Celgene has announced results of phase II trial ( BCT-001 ) on Apremilast, a oral targeted inhibitor of phosphodiesterase 4 ( PDE4 ), in patients with Behçet’s disease.
These data have showed that significantly more patients on Apremilast achieved a complete response ( were free from active oral ulcers ) at week 12 compared with those on placebo ( Apremilast, 71%; placebo, 29%; p less than 0.0001 ). Among patients with genital ulcers at baseline ( n=16 ), 100% of those receiving Apremilast had a complete response at week 12 compared with 50% of those receiving placebo ( p=0.036 ).
The beneficial effect of Apremilast on oral ulcers reached a stable effect within two weeks and was sustained while patients remained on treatment.
At week 12, Apremilast also improved several patient-reported outcome scores, including the Behçet’s disease current activity form ( BDCAF ), Behçet’s syndrome activity score ( BSAS ) and Behçet’s disease quality of life ( QoL ) instrument. Improvement in oral ulcer pain was also significantly higher with Apremilast than with placebo ( Apremilast, -44.7 ± 24.30; placebo, -16.0 ± 32.54; p less than 0.0001 ).
The type and severity of adverse events were comparable to the known Apremilast safety profile. In BCT-001, treatment-emergent adverse events ( TEAE ), including severe and serious adverse events ( SAEs ) and withdrawal due to adverse events, were comparable between 30 mg twice daily ( BID ) and placebo. None of the SAEs in the Apremilast group were reported more than once. Out of the five most common TEAEs in the 30 mg BID group, two ( headache and Behçet’s syndrome / flare ) were comparable to placebo, while nausea, diarrhea and vomiting were reported more frequently with Apremilast 30 mg BID.
Limited therapies are available to treat this rare, chronic inflammatory disorder of unknown cause. The treatment options depend largely on the manifestations of the different organ systems involved. Treatment options recommended by physicians are largely aimed at alleviating specific patient symptoms and may include non-steroidal anti-inflammatory drug ( NSAID ), immunosuppressive medications and disease-modifying antirheumatic drugs ( DMARDs ) approved for other indications.
BCT-001 is a phase 2, multi-center, randomized, placebo-controlled, double-blind, parallel-group study with two treatment arms ( Apremilast 30 mg BID and placebo ) in Behçet’s disease. The study consisted of a 90-day pre-randomization phase, a 12-week treatment phase, a 12-week extension phase and a four-week post-treatment observational follow-up phase. A total of 111 subjects with active Behçet’s disease were randomized 1:1 to receive either Apremilast 30 mg BID or identically appearing placebo, stratified by gender. The primary endpoint of the study was the number of oral ulcers at day 85 ( 12 weeks ). Because virtually all patients with Behçet’s disease have painful oral ulcers, this manifestation was chosen as the primary efficacy measure. Less common manifestations of Behçet’s disease, including genital ulcers, skin lesions, inflammatory eye disease, involvement of the gastrointestinal, vascular and central nervous systems, and pain from oral and genital ulcers, were chosen as secondary/exploratory efficacy variables or safety measures.
Apremilast, an oral, targeted inhibitor of phosphodiesterase 4 ( PDE4 ), intracellularly modulates the expression of a network of pro-inflammatory and anti-inflammatory cytokines.
PDE4 is a cyclic adenosine monophosphate ( cAMP )-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-alpha, IL-23, and other inflammatory cytokines. Elevation of cAMP also increases anti-inflammatory cytokines such as IL-10.
Behçet’s disease is a chronic inflammatory vasculitis of unknown cause characterized by recurrent oral and genital ulcers, multiple skin lesions ranging from acne to vasculitic ulcerations, vascular involvement, including venous thrombosis and aneurysms which may be life threatening, and inflammatory disease of the eye manifesting as uveitis, neurologic involvement and gastrointestinal involvement.
Prevalence of Behçet’s disease is highest in the Middle East, Asia and Japan, but it is classified as a rare or orphan disease by the National Institutes of Health ( NIH ) in the United States.
In some cases, uncontrolled inflammation may lead to blindness, intestinal perforations, stroke, and even aneurismal bleeding which can be fatal. Although the root cause of Behçet’s disease is unknown, the disease is associated with abnormalities of the immune system. ( Xagena )
Source: American College of Rheumatology ( ACR ) / Association of Rheumatology Health Professionals ( ARHP ) Meeting, 2013