市場調查報告書
商品編碼
1422231
PRMT5 標靶療法的全球市場和臨床試驗機會展望:2024 年Global PRMT5 Targeted Therapy Market & Clinical Trials Opportunity Outlook 2024 |
PRMT5(蛋白質精氨酸甲基轉移□5)是細胞內具有多種功能的重要酵素。PRMT5 通常催化組蛋白的對稱和不對稱二甲基化,並在翻譯後修飾中發揮重要作用。然而,過去二十年進行的研究表明,PRMT5 失調會促進多種疾病進程,使其成為有吸引力的治療標靶。儘管 PRMT5 標靶治療市場仍處於早期階段,並且由於有前景的候選藥物停產而遭受了一些挫折,但當前的市場狀況表明 PRMT5 標靶療法有潛力成為多種治療方案的重要組成部分。疾病,它指向某個未來。
PRMT5 的初步研究集中在癌症上,發現 PRMT5 甲基化屬於不同蛋白質亞類的眾多底物,從而產生多種促癌作用。例如,當 PRMT5 甲基化轉錄調節因子 E2F1 時,其半衰期會縮短,這表明大腸直腸癌具有致癌潛力。同樣,DNA 損傷反應蛋白 TDP1 的甲基化會增加其活性並防止癌細胞死亡。PRMT5 介導的剪接蛋白 SRSF1 甲基化也與急性骨髓性白血病的致癌活性有關。因此,抑制 PRMT5 對實體癌和血液癌均具有廣泛的抗癌作用。
除了癌症之外,PRMT5 還與自體免疫疾病和發炎性疾病有關,其中 PRMT5 透過很大程度上未知的途徑觸發異常的免疫反應和發炎。PRMT5 透過 NF-kB 途徑促進 CD4+ T 細胞發育,並增加 IL-2 的產生和增殖。此外,PRMT5 水平在記憶 Th 細胞增殖高峰期間升高。同樣,在微生物感染,尤其是病毒感染中,PRMT5 參與病原體存活以及抗病毒和抗菌反應。越來越多的檢查 PRMT5 治療效果的臨床研究表明,這一領域的研究尚未充分,但有可能使用 PRMT5 抑制劑進行治療。
幾種小分子 PRMT5 抑制劑目前正在進行研究和臨床試驗。2015年Epizyme和GSK共同開發的EPZ015666標誌著PRMT5標靶藥物領域的分水嶺時刻。EPZ015666 是第一個 PRMT5 小分子化學抑制劑,其選擇性比其他 20 種蛋白質甲基轉移□高 20,000 倍以上。兩家公司也開發了 EPZ015938,這是 EPZ015666 的類似產品,但由於策略考慮,這兩個項目都被放棄了。儘管如此,兩家公司都創建了一個框架,將 PRMT5 作為抗癌藥物的治療靶點,並證明了小分子抑制劑限制 PRMT5 作用的潛力。
AMG 193、AZD3470、TNG462 和 SCR-6920 等下一代抑制劑透過優化與 PRMT5 上特定位點的相互作用,顯示出更高的特異性。這些在異種移植模型中顯示出腫瘤生長抑製作用。此外,鑑於 PRMT5 在癌症以外的多種疾病中具有基於背景的功能,蛋白水解靶向嵌合體 (PROTAC) 技術和 PRMT5 活化劑也提供了替代的靶向方法。
為了增強PRMT5抑制的有效性,臨床前和臨床研究中不僅考慮單一療法,還考慮合併療法。PRMT5 和 BCL-2 的雙重抑制已顯示出比單一療法增強治療效果的潛力。這種組合旨在克服限制單一藥物治療功效的補償性生存訊號。Amgen company也正在評估 PRMT5 抑制劑 AMG193 與現有化療藥物多西紫杉醇的組合。
本報告考察了全球 PRMT5 標靶治療市場,概述了 PRMT5 標靶治療的歷史和演變,以及臨床試驗機會、按適應症和地區劃分的趨勢以及進入市場的公司概況。
“Global PRMT5 Targeted Therapy Market & Clinical Trials Opportunity Outlook 2024 ” Report Highlights:
PRMT5, or Protein Arginine Methyltransferase 5, is an important enzyme with a variety of functions in cells. PRMT5 normally catalyzes the symmetrical and asymmetrical dimethylation of histone proteins, which plays an important role in post translational modifications. However, research studies conducted over the last two decades have revealed that its dysregulation promotes various disease processes, making it an attractive therapeutic target. Though the PRMT5 targeted therapies market is still in its early stages, with setbacks caused by the discontinuation of promising candidates, the current market landscape points to a future in which PRMT5 targeted therapies may become essential components of various treatment regimens for a wide range of diseases.
The initial research efforts for PRMT5 were focused on cancer, where it was discovered that PRMT5 methylates numerous of its substrates, which belong to diverse protein subclasses, resulting in varying pro-cancer effects. For example, PRMT5's methylation of the transcription regulator E2F1 shortens its half-life, which has oncogenic implications in colon cancer. Similarly, methylation of TDP1, a DNA damage response protein, increases its activity, hence preventing cancer cell death. PRMT5-mediated methylation of SRSF1, a splicing protein, has also been linked to carcinogenic activities in acute myeloid leukemia. As a result, inhibiting PRMT5 has a wide anticancer effect on both solid and hematological malignancies.
Beyond cancer, PRMT5 is linked in autoimmune and inflammatory diseases, where PRMT5 causes abnormal immune responses and inflammations via largely unknown pathways. PRMT5 promotes CD4+ T cell development via the NF-κB pathway, leading to elevated IL-2 production and proliferation. Furthermore, PRMT5 levels were elevated during the height of memory Th cell proliferation. Similarly, in microbial infections, particularly viral infections, PRMT5 has been linked to pathogen survival as well as antiviral and antibacterial responses. Again, this area is under-researched, but it has the potential to be treated with PRMT5 inhibitors, according to an increasing body of clinical investigations looking into the therapeutic benefits of PRMT5.
Multiple small-molecule PRMT5 inhibitors are now under research and clinical testing. The development of EPZ015666 by Epizyme and GSK in 2015 was a watershed moment in the field of PRMT5-targeted medicines. EPZ015666 was the first small chemical inhibitor of PRMT5 with over 20000-fold selectivity over 20 other protein methyltransferases. The two companies also developed EPZ015938, an analog of EPZ015666, but both programs were abandoned due to strategic considerations. Nonetheless, they laid the framework for establishing PRMT5 as a therapeutic target for anticancer therapies, as well as the potential of small molecule inhibitors to limit PRMT5 actions, both of which are still being widely investigated in research.
Next-generation inhibitors like AMG 193, AZD3470, TNG462 and SCR-6920 demonstrate improved specificity by optimizing interactions with particular sites on PRMT5. These have shown tumor growth inhibition in xenograft models. In addition, proteolysis targeting chimeras (PROTACs) technology and PRMT5 activators also offer alternative targeting approaches, considering PRMT5 has context-based functions in several diseases outside cancer.
Beyond monotherapies, combination strategies are also being explored in preclinical and clinical trials to enhance PRMT5 inhibition efficacy. Dual inhibition of PRMT5 and BCL-2 has shown potential for enhanced therapeutic effects, better than what was seen by the therapies alone. Such combinations aim to overcome compensatory survival signaling that can limit the therapeutic benefits of single agents. Amgen is also assessing the combination of its PRMT5 inhibitor AMG 193 in combination with the established chemotherapy drug, Docetaxel.
Regulatory bodies such as the FDA have also aided the development of PRMT5-targeted therapies by granting them designations, allowing their developers to obtain certain benefits. For example, in February 2023, the FDA designated JBI-778, a highly differentiated, substrate competitive PRMT5 inhibitor being developed by Jubilant Therapeutics, as an orphan drug for the treatment of Glioblastoma Multiforme. JBI-778 is being developed as an oral, brain-penetrant PRMT5 inhibitor for the treatment of both brain metastases and primary brain cancers. The Orphan Drug Designation grants tax breaks and market exclusivity upon approval, which can assist JBI-778 establish itself as a preferred therapy after marketing approval.
Commercially, targeting PRMT5 in order to inhibit or activate its functions represents a novel and viable strategy; however, this entirely depends on clinical benefits demonstrated in preclinical and clinical trials in specific indications. Given the potential broad applicability of PRMT5-targeting therapies, the first-in-class therapeutic to target PRMT5 may achieve high sales. Combination therapies could further expand market size. However, realizing the full clinical and commercial potential will require validating efficacy and defining suitable patient populations through biomarker-guided trials.