Apremilast Phase III Studies Show Encouraging Results In PsA
At the 2013 European League Against Rheumatism (EULAR) Annual Congress, held from 12th to 15th June, in Madrid, Spain, results from two Phase III studies, a 52-week PALACE 1 and a separate PALACE 3 study, of Celgene's apremilast in psoriatic arthritis (PsA) were presented. Apremilast is an oral, small-molecule inhibitor of PDE-IV.
Long-term results from PALACE 1 revealed meaningful improvements in ACR 20 scores from week 24 through week 52. Patients who received apremilast for 52 weeks demonstrated ACR scores of 63 per cent for apremilast 20mg twice daily (bid) and 55 per cent for apremilast 30mg bid. Similar improvements over time were observed in the ACR 50 and ACR 70 scores.
The safety and tolerability profile of apremilast in PALACE 1 during the 52-week period was consistent with what was observed in the placebo-controlled portion of the trial (zero to 24 weeks) and with what was observed in other PALACE trials to date. Importantly, there were no safety signals with respect to major cardiac events, malignancies, including lymphoma or systemic opportunistic infections, and no cases of reactivations of tuberculosis were reported for the 52-week period. At week 52, the most common treatment-emergent adverse events (AEs) reported (>5 per cent) included nausea, diarrhoea, headache, upper respiratory tract infection (URTI) and nasopharyngitis.
The PALACE 3 study, which evaluated 495 patients, demonstrated statistical significance in achieving the primary endpoint of ACR 20 score at week 16 for patients receiving apremilast compared with placebo (placebo, 19 per cent; apremilast 20mg bid, 29 per cent; apremilast 30mg bid, 43 per cent; p<0.05 and p<=0.0001, respectively). In this study, apremilast treatment was used alone or in combination with oral disease-modifying antirheumatic drugs (DMARDs).
Patients in the 30mg bid active treatment arm also demonstrated significant and sustained improvements in psoriasis-related endpoints, including Psoriasis Area Severity Index (PASI) 50 and PASI 75 at week 24. Similar improvements in 30mg bid-treated patients were also observed in key secondary endpoints, including various measures of physical function, signs and symptoms and quality of life.
The safety and tolerability profile of apremilast in PALACE 3 was consistent with other previously-reported Phase III studies of the therapy in PsA.
Additionally, results from a pooled safety data analysis encompassing multiple randomised, controlled Phase III studies, PALACE 1, 2 and 3, were also presented.
In the 24-week, placebo-controlled analysis, which included nearly 1,500 patients from the three Phase III studies (PALACE 1, 2 and 3), the most common AEs (>=5 per cent) were diarrhoea, nausea, headache and URTI. The majority of AEs (93 to 96 per cent) were mild or moderate in severity, with discontinuation rates due to AEs (placebo, 4.2 per cent; apremilast 20mg bid, 5.6 per cent; apremilast 30mg bid, 7.2 per cent). Serious AEs occurred in 3.8, 3.4 and 3.8 per cent of placebo, apremilast 20mg bid and apremilast 30mg bid, respectively. Importantly, there were no safety signals with respect to major cardiac events, malignancies, including lymphoma or systemic opportunistic infections, and no cases of reactivations of tuberculosis.
PALACE 1, 2, 3 and 4 are four pivotal multi-centre, double-blind, placebo-controlled, parallel-group, Phase III studies with two active treatment groups. In PALACE 1, 2 and 3, approximately 1,500 subjects were randomised 1:1:1 to receive either apremilast 20mg bid, 30mg bid or identically-appearing placebo for 24 weeks, with a subsequent extension in which all patients are treated with apremilast. The three PALACE studies included a wide spectrum of patients with active PsA, including those who had been previously treated with DMARD, biologic DMARD, as well as patients who had previously failed a TNF blocker. PALACE-3 includes a subset of 270 patients with significant skin involvement with psoriasis. In PALACE 4, more than 500 DMARD-naÃ¯ve patients were randomised 1:1:1 to receive either apremilast 20mg bid, 30mg bid or identically-appearing placebo for 24 weeks, with a subsequent extension in which all patients are treated with apremilast. PALACE 2 and PALACE 3 have completed the primary endpoint phases and are in long-term follow-up.
The primary endpoint of the PALACE 1, 2 and 3 studies is the proportion of patients in each treatment group who achieved ACR 20 compared with baseline at week 16. Secondary endpoints include other measures of signs and symptoms, physical function and patient-reported outcomes.
The NDA/NDS submissions, based on the combined data from PALACE 1, 2 and 3 for PsA, were submitted to health authorities in the US and Canada in the first quarter of 2013 and the second quarter of 2013, respectively. The company previously announced that it expects to file a separate NDA/NDS in the US/Canada for psoriasis and a combined PsA/psoriasis MAA submission in Europe in the second half of 2013.