Findings were published in the study, “A multicenter randomized, double-blind, placebo-controlled pilot study to assess the efficacy and safety of riociguat in systemic sclerosis-associated digital ulcers,” in the journal Arthritis Research & Therapy.
Many patients with scleroderma, or systemic sclerosis, develop Raynaud’s phenomenon, which is characterized by deficient blood flow to fingers and toes due to the constriction of blood vessels. This can lead to tissue damage and the development of digital ulcers, or small sores on the fingers and toes.
Digital ulcers may be difficult to manage and can significantly affect a person’s quality of life. While Tracleer (bosentan, by Actelion Pharmaceuticals) has been approved in Europe to reduce the number of new digital ulcers in scleroderma patients, no therapies have been approved in the United States.
Bayer‘s Adempas has been approved by the U.S. Food and Drug Administration to treat pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. In preclinical studies, the therapy showed vasodilatory (blood vessel widening), anti-fibrotic (scarring), and anti-inflammatory properties.
Previous Phase 2 trials (NCT01926847 and NCT02283762) showed that treatment with Adempas was well-tolerated, improved blood flow in fingers and toes, and showed a tendency toward a reduction of Raynaud’s phenomenon symptoms.
These results suggested that Adempas has the potential to reduce the number of digital ulcers in scleroderma patients.
The double-blind RESCUE Phase 2 trial (NCT02915835) evaluated the safety and effectiveness of Adempas in 17 adults (13 women and four men; mean age 51 years) with scleroderma-associated digital ulcers. The study, partially funded by Bayer, was conducted at five U.S. scleroderma centers.
Participants were randomly assigned to receive either Adempas (nine patients, maximum 2.5 mg) or a placebo (eight patients) three times daily over an eight-week period, at which point the optimal Adempas dose was determined for each patient. This was followed by eight weeks of treatment with the selected dose.
Those who still had active digital ulcers at the end of the 16 weeks of treatment, or experienced recurrences within one month, could enter an open-label extension phase (in which all patients received Adempas) for an additional 16 weeks.
The study’s main goal was to assess whether Adempas led to a greater reduction in net ulcer burden (NUB) — defined as the total number of active and painful (unhealed) digital ulcers — than placebo after 16 weeks of treatment.
Demographic and clinic characteristics were similar between the placebo and Adempas groups, although people in the placebo group had longer disease duration (15 vs. 6.2 years), and of non-Raynaud’s symptoms (17.5 vs. 7.1 years) than those on Adempas. At the beginning of the study, mean NUB was similar in the Adempas (2.4) and placebo (2.5) groups.
After 16 weeks of treatment, no significant differences in the number of unhealed digital ulcers were found between the two groups. Two patients (25%) in each group had no digital ulcers. In contrast, three patients in the Adempas group (38%) and four on placebo (50%) developed new ones.
Results of the open-label extension part — which included six people from each group — showed that patients who continued on Adempas for an additional 16 weeks had a complete healing of their digital ulcers.
Adempas’ safety profile was consistent with that reported in previous studies, with no new adverse events identified. In total, 13 serious adverse events occurred: five in the first phase of the study (four in the Adempas group), and eight in the extension phase (six in the placebo-to-Adempas group). None were considered related to treatment.
The only biomarker with significantly different levels after treatment with Adempas was soluble guanylate cyclase, which was higher. This enzyme is specifically activated by Adempas to ease fibrosis and inflammation.
Results suggest that longer-term treatment with Adempas “is needed to promote [digital ulcer] healing,” in scleroderma patients, the researchers wrote.
However, they also noted that due to the small number of participants in this study, future larger and longer trials are required to confirm the therapeutic benefits of the therapy in this patient population.