Background/Purpose:

There are few disease-modifying therapies for the treatment of systemic sclerosis (SSc), particularly the more severe diffuse cutaneous form (dcSSc). The soluble guanylate cyclase stimulator riociguat showed antifibrotic effects in animal models and efficacy in patients with pulmonary arterial hypertension associated with connective tissue disease. It was therefore hypothesized that patients with dcSSc might benefit from riociguat therapy. We present results from the Phase IIb, multicenter, randomized, double-blind, placebo-controlled RISE-SSc study (NCT02283762), which investigated the efficacy and safety of riociguat in patients with early dcSSc.

Methods:

Inclusion criteria were a diagnosis of SSc (fulfilling 2013 ACR/EULAR criteria) with diffuse cutaneous involvement (based on LeRoy criteria), disease duration ≤18 months, modified Rodnan skin score (mRSS) ≥10 and ≤22 units, forced vital capacity (FVC) ≥45% of predicted, and diffusion capacity of the lung for carbon monoxide ≥40% of predicted at screening. Patients were randomized to either placebo or riociguat individually adjusted from 0.5 mg up to 2.5 mg 3 times daily. The primary endpoint was change in mRSS from baseline to Week 52. Secondary endpoints included ACR Combined Response Index for Systemic Sclerosis (CRISS), Health Assessment Questionnaire-Disability Index (HAQ-DI), and change in FVC % predicted. A prespecified exploratory analysis investigating mRSS progression rate (increase in mRSS >5 units and ≥25% from baseline) and a post hoc analysis on prevention of lung function decline (FVC % predicted decline ≥10% absolute) were also performed. The primary endpoint was analyzed using mixed-model repeated measures including all mRSS assessments from baseline up to Week 52.

Results:

In total, 121 patients (riociguat n=60, placebo n=61) were randomized (mean±SD age 51±12 years; 76% female). Baseline mRSS was comparable in riociguat and placebo groups (mean±SD 16.88±3.38 and 16.71±4.06, respectively). At Week 52, mean±SD mRSS was 14.63±6.56 for riociguat vs 15.73±10.48 for placebo (least squares mean treatment difference –2.34 [95% CI –4.99, 0.30; p=0.08]). The difference in mRSS progression rate showed significant effects favoring riociguat (riociguat – placebo: –18% [95% CI –33.57, –2.40; p=0.02, Mantel–Haenszel method]). The proportion of patients with ACR CRISS probability ≥0.60 (considered improved) at Week 52 was the same in both treatment arms (18%). Mean±SD change from baseline to Week 52 in other secondary endpoints for riociguat vs placebo: FVC % predicted, –2.38±7.52 vs –2.95±9.73; HAQ-DI, +0.05±0.38 vs +0.13±0.42, respectively. At Week 52, prevention of lung function decline was observed in 89% of riociguat patients vs 80% with placebo. Fewer serious adverse events occurred with riociguat vs placebo (15% vs 25%, respectively) and no new safety signals were observed.

Conclusion:

The primary efficacy endpoint of mean change in mRSS did not reach statistical significance. Exploratory data suggest prevention of disease progression with riociguat in this early dcSSc population.

Medical writing support was provided by Adelphi Communications Ltd, Bollington, UK.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/riociguat-in-patients-with-early-diffuse-cutaneous-systemic-sclerosis-a-randomized-double-blind-placebo-controlled-phase-iib-study-rise-ssc/