Riociguat: beneficial for cutaneous systemic sclerosis patients?

The sGC* stimulator riociguat did not offer substantial benefit for patients with early, diffuse cutaneous systemic sclerosis (SSc) who are at high risk for skin fibrosis progression; however, other potential efficacy signals should not be discounted, the phase IIb RISE-SSc** trial has shown.

Nintedanib is the only approved therapy for SSc-ILD*** to date, hence the significant unmet need for therapeutic alternatives for this patient group. [Lancet 2017;390:1685-1699; N Engl J Med 2019;380:2518-2528] “Riociguat has antiproliferative, anti-inflammatory, and antifibrotic effects in vitro and in animal models of tissue fibrosis and has been shown to increase digital blood flow in patients with Raynaud’s phenomenon,” said the researchers.

“[However,] the … study failed to meet its primary endpoint. [Nonetheless,] this study provides important information that can inform future study design and gives preliminary findings that could be explored in future trials,” said the researchers.

The team randomized 121 patients 1:1 to receive oral riociguat or placebo. Doses were individually adjusted Q2W from 0.5–2.5 mg thrice daily over 10 weeks and continued throughout the treatment phase. By week 52, 81 percent of riociguat recipients were already receiving 2 or 2.5 mg doses. [Ann Rheum Dis 2020;79:618-625]

At week 52, mean change in modified Rodnan skin score was –2.09 vs –0.77 with riociguat vs placebo (least squares mean difference, –2.34; p=0.08). “The between-group difference … was less than expected. This low treatment effect was probably the main reason why the primary endpoint was not met,” explained the researchers.

Potential efficacy signals?

Stratifying by diagnostic subgroups^#, mean change in FVC%^## ranged from +0.7 to –2.7 percent and from –7.6 to –8.7 percent in the respective riociguat and placebo arms. Furthermore, DL_CO%^### dropped by –2.31 percent and –4.09 percent in the respective riociguat and placebo arms, while for patients with pre-existing ILD, changes were –4.55 percent and –7.63 percent, respectively.

At week 14, changes in Raynaud’s attack duration, frequency, and symptoms favoured riociguat over placebo, with the average Raynaud’s condition score improving by ≥50 percent in 41 percent and 26 percent of riociguat and placebo recipients, respectively. However, between-group difference was not significant.

These secondary endpoints should therefore be considered as potential efficacy signals requiring further investigation, underscored the researchers.

Favourable safety profile

Adverse event (AE) rates were higher with riociguat vs placebo (97 percent vs 90 percent); however, most were mild-to-moderate gastrointestinal events or nervous system disorders. “These events are consistent with the effects of riociguat … and did not increase the incidence of withdrawal due to AEs,” said the researchers.

SAE rates were lower with riociguat vs placebo (15 percent vs 25 percent). While each arm had 11 patients discontinuing treatment due to AEs, no events of serious haemoptysis were reported. These suggest that riociguat was well tolerated.

Of note was the lower AE rates in riociguat-treated patients with ILD vs those receiving placebo (83 percent vs 92 percent). “[This] is important given the increased … death and SAE [rates] with riociguat in a study of patients with pulmonary hypertension associated with idiopathic interstitial pneumonia,” they said.

Compared with other SSc trials, discontinuation rates were higher in the current study. [Arthritis Rheumatol 2020;72:125-136]. As per the researchers, this could be due to the expected worsening in early disease and withdrawal due to AEs. Conversely, another study reflecting a high discontinuation rate in a similar population supported the current data, which was attributed to the anxiety among patients with early disease. [Arthritis Rheum 2007;56:323-333] These discrepancies warrant further exploration, they said.