Oral OTEZLA® (Apremilast) Long-Term Safety Data Presented at American Academy of Dermatology Congress
Celgene Corporation (NASDAQ: CELG) today announced that long-term safety findings from ongoing clinical trials of OTEZLA® (apremilast), the Company's oral, selective inhibitor of phosphodiesterase 4 (PDE4), were presented at the American Academy of Dermatology's Annual Meeting in Washington, D.C. The analyses of pooled 182-week (3.5-year) safety data from the ESTEEM 1 and 2 trials of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy and pooled 3-year safety data from the PALACE 1-3 trials of patients with active psoriatic arthritis were presented in the “Pearls from the Posters” symposium session.
“Physicians treat their psoriasis and psoriatic arthritis patients for a long time,” said Jeffrey Sobell, M.D., Tufts University School of Medicine. “Long-term use of apremilast in plaque psoriasis or psoriatic arthritis trials showed no new safety signals. These findings reinforce the known safety profile of apremilast in plaque psoriasis and psoriatic arthritis, and can help doctors make an informed decision about whether to use this oral, non-biologic option as a long-term treatment.”
Safety data from the 1-year and 2-year open-label extension phase of the ESTEEM trials have been previously reported. In this analysis, safety data were collected from 1,184 patients in ESTEEM 1 and 2 who were initially treated with OTEZLA 30 mg twice daily for a duration up to 182 weeks. This represents a total patient exposure to OTEZLA of 1902.2 patient-years for the 182-week exposure period versus a total exposure of 915.7 patient-years for the 52-week exposure period.
Compared with the first 52 weeks of treatment, the 182-week data showed no increase in exposure-adjusted incidence rates (EAIR) of adverse events, serious adverse events or drug discontinuations. The rates of major cardiac events (EAIR of 0.4 for 52 weeks vs. 0.5 for 182 weeks), malignancies (EAIR of 1.6 vs. 1.2), depression (EAIR of 2.7 vs. 1.8) and attempted suicide (EAIR 0.1 vs. 0.1), respectively, were comparable across the OTEZLA-exposure periods. No serious opportunistic infections, reactivation of tuberculosis infection, completed suicide or clinically meaningful effects on laboratory measurements were reported. Weight loss above 5 percent of body weight was experienced by 21.9 percent of participants compared with 18.8 percent during the first 52 weeks.
The most common adverse events (AEs) were upper respiratory tract infection (EAIR of 22.6 for 52 weeks vs. 14.6 for 182 weeks), diarrhea (EAIR of 26.4 vs. 14.1), nausea (EAIR of 23.6 vs. 12.2), nasopharyngitis (EAIR of 20.2 vs. 12.1), tension headache (EAIR of 12.6 vs. 6.8) and headache (EAIR of 8.6 vs. 4.8), respectively. A majority of the reported AEs occurred in the first 52 weeks of treatment. There were no increases in the severity or frequency of AEs with long-term (182-week) exposure. Most cases of diarrhea and nausea were mild to moderate in severity, occurred during the first week of dosing, and generally resolved within one month.
Pooled safety data from the PALACE 1-3 trials of 721 patients with active psoriatic arthritis who were treated with OTEZLA 20 mg or 30 mg twice daily and received concomitant disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate, for up to 156 weeks were generally consistent with the ESTEEM trial analysis.
ESTEEM 1 and 2 are two large pivotal phase 3 randomized, placebo-controlled studies evaluating OTEZLA in patients with a diagnosis of moderate to severe plaque psoriasis for at least 12 months prior to screening, and who were also candidates for phototherapy and/or systemic therapy. Approximately 1,250 patients were randomized 2:1 to receive either OTEZLA 30 mg twice daily or placebo after an initial five-day titration period, for the first 16 weeks, followed by a maintenance phase from weeks 16-32 in which placebo patients were switched to OTEZLA 30 mg twice daily through week 32, and a randomized withdrawal phase for responders from week 32 to week 52 based on their initial OTEZLA randomization and Psoriasis Area and Severity Index (PASI)-75 response (ESTEEM 1) or (PASI)-50 (ESTEEM 2). A 5-year extension study of ESTEEM 1 and 2 is ongoing.
PALACE 1, 2 and 3 are the pivotal phase 3 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, (the majority of whom received concomitant DMARDs, including methotrexate). 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 U.S.:
- For the treatment of adults with active psoriatic arthritis
- For the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy
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
- For the treatment of adult patients with moderate to severe plaque psoriasis who have not responded to another systemic therapy or do not tolerate such therapy or where such therapy is contraindicated
- As monotherapy or in combination with disease-modifying anti-rheumatic drugs (DMARDs) for the treatment of active psoriatic arthritis in adults who have not responded to a previous DMARD therapy, who have not tolerated it, or where DMARD therapy is contraindicated
- For the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy
- For the treatment of active psoriatic arthritis, alone or in combination with methotrexate, in adult patients who have had an inadequate response, intolerance or contraindication to a prior disease-modifying anti-rheumatic drug (DMARD)
- 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, 1.3% (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.
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% 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. 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 (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended.
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).
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 Corporation, headquartered in Summit, New Jersey, is an integrated global biopharmaceutical company engaged primarily in the discovery, development and commercialization of innovative therapies for the treatment of cancer and inflammatory diseases through next-generation solutions in protein homeostasis, immuno-oncology, epigenetics, immunology and neuro-inflammation. For more information, please visit www.celgene.com . Follow Celgene on Social Media: @Celgene , Pinterest , LinkedIn , FaceBook and YouTube .
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. Celgene Corporation undertakes 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 Celgene’s 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 Celgene’s Annual Report on Form 10-K and other reports filed with the U.S. Securities and Exchange Commission.
For Celgene Corporation
Patrick E. Flanigan III, 908-673-9969
Vice President, Investor Relations
Catherine Cantone, 908-897-4256
Senior Director, Corporate Communications
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