Apremilast Clears Oral Ulcers in Behcet's

Patients with Behçet's syndrome who had active oral ulcers had improvements in these ulcers and multiple other outcomes during treatment with apremilast (Otezla), a phase III multinational trial found.

In a randomized study that included 207 patients, the area under the curve for the number of oral ulcers during 12 weeks of treatment was 129.5 for apremilast compared with 222.1 for placebo, according to Gülen Hatemi, MD, of Istanbul University and the Behçet's Disease Research Center in Turkey, and colleagues.

That represented a least-squares mean difference of -92.6 (95% CI -130.6 to -54.6, P<0.001), the investigators reported in the New England Journal of Medicine.

However, the incidence of adverse events such as diarrhea, nausea, and headache was higher in the active treatment group.

Apremilast is an oral small-molecule phosphodiesterase 4 inhibitor that inhibits the release of proinflammatory markers such as interleukins 2, 8, 12, and 17 while increasing the production of anti-inflammatory mediators. In a phase II study, the drug decreased the number of oral ulcers, the associated pain, and disease activity in general.

To extend the efficacy and safety data in Behçet's disease, Hatemi and colleagues conducted a larger trial, drawing patients from 53 centers in 10 countries during the years 2014 to 2017. The study was sponsored by Celgene.

Participants were randomized to receive apremilast, 30 mg twice daily, or placebo for 12 weeks, after which time all patients were eligible to enter a 52-week extension phase. The apremilast dose was increased gradually during the first week, to lessen the likelihood of gastrointestinal side effects.

Patients had to have oral ulcers at least three times during the previous year despite treatment with one or more nonbiologic agent such as glucocorticoids, immunosuppressants, colchicine, or thalidomide.

The participants' mean age was 40, 61% were women, and the mean duration of Behçet's was 6.8 years. The mean number of oral ulcers at baseline was 4.1.

At week 12, the change in ulcer pain scores was -42.7 among patients receiving apremilast compared with -18.7 for those given placebo, for a least-squares mean difference of -24.1 (95% CI -32.4 to -15.7). At that time point, change from baseline on the Behçet's Syndrome Activity Scale was -19.8 in the apremilast group compared with -8.8 in the placebo group, for a least-squares mean difference of -11 (95% CI -15.6 to -6.4).

The percentage of patients who had a complete response for their oral ulcers at week 12 was 53% in the apremilast group versus 22% in the placebo group, and the median times to complete response were 2.1 weeks versus 8.1 weeks.

The percentage of patients who had no ulcers by week 6 and remained free of ulcers for another 6 weeks was 30% in the apremilast group vs 5% in the placebo group.

The change from baseline in the Behçet's Disease Quality of Life score was -4.3 vs -1.2, for a least-squares difference of -3.1 (95% CI -4.9 to -1.3).

Among patients who had genital ulcers present at baseline (17 in each group), complete responses were seen at week 12 in 71% vs 41%, which was not a significant difference.

Thus far, 46 patients in the original apremilast group and 47 in the placebo/apremilast group have completed the study.

The safety analysis included both the 12-week controlled phase plus the overall apremilast exposure period. During the placebo-controlled phase, more patients in the active treatment group reported adverse events:

• Diarrhea, 41% vs 20%

• Nausea, 19% vs 11%

• Headache, 14% vs 11%

• Upper respiratory tract infection, 12% vs 5%

Two patients in the placebo group had flares of uveitis; none of the patients in the apremilast group developed uveitis.

In the longer apremilast exposure period, the incidence rates of diarrhea were 49.7 per 100 patient-years for the placebo/apremilast group and 89.7 per 100 in the apremilast/apremilast group, while nausea was reported by 16.9 and 32.0 per 100 patient-years in the two groups, respectively.

While this study demonstrated the efficacy of apremilast for the oral ulcers characteristic of Behçet's syndrome, further studies with an active comparator and more extensive follow-up will be needed to explore the longer-term efficacy and safety of this treatment, Hatemi and colleagues concluded.

A limitation of the study, the researchers said, was that it was not designed to assess the effects of apremilast on mucocutaneous symptoms other than the oral ulcers.

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