近日，欧洲药品管理局（EMA）人用医药产品委员会（CHMP）已批准Otezla，用于2种适应症。这意味着Otezla将在未来2-3个月在欧盟获批上市。 在美国，FDA分别于2014年3月和9月批准Otezla用于活动性银屑病关节炎（PsA）及中度至重度斑块型银屑病（plaque psoriasis）适应症。 在欧盟，具体而言，CHMP已批准Otezla： （1）用于对其他系统疗法（包括环孢素、甲氨蝶呤或补骨脂素紫外线疗法（PUVA））治疗无响应、有禁忌或不耐受的中度至重度慢性斑块型银屑病（plaque psoriasis）成人患者的治疗； （2）作用单药或联合其他疾病修饰抗风湿药物（DMARDs）用于对先前DMARD疗法响应不足或已经不能耐受的活动性银屑病关节炎（PsA）成人患者的治疗。 Otezla是一种口服、选择性磷酸二酯酶4（PDE4）抑制剂，该药是FDA批准的首个也是唯一一个用于斑块型银屑病治疗的PDE4抑制剂，为广泛的斑块型银屑病患者群体提供了一种有价值的治疗选择，包括以前使用过生物制剂或常规系统性药物治疗的患者群体。 银屑病（psoriasis）是一种由不受控免疫反应导致的皮肤慢性炎症性疾病，欧洲患者总数约为1400万例，全球患者总数超过1.25亿例。斑块型银屑病（plaque psoriasis）是最常见的疾病形式，约占银屑病病例的80%。约30%的银屑病患者可能发展为银屑病关节炎（PsA）。 关于Otezla（apremilast）： Otezla（apremilast）是一种口服小分子磷酸二酯酶(PDE4)抑制剂，在细胞内调控促炎症和抗炎介质的网络。PDE4是一种环磷酸腺苷(cAMP)特异性PDE，是炎性细胞中主要的PDE。PDE4抑制可提升细胞内cAMP水平，通过调控TNF-α、IL-23和其他炎性细胞因子的表达相应下调炎性反应。cAMP升高也会增加抗炎细胞因子，例如IL-10。 New Drugs Online Report for apremilast Information Generic Name: apremilast   Trade Name: Otezla  Synonym: CC 10004  Entry Type: Licence extension   Developmental Status UK: Approved (Licensed)  EU: Approved (Licensed)  US: Launched  UK launch Plans: Available only to registered users Actual UK launch date:   Comments Jan 15: Approved in the EU for moderate-to-severe chronic plaque psoriasis in adults who have failed to respond to systemic therapy including ciclosporin, methotrexate or psoralen and ultraviolet-A light (PUVA). Also approved for PsA in adults who fail on non-biological DMARDs [19]. 19/01/2015 17:38:42  Nov 14: EU positive opinion for apremilast in the treatment of moderate to severe chronic plaque psoriasis in adults 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) [18]. 21/11/2014 12:37:59  Sep 14: Licence extension for moderate to severe plaque psoriasis approved in the US [17]. 24/09/2014 12:45:48  Mar 14: A decision on approval of apremilast for psoriasis is expected in 2014; apremilast was filed for psoriasis in 2013 [15]. 24/03/2014 11:46:56  Jan 14: Filed in the EU [14]. 22/01/2014 17:44:27  Oct 13: The company plans to file in the EU for psoriasis and psoriatic arthropathy in Q4 2013. The US filing for psoriasis is also planned for Q4 2013 [13]. 04/10/2013 09:19:06  Jul 12: Plan to file in US H1 2013; a combined filing for psoriatic arthritis and psoriasis in the EU expected 2H 2013 [9].  10/07/2013 13:26:41  Apr 10: PIII trials to begin later in 2010 [4]. 11/04/2010 18:11:07  PII trials (1). Trial or other data Mar 14: New data from PIII studies (ESTEEM 1 and 2) presented at the American Academy of Dermatology Annual Meeting. Otezla demonstrated stable improvements in PASI response up to week 52 in ESTEEM 1. Otezla significantly improved signs and symptoms of psoriasis, including scalp and nails, compared with placebo in ESTEEM 2 at week 16, consistent with previously-reported ESTEEM 1 data. Long term safety and tolerability profile in ESTEEM 1 was consistent with previously-reported long-term data from Otezla clinical trial programs. No clinically meaningful changes in laboratory measurements compared with placebo observed in ESTEEM 1 or 2 [16]. 27/03/2014 11:40:45 Oct 13: Results of pre-specified sub-analyses from ESTEEM 1 on nail (n=558) and scalp psoriasis (n=563) and on health-related quality-of-life outcomes (n=844) reported. Apremilast 30mg twice daily was associated with a 22.5% improvement in the Nail Psoriasis Severity Index (NAPSI) scores vs a worsening of 6.5%, with placebo at 16 weeks. In patients with scalp psoriasis significantly more on apremilast 30mg achieved a ScPGA score of 0-1 (clear or almost clear) (46.5% vs. 17.5%, respectively). Apremilast also significantly improved health-related Q0L, as assessed by a variety of standardized 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) at 16 weeks. Improvements were maintained up to 32 weeks [13]. 04/10/2013 09:16:13 Mar 13: ESTEEM 1 data (n=844) presented at the American Academy of Dermatology annual meeting. 33.1% of pts randomised to apremilast demonstrated PASI-75 (i.e. a 75% reduction in symptoms such as in pruritus, nail and scalp psoriasis) at week 16 vs. 5.3% for the placebo arm [P<0.0001]. One-third of the study population was systemic and/or phototherapy treatment-naïve and nearly 30% of the overall study population had prior biological therapy, which included biologic-failures. Higher PASI-75 scores at week 16 were seen in systemic-naïve and biologic-naïve subjects vs placebo (38.7% vs. 7.6%; P<0.0001 and 35.8% vs. 5.9%; P<0.0001 respectively). Apremilast demonstrated maintenance of effect over time; the mean % change from baseline in PASI score was a 54.9% reduction at week 16 and a 61.9% reduction at week 32. No cases of tuberculosis or lymphoma were observed through week 16, and there was no increased risk of CV events or serious opportunistic infection. The most common adverse events were diarrhoea & nausea but those issues were resolved after 15 days of treatment [12].  05/03/2013 14:30:11 Jan 13: Results from ESTEEM 1 and 2 showed that statistical significance for the primary endpoint of PASI 75 at week 16 was achieved for patients receiving apremilast 30 mg BID monotherapy. Patients on apremilast also achieved a statistically significant benefit over placebo in the major secondary endpoint, Static Physician Global Assessment (sPGA). [11]  08/01/2013 09:52:16 Jun 12: PIIb study (n=352) published early online in the Lancet. Treatment was double-blind for the first 16 weeks of the 24-week treatment phase & at week 16, pts in the placebo group were assigned apremilast 20 or 30 mg twice daily until week 24. During weeks 16-24, investigators and participants were unblinded to treatment, but the dose was concealed. At week 16, PASI-75 was achieved in 6% of 88 pts assigned placebo, 11% of 89 assigned apremilast 10 mg (p=0.19), 29% of 87 assigned apremilast 20 mg (p<0.0001), & 41% of 88 assigned apremilast 30 mg (p<0.0001). The primary endpoint was achieved by significantly more pts assigned apremilast 20 mg (odds ratio [OR] 6.69; 95% CI 2.43–18.5; p<0.0001) & apremilast 30 mg (11.5 [4.24–31.2]; p<0.0001) than placebo; apremilast 10 mg did not significantly differ from placebo in achievement of this endpoint (2; 0.69–6.42). Most adverse events (96%) were mild or moderate; at least 5% of pts had nausea, upper respiratory tract infection, diarrhoea, nasopharyngitis, headache, arthralgia (placebo), gastroenteritis, or dyspepsia. Eight serious adverse events occurred (three each, placebo and apremilast 20 mg; two, apremilast 30 mg); none were judged to be related to apremilast. Apremilast had no apparent effect on the results of haematological, urinalysis, immunological or inflammation, serum chemistry, or electrocardiographic tests [8]. 02/07/2012 10:10:50 May 12: Enrollments in ESTEEM 1 completed in October 2011. ESTEEM 2 enrollment also complete in US, Canada, France and Spain. [7] 31/05/2012 11:04:52 Nov 10: NCT01232283 (ESTEEM 2) is a phase 3, multicentre, randomized, double-blind, placebo-controlled, efficacy and safety study in 405 subjects with moderate to severe plaque psoriasis. The primary outcome is proportion of subjects who achieve at least a PASI-75 score at week 16 from baseline. The study will start Nov 10 and complete July 16 [6].  04/11/2010 09:18:54 Sep 10: NCT01194219 (ESTEEM 1) - A PIII, multicentre, randomized, double-blind efficacy and safety 1-year study of apremilast in 825 subjects with moderate to severe plaque psoriasis. Primary outcome: % of patients achieving PASI 75 response at week 16. Subjects will be randomized to either placebo or apremilast 30 mg twice a day. Those initially randomized to placebo will assigned to apremilast beginning at Week 16 for the duration of their participation in the study. Subjects initially randomized to apremilast and who demonstrate a PASI 75 response at Week 32 will be randomized (1 to 1) to either continue to receive apremilast or to placebo (until effect is lost). At the time effect is lost, subjects will be treated with apremilast for the duration of their participation in the study. Non-responders or partial responders (PASI response <75) in both arms may receive additional topical or phototherapy beginning at Week 32. Study to start Aug 10 and due to complete Jun 16 [5]. 13/09/2010 13:19:18 Dec 09: Company report results from PIIb study in 352 patients with moderate-to-severe plaque-type psoriasis. Patients received 10mg, 20mg or 30mg of apremilast twice per day or placebo. 41% of patients on 30mg apremilast achieved a PASI-75 after 16 weeks vs 6% on placebo (vs 29% on 20mg apremilast and 11% on 10mg). Common AEs included headache, nausea, upper respiratory tract infection and diarrhoea. Infections occurred in 48% on 30mg apremilast vs 33% on placebo, and 14% vs 6% respectively, discontinued therapy due to AEs [3].  16/12/2009 09:43:54 Jun 09: Apremilast (20mg and 30mg twice daily) is being investigated in a PIIb study which started in Feb 2008 in moderate-to-severe plaque-type psoriasis with results expected in the 2H 2010. If positive, a PIII study is expected to begin in 2010 [2]. 16/06/2009 21:04:36 PII trial data - PASI-75 and -50 scores achieved by 24% and 57% of pts on apremilast vs. 10% and 23% on placebo. ADRs mild and well tolerated (1).  Evidence Based Evaluations NICE scope  http://www.nice.org.uk/Guidance/InDevelopment/GID-TAG468/Documents  NICE scope  http://www.nice.org.uk/Guidance/InDevelopment/GID-TAG469/Documents  NHSC  References   Available only to registered users  Category BNF Category: Preparations for eczema and psoriasis (13.05) Pharmacology: Oral inhibitor of multiple pro-inflammatory mediators including, TNF-alpha, interleukins (IL) 6, 17 and 23, and interferon-gamma   Epidemiology: The estimated UK prevalence of psoriasis is 1.63%;1.1% of people with psoriasis have severe disease [10].   Indication: Psoriasis  Additional Details:   Method(s) of Administration   Oral  Company Information Name: Celgene  US Name: Celgene  NICE Information Anticipated Commissioning route (England) -  In timetable: Yes   When: Aug / 2015  Note: www.nice.org.uk/Guidance/InDevelopment/GID-TAG469  PbR Awaiting Update PBR Likely specified high cost drug. Implications Available only to registered users