GLASGOW -- Interleukin (IL)-6 inhibition with tocilizumab (Actemra) may offer benefit in the treatment of systemic sclerosis, a phase II proof-of-concept study suggested.
At week 48, the change in mean Rodnan skin score from baseline among patients receiving tocilizumab was -6.33 compared with a change of -2.77 among those given placebo, for a difference of -3.55 (95% CI -7.23 to 0.12, P=0.06), according to Christopher Denton, MD, of University College London.
"Interleukin-6 appears to play an important role in the pathogenesis of systemic sclerosis, a debilitating disease with high mortality that has limited treatment options," Denton said at the British Society for Rheumatology (BSR) annual meeting here.
High levels of IL-6 have been detected in the serum and skin of patients with systemic sclerosis, and models have shown that blocking this cytokine may be helpful for fibrosis.
And despite the lack of statistical significance in this study, known as FASSCINATE, the FDA has accorded tocilizumab breakthrough therapy designation. "I believe that for the first time, the FDA has given a drug accelerated status following a negative study," commented Paul Emery, MD, of Leeds University in Leeds, England, who was not involved in the study.
FASSCINATE included 87 patients who were randomized to receive subcutaneous tocilizumab, 162 mg weekly, or placebo, for 48 weeks. The primary endpoint was change in modified Rodnan skin score at week 24.
At last year's annual BSR meeting, Denton reported on that primary endpoint, which was a change from baseline of -3.92 for the tocilizumab group versus -1.22 for the placebo group. This was a difference of -2.70 (95% CI -5.85 to 0.45, P=0.09).
"The 48-week data now give us a more robust picture," he said.
At baseline, patients' mean age was 50 and mean disease duration was 18 months. A total of 80% were women.
Baseline Rodnan skin score was 26, which is moderately severe. Scores on the Health Assessment Questionnaire averaged 1.4, and mean C-reactive protein was 10 mg/L.
On other endpoints that could be clinically meaningful to patients, tocilizumab again showed improvements, trending in the right direction, according to Denton. A 20% improvement in skin symptoms was seen in 40% of the tocilizumab group and 27% of the placebo group at 48 weeks, and a 40% improvement was seen in 21% and 7%, respectively.
A 60% improvement was reported by 12% of the tocilizumab patients but by none of the placebo patients. "That really substantial 60% impact on skin scores was only seen in the tocilizumab group," he said.
Change in patient global assessment on a visual analog scale was -11 at week 48 in the tocilizumab group compared with -2.70 in the placebo group, for a difference of -8.30 (95% CI -19.31 to 2.71, P=0.14).
And on fatigue scores, the change from baseline was 3.11 in the active treatment group versus 0.36 in the placebo group, which represented a difference of 2.75 (95% CI -1.38 to 6.88, P=0.19).
"We were also very interested to see the potential impact of tocilizumab on lung function because of the signals that IL-6 might be key in the pathogenesis of scleroderma lung fibrosis," he said.
In general, there was greater decline in lung function in the placebo group, with 84% showing some decline over 48 weeks compared with 57% of those in the tocilizumab group. In addition, more than twice the number of patients on placebo had the more meaningful 10% decrease in percent of forced vital capacity (23% versus 10%), he reported.
The mechanism for the drug's possible effect on lung fibrosis may be through a decline in numbers of the chemokine CCL-18. The literature has suggested that this chemokine might be important in macrophage polarization and degeneration of profibrotic macrophages, he explained.
Safety of course is paramount in these patients who have a high risk of serious complications and high mortality, he said.
There were no new or unexpected safety signals, although there were more infectious serious adverse events (16%) and deaths (7%) in the tocilizumab group.
"Having deaths in a clinical trial of systemic sclerosis occurs regularly, which unfortunately is a reflection of the severity of this condition," he said.
"This is a landmark study, in that it showed a difference from placebo. The data are encouraging for skin scores and also possibly for lung function," he concluded.
A phase III study has been initiated.
Denton disclosed relevant relationships with Roche, Actelion, GlaxoSmithKline, and Novartis.
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