City Therapeutics Launches Phase 1 Trial of CITY-FXI siRNA for Inherited Thrombophilia

# City Therapeutics Begins First-in-Human Testing of CITY-FXI, an siRNA Designed to Silence Factor XI in Inherited Thrombophilia City Therapeutics, Inc. has begun dosing participants in a [Phase 1 clinical trial](https://clinicaltrials.gov/study/NCT07430397) of CITY-FXI, a small interfering RNA (siRNA) that targets Factor XI (FXI) mRNA in the liver. The CITY-FXI clinical trial marks the first time this molecule has been administered to humans and is recruiting both healthy volunteers and adults carrying Factor V Leiden (FVL) or prothrombin G20210A mutations, two of the most prevalent inherited thrombophilias. The Cambridge, Massachusetts–based company is developing the drug as a subcutaneous injection intended to lower circulating FXI protein levels and thereby reduce thrombotic risk. What sets this program apart from the broader FXI-targeting field — which has largely pursued stroke prevention in atrial fibrillation and post-surgical venous thromboembolism (VTE) prophylaxis — is its deliberate focus on a genetically defined, chronically at-risk population for whom no approved preventive pharmacotherapy currently exists. The City Therapeutics first-in-human study enters a competitive but still-maturing landscape in which several FXI-directed candidates from larger companies have reached Phase 3, though none has yet secured regulatory approval. ## Trial Design and Endpoints The study, registered as NCT07430397 and cross-listed on the ISRCTN registry (ISRCTN45090913), is a single-center, randomized, double-blind, placebo-controlled single ascending dose (SAD) trial conducted at Richmond Pharmacology in London. It is structured in two parts. Part A enrolls healthy male adults and women of non-childbearing potential aged 18 to 45 years. Part B enrolls male and female adults aged 18 to 60 with a genetically confirmed diagnosis of heterozygous FVL or prothrombin G20210A mutation. Across both parts, the trial plans to enroll up to 128 participants. Those with homozygous mutations, combined thrombophilic defects, a history of clinically relevant spontaneous bleeding, or prior investigational drug exposure are excluded. Body mass index must fall between 18 and 25 kg/m², with a minimum weight of 50 kg. CITY-FXI is administered as a single subcutaneous injection at ascending dose levels in a sequential cohort design. The primary endpoint is the incidence, severity, and investigator-assessed relationship of treatment-emergent adverse events (TEAEs), measured through study completion at up to Day 360. Secondary pharmacodynamic endpoints include change from baseline in activated partial thromboplastin time (aPTT), plasma FXI antigen levels, and FXI activity — all tracked to Day 360, a follow-up duration consistent with the long pharmacodynamic tail expected of GalNAc-conjugated siRNA therapeutics. Pharmacokinetic parameters, including maximum plasma concentration (Cmax), area under the plasma concentration–time curve (AUC), and urinary excretion (Ae), are being assessed from Day −1 through Day 3. The trial began dosing on January 22, 2026, with primary completion anticipated in Q3 2027 and full study completion in Q4 2027. No regulatory pathway designation (such as FDA Breakthrough Therapy or IND status) has been disclosed in the public record; the study is being conducted under a Clinical Trial Application (CTA) filed with the UK Medicines and Healthcare products Regulatory Agency (MHRA). ## The Biological Logic of Silencing Factor XI The rationale for targeting FXI rests on a well-characterized epidemiological and genetic observation: individuals with inherited FXI deficiency — a condition known as hemophilia C — experience a reduced incidence of thrombotic events but rarely suffer spontaneous bleeding of clinical consequence. This stands in contrast to deficiencies of factors further downstream in the coagulation cascade, where even partial reductions in factor activity can produce life-threatening hemorrhage. FXI occupies a position in the intrinsic (contact activation) pathway where it amplifies thrombin generation through a positive feedback loop. Activated by either Factor XIIa or thrombin itself, FXI in turn activates Factor IX, driving further thrombin production and clot stabilization. Dampening this amplification loop — rather than blocking the common pathway factors (Xa, thrombin) that conventional anticoagulants target — is hypothesized to uncouple antithrombotic efficacy from bleeding risk. The City Therapeutics FXI siRNA approach uses RNA interference to degrade FXI mRNA in hepatocytes, the primary site of FXI synthesis. The molecule is presumed to employ GalNAc (N-acetylgalactosamine) conjugation, a delivery strategy that exploits the asialoglycoprotein receptor on liver cells and has been validated clinically by drugs such as inclisiran (for PCSK9) and fitusiran (for antithrombin in hemophilia). Once inside the hepatocyte, the siRNA guide strand loads into the RNA-induced silencing complex (RISC), which then cleaves complementary FXI mRNA, producing a sustained reduction in circulating FXI protein. The 360-day pharmacodynamic follow-up window in this trial suggests the company anticipates a prolonged duration of effect from a single dose — a feature that could translate into quarterly or even less frequent dosing in a chronic prevention setting. For carriers of FVL or prothrombin G20210A mutations, the clinical calculus is straightforward in principle but has been difficult to act on in practice. These mutations, present in roughly 5% and 2–3% of individuals of European descent respectively, elevate the lifetime risk of VTE. Yet current guidelines generally advise against chronic anticoagulation in carriers who have not yet experienced a thrombotic event, because the bleeding risk associated with warfarin, direct oral anticoagulants (DOACs), and heparins outweighs the expected benefit in primary prevention. A therapy that could lower thrombotic risk without proportionally increasing hemorrhage could alter that risk-benefit equation and open a treatment paradigm — chronic primary thromboprophylaxis in genetically at-risk individuals — that does not currently exist. ## A Crowded but Unfinished Competitive Landscape The FXI-targeting siRNA single ascending dose study from City Therapeutics enters a field that has attracted considerable investment across multiple modalities, though no FXI-directed therapy has yet reached the market. The most clinically advanced program is abelacimab (MAA868), a monoclonal antibody developed by Anthos Therapeutics with backing from Novartis. Abelacimab locks FXI in its inactive zymogen form and is in Phase 3 testing (the LILAC-AF program) for stroke prevention in atrial fibrillation. Data from the Phase 2 AZALEA-TIMI 71 trial, which was stopped early after an independent monitoring committee observed both efficacy and a reduction in bleeding relative to rivaroxaban, prompted FDA Breakthrough Therapy Designation. Abelacimab is also being studied in cancer-associated thrombosis. Bristol-Myers Squibb and Janssen are jointly developing milvexian (BMS-986177), an oral small-molecule FXIa inhibitor now in Phase 3 across the LIBREXIA program, which encompasses both stroke prevention in atrial fibrillation and secondary stroke prevention. The oral route of administration offers convenience, though the degree of FXI pathway suppression achievable with a small molecule remains an open question — one sharpened by the failure of Bayer's competing oral FXIa inhibitor, asundexian (BAY 2433334). The Phase 3 OCEANIC-AF trial of asundexian was discontinued in late 2023 after an interim analysis found it unlikely to demonstrate non-inferiority to apixaban for stroke prevention. In the nucleic acid space, fesomersen (IONIS-FXI-LRx / BAY 2976217), a GalNAc-conjugated antisense oligonucleotide (ASO) developed by Ionis Pharmaceuticals and licensed to Bayer, has entered Phase 3 under the RE-THINc program for stroke prevention in atrial fibrillation. Fesomersen shares the hepatic gene-silencing approach with CITY-FXI but uses ASO chemistry rather than siRNA — a distinction that may affect potency, duration of knockdown, and dosing frequency. Separately, Sirnaomics has a [Phase 1 FXI-GalNAc-siRNA program](https://app.allsci.com/clinical-trial/ASC-CT-0000000110178-1.0-1745770020) (NCT05844293) recruiting healthy subjects, making it the most directly comparable competitor to CITY-FXI in terms of both modality and development stage. Other FXI-directed programs include osocimab (BAY 1213790), a Bayer monoclonal antibody targeting activated FXIa that completed Phase 2 in post-surgical VTE prevention, and gruticibart (AB023 / REGN9933), a Regeneron antibody in Phase 2 for thrombosis prevention in patients with end-stage renal disease on hemodialysis. Hengrui Pharmaceuticals' SHR2285, an oral FXIa inhibitor, is also in Phase 2. A pattern emerges across these programs: nearly all are being developed for atrial fibrillation, post-surgical VTE, or secondary stroke prevention. None is specifically targeting inherited thrombophilia as a primary indication. The CITY-FXI Phase 1 study's inclusion of FVL and prothrombin G20210A carriers in Part B represents a deliberate divergence from this consensus development strategy, potentially positioning City Therapeutics to address a population that the larger programs have not prioritized. Whether this focus reflects a long-term commercial strategy or an early-stage pharmacology decision — using a genetically enriched population to detect pharmacodynamic signals at lower doses — remains unclear. The company has not disclosed details about the origin of the molecule, whether it was developed entirely in-house or involves licensed technology, nor has it published preclinical data in peer-reviewed journals. The 128-participant enrollment target is relatively large for a first-in-human SAD study, suggesting the company may be planning a broad dose range exploration or intends to generate a pharmacodynamic dataset in the thrombophilia cohort that could inform later-stage trial design. The Factor XI siRNA anticoagulant concept has strong biological grounding and a growing body of clinical validation from adjacent programs. The central question for CITY-FXI — and for the field as a whole — is whether the theoretical bleeding advantage of FXI inhibition will hold up in larger, longer trials against established anticoagulants that, for all their limitations, have decades of outcomes data behind them. The asundexian discontinuation served as a reminder that clinical translation of the FXI hypothesis is not guaranteed, though the mechanism of failure in that case (insufficient pathway suppression with an oral small molecule) may not apply to biologics capable of near-complete FXI knockdown. City Therapeutics' Phase 1 data, expected by late 2027, will provide the first indication of whether CITY-FXI can achieve the depth and duration of FXI suppression needed to test that proposition. City Therapeutics initiates Phase 1 first-in-human trial of CITY-FXI, an FXI-targeting siRNA, in healthy adults and inherited thrombophilia carriers. --- Spot something wrong? 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