Celgene International Sàrl, a wholly-owned subsidiary of Celgene Corporation (NASDAQ:CELG), today announced that the findings from a long-term (104-week) post-hoc analysis of pooled data from the PALACE phase III clinical trial program of Otezla® (apremilast) will be presented at the European League Against Rheumatism (EULAR) Annual Congress in Rome, Italy. OTEZLA is the Company’s oral, selective inhibitor of phosphodiesterase 4 (PDE4) approved for the treatment of adults with active psoriatic arthritis.
“Dactylitis and enthesitis are common, painful manifestations of psoriatic arthritis that can be difficult to treat,” said Dafna Gladman, M.D., FRCPC, Professor of Medicine, University of Toronto. “Oral OTEZLA can improve these challenging manifestations.”
Dr. Gladman, the lead investigator of the study, will present the analysis of pooled data from the PALACE 1, 2 and 3 phase III clinical trials in which patients with enthesitis and dactylitis at baseline were allowed to be evaluated for the therapeutic benefit of OTEZLA on enthesitis and dactylitis over 104 weeks. In the PALACE trials, patients were randomized to receive either OTEZLA 20 mg twice daily, OTEZLA 30 mg twice daily or identically appearing placebo for the first 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. At week 24, patients either continued on OTEZLA or were switched from placebo to OTEZLA 20 mg or 30 mg twice daily in a long term, open-label, active treatment phase. Although enthesitis and dactylitis involvement were not required for patients to enter the study, and patients were not stratified according to baseline enthesitis or dactylitis, approximately 63 percent (945/1,493) of patients had pre-existing enthesitis at baseline and approximately 42 percent (633/1,493) of patients had pre-existing dactylitis at baseline. A post-hoc analysis on the effect of OTEZLA on enthesitis and dactylitis in patients with pre-existing enthesitis or dactylitis was performed on as-observed pooled data from PALACE 1, 2 and 3.
The study abstract states that treatment with OTEZLA 30 mg twice daily in patients with pre-existing enthesitis (inflammation at sites where tendons or ligaments insert into bone) or dactylitis (inflammation of an entire digit) — two distinct manifestations of psoriatic arthritis — demonstrated improvements in these symptoms at 52 weeks and that improvements were sustained through week 104. For patients taking OTEZLA 30 mg twice daily, the mean Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) was reduced by 43.5 percent at week 52 (n=377) and by 57.5 percent at week 104 (n=302). A score of 0, indicating no pain at any of the sites assessed, was achieved by 37.7 percent of patients at week 52 and 48.7 percent at week 104.
OTEZLA 30 mg twice daily also resulted in a mean 67.9 percent decrease in dactylitis count at week 52 (n=249) and 80.0 percent decrease at week 104 (n=200). A dactylitis count of 0, indicating no signs of dactylitis, was achieved by 67.5 percent of patients at week 52 and 77.5 percent of patients at week 104.
During weeks 0 to 52, adverse events (AEs) occurring in at least five percent of patients treated with OTEZLA were diarrhea, nausea, headache, upper respiratory tract infection (URTI) and nasopharyngitis. Rates of URTI, nasopharyngitis, diarrhea, nausea and headache between weeks 52 and 104 were 6.5 percent, 5.8 percent, 2.9 percent, 1.8 percent and 3.0 percent, respectively. No new safety concerns were identified, and no increases were seen in AE incidence or severity with longer exposure.
About PALACE Program
PALACE 1, 2 and 3 are the pivotal phase III multi-center, double-blind, placebo-controlled, parallel-group studies with two active-treatment groups. 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.
The primary endpoint of the PALACE 1, 2 and 3 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.
Taken together, the PALACE program is the largest psoriatic arthritis program to date intended for regulatory submission.
OTEZLA is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased intracellular cAMP levels which is thought to indirectly modulate the production of inflammatory mediators. The specific mechanism(s) by which OTEZLA exerts its therapeutic action in patients with psoriasis or psoriatic arthritis is not well defined.
OTEZLA is approved:
- In the European Union:
- For the treatment of moderate-to-severe chronic plaque psoriasis in adult patients who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or psoralen and ultraviolet-A light (PUVA)
- Alone or in combination with Disease Modifying Antirheumatic Drugs (DMARDs), for the treatment of active psoriatic arthritis (PsA) in adult patients who have had an inadequate response or who have been intolerant to a prior DMARD therapy
- In the U.S. for the treatment of adults with active psoriatic arthritis and the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy
- In Canada for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy
- In Australia:
- For the treatment of signs and symptoms of active psoriatic arthritis in adult patients
- For the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy
Important Safety Information (based on US labeling)
Otezla® (apremilast) is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation.
Warnings and Precautions
Depression: Treatment with OTEZLA is associated with an increase in adverse reactions of depression. During clinical trials, 1.0% (10/998) of patients treated with OTEZLA reported depression or depressed mood compared to 0.8% (4/495) treated with placebo; 0.3% (4/1441) of patients treated with OTEZLA discontinued treatment due to depression or depressed mood compared with none in placebo treated patients (0/495). Depression was reported as serious in 0.2% (3/1441) of patients exposed to OTEZLA, compared to none in placebo treated patients (0/495). Suicidal ideation and behavior were observed in 0.2% (3/1441) of patients on OTEZLA, compared to none on placebo (0/495). Two patients who received placebo committed suicide compared to none on OTEZLA.
Carefully weigh the risks and benefits of treatment with OTEZLA for patients with a history of depression and/or suicidal thoughts/behavior, or in patients who develop such symptoms while on OTEZLA. Patients, caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and they should contact their healthcare provider if such changes occur.
Weight Decrease: Body weight loss of 5-10% was reported in 10% of patients taking OTEZLA and in 3.3% of patients taking placebo. Monitor body weight regularly; evaluate unexplained or clinically significant weight loss, and consider discontinuation of OTEZLA.
Drug Interactions: Apremilast exposure was decreased when OTEZLA was co-administered with rifampin, a strong CYP450 enzyme inducer; loss of OTEZLA efficacy may occur. Concomitant use of OTEZLA with CYP450 enzyme inducers (eg, rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended.
Adverse reactions reported in at least 2% of patients taking OTEZLA, that occurred at a frequency at least 1% higher than that observed in patients taking placebo, for up to 16 weeks (after the initial 5-day titration), were (OTEZLA%, placebo%): diarrhea (7.7, 1.6); nausea (8.9, 3.1); headache (5.9, 2.2); upper respiratory tract infection (3.9, 1.8); vomiting (3.2, 0.4); nasopharyngitis (2.6, 1.6); upper abdominal pain (2.0, 0.2).
Use in Specific Populations
Pregnancy and Nursing Mothers: OTEZLA is Pregnancy Category C; it has not been studied in pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known whether apremilast or its metabolites are present in human milk. Caution should be exercised when OTEZLA is administered to a nursing woman.
Renal Impairment: OTEZLA dosage should be reduced in patients with severe renal impairment (creatinine clearance less than 30 mL/min); for details, see Dosage and Administration, Section 2, in the Full Prescribing Information.
Please click here for Full Prescribing Information.
Celgene International Sàrl, located in Boudry, Switzerland, is a wholly-owned subsidiary and international headquarters of Celgene Corporation. Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global pharmaceutical company engaged primarily in the discovery, development and commercialization of innovative therapies for the treatment of cancer and inflammatory diseases through gene and protein regulation. For more information, please visit www.celgene.com. Follow Celgene on Social Media: @Celgene, Pinterest, LinkedIn and YouTube.
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