Introduction: Systemic sclerosis is a rare autoimmune connective tissue disease characterised by (1) microvasculopathy; (2) immune dysregulation; and (3) progressive fibrosis of the skin and internal organs. Soluble guanylate cyclase plays an important role in maintaining vascular and immunological homeostasis and preventing organ fibrosis. Pharmacological modulation of soluble guanylate cyclase with soluble guanylate cyclase stimulators has shown anti-inflammatory and antifibrotic effects in animal models of systemic sclerosis, with a trend towards clinical efficacy in a Phase II study (RISE-SSc). However, the efficacy of soluble guanylate cyclase stimulators may be reduced under conditions of hypoxia and oxidative stress. Soluble guanylate cyclase activators have the potential to overcome this limitation. This paper describes the study design of VITALISScE™, a Phase II clinical trial assessing the efficacy, safety and tolerability of avenciguat, a novel soluble guanylate cyclase activator in patients with active systemic sclerosis at risk of progression.
Methods: The VITALISScE™ study (NCT05559580) is evaluating the action of avenciguat on all three aspects of systemic sclerosis pathophysiology. The primary endpoint is the rate of decline in forced vital capacity (mL) over 48 weeks. Secondary endpoints include absolute change from baseline at Week 48 in modified Rodnan skin score, Health Assessment Questionnaire Disability Index score and the proportion of responders based on the revised Composite Response Index in Systemic Sclerosis. Additional endpoints include a composite assessment of Raynaud's phenomenon, digital ulcer burden, functional outcomes and quality of life, safety, pharmacokinetics, and biomarkers associated with systemic sclerosis and the mechanism of action of avenciguat.
Results: VITALISScE™ is an ongoing, multicentre (180 sites; 38 countries), placebo-controlled, double-blind, parallel-group, Phase II clinical study. Recruitment is currently ongoing.
Conclusions: The VITALISScE™ study is assessing the efficacy, safety and tolerability of avenciguat in patients with active systemic sclerosis at risk of progression. Results will inform further development of avenciguat.
Trial registration: VITALISScE™; EU CT No. 2022-500332-11-00; Clinicaltrials.gov: NCT05559580 (https://www.clinicaltrials.gov/study/NCT05559580).
Keywords: SSc; clinical trial; fibrosis; microvasculopathy; sGC activator.
Systemic sclerosis, or SSc, is a rare autoimmune disease where a person’s immune system attacks their body and causes thickening or scarring, known as fibrosis. Fibrosis can happen in the skin and in other tissues, such as the lungs, and may cause bothersome symptoms throughout the body. Alongside fibrosis, patients with SSc may also have damage to their blood vessels and problems with their immune system. Some treatments for SSc work by targeting an enzyme in the blood called soluble guanylate cyclase, or sGC for short. These treatments either stimulate or activate sGC, which helps to maintain normal blood vessel and immune system activity. Effects of the sGC pathway can also help to prevent fibrosis. The activity of sGC stimulators may decrease when there are low oxygen levels in tissues affected by fibrosis. sGC activators have been suggested to work well in low-oxygen environments and may be useful treatments for patients with SSc. The VITALISScE™ study is looking at an sGC activator called avenciguat in patients with SSc. This study is currently ongoing across multiple countries. It includes patients with SSc at risk of their disease getting worse. During the study, patients will randomly receive either avenciguat or a placebo (non-active drug). Patients can take some of their usual medications for SSc, with some restrictions. The impact on lung function will be measured over 48 weeks. Through the study, the investigators will look at changes in participants’ lung function, skin thickness, ability to carry out daily activities, quality of life and any other effects of the medicine. Researchers want to understand if it is possible to reduce fibrosis by targeting the sGC pathway.
© The Author(s) 2024.