Forigerimod

自身免疫疾病是仅次于肿瘤领域的第二大药物市场，而在生物治疗范畴中，与类风湿关节炎、银屑病关节炎和强直性脊柱炎患者的疗效取得突破性进展相比，系统性红斑狼疮的靶向治疗明显落后许多年。虽然近年的阿尼鲁单抗(Anifrolumab)在重症狼疮中显示出积极作用，环孢素(Voclosporin)和贝利尤单抗(Belimumab)治疗狼疮肾炎也取得一定成功，但更令人沮丧的是诸多靶向药物在II期试验中取得积极疗效后转而在III期试验中均未达到主要终点，进而宣告试验失败。回顾与反思这些药物未达标的原因及总结可能影响II期试验过度乐观结果的因素是必要的。系统性红斑狼疮(Systemic lupus erythematosus，SLE)是一个病因不明的自身免疫疾病，特点是自身抗体的大量分泌和免疫细胞的过度活化，目前无法根治，即使接受药物全程治疗后病情缓解，也面临复发危险。目前临床上被批准用于SLE治疗的药物主要包括羟氯喹、糖皮质激素和他克莫司、环孢素、环磷酰胺、甲氨蝶呤等免疫抑制剂，而贝利尤单抗(Belimumab)和阿尼鲁单抗(Anifrolumab)是唯二被FDA批准治疗SLE的生物制剂且只适用于中重度患者。这表明，需要更有效的药物及治疗策略来管理SLE的病情控制。SLE发病机制近年来发现多种炎症因子、粘附分子及通路蛋白在SLE的促炎因子网络信号转导中发挥中介作用，理论上或可成为候选治疗药物。令人沮丧的是，这些药物在II期临床试验成功后不久就陆续报出III期临床试验失败的结果。近期，发表在Ann Rheum Dis (IF=27.973)上的一篇文章重点关注了靶向CD22单抗(Epratuzumab)、Janus激酶抑制剂(Baricitinib)、P140肽(Rigerimod)和IL-12/IL-23抑制剂(Ustekinumab)的II期和III期临床试验结果，分析了这些药物治疗未达标的原因，并解释了影响II期试验获得良好结果而导致过度乐观的可能原因。01过度解读II期试验的积极疗效第一种解释就是制药公司过度解读了II期试验的积极疗效，鼓励药品进入III期试验，而后续更详细的数据分析表明这些药物在II期试验取得的成功是有限制的，且不太可能在III期试验中依旧观察到。在CD22单抗和IL-12/IL-23抑制剂的临床试验就出现类似结果。2014年，一项多剂量CD22单抗(Epratuzumab)对中/重度活动性系统性红斑狼疮患者的疗效和安全性的EMBLEM IIb期临床试验中，其中患者12周内每隔一周接受Epratuzumab1200mg或每周600mg或安慰剂的组别（其余剂量组均未达到主要终点），Epratuzumab组和安慰剂组患者的BICLA应答率 分别为45.9%和21.1%（BICLA/BICLG：大不列颠群岛狼疮评估小组制定的狼疮综合评估，作为SLE全球临床试验有效治疗反应的统一测量之一）。Epratuzumab亚组显著地提高了BICLA应答率，加上不良反应率的对比，错误导向地认定Epratuzumab是一个很有前景的治疗选择，从而开启后续的III期试验。而在III期试验中，接受Epratuzumab治疗的患者虽也观察到更高的SRI有效率（SRI：SLE Responder Index，作为狼疮的疾病活动度评估，包括PGA、BICLA/BICLG、SELENA-SLEDAI三个国际认定评分），但这种差异并不显著。类似的评估IL-12/IL-23抑制剂(Ustekinumab)疗效中，II期试验中接受Ustekinumab和安慰剂组患者SRI应答率分别为62%和33%，而在III期试验结果并没有得到证实，其中Ustekinumab组的SRI应答率为44%，安慰剂组为56%。Ustekinumab的SLE三期临床结果02选择偏移在解释结果时还需要考虑选择偏倚的影响。在Ustekinumab的临床试验中，II期高疾病活动状态患者(BILAG=A≥1)的比例在安慰剂组 (52%)明显高于Ustekinumab组(45%)，而在III期(LOTUS)中，BILAG=A的患者在Ustekinumab组更常见。类似这样的选择偏差或许可以解释为什么安慰剂应答率在Ustekinumab(33%)和Epratuzumab(21%)的II期试验结果比较低，而在III期试验中变为56%和33.5%。随着安慰剂应答率的增加，试验更难取得显著的结果，而药物也更难被认为是有效的。03试验中断率试验中断率的差异可能会导致I 期和 III 期试验获得不一致结果。在Ustekinumab试验中，12.7%的患者在第52周之前停止了II期试验，而50%的患者在第52周之前停止了III期试验。而Epratuzumab试验中得到了更高的停药率：12.3% 的II 期试验，33.4%( EMBODY-1) 和32.6%(EMBODY-2) 的 III 期试验。对于Epratuzumab的高停药率可能是由于在III期试验明确指出如果患者在第 16 周或更长时间由于缺乏疗效可以停止试验去更换药物，促使很多患者中止试验。因此，III期试验或许可以有更好的结果，可惜试验得到的结果被转移到后续其他药物的疗效中了。04样本量和试验持续时间II期试验中较小的样本量和较短的持续时间也会对某些亚组产生有利影响，进而高估了试验中观察到的结果。这种现象的例子见于纳入90名患者的Epratuzumab IIb期临床试验ALLEVIATE中，接受360 mg/m2剂量的患者中有44.1%达到主要终点，接受720 mg/m2剂量治疗的患者只有20%达到主要终点，而在安慰剂组的比例却有30.3% (p=0.177)。在纳入了更多患者(N=1257)、持续更长时间(48周)的III期试验中，Epratuzumab组达到主要终点的患者比例略高于安慰剂组，但这些结果并不显著(600mg/周组为37.5%，1200mg EOW组为39.8%，安慰剂组为34.1%）。因此，为了避免过早地得出有利于特定治疗的乐观结论，更长的治疗周期和更多的患者数量似乎是获得更切合实际结果的必要条件。05安慰剂的高应答率在许多 III 期试验中可以注意到安慰剂的高应答率。例如，在使用Ustekinumab (LOTUS) 和 rigerimod 的试验可能反映了这样一个事实，即随着治疗时间的推移，糖皮质激素搭配免疫抑制剂的治疗可以在许多患者中达到很大程度缓解。结语 综上所述，在评估SLE II期临床试验表面上的成功时，必须高度关注细节。尤其是安慰剂应答率低于30%、随访时间短、患者研究数量少，都可能会导致过度乐观。参考文献：Lorenzo-Vizcaya A, Isenberg DA. Clinical trials in systemic lupus erythematosus: the dilemma-Why have phase III trials failed to confirm the promising results of phase II trials? Ann Rheum Dis. 2023;82(2):169-74Van Vollenhoven RF, et al. Ann Rheum Dis. 2022作者：琢小七封面图来源：pixabay推荐阅读【药时代学苑】福利制度——面向持有药时代学号的广大同药们还有多少人要钻进「ADC陷阱」20%的钱存在「硅谷银行」，关键临床试验还失败了，扎心……点击在看，共济新药研发浪潮

Systemic Lupus Erythematosus market size increment is a direct consequence of expected entry of promising emerging therapies, increasing awareness of the disease, and recent advancements in research and development in the 7MM LAS VEGAS, June 14, 2022 /PRNewswire/ -- DelveInsight's Systemic Lupus Erythematosus Market Insights report proffers a detailed comprehension of the Systemic Lupus Erythematosus market size by treatment, epidemiology, emerging therapies, market share of the individual therapies, current and forecasted Systemic Lupus Erythematosus market size from 2018 to 2030 segmented into the 7MM (the USA, EU5 ( Germany, France, Italy, Spain and the UK), and Japan). Some of the salient features from the Systemic Lupus Erythematosus Market Report: DelveInsight analysts suggested that the Systemic Lupus Erythematosus market size in the 7MM was valued at USD 1,462 Million in 2020 and is expected to increase drastically owing to the launches of several potential emerging therapies during the study period (2018-2030). Key pharmaceutical Systemic Lupus Erythematosus companies such as GlaxoSmithKline, AstraZeneca, Sanofi, Eli Lilly and Company/Nektar Therapeutics, UCB Pharma, Hoffmann-La Roche, Biogen, ImmuPharma, Xencor, Bristol Myers Squibb, Alpine Immune Sciences, Johnson & Johnson (Janssen), Idorsia Pharmaceuticals, Resolve Therapeutics, Amgen, AbbVie, Novartis, Corestem, Horizon Therapeutics, Boston Pharmaceuticals, InnoCare Pharma, Landos Biopharma, Equillium, Merck Healthcare KGaA, Gilead sciences, I-Mab Biopharma/MorphoSys AG, Chipscreen Biosciences, and others are reported to bring a significant shift in the Systemic Lupus Erythematosus. The Systemic Lupus Erythematosus emerging therapies that are expected to launch in the forecast period include Dapirolizumab pegol, BIIB059, Obinutuzumab (Gazyva/Gazyvaro), IPP-201101 (Lupuzor), and others. As per DelveInsight analysis, the United States accounted for the largest Systemic Lupus Erythematosus market size that was valued at USD 1,181 million in 2020, in comparison to EU5 (the United Kingdom, Germany, Italy, France, and Spain) and Japan. The current Systemic Lupus Erythematosus therapeutic landscape in the 7MM is driven by current treatment practices and the expected launch of emerging therapies. For further information on the market impact by therapies, download the Systemic Lupus Erythematosus sample @ Systemic Lupus Erythematosus Therapeutic Scenario Systemic Lupus Erythematosus Overview Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease with multisystem involvement and is associated with significant morbidity and mortality. Genetic, immunological, endocrine, and environmental factors influence the loss of immunological tolerance against self-antigens leading to the formation of pathogenic autoantibodies that cause tissue damage through multiple mechanisms. The pathogenesis of Systemic Lupus Erythematosus is complex, and the understanding of SLE pathogenesis is constantly evolving. A break in the tolerance in genetically susceptible individuals, on exposure to environmental factors, leads to the activation of autoimmunity. Systemic Lupus Erythematosus Epidemiology Segmentation As per the assessment of DelveInsight, the total diagnosed prevalent Systemic Lupus Erythematosus population in the 7MM was found to be 651,965 in 2020 which is expected to increase during the study period. As per DelveInsight's estimates, the United States accounted for 351,176 Systemic Lupus Erythematosus prevalent cases. The Systemic Lupus Erythematosus Market report offers epidemiological analysis for the study period 2018-2030 in the 7MM segmented into Total Diagnosed Prevalent Population of Systemic Lupus Erythematosus Gender-specific Diagnosed Prevalent Population of Systemic Lupus Erythematosus Age-specific Diagnosed Prevalent Population of Systemic Lupus Erythematosus Severity-specific Diagnosed Prevalent Population of Systemic Lupus Erythematosus Keen to learn how Systemic Lupus Erythematosus Epidemiological Trends are going to appear in 2030 for the 7 MM, Download @ Systemic Lupus Erythematosus Epidemiological Insights Systemic Lupus Erythematosus Market Outlook There is no complete cure for Systemic Lupus Erythematosus currently, but there are many treatments available to help particular symptoms. Systemic Lupus Erythematosus involves a wide range of clinical features that encompasses vascular, immune, and fibrotic manifestations along with the involvement of many organs. Systemic Lupus Erythematosus treatment includes NSAIDs and antimalarial agents, which are the first-line therapies for mild Systemic Lupus Erythematosus. In addition, glucocorticoids and cytotoxic or immunosuppressive agents—such as azathioprine, mycophenolate mofetil, cyclophosphamide, cyclosporine, and methotrexate —are used for Systemic Lupus Erythematosus treatment with organ involvement. The current Systemic Lupus Erythematosus market possesses two approved products, Benlysta (belimumab) and Saphnelo (anifrolumab-fnia). The dynamics of the Systemic Lupus Erythematosus market is anticipated to change in the coming years owing to the improvement in the research and development activities for efficient treatment options to be available in the market. It includes several Systemic Lupus Erythematosus pipeline therapies such as Lupuzor (also known as IPP-201101), being developed by ImmuPharma, is a 21-mer linear peptide fragment analog. ImmuPharma has completed the Phase III clinical trial for the treatment of SLE. Lupuzor demonstrated a superior response rate over placebo (61.5% vs 47.3%). ImmuPharma and Avion Pharmaceuticals signed exclusive license and development agreement for Lupuzor to fund a new 'optimized' international Phase III trial which is expected to start by 2022. Avion Pharmaceuticals has the exclusive rights for the commercialization of Lupuzor in the US. ImmuPharma retains all the rights to commercialize Lupuzor outside the US. Apart from this, Biogen is developing, BIIB059, is an investigational humanized monoclonal antibody that specifically recognizes and binds to blood DC antigen 2 (BDCA2), a pDC-specific receptor that inhibits the production of IFN-I and other inflammatory mediators when ligated. Biogen is conducting Phase III clinical trials for the treatment of patients receiving Active SLE receiving background nonbiologic lupus standard of care. In addition, Dapirolizumab pegol is being developed by UCB Pharma in partnership with Biogen. It is an investigational humanized anti-CD40L antibody fragment that acts by preventing the interaction between CD40L on T-cells with CD40 on antigen-presenting cells through interactions with its receptor-CD40. The drug failed to meet its primary endpoint in the Phase II trial. However, the company continued the development of dapirolizumab pegol. The product is currently being developed jointly by UCB and Biogen to treat SLE in a Phase III trial. The topline results are expected in the first-half of 2024. Discover more about therapy set to grab substantial Systemic Lupus Erythematosus share @ Systemic Lupus Erythematosus Market Landscape Systemic Lupus Erythematosus Pipeline Therapies and Key Companies Itolizumab: Equillium/Biocon Limited ICP-022: InnoCare Pharma BOS161721: Boston Pharmaceuticals NKTR-358: Nektar Therapeutics/Eli Lilly ABBV-599: AbbVie Deucravacitinib: Bristol Myers Squibb BIIB059: Biogen Gazyva/Gazyvaro (Obinutuzumab): Hoffman-La-Roche Lupuzor: ImmuPharma SAR441344: Sanofi To know about more pipeline therapies covered in the report, visit @ Systemic Lupus Erythematosus Pipeline Analysis, Clinical Trials, and Emerging Therapies Systemic Lupus Erythematosus Market Dynamics The expected launch of potential SLE therapies is the main factor responsible for an increase in the Systemic Lupus Erythematosus market size in the coming years, assisted by an increase in the diagnosed Systemic Lupus Erythematosus prevalent population. Also, owing to the positive outcomes of the several products during the developmental stage by many key players, and improvement in the research and development activities for efficient treatment options to be made available in the market will directly boost the Systemic Lupus Erythematosus market. The increased awareness of the disease is also considered an aspect driving the Systemic Lupus Erythematosus market growth. On the other hand, factors such as a high annual cost and the hit and trial approach of researchers serve as setbacks for the Systemic Lupus Erythematosus market growth. The high failure rate of emerging drugs makes entering the SLE market challenging for the pharmaceutical key players. Also, several obstacles experienced in the Systemic Lupus Erythematosus pipeline, undiagnosed and unreported cases might also play as obstructions in the Systemic Lupus Erythematosus market in the future. Know which therapy is expected to score the touchdown first @ Systemic Lupus Erythematosus Market Landscape and Forecast Scope of the Systemic Lupus Erythematosus Market Report Study Period: 2018-30 Coverage: 7MM [The United States, EU5 (Germany, France, Italy, Spain, and the United Kingdom), and Japan] Key Systemic Lupus Erythematosus Companies: GlaxoSmithKline, AstraZeneca, Sanofi, Eli Lilly and Company/Nektar Therapeutics, UCB Pharma, Hoffmann-La Roche, Biogen, ImmuPharma, Xencor, Bristol Myers Squibb, Alpine Immune Sciences, Johnson & Johnson (Janssen), Idorsia Pharmaceuticals, Resolve Therapeutics, Amgen, AbbVie, Novartis, Corestem, Horizon Therapeutics, Boston Pharmaceuticals, InnoCare Pharma, Landos Biopharma, Equillium, Merck Healthcare KGaA, Gilead sciences, I-Mab Biopharma/MorphoSys AG, Chipscreen Biosciences, and many others. Key Systemic Lupus Erythematosus Pipeline Therapies: Dapirolizumab pegol, Itolizumab, ICP-022, NKTR-358, ABBV-599, Deucravacitinib, BIIB059, Gazyva/Gazyvaro, Lupuzor, and several others. Systemic Lupus Erythematosus Therapeutic Assessment: Systemic Lupus Erythematosus current marketed and emerging therapies Systemic Lupus Erythematosus Dynamics: Systemic Lupus Erythematosus drivers and barriers Competitive Intelligence Analysis: SWOT analysis, PESTLE analysis, Porter's five forces, BCG Matrix, Market entry strategies Unmet Needs KOL's views Analyst's views Systemic Lupus Erythematosus Access and Reimbursement Request for a Webex demo of the report @ Systemic Lupus Erythematosus Therapeutics Market Table of Contents Get in touch with our Business executive @ Systemic Lupus Erythematosus Regulatory and Patent Analysis Related Reports Cutaneous Lupus Erythematosus Market DelveInsight's "Cutaneous Lupus Erythematosus - Market Insights, Epidemiology, and Market Forecast-2032" report delivers an in-depth understanding of the Cutaneous Lupus Erythematosus, historical and forecasted epidemiology, market drivers, market barriers and key companies included like Centessa Pharmaceuticals, Bristol-Myers Squibb, Merck, Biogen, Sanofi, Zylo Therapeutics, Galapagos, Gilead Sciences, Viela Bio, Rigel Pharmaceuticals, and others. 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