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Oral apremilast phase III ESTEEM 1 study



Celgene International Sàrl, a wholly-owned subsidiary of Celgene Corporation (NASDAQ: CELG), has announced results of pre-specified sub-analyses from ESTEEM 1 on nail and scalp psoriasis, as well as health-related quality-of-life outcomes, from the Company’s first phase III study in psoriasis, at the 22nd Congress of the European Academy of Dermatology and Venereology annual meeting in Istanbul, Turkey.
ESTEEM 1 is the largest of two registrational, randomised, placebo-controlled studies evaluating apremilast, an oral small-molecule specific inhibitor of phosphodiesterase 4 (PDE4), in more than 1,200 patients with moderate-to-severe plaque psoriasis. Previously reported findings from ESTEEM 1 showed that apremilast significantly improved general signs and symptoms of psoriasis across a wide-range of patient types.
“Up to 55% of patients with psoriasis at any given time have nail involvement, and more than half have scalp psoriasis, which can be particularly debilitating for individuals dealing with this difficult-to-treat disease,” said Professor Kristian Reich, MD, SCIderm Research Institute and Dermatologikum, Hamburg, Germany. “These analyses demonstrate that apremilast may improve these conditions and may offer a much-needed new oral treatment option for psoriasis patients. Moreover, the encouraging health-related quality-of-life findings suggest that long-term treatment with oral apremilast may improve the mental and physical well-being of these patients.”
New analyses (abstract #2033) assessed the effects of apremilast on 558 patients in ESTEEM 1 with nail psoriasis and on 563 patients with at least moderate scalp psoriasis.
After 16 weeks of treatment, patients in the apremilast 30mg twice daily (BID) group had significantly greater improvements in the Nail Psoriasis Severity Index (NAPSI) scores than the patients treated with placebo, showing an improvement of 22.5% vs. a worsening of 6.5%, respectively; p<0.0001. Improvements continued through 32 weeks of treatment for those patients on apremilast 30mg BID (an improvement of 43.6%).
Psoriasis of the scalp, another difficult-to-treat area, was also improved by treatment with apremilast 30mg BID. After 16 weeks of therapy, significantly more patients treated with apremilast 30mg achieved a ScPGA score of 0-1 (clear or almost clear) compared with those in the placebo group (46.5% vs. 17.5%, respectively; p<0.0001). This effect was generally maintained for those patients who remained on apremilast through week 32.
As shown in a separate analysis (abstract #0237), the treatment of 844 patients in ESTEEM 1 with apremilast also significantly improved health-related quality-of-life, as assessed by a variety of standardised measurements, including the Dermatology Quality of Life Index (DLQI), the Patient Health Questionnaire (PHQ-8), the European Quality of Life 5 Dimensions Questionnaire (EQ-5D), and the 36-item Short-Form Health Survey (SF-36) mental component summary (MCS).
Significant improvements in these measurement tools were seen after 16 weeks of treatment with apremilast; improvements were maintained through 32 weeks of treatment. Patients initially treated with placebo for 16 weeks who were then treated with apremilast for a subsequent 16 weeks also showed improvements in these measures.
In these analyses, the overall safety and tolerability profile of apremilast in patients with moderate to severe psoriasis was consistent with previously reported findings. The most commonly observed adverse events included diarrhoea, nausea, upper respiratory tract infection, nasopharyngitis, tension headache, and headache. Adverse events were generally mild to moderate in severity. Nausea, vomiting, and diarrhoea tended to occur most frequently during the first week of dosing and subsequently decreased. The discontinuation rate due to these AEs was low.
A New Drug Application (NDA) to the US Food and Drug Administration for psoriasis, in addition to a combined PsA/psoriasis Marketing Authorization Application (MAA) in Europe, is on-track for the fourth quarter of 2013. The Company previously announced it filed a separate NDA for psoriatic arthritis in the US and Canada in Q1 2013 and Q2 2013 respectively.
Earlier this year, Celgene announced that ESTEEM 1 and ESTEEM 2 had reached their primary endpoints. The ongoing studies included more than 1,200 patients with moderate-to-severe psoriasis. Approximately one-third of the ESTEEM 1 study population was naïve to systemic therapy or phototherapy. Nearly 30% of the overall study population had prior biologic therapy, including patients who did not respond to these therapies.
About ESTEEM 1 and 2
ESTEEM 1 and 2 are two large pivotal phase III randomised, placebo-controlled studies evaluating apremilast in subjects with a diagnosis of moderate to severe  plaque psoriasis for at least 12 months prior to the screening, and at baseline, and who were also candidates for phototherapy and/or systemic therapy. Approximately 1,250 patients were randomised 2:1 to receive either apremilast 30mg BID or placebo for the first 16 weeks, followed by a maintenance phase from weeks 16-32 in which placebo subjects were switched to apremilast 30mg BID through week 32, and a randomised withdrawal phase for responders from Week 32-Week 52 based on their initial apremilast randomisation and PASI response.
About apremilast 
Apremilast, an oral small-molecule specific inhibitor of phosphodiesterase 4 (PDE4), intracellularly modulates a network of pro-inflammatory and anti-inflammatory mediators. PDE4 is a cyclic adenosine monophosphate (cAMP)-specific PDE and the dominant PDE in inflammatory cells. PDE4 inhibition elevates intracellular cAMP levels, which in turn down-regulates the inflammatory response by modulating the expression of TNF-α, IL-23, and other inflammatory cytokines. Elevation of cAMP also increases anti-inflammatory cytokines such as IL-10.
About psoriasis
Psoriasis is an immune-mediated, non-contagious chronic inflammatory skin disorder of unknown cause. The disorder is a chronic recurring condition which varies in severity from minor localised patches to complete body coverage. Plaque psoriasis is the most common type of psoriasis. About 80% of people who develop psoriasis have plaque psoriasis,(1) which appears as patches of raised, reddish skin covered by silvery-white scales. These patches, or plaques, frequently form on the elbows, knees, lower back, and scalp. Psoriasis occurs nearly equally in males and females. Recent studies show that there may be an ethnic link. Psoriasis is believed to be most common in Caucasians and slightly less common in other ethnic groups. Worldwide, psoriasis is most common in Scandinavia and other parts of northern Europe. About 10% to 30% of patients with psoriasis also develop a condition called psoriatic arthritis,(2) which causes pain, stiffness and swelling in and around the joints.

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