New Oral Treatment Shows Significant Promise in the Treatment of Mouth and Genital Ulcers in People with Behcet’s Syndrome

Released: 18-Oct-2013 3:00 PM EDT
Embargo expired: 26-Oct-2013 4:30 PM EDT
Source Newsroom: American College of Rheumatology (ACR)
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Citations American College of Rheumatology Annual Scientific Meeting

Newswise — SAN DIEGO – Apremilast, an orally available small molecule modulating several inflammatory pathways, which is pending approval by the United States Food and Drug Administration, is showing promise in the treatment of mouth and genital ulcers in people with Behcet’s syndrome, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in San Diego.

Behcet’s syndrome is a type of vasculitis that causes inflammation in the blood vessels throughout the body. Among other symptoms, the main symptom of Behcet’s is painful ulcers in the mouth and genital areas, and researchers recently discovered Apremilast is both safe and effective in treating these ulcers
– a promising finding for the 5,000 to 15,000 Americans who suffer from the disease.

“Mucocutaneous lesions in Behçet’s syndrome can be painful and occasionally disabling, impairing the quality of life of patients,” explains Gulen Hatemi, MD, the lead investigator in the study. “Currently available drugs may not control mouth or genital ulcers in some patients, or have potential adverse events that may limit their use. There is an unmet need for effective and safe treatment modalities that are easy to tolerate for these lesions.

In this phase-two study, which took place across multiple sites, 111 people with Behcet’s (who did not have any organs affected by disease and had at least two ulcers at the beginning of the study) were randomly assigned to either take 30mg of Apremilast or placebo twice a day for 12 weeks. After the first
12 weeks, all participants were treated with Apremilast for an additional 12 weeks, and all patients were observed at a follow up appointment 28 days after the last dose of the drug.

Dr. Hatemi’s team was primarily interested in noting the number of mouth ulcers and amount of pain each participant had at 12 weeks into the study, but they also noted the number of genital ulcers at the same point in time, pain of oral ulcers, the effectiveness of the treatment over time, each participant’s disease activity, changes in health as reported by participants and any negative reactions patients had to the treatment.

Ninety-five of the 111 participants (who were, on average 34.5 years old and predominately female) completed the study. At 12 weeks, the average number of mouth ulcers among 50 participants on Apremilast was 0.5, compared to 2.1 in the 45 participants taking placebo. Notably, the beneficial effect of Apremilast began within two weeks of starting the treatment, and these benefits continued as long as the participants were receiving Apremilast. But, the beneficial effect disappeared shortly after Apemilast was stopped at 24 weeks.

Pain was also noted as being significantly lower in those on Apremilast; and at 12 weeks, significantly more participants on the treatment were completely free of mouth ulcers (71 percent on the treatment versus 29 percent on placebo).

Among the 16 participants who began the study with genital ulcers, 10 received Apremilast and six received placebo. The 10 on Apremilast were completely genital ulcer free at 12 weeks, compared to three of the six in the placebo group. Additionally, the average disease activity scores were found to have greater improvement among those who were given Apremilast versus those who received placebo. Finally, the researchers noted two serious medical events among those taking Apremilast: one participant experienced diplegia — a type of paralysis — which the researchers deemed unrelated to the treatment, and one patient worsened anal fissure and hemorrhoids while having diarrhea. Among the participants taking placebo, two had flares of their Behcet’s and one experienced fever.

“In this study Apremilast decreased the number of oral ulcers and the associated pain, starting from two weeks of treatment onset. The drug was generally well tolerated with few adverse events. An improvement in quality of life and decrease in disease activity, as reported by the patient, was observed,” says Dr. Hatemi. “These results warrant further work on the possible efficacy of Apremilast on other manifestations of Behçet’s syndrome, including genital ulcers. Considering the important down regulating effect of Apremilast on the inflammatory cascade, such work also can also help us to better explain the disease mechanism(s) in Behçet’s syndrome.”

Patients should talk to their rheumatologists to determine their best course of treatment.

The American College of Rheumatology is an international professional medical society that represents more than 9,000 rheumatologists and rheumatology health professionals around the world. Its mission is to advance rheumatology. The ACR/ARHP Annual Meeting is the premier meeting in rheumatology. For more information about the meeting, visit http://www.acrannualmeeting.org/ or join the conversation on Twitter by using the official hashtag: #ACR13.

Editor’s Notes: Dr. Hatemi will present this research during the ACR Annual Meeting at the San Diego Convention Center at 11:15 AM on Sunday, October 27 in Hall B1.

Abstract Number: 761

Apremilast For The Treatment Of Behçet’s Syndrome: A Phase II Randomized, Placebo-Controlled, Double-Blind Study

Gulen Hatemi1, Melike Melikoglu1, Recep Tunc2, Cengiz Korkmaz3, Banu Turgut Ozturk2, Cem Mat4, Peter A. Merkel5, Kenneth Calamia6, Ziqi Liu7, Lilia Pineda7, Randall M. Stevens7, Hasan Yazici1 and Yusuf Yazici8,

1Istanbul University, Cerrahpasa Medical Faculty, Rheumatology, Istanbul, Turkey, 2Selçuk University, Konya, Turkey, 3Eskisehir Osmangazi University, Eskisehir, Turkey, 4Istanbul University, Cerrahpasa Medical Faculty, Dermatology, Istanbul, Turkey, 5University of Pennsylvania, Philadelphia, PA, 6Mayo Clinic, Jacksonville, FL, 7Celgene Corporation, Warren, NJ, 8NYU Hospital for Joint Diseases and New York University School of Medicine, New York, NY

Apremilast for the Treatment of Behçet's Syndrome: A Phase II Randomized, Placebo-Controlled, Double-Blind Study

Background/Purpose: Mucocutaneous manifestations of Behçet's syndrome (BS) can be resistant to conventional treatment and at times disabling. Apremilast (APR), an oral phosphodiesterase 4 inhibitor, modulates inflammatory pathways. This study investigated the efficacy of APR in BS patients with active oral ulcers (OU).

Methods: This was a phase II, multicenter, randomized, placebo (PBO)-controlled study with an open-label extension. Patients with BS without major organ involvement but ≥2 OU were randomized to APR 30 mg BID or PBO for 12 weeks followed by a 12-week active-treatment period for all patients and a 28- day post-treatment observational follow-up. The primary endpoint was the number of OU at week 12. Secondary endpoints were the number of genital ulcers (GU) at week 12, efficacy over time (AUC for OU and GU, first 12 weeks), disease activity (BSAS, BDCAF), patient-reported outcomes (BDQOL, SF-36), and adverse events (AEs).

Results: 111 patients (mean age 34.5 ± 10.1 years, 69% women) were randomized (55 APR, 56 PBO) and 95 completed the treatment phase (50 APR, 45 PBO). Mean (±SD) number of OU at week 12 was 0.5 ± 1.03 with APR and 2.1 ± 2.58 with PBO (P<0.0001). The figure shows the mean number of OU over time.
Notably, the beneficial effect of APR on OU started within 2 weeks. There was a sustained effect while on APR, but the effect disappeared shortly after APR was stopped at week 24. Improvement in OU pain (VAS) was significantly higher with APR (-44.7 ± 24.30 vs -16.0 ± 32.54; P<0.0001). At week 12, significantly more patients receiving APR had a complete response (OU-free) (71% [39/55], APR; 29% [16/56], PBO; P<0.0001). Among the limited number of patients with GU at baseline (n=16), 10/10 receiving APR had a complete response at week 12 vs 3/6 receiving PBO (p=0.036). The mean change from baseline in the BDCAF, BSAS and BDQOL scores were significantly higher in the APR group (APR vs PBO -1.5 ± 1.84 vs -0.1 ± 1.51; P=0.0007, -21.2 ± 17.9 vs -5.9 ± 18.2; p<0.0001 and -4.5 ± 7.61 vs -1.6 ±5.3 P=0.0397 respectively). There were 2 serious AEs with APR (1 diplegia, 1 anal fissure and hemorrhoids) and 3 with PBO (2 disease flares, 1 fever episode). The diplegia in 1 patient was transient and was not thought to be related to APR.

Conclusion: APR was effective in the treatment of OU, the cardinal manifestation of BS, with an acceptable safety profile. There were also indications of efficacy in several secondary endpoints, including GU, a highly specific lesion for BS. Further trials are warranted to test the efficacy of APR for other manifestations of BS.

Disclosures: G. Hatemi, None.
M. Melikoglu, None.
R. Tunc, None.
C. Korkmaz, None.
B. Turgut Ozturk, None.
C. Mat, None.
P. A. Merkel, Celgene Corporation, 2 K. Calamia, None.
Z. Liu, Celgene Corporation, 3 L. Pineda, Celgene Corporation, 1, Celgene Corporation, 3 R. M. Stevens, Celgene Corporation, 1, Celgene Corporation, 3 H. Yazici, None.
Y. Yazici, Celgene Corporation, 2, Celgene Corporation, 5


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