【转】诺华单抗药secukinumab III期研究击败安进Enbrel

仲夏秋夜云

诺华单抗药secukinumab III期研究击败安进Enbrel
根据第22届欧洲皮肤病与性病学会（EADV）上公布的数据，在一项关键性头对头（head-to-head）III期FIXTURE研究中，诺华（Novartis）开发的实验性单抗药secukinumab（AIN457）击败了安进（Amgen）的Enbrel（etanercept，依那西普）。该项研究在中度至重度斑块型银屑病中开展，研究中secukinumab疗效显著优于Enbrel。目前，Enbrel是一种抗TNF标准护理药物，已获批用于治疗中度至重度斑块型银屑病。
FIXTURE研究中，将2种剂量secukinumab（300mg和150mg）与Enbrel（50mg）和安慰剂进行了对比，共同主要终点是12周时的银屑病面积和严重性指数75（PASI 75）及研究者全球评估（IGA mod 2011）。
该项研究达到了所有的主要终点和既定关键次要终点（安慰剂比较：p＜0.0001，Enbrel比较：p=0.0250）。与Enbrel相比，2种剂量secukinumab（300mg 和150mg）在整个52周治疗期间均表现出了改善的疗效。重要的是，与Enbrel相比，secukinumab治疗组更多的患者经历了几乎清晰的皮肤（PASI评分90）和彻底清晰的皮肤（PASI评分100）。
此外，研究结果还表明，300mg secukinumab治疗组，72%的患者在研究的16周时皮肤发红、厚度和结垢至少减少了90%（PASI 90），54%的患者在研究的12周时便实现了PASI 90，而Enbrel治疗组在12周时实现PASI 90的患者比例仅为24%。此外，与Enbrel治疗组相比，300mg secukinumab治疗组在12周时更容易实现PASI 100（24% vs 4%）。
关于secukinumab：
secukinumab是一种全人源化IgG1单克隆抗体，选择性地结合和中和IL-17A，IL-17A是一种关键的促炎性细胞因子。在中度至重度斑块型银屑病和关节炎疾病（银屑病关节炎、强直性脊柱炎、类风湿性关节炎）中开展的概念验证试验和II期研究数据表明，secukinumab可能提供一种新的作用机制，有望成功治疗免疫介导疾病。
关于Enbrel：
Enbrel，中文名为恩利（商品名），通用名为注射用依那西普（Etanercept ），是安进（Amgen）经生物工艺生产、由人p75肿瘤坏死因子受体与人免疫球蛋白G1的Fc端连接组成的二聚体融合蛋白，该药是全球首个全人源化的、第一个用于治疗类风湿关节炎和强直性脊柱炎的可溶性肿瘤坏死因子拮抗剂。除治疗类风湿关节炎和强直性脊柱炎外，该药还已批准用于银屑病性关节炎、幼年慢性关节炎和银屑病的治疗。
英文原文：Secukinumab (AIN457) showed superiority over Enbrel in clearing skin, according to pivotal Novartis Phase III psoriasis results at EADV
*Secukinumab (AIN457) patients' skin cleared faster and for longer than Enbrel? (etanercept) patients, beginning as early as Week 2[1]
*Study also showed twice as many secukinumab patients experienced clear or almost clear skin by Week 12 versus Enbrel[1]
*Head-to-head study of secukinumab and Enbrel part of largest clinical program completed in moderate-to-severe plaque psoriasis with more than 3,300 patients
*Secukinumab is the first IL-17A inhibitor with Phase III data and is on track to be the first psoriasis medication filed targeting IL-17A
Basel, October 3, 2013 - Novartis announced today results from the head-to-head Phase III FIXTURE study showing secukinumab (AIN457), an interleukin-17A (IL-17A) inhibitor, was significantly superior to Enbrel?* (etanercept) in moderate-to-severe plaque psoriasis[1]. Enbrel is a current standard-of-care anti-TNF medication approved to treat moderate-to-severe plaque psoriasis. These new results were presented today at the 22nd Congress of the European Association of Dermatology and Venereology (EADV) in Istanbul, Turkey[1].
The pivotal FIXTURE study met all primary and pre-specified key secondary endpoints(p<0.0001 for placebo comparisons and p=0.0250 for Enbrel comparisons)[1]. Both doses of secukinumab showed improved efficacy to Enbrel throughout the 52 week study, beginning as early as Week 2 and confirmed by Week 12 when the primary endpoints were assessed[1]. Importantly, more secukinumab patients experienced almost clear skin (described as PASI 90) and completely clear skin (PASI 100) compared to Enbrel[1], which are higher standards of skin clearance compared to the standard efficacy measures used in most psoriasis clinical studies.
"These exciting data suggest that with secukinumab, we have the potential to help more patients achieve clear skin, which is the ultimate treatment goal," said David Epstein, Head of the Pharmaceuticals Division of Novartis Pharma AG. "The data also show that specifically targeting IL-17A may offer a new and effective treatment approach for people living with moderate-to-severe plaque psoriasis."
FIXTURE compared two doses of secukinumab (300 mg and 150 mg) with Enbrel 50 mg and placebo[1]. The co-primary endpoints were assessed at Week 12 and compared secukinumab efficacy versus placebo according to the Psoriasis Area and Severity Index 75 (PASI 75) and the Investigator's Global Assessment (IGA mod 2011)[1].
The study also showed that 72% of secukinumab 300 mg patients experienced at least a 90% reduction in skin redness, thickness and scaling (PASI 90)[1] by Week 16 of the study. More than half (54%) of secukinumab 300 mg patients achieved PASI 90 as early as Week 12, compared to 21% of Enbrel patients[1]. Secukinumab 300 mg patients were also more likely to experience completely clear skin compared to those taking Enbrel in the study, as measured by PASI 100 at Week 12 (24% versus 4%)[1].
Secukinumab-treated patients also had their symptoms resolved faster than those treated with Enbrel in the study[1]. Clinically relevant differences were observed as early as Week 2, and on average secukinumab 300 mg patients had their symptoms halved by Week 3, compared to Week 8 for Enbrel patients[1].
Secukinumab efficacy was sustained over the full one year duration of the study. In FIXTURE, nearly twice as many patients treated with secukinumab 300 mg had a PASI 90 response at Week 52 compared to Enbrel (65% vs. 33%)[1].
There were no major safety signals identified in FIXTURE or the broader secukinumab Phase III clinical trial program in moderate-to-severe plaque psoriasis. In FIXTURE, the incidence of adverse events (AEs) was similar between both secukinumab treatment arms (300 mg and 150 mg), and was comparable to Enbrel[1]. The most common AEs in any treatment group (including placebo) throughout the 52 week treatment period were nasopharyngitis and headache (occurring in between 12-36 patients per 100 patient years in all groups)[1]. At the same time point, serious AEs (SAEs) were experienced by 6% of secukinumab 300 mg, 5% of secukinumab 150 mg and 6% of Enbrel patients[1]. There were no deaths reported during the study[1].
Secukinumab is the first therapy selectively targeting IL-17A to have Phase III results presented. IL-17A is a central cytokine (messenger protein) involved in the development of psoriasis, and is found in high concentrations in psoriasis skin plaques[2]-[4]. Research shows that IL-17A, in particular, plays a key role in driving the body's autoimmune response in disorders such as moderate-to-severe plaque psoriasis and is a preferred target for investigational therapies[2]-[6].
Nearly 3% of the world's population, or more than 125 million people, are affected by plaque psoriasis[7]. This is a common and debilitating disease - even those with very mild symptoms find their condition affects their everyday lives[8]. Psoriasis is also associated with psychosocial effects and those with more severe disease are at a greater risk of death from comorbid diseases such as heart disease and diabetes[9],[10].
Novartis announced top-line results from the FIXTURE study earlier this year. FIXTURE forms part of the robust secukinumab Phase III clinical trial program in moderate-to-severe plaque psoriasis that involved more than 3,300 patients in over 35 countries worldwide. Regulatory submissions of secukinumab in moderate-to-severe plaque psoriasis remain on track in the EU and US for the second half of 2013.
About FIXTURE and the secukinumab data presented at EADV
FIXTURE (the Full year Investigative eXamination of secukinumab vs. eTanercept Using 2 dosing Regimens to determine Efficacy in psoriasis) was a randomized double-blind, placebo-controlled, multicenter, global pivotal Phase III registration study involving 1,306 patients.
The co-primary endpoints were assessed at Week 12 and compared secukinumab efficacy versus placebo according to PASI 75 and IGA mod 20111. These endpoints were used also to demonstrate superiority of secukinumab vs. etanercept. Secondary measures included PASI 50, 75, 90 and 100 at different time points. In addition, the likelihood of loss of response at Week 52 was calculated by determining the proportion of patients who lost PASI 75 at Week 52, after initially achieving it at Week 12[1].
Data from an additional Phase III study of secukinumab in moderate-to-severe plaque psoriasis was also presented today at EADV[13]. The SCULPTURE (Study Comparing secukinumab Use in Long-term Psoriasis maintenance therapy: fixed regimens vs reTreatment Upon start of RElapse) trial found that patients who initially achieved PASI 75 at Week 12 were more likely to maintain their response if they received secukinumab at fixed monthly intervals, compared to treatment only on 'start of relapse'[13]. Results of two additional studies will also become available tomorrow.
About secukinumab (AIN457)
Secukinumab (AIN457) is a fully human IgG1 monoclonal antibody that selectively binds to and neutralizes IL-17A, a key pro-inflammatory cytokine[2]-[4]. Proof-of-concept and Phase II studies in moderate-to-severe plaque psoriasis and arthritic conditions (psoriatic arthritis, ankylosing spondylitis and rheumatoid arthritis) have suggested that secukinumab may potentially provide a new mechanism of action for the successful treatment of immune-mediated diseases[14]-[18]. Phase III results from two additional Phase III studies in moderate-to-severe plaque psoriasis will be presented in 2014, and in 2014 and beyond for arthritic conditions. Phase II studies are also ongoing in other areas, including multiple sclerosis.