Celgene Corporation
Apr 15, 2015
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Phase II Data for Apremilast in Behçet's Disease Published in The New England Journal Of Medicine

Publication highlights safety and efficacy data, including disease-related quality of life measures, for apremilast in rare inflammatory disorder

Global phase III clinical trial now enrolling patients

Summit, N.J. - (April 15, 2015) - Celgene Corporation (NASDAQ: CELG) today announced that results from a multicenter, randomized, placebo-controlled phase II trial (BCT-001) of apremilast (Otezla®) in patients with Behçet's disease were published in the April 16 issue of The New England Journal of Medicine. Behçet's disease is a rare, chronic inflammatory disorder characterized by recurrent oral and genital ulcers, which are considered a hallmark of the disease. Joint inflammation and recurrent skin and eye lesions may also occur.  

"Painful oral ulcers due to Behçet's disease are the hallmark of the condition and can have a significant impact on the lives of many patients. Currently used drugs for this condition may not control oral or genital ulcers in some patients or have potential adverse events that may limit their use," said Gulen Hatemi, M.D., Associate Professor, Cerrahpasa Medical School, Istanbul, Turkey. "The publication of these phase II data in The New England Journal of Medicine is critical to disseminating the findings to the healthcare professional community, to keep them informed of the latest developments in research on this rare, chronic disease."

Findings from this study, including the primary endpoint (reduction in mean number of oral ulcers following 12 weeks of treatment), were initially presented at the European League against Rheumatism (EULAR) and the American College of Rheumatology (ACR) annual meetings in 2013 (P<0.001). In addition to the previously reported results, the publication includes findings that the median (min, max) number of oral ulcers was also reduced following 12 weeks of treatment with apremilast compared with placebo (0.0 (0, 6) vs. 2.0 (0, 13), respectively).

Findings from the full 24-week treatment phase were also included in the publication. After 12 weeks, patients in the placebo group were crossed over to apremilast treatment, and those in the apremilast arm continued treatment. For those treated with apremilast for the full 24 weeks, the decrease in the mean number of oral ulcers was evident by week 2 (0.3 at week 2 vs. 2.7 at baseline) and this decrease was sustained through week 24 (0.6). In the placebo arm, the mean number of oral ulcers was 2.9 at baseline and 1.7 at week 2. At week 24, following 12 weeks of apremilast treatment, the mean number of oral ulcers in the placebo group was 0.4.

A decrease in pain associated with oral ulcers paralleled this decrease in ulcers over time. Mean pain scores, measured using a visual analog scale, decreased from 54.3 at baseline to 12.0 at week 2 and 9.7 at week 24. In the placebo arm, pain scores were 51.7 at baseline and 29.8 at week 2. At week 24, following 12 weeks of apremilast treatment, mean pain score in this group was 9.7.

Apremilast also significantly improved several measures of disease activity and quality of life at week 12. Mean change from baseline at week 12 was significantly better for scores on the Behçet's disease current activity form (-1.5 with apremilast vs. -0.1 for placebo; P<0.001), the Behçet's syndrome activity scale (-21.2 vs. -6.0, respectively; P<0.001), the Behçet's disease quality of life instrument (-4.5 vs. -1.6; P=0.040), and the short form 36 version 2 physical component summary (4.7 vs. -1.7; P=0.001). No significant improvement was seen in the short form 36 version 2 mental component summary (2.0 vs. 1.6; P=NS).  

The safety and tolerability data for apremilast observed in this study were consistent with previously reported data from six other phase III studies of apremilast in psoriatic arthritis or plaque psoriasis. The percentages of patients who developed at least one adverse event (AE) during the placebo-controlled phase were comparable between apremilast (85.5 percent) and placebo (80.4 percent). Serious AEs occurred in two patients receiving apremilast and none receiving placebo. AEs leading to drug discontinuation occurred in four patients receiving apremilast and none receiving placebo. Nausea, vomiting and diarrhea were more common with apremilast compared with placebo.

"Celgene is dedicated to investigating and delivering to patients new treatment options for rare, chronic inflammatory disorders such as Behçet's disease," said Scott Smith, President, Celgene Inflammation & Immunology. "Based on these phase II results, Celgene has filed with regulatory authorities in Turkey and has initiated a global phase III trial of OTEZLA in this debilitating disease."

These results are from an investigational phase II study. Apremilast is not approved for the treatment of patients with Behçet's disease in any country.

About Behçet's Disease
Although the root cause is unknown, Behçet's disease is associated with abnormalities of the immune system and inflammation of the blood vessel network. Behçet's is characterized by recurrent oral and genital ulcers and skin lesions ranging from acne to ulcerations. It can also involve venous thrombosis, aneurysms, inflammation of the eye manifesting as uveitis, and neurologic and gastrointestinal symptoms.

Prevalence of Behçet's disease is highest in the Middle East, Asia and Japan. About one in every 250 people in Turkey has Behçet's, translating to about 300,000 cases. The disease is much less common in the United States (U.S.) and United Kingdom, where it affects only one in every 100,000. Behçet's has been classified in the U.S. as a rare or "orphan" disease by the National Institutes of Health. At this time, there are limited therapies to treat Behçet's in the U.S. and throughout Europe.

About BCT-001
BCT-001 is a phase II, multi-center, randomized, placebo-controlled, double-blind, parallel-group study of 111 subjects with active Behçet's disease. The study was mainly conducted in Turkey with a small number of patients from the U.S. After a screening period of up to 90 days, patients were randomized 1:1 to receive apremilast 30 mg twice daily or placebo for 12 weeks after an initial seven-day titration period, followed by a 12-week blinded extension, where the placebo group was switched to apremilast, and a 28-day post-treatment observational follow-up.

The primary endpoint of the study was the number of oral ulcers at day 85 (12 weeks). Less common manifestations of Behçet's disease, including genital ulcers, skin lesions, inflammatory eye disease, involvement of the gastrointestinal, vascular and central nervous systems, and pain from oral and genital ulcers, were chosen as secondary/exploratory efficacy variables or safety measures.

About Apremilast
Apremilast 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 apremilast exerts its therapeutic action in patients with psoriasis or psoriatic arthritis is not well defined.

Apremilast, marketed as OTEZLA, is approved:

Important Safety Information (based on U.S. labeling)
Otezla 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.

Adverse Reactions
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 Celgene
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, and on Pinterest and LinkedIn.

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