P146 A phase II, randomised, double-blind, placebo-controlled trial exploring pharmacokinetics, safety and efficacy of intravenous factor XIII treatment in adults with systemic sclerosis
Authors: Leslie Anna , Vigneswaran Shivanee , Khan Kiran , Ong Voon , Denton Christopher P 
Published: April 2024

Abstract

Background/Aims
Systemic sclerosis (SSc) is a multi-system autoimmune disease with significant morbidity and mortality, and an unmet therapeutic need. The pathogenesis of SSc involves dysfunctional immune signalling, fibroblast behaviour and vascular development. Factor XIII (FXIII) is an enzyme involved in coagulation, and in wound healing where it promotes angiogenesis via inhibition of thrombospondin-1 (TSP-1). Therapeutic administration of FXIII in SSc is proposed to increase angiogenesis via suppression of TSP-1, which is known to be dysregulated in SSc. Previous preclinical and clinical studies suggest that therapeutic administration of factor XIII could improve vascular function in SSc.

Methods
Two interlinked clinical trials were conducted at a single centre. First, a single-dose open-label study was performed to assess the safety and pharmacokinetics of FXIII treatment in SSc. Eight adult patients with limited or diffuse SSc received a single dose of intravenous purified human FXIII, followed by a 6-week monitoring period. Second, a phase II, double-blind, randomised, placebo-controlled study was performed to investigate the safety and efficacy of factor XIII treatment in SSc. 18 adult patients with limited or diffuse SSc were randomised 2:1 to receive study intervention (intravenous purified human FXIII) or placebo (intravenous 0.9% sodium chloride solution). Safety endpoints were assessment of the safety and tolerability of FXIII treatment via review of adverse events, physical examination and monitoring of physiological function. Efficacy was explored as change in skin severity by modified Rodnan skin score (mRSS) at week 24 compared to baseline, and change in severity of Raynaud’s phenomenon, assessed by review of the Raynaud’s Condition Score (RCS) at week 24, compared to baseline. The study is registered with ClinicalTrials.gov (number NCT02551042).

Results
The main objective of the clinical trial was met by demonstrating that FXIII is safe and well tolerated in SSc. Pharmacokinetic analysis showed a predictable rise and fall in FXIII level following therapeutic administration, with the mean time taken for the FXIII level to return to within 10 IU/dL of the endogenous level being 16.6 days (SD 8.7). Adverse event and safety monitoring did not reveal any concerning pattern. Study intervention-related adverse events were self-resolving and tolerable. There was no statistically significant change in mRSS or RCS during the trial, but there was a trend towards improvement in RCS in the FXIII group (mean change in RCS of -1.2 (95% CI -2.26 to -0.14) in the FXIII group versus -0.83 (95% CI -3.44 to 1.77) in the placebo group).

Conclusion
Our results suggest that therapeutic strategies to modulate links between coagulation and tissue repair using FXIII are safe and feasible. Further studies with different patient populations and FXIII doses could investigate the role of FXIII in SSc further.

Disclosure
A. Leslie: Other; A.L. is an employee of GSK. S. Vigneswaran: None. K. Khan: None. V. Ong: None. C.P. Denton: Consultancies; C. D. has received consulting fees from Roche, Janssen, GlaxoSmithKline, Sanofi, Galapagos, Boehringer Ingelheim, and CSL Behring, and Acceleron. Grants/research support; C. D. has received research funding from CSL Behring, Horizon, Abbvie, and GlaxoSmithKline.