Ab0877 targeting vasculopathy to slow fibrosis in systemic sclerosis (ssc): design of a phase ii study with a soluble guanylate cyclase activator (sgca)

Background The pathophysiology of SSc involves a complex interplay between immune dysfunction, vasculopathy, and fibrosis. The soluble guanylate cyclase (sGC) pathway has been shown to improve vascular endothelial function. We designed a Phase II study to test whether treatment of vasculopathy with an sGCa could slow the progression of fibrosis in patients with early progressive SSc and vasculopathy. Objectives To design a randomized, double-blind, placebo-controlled trial to evaluate the progression of fibrosis in patients with SSc treated with an sGCa. Methods We reviewed criteria used in published clinical trials to define early progressive disease, as well as clinical and biomarker features from existing studies and registries that are predictive of more rapid progression of fibrosis [1, 2]. Specifically, we looked for features of vasculopathy associated with progression of skin and lung fibrosis [3]. We performed a rigorous review of investigator- and patient-reported outcomes to test the hypothesis that amelioration of vascular symptoms could slow the progression of fibrosis in patients with SSc. Results Progressive disease was defined as having diffuse cutaneous SSc with evidence of active disease as defined by clinical and biomarker criteria. The clinical criteria were similar to those used in previous trials, but we developed a novel biomarker strategy using KL-6 in addition to C-reactive protein (CRP) and erythrocyte sedimentation rate. These biomarkers identify additional patients at risk for progressive lung fibrosis. Significant vasculopathy was defined as having digital ulcers or a history of digital ulcers and/or Raynaud’s phenomenon requiring medical treatment or associated with elevated CRP. We developed a hierarchy of primary, key secondary, and secondary endpoints, including forced vital capacity, modified Rodnan skin score, revised Composite Response Index in Systemic Sclerosis, Health Assessment Questionnaire-Disability Index, digital ulcer burden, and Raynaud’s symptom scoring, to investigate whether amelioration of vascular symptoms could slow decline in lung function over 48 weeks and reduce the progression of skin fibrosis and other disabilities associated with SSc. We determined that a sample size of 100 patients was sufficient to obtain 80% power to observe changes in lung and skin fibrosis. Conclusion We designed a 48-week randomized, double-blind, placebo-controlled Phase II trial enrolling 200 patients with early progressive SSc and significant vasculopathy to test whether targeting vasculopathy with a novel sGCa can slow the progression of fibrosis in patients with SSc. The trial is now active, and additional details are available at NCT05559580 . References [1]Distler O, et al. Eur Respir J 2020;55:1902026 [2]Khanna D, et al. Lancet 2016;387:2630–2640 [3]Khanna D, et al. Ann Rheum Dis 2022;81:102–103 Acknowledgements: NIL. Disclosure of Interests Dinesh Khanna Shareholder of: Eicos, Speakers bureau: AbbVie, Boehringer Ingelheim, CSL Behring, Genentech, Horizon Therapeutics, Janssen, Consultant of: AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Genentech, Horizon Therapeutics, Janssen, Prometheus, Talaris, Theraly, Grant/research support from: Bristol Myers Squibb, Horizon Therapeutics, Pfizer, Mary Flack Employee of: Boehringer Ingelheim Pharmaceuticals, Inc, Tobias Litzenburger Employee of: Boehringer Ingelheim Pharma GmbH & Co. KG, Nora Fagan Employee of: Boehringer Ingelheim Pharmaceuticals, Inc., Oliver Distler Speakers bureau: Bayer, Boehringer Ingelheim, Janssen, Medscape, Consultant of: 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant Siences, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Pfizer, Prometheus, Redxpharna, Roivant, Sanofi and Topadur, Galderma Gossamer, iQvia, Janssen, Medscape, Merck, Grant/research support from: Kymera, Mitsubishi Tanabe, Boehringer Ingelheim.