MANCHESTER, U.K. – Tocilizumab showed signs of improving skin and other symptoms in patients with systemic sclerosis (SSc) in an ongoing proof-of-concept study.
Although the primary endpoint of a significant change in the modified Rodan skin score (mRSS) at 24 weeks was not met, there was a numerically greater decrease in mRSS among patients who took tocilizumab versus those who took placebo. The mean change in mRSS was –3.92 units vs. –1.22 units, respectively, giving a difference of –2.70 units (P = .09).
Dr. Christopher P. Denton
“We were more encouraged by the 48-week data because we saw a much clearer fall in the mRSS,” said Dr. Christopher P. Denton, who presented these early findings from the phase II/III faSScinate trial at the British Society for Rheumatology annual conference.
At 48 weeks, there was a decrease of 6.33 units in the tocilizumab-treated patients vs. a decrease of 2.77 units in the placebo arm (mean change of –3.55 units; P = .06). A drop of 4 units in the mRSS is deemed to be a minimally clinically important difference.
“There is a reasonable rationale for looking at the IL [interleukin]-6 axis in systemic sclerosis as a target for therapy,” explained Dr. Denton, who is a consultant rheumatologist and professor of experimental rheumatology at University College London.
Indeed, preclinical data have indicated that IL-6 expression is elevated in SSc skin and that an antibody targeting IL-6 inhibited collagen synthesis in cultured fibroblasts and IL-6 receptor antibody reduced skin fibrosis in an animal model.
There also were early clinical data in SSc patients from Dr. Denton’s group that supported conducting a phase II study with tocilizumab (Ann. Rheum. Dis. 2012;71:1235-42).
The faSScinate trial started in 2012 and included 87 patients with active diffuse SSc of 5 years’ or less duration. For inclusion, patients had to have an mRSS of between 15 and 40 units at baseline and elevated acute phase reactants. Patients were randomized to treatment with tocilizumab, which was given at a dose of 162 mg by subcutaneous injection every week, or matching placebo. Treatment was blinded for 48 weeks, followed by an open-label period for a further 48 weeks, during which all patients received tocilizumab.
Dr. Denton said that there were clear and consistent trends towards continuous improvement in skin scores from baseline out to week 48 in the tocilizumab arm. There also were “encouraging trends” favoring tocilizumab in improvement in a number of secondary endpoints, including the Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient and Clinician Global Assessment, FACIT-Fatigue score, and pruritus measured using the 5-D Itch Scale.
More patients treated with placebo than with tocilizumab experienced a worsening in lung function during the trial. This was an exploratory endpoint with an “intriguing” result, Dr. Denton said. A clinically meaningful drop of 10% or more in forced vital capacity was seen in just 3.3% of tocilizumab-treated patients, compared with 19.4% of placebo-treated patients (P = .009).
“Treatment was not entirely benign,” he acknowledged, adding that “noninfective adverse events were more common in the placebo-treatment arm and infective adverse events were more common in the tocilizumab-treated arm.” The increase in infective side effects was not surprising and generally treatable, he said, and serious adverse events were potentially due to complications of SSc rather than treatment.
“This was a small study, but relatively large for a proof-of-concept trial in systemic sclerosis,” Dr. Denton observed.
“We do feel the benefit-to-safety ratio does favor further investigation and that tocilizumab is likely to benefit a subset of patients with SSc who would otherwise have a particularly poor outcome.”
A phase III study is now being planned, with recruitment likely to start later this year.
Tocilizumab is currently indicated for use in the United States as Actemra and in Europe as RoActemra in combination with methotrexate for the treatment of severe, active, and progressive rheumatoid arthritis and for active juvenile idiopathic systemic or polyarthritis.
The faSScinate study was funded by F. Hoffman La Roche. Dr. Denton has acted as a consultant for Actelion Pharmaceuticals US, Biogen-Idec, CSL Behring, Genentech/Roche, GlaxoSmithKline, and Sanofi-Aventis. His coinvestigators also reported financial relationships with other pharmaceutical companies, including Roche.