of September, City said its unaudited cash position was $141.9 million. Combined with the IPO proceeds, the company estimates its capital will last into late 2028. City plans to spend $30 million for CITY-FXI’s ongoing Phase 1 trial and the start of a Phase 2 test in total knee arthroplasty. Another $20 million is budgeted for CITY-RBP4’s Phase 1 study and preparation for later-stage clinical testing in Stargardt disease and geographic atrophy.
About $40 million is budgeted for CITY-TFR2’s investigator-initiated study in China and a Phase 1/2 study, both in anemia associated with myelofibrosis. The company will also spend about $70 million to advance its platform technology and continue development of its preclinical drug candidates.
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