A Phase 1, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneously Administered SRSD107 in Healthy Subjects

Background: While anticoagulation therapy is a cornerstone of the prevention and treatment of thrombosis, a safer anticoagulant remains an important therapeutic goal. The available evidence suggests that factor XI (FXI) is important for thrombosis but has a minor role in hemostasis. Epidemiological studies suggest that severe FXI deficiency confers a reduced risk of ischemic stroke and deep vein thrombosis (DVT), whereas increased levels of FXI confer a higher risk for DVT, myocardial infarction, and ischemic stroke. Individuals with congenital FXI deficiency rarely have spontaneous bleeding, and FXI inhibition attenuates arterial and venous thrombosis in animals without increasing bleeding. Therefore, FXI is a promising target for the development of safer anticoagulants SRSD107 is a synthetic, chemically modified, double-stranded, small interfering ribonucleic acid (siRNA) that specifically targets human FXI mRNA. In studies in cynomolgus monkeys, SRSD107 was well tolerated and produced dose-dependent reductions in circulating FXI levels for at least 12 weeks, with maximal reductions in FXI antigen > 90%, after single subcutaneous doses up to 5 mg/kg. By selectively modulating coagulation through inhibition of FXI, SRSD107 could prevent thromboembolic events without significantly increasing the risk of bleeding. Methods: This is a first-in-human, Phase 1, single-site, randomized, double-blind, placebo-controlled, single ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of subcutaneously administered SRSD107 in healthy subjects in Australia (Clinicaltrials.gov NCT03702725). Eligible subjects were males or females 18 to 65 years of age, with a body mass index between 18.0 and 32.0 kg/m2. Five cohorts comprising 8 subjects apiece (randomized 6:2 to SRSD107 and placebo, respectively) evaluated 5 doses (15, 45, 120, 240 and 450 mg). The PK of SRSD107, as well as its PD effect on FXI, activated partial thromboplastin time (aPTT), and prothrombin time (PT) were investigated. Results: Forty subjects were enrolled from January to June 2024. The median age was 33 years (range: 18-57 years) and 18 were male. All subjects received a single dose of investigational drug or placebo. One serious adverse event occurred, acute appendicitis, which was not related to the study drug. There was no excess bleeding during laparoscopic appendectomy. Other treatment-emergent adverse events (AE) were all Grade 1 or Grade 2. The tmax (2-4 hours) and t1/2 (~6 hours) showed moderate absorption and rapid elimination, respectively. The increase in Cmax and AUC was generally proportional to the dose. Marked changes from baseline in PD biomarkers were observed, with maximal reductions in FXI antigen and activity > 85% and an aPTT increase > 100% (i.e., an aPTT ratio > 2.0) at the highest doses tested. No meaningful changes in the PT were observed. The PD effects were durable, with FXI antigen and activity levels remaining suppressed at least 12 weeks after dosing. Conclusions: In healthy volunteers, a single dose of SRSD107 was safe and well tolerated, with PK parameters consistent with a typical siRNA product. Marked, prolonged changes from baseline in FXI activity and aPTT were observed, suggesting that SRSD107 could be a potent anticoagulant with a sustained effect over time.

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