Oral OTEZLA(R) (Apremilast) Showed Sustained Clinical Response over Two Years in Patients with Active Psoriatic Arthritis
Celgene Corporation (NASDAQ:CELG) , today announced that results from long-term (104-week) efficacy and safety analyses of OTEZLA(R) (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. OTEZLA is the Company’s oral, selective inhibitor of phosphodiesterase 4 (PDE4), approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with active psoriatic arthritis and for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.
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-na”ive 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.
“Given the chronic nature of this condition, dealing with psoriatic arthritis can be an ongoing struggle for many people,” said Alvin Wells, M.D., Ph.D., director, Rheumatology and Immunology Center, Franklin, WI. “Evidence-based data show that different treatment options are frequently required to continue to manage a patient’s symptoms. At our center, we see patients with active psoriatic arthritis who present with significant disease activity despite effective prior treatments. These new data from ongoing open-label studies add to our understanding of how apremilast may help meet treatment goals in such patients.”
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.
About PALACE Program
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-na”ive 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.
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 was approved on March 21, 2014 by the FDA for the treatment of adults with active psoriatic arthritis and on September 23, 2014 for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. A combined psoriatic arthritis/plaque psoriasis Marketing Authorization Application (MAA) in Europe was submitted to health authorities in the fourth quarter of 2013.
Important Safety Information
Otezla(R) (apremilast) is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation.
Warnings and Precautions
Depression: 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.
Psoriasis: Treatment with Otezla is associated with an increase in adverse reactions of depression. During clinical trials, 1.3% (12/920) of patients treated with Otezla reported depression compared to 0.4% (2/506) on placebo; 0.1% (1/1308) of Otezla patients discontinued treatment due to depression compared with none on placebo (0/506). Depression was reported as serious in 0.1% (1/1308) of patients exposed to Otezla, compared to none in placebo-treated patients (0/506). Suicidal behavior was observed in 0.1% (1/1308) of patients on Otezla, compared to 0.2% (1/506) on placebo. One patient treated with Otezla attempted suicide; one patient on placebo committed suicide.
Psoriatic Arthritis: 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.
Weight Decrease: Monitor body weight regularly; evaluate unexplained or clinically significant weight loss, and consider discontinuation of Otezla.
Psoriasis: Body weight loss of 5-10% occurred in 12% (96/784) of patients treated with Otezla and in 5% (19/382) of patients treated with placebo. Body weight loss of >=10% occurred in 2% (16/784) of patients treated with Otezla compared to 1% (3/382) of patients treated with placebo.
Psoriatic Arthritis: 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.
Psoriasis: Adverse reactions reported in >=5% of patients were (Otezla%, placebo%): diarrhea (17, 6), nausea (17, 7), upper respiratory tract infection (9, 6), tension headache (8, 4), and headache (6, 4).
Psoriatic Arthritis: Adverse reactions reported in >=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.
About Psoriatic Arthritis
Psoriatic arthritis is a painful, chronic inflammatory disease characterized by pain, stiffness, swelling and tenderness of the joints, inflammation of specific ligaments and tendons, and decrease in physical functioning. It is estimated that nearly 38 million people worldwide have psoriatic arthritis. Psoriatic arthritis can impact day-to-day activities and has been reported to increase work disability. Common signs and symptoms of psoriatic arthritis include pain, stiffness, and swelling in joints. To learn more about psoriatic arthritis, go to www.discoverpsa.com. To learn more about the role of PDE4 in inflammatory diseases, go to www.discoverpde4.com.
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 Twitter @Celgene. Follow Celgene on Pinterest @Celgene Corporation. Follow Celgene on Twitter @Celgene, and on Pinterest and LinkedIn.
This press release contains forward-looking statements, which are generally statements that are not historical facts. Forward-looking statements can be identified by the words “expects,” “anticipates,” “believes,” “intends,” “estimates,” “plans,” “will,” “outlook” and similar expressions. Forward-looking statements are based on management’s current plans, estimates, assumptions and projections, and speak only as of the date they are made. We undertake no obligation to update any forward-looking statement in light of new information or future events, except as otherwise required by law. Forward-looking statements involve inherent risks and uncertainties, most of which are difficult to predict and are generally beyond our control. Actual results or outcomes may differ materially from those implied by the forward-looking statements as a result of the impact of a number of factors, many of which are discussed in more detail in our Annual Report on Form 10-K and other reports filed with the Securities and Exchange Commission.
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