Clinical Trials

Date: 2016-09-28

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the European Academy of Dermatology and Venereology (EADV) Annual Congress in Vienna, Austria

Company: Celgene (USA - NJ)

Product: Otezla® (apremilast)

Action mechanism:

• phosphodiesterase 4 inhibitor. Otezla® is an oral, small-molecule, selective inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased intracellular cAMP levels. Otezla® was approved on March 21, 2014 by the FDA for the treatment of adults with active psoriatic arthritis. A combined psoriatic arthritis/psoriasis Marketing Authorization Application (MAA) in Europe was submitted to health authorities in the fourth quarter of 2013.

 

Disease: psoriatic arthritis>

Therapeutic area: Autoimmune diseases – Inflammatory diseases - Rheumatic diseases

Country:

Trial details:

• PALACE 1, 2, 3 and 4 are the pivotal phase III multi-center, double-blind, placebo-controlled, parallel-group studies with two active-treatment groups. In PALACE 1, 2 and 3, approximately 1,500 patients were randomized 1:1:1 to receive either OTEZLA 20 mg twice daily, OTEZLA 30 mg twice daily or identically-appearing placebo, for 16 weeks. At week 16, some placebo-treated patients were randomized to one of the two OTEZLA groups, while others remained on placebo through week 24. After week 24, patients began a subsequent long term, open-label, active treatment phase. The PALACE 1, 2 and 3 studies included a wide spectrum of patients with active psoriatic arthritis, including those who had been previously treated with oral disease-modifying antirheumatic drugs (DMARDs), and/or biologics, with some patients who had previously failed a tumor necrosis factor (TNF) blocker. In PALACE 4, more than 500 DMARD-naïve patients were randomized 1:1:1 to receive either OTEZLA 20 mg or 30 mg twice daily, or identically appearing placebo, for 24 weeks, with a subsequent active treatment phase up to 52 weeks, followed by a long-term safety phase in which all patients are treated with OTEZLA.
• The primary endpoint of the PALACE 1, 2, 3 and 4 studies was the modified American College of Rheumatology criteria for 20 percent improvement (ACR20) at week 16. Secondary endpoints included other measures of signs and symptoms of psoriatic arthritis, physical functioning and patient-reported outcomes.

Latest news:

• • On September 28, 2016, Celgene announced that long-term safety findings from ongoing clinical trials of apremilast were presented at the European Academy of Dermatology and Venereology (EADV) Annual Congress in Vienna, Austria . Analyses of pooled 156-week (3-year) safety data from the ESTEEM 1 and 2 and PALACE 1-3 trials were presented, which included patients with moderate to severe plaque psoriasis (ESTEEM) and active psoriatic arthritis (PALACE) who were treated with apremilast 30 mg twice-daily. Patients with psoriatic arthritis were treated with Otezla® alone or in combination with concomitant disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate. 2,242 patients were included in the pooled safety analysis up to 16 weeks (placebo n=913; APR30 n=1,329), with 1,905 patients (3,527.5 patient years) receiving apremilast in the APR-exposure period up to 156 weeks.1 Across both trial programmes up to 16 weeks, the most common adverse events (AEs) (?5 percent of patients) among patients on apremilast were diarrhoea, nausea, headache, upper respiratory tract infection, and nasopharyngitis. Most cases of diarrhoea/nausea were mild to moderate in severity, occurred during the first 2 weeks of apremilast dosing and generally resolved in one month. Discontinuation rates of apremilast due to diarrhoea and nausea occurred at rates of 1.3 percent and 1.7 percent, respectively, during the 0 to ?52 week apremilast exposure period and 0.0 percent for both AEs during the > 104 to ?156 week apremilast exposure period. The exposure-adjusted incidence rates ( EAIR /100 patient years) for AEs, serious AEs and discontinuations due to AEs did not increase with increasing cumulative exposure during the apremilast-exposure period (0 to ?156 weeks; 3,527.5 patient-years); this was confirmed by assessment of rates on a year-by-year exposure basis.1 The incidences ( EAIR /100 patient years) of major adverse cardiovascular events (MACE), malignancies, and serious infections for patients on apremilast were comparable to placebo up to 16 weeks and remained low with prolonged exposure. No serious opportunistic infections or clinically meaningful effects on laboratory measurements were reported. Rates for depression or suicidality did not increase with increasing cumulative long-term apremilast exposure. Most patients taking apremilast maintained body weight within 5 percent of baseline; with 21.1 percent experienced > 5 percent weight loss over the 156 week apremilast-exposure periods. The rate of treatment discontinuation due to weight loss was low. In addition, a retrospective analysis of results from ESTEEM 1 and 2 trials examined the potential of an alternative tool to measure psoriasis disease severity. Improvement in Psoriasis Area and Severity Index (PASI) score remains the most commonly used severity assessment in clinical development and in practice, however its limitations - including scoring complexity and insensitivity to changes - mean that there may be opportunities to improve how psoriasis patients are assessed. The combination of the Physician's Global Assessment (PGA) and Body Surface Area (BSA) - the PGAxBSA composite tool - is a simple assessment which was shown to measure meaningful clinical responses of psoriasis patients in the ESTEEM trials including minimal disease activity and is sensitive to change in disease severity.
• • On November 18, 2014, Celgene announced that results from long-term (104-week) efficacy and safety analyses of Otezla® (apremilast) from the open-label phase of two PALACE phase III clinical trials were presented at the 2014 American College of Rheumatology (ACR)/ Association of Rheumatology Health Professionals (ARHP) annual meeting in Boston. In PALACE 1, 84 percent (144/171) of patients who completed one year (52 weeks) of 30 mg twice daily therapy continued to receive Otezla® at two years (104 weeks). Improvements in efficacy measures observed at 52 weeks were sustained through 104 weeks of treatment. At week 104, among patients receiving Otezla® 30 mg twice daily, the ACR20 response rate was 65.3 percent. ACR50 and 70 response rates were 34.0 percent and 19.6 percent, respectively, at week 104.
• Similar findings were observed in PALACE 4. In this trial, nearly 84 percent (168/201) of DMARD-naïve patients who completed one year of Otezla®  30 mg twice daily monotherapy continued to receive Otezla®  at two years. At week 104, among patients treated with Otezla® 30 mg twice daily monotherapy, an ACR20, 50 and 70 response was reached by 61.4 percent, 40.7 percent and 19.2 percent of patients, respectively.
• In both PALACE 1 and PALACE 4, changes in other efficacy measures—including the HAQ-DI, which assesses improvements in physical function, and swollen and tender joint counts—were also generally sustained between weeks 52 and 104 with continued Otezla®  treatment. In PALACE 4, treatment with Otezla® in patients with pre-existing enthesitis (inflammation at sites where tendons or ligaments insert into bone) or dactylitis (inflammation of an entire digit), two key manifestations of psoriatic arthritis, resulted in improvements in enthesitis and dactylitis that were sustained through 104 weeks of treatment. Similar to adverse events (AEs) reported during weeks 0 to 52 in PALACE 1 and 4, most AEs reported during weeks 52 to 104 were mild or moderate in severity. The rates of diarrhea, nausea, headache and upper respiratory tract infection (URTI)—AEs reported in at least five percent of patients receiving OTEZLA 30 mg twice daily at 52 weeks in both studies—decreased or were similar between weeks 52 to 104 compared with the 0 to 52 week period. Rates of diarrhea, nausea, headache and URTI at week 104 in PALACE 1 and 4 respectively, were as follows: diarrhea (1.8 percent and 2.0 percent), nausea (0.6 percent and 2.0 percent), headache (4.7 percent and 1.0 percent) and URTI (4.7 percent and 4.5 percent). Serious AEs occurred in 4.7 percent and 5.0 percent of patients, respectively. In addition, discontinuation rates due to AEs in both studies decreased during the 52 to 104 week period compared with the 0 to 52 week period.
• • On October 7, 2014, Celgene announced that the latest research findings on Otezla® (apremilast), the Company's oral, selective inhibitor of phosphodiesterase 4 (PDE4), in psoriatic arthritis will be presented at the 23rd European Academy of Dermatology and Venereology (EADV) Congress in Amsterdam, October 8 - 12, 2014.  An analysis of long-term results from the PALACE clinical trial program evaluating Otezla® in patients with active psoriatic arthritis will be presented at the meeting. The analysis assesses the effect of Otezla® treatment through 52 weeks on the signs and symptoms of psoriatic arthritis, including enthesitis (inflammation at sites where tendons or ligaments insert into bone) and dactylitis (inflammation of an entire finger or toe) in patients with pre-existing enthesitis or dactylitis. (Abstract : The Impact of Apremilast Therapy on Work Productivity Among Patients with Moderate to Severe Plaque Psoriasis: Pooled Analysis of 2 Phase 3 Studies; Tom Tencer, MD).

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