Otezla is approved for the treatment, alone or in combination with disease-modifying antirheumatic drugs (DMARDs), of active psoriatic arthritis in adults who have had an inadequate response or are intolerant to prior DMARD therapy, and moderate to severe chronic plaque psoriasis in adults who have failed to respond to, or who have a contraindication or intolerance to, other systemic therapy including ciclosporin, methotrexate or PUVA.
Apremilast inhibits phosphodiesterase 4 (PDE4), causing elevation of intracellular cAMP levels and in turn downregulating the inflammatory response by modulating the expression of TNF, IL-23, IL-17 and other inflammatory cytokines.
Otezla is supplied as film-coated tablets. An initial titration schedule is required over 6 days to reach the maintenance dose of apremilast 30mg twice daily. Clinical study data showed the greatest improvement within the first 24 weeks of treatment; if there is no evidence of therapeutic benefit after 24 weeks, treatment should be reconsidered.
The safety and efficacy of apremilast for the treatment of psoriatic arthritis were evaluated in three randomised, double-blind, placebo-controlled studies of similar design (PALACE 1, PALACE 2 and PALACE 3) which enrolled a total of 1493 adults with active disease despite treatment with DMARDs. Participants received apremilast or placebo twice daily as monotherapy or alongside low doses of methotrexate, sulfasalazine or leflunomide.
Pooled data from the three studies showed that patients treated with apremilast 30mg twice daily had a significantly higher American College of Rheumatology 20 (ACR20) response rate at 16 weeks (primary endpoint) than those who received placebo (37.0% vs 18.8%, p≤0.001). ACR50 response rates at 16 weeks were also significantly greater in the apremilast group than the placebo group (13.9% vs 6.5%, p≤0.001). The efficacy of apremilast 30mg twice daily was maintained at 52 weeks, with ACR20 and ACR50 response rates of 57% and 25%, respectively. Response rates did not differ significantly between patients receiving and not receiving concomitant DMARDs.
Apremilast also produced significant improvements in physical function and health-related quality of life at week 16, as assessed by the disability index of the health assessment questionnaire (HAQ-DI) and the physical functioning domain of the Short Form Health Survey version 2 (SF-36v2).
Two randomised, double-blind, placebo-controlled studies (ESTEEM 1 and ESTEEM 2) investigated the effects of apremilast in a total of 1257 patients with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy.
In both studies, the proportion of patients who achieved at least a 75% reduction in their Psoriasis Area and Severity Index score (PASI-75) at 16 weeks (primary endpoint) was significantly greater among those treated with apremilast 30mg twice daily than among those given placebo, with response rates of 33.1% vs 5.3% in ESTEEM 1 and 28.8% vs 5.8% in ESTEEM 2 (p<0.0001 for both).
The key secondary endpoint, a static Physician Global Assessment (sPGA) score of clear (0) or almost clear (1) at week 16, was achieved by 21.7% and 20.4% of apremilast-treated patients in ESTEEM 1 and ESTEEM 2 respectively, compared with 3.9% and 4.4% of placebo-treated individuals (p<0.0001 for both).
The response to apremilast was rapid; relative to placebo, significantly greater improvements in the signs and symptoms of psoriasis were seen by week 2. In general, PASI responses were maintained at week 32 and the mean percent improvement in PASI from baseline remained stable in responders who were re-randomised to receive apremilast for the randomised treatment withdrawal phase from weeks 32 to 52.
Significant improvements in quality of life, as measured by the Dermatology Life Quality Index (DLQI) and the mental component summary of the Short Form Health Survey version 2 (SF-36v2), were seen in patients receiving apremilast compared with placebo-treated patients in both studies.
The most commonly reported adverse effects of apremilast were gastrointestinal disorders, including diarrhoea (15.7%) and nausea (13.9%). These were mostly mild to moderate in severity, and generally resolved within 4 weeks. Other commonly reported adverse reactions included upper respiratory tract infections (8.4%), headache (7.9%), and tension headache (7.2%).