總緩解率達96%的創新抗癌療法；使多種癌症類型患者腫瘤縮小的合成致死療法…… | 一週盤點

▎藥明康德內容團隊編輯

本期看點

1. 阿斯利康（AstraZeneca）雙特異性T細胞接合器AZD0486治療復發/難治性濾泡性淋巴瘤（R/R FL）患者的1期臨牀試驗結果亮眼，接受2.4 mg及以上劑量患者的總緩解率（ORR）高達96%，完全緩解（CR）率達85%。

2. 潛在“first-in-class”的menin抑制劑revumenib聯用venetoclax和去甲基化劑（HMA）ASTX727治療攜帶特定基因變異的急性白血病患者，在一項1/2期研究中的ORR達88%。

3. 潛在“best-in-class”合成致死療法TNG462的早期臨牀結果積極，多種癌症類型患者的腫瘤有縮小。

藥明康德內容團隊整理

AZD0486：公佈1期臨牀試驗數據

阿斯利康宣佈將在今年的美國血液學會（ASH）年會上公佈旗下多款血液學管線的臨牀結果，其中包括該公司的CD19 x CD3靶向雙特異性T細胞接合器AZD0486用於復發/難治性濾泡性淋巴瘤患者的 。

結果顯示，R/R FL患者對2.4 mg及以上劑量的AZD0486高度應答，患者的ORR高達96%，CR達85%，且患者的最小殘留病竈（MRD）陰性比率很高。此外，1期試驗中期結果也顯示，接受過大量治療的瀰漫大B細胞淋巴瘤（DLBCL）患者也對AZD0486高度應答，患者的CR率高。最新數據還顯示AZD0486具有良好的安全性，雙倍遞增給藥方案可有效緩解患者發生細胞因子釋放綜合徵（CRS）和免疫效應細胞相關神經毒性綜合徵（ICANS）事件。

Revumenib：公佈1/2期臨牀試驗數據

Syndax Pharmaceuticals公司宣佈將在ASH年會上公佈其在研療法revumenib聯用venetoclax和去甲基化劑ASTX727（decitabine/cedazuridine）治療攜帶KMT2A重排、NUP98重排或NPM1突變的復發/難治性急性髓系白血病（r/r AML）或混合譜系急性白血病（MPAL）兒童和成人患者的1/2期臨牀試驗結果。Revumenib是一種針對menin-KMT2A相互作用的強效、選擇性小分子抑制劑。

截至2024年7月的數據，共有26名患者入組該試驗，ORR爲88%（23/26），CR或帶部分血液學恢復的完全緩解（CRh）率爲58%（15/26）。15名達到CR/CRh的患者中有14名的MRD狀態可評估，其中93%（13/14）爲MRD陰性。中位隨訪時間爲6.6個月時，患者6個月時的無復發生存率爲59%，總生存率爲74%。CR/CRh患者的中位緩解持續時間尚未達到。該組合療法總體上耐受性良好。

TNG462：公佈1/2期臨牀試驗數據

Tango Therapeutics公司宣佈，基於在研療法TNG462在1/2期臨牀試驗劑量遞增和早期劑量擴展隊列中獲得的 ，該公司已選擇TNG462進入全面開發。新聞稿指出，TNG462是一種潛在“best-in-class”的甲硫腺苷（MTA）協同的蛋白精氨酸甲基轉移酶5（PRMT5）抑制劑。PRMT5是甲硫腺苷磷酸化酶（MTAP）突變的合成致死靶點。MTAP基因缺失發生在大約10%的癌症中，包括胰腺癌、肺癌和膀胱癌，這些患者體內存在異常升高的MTA水平，從而抑制PRMT5的活性。PRMT5是一種參與基本細胞功能的酶，MTA的升高使得腫瘤細胞對額外PRMT5的抑制變得更爲敏感。TNG462是一款基於合成致死理念設計的精準抗癌療法，它可在抑制MTAP缺失細胞中PRMT5功能的同時，保留健康細胞中的PRMT5功能，從而選擇性地殺死腫瘤細胞。

截至2024年10月20日，共有59名患者入組，其中39名患者可評估，涵蓋13種癌症類型。數據顯示，TNG462在多種腫瘤類型中展現了抗癌活性且耐受性良好，包括非小細胞肺癌（NSCLC）和胰腺癌。多種腫瘤類型的腫瘤體積隨着持續治療而縮小，約60%最初被評估爲疾病穩定（SD）的患者在之後出現部分緩解（PR）。儘管目前大多數癌症類型的患者數和隨訪時間不足以準確估算客觀緩解率，但在已入組的7名膽管癌患者中，觀察到其中3名（43%）患者獲得確認的客觀緩解。此外，TNG462在活性劑量下具有良好的安全性和耐受性，劑量限制性毒性（DLT）爲血小板減少。該藥物的其他不良事件（如噁心、嘔吐、腹瀉和疲勞）發生率低於20%，且主要爲1級。

▲TNG462治療膽管癌患者的臨牀試驗結果（圖片來源：參考資料[4]）

ISB 2001：公佈1期臨牀試驗的新數據

Ichnos Glenmark Innovation公司宣佈將在ASH年會上進行口頭報告，展示其三特異性抗體ISB 2001用於復發/難治性多發性骨髓瘤（r/r MM）的1期研究的數據。ISB 2001同時靶向MM細胞上的BCMA和CD38，以及T細胞上的CD3，旨在增加對MM細胞的特異性結合，同時最大限度地減少脫靶效應。

截至2024年7月的數據，12名可評估療效患者的ORR爲75%（9/12），其中包括1例MRD陰性的嚴格CR。安全性方面，ISB 2001具有良好的安全性和耐受性，未觀察到DLT，僅有一例高於2級的特殊關注不良事件，且沒有因治療而停藥的情況。

Vilastobart（XTX101）：公佈1c期臨牀試驗數據

Xilio Therapeutics公司公佈了其正在進行的1c期臨牀試驗的初步臨牀數據，該試驗評估了vilastobart（XTX101）聯用PD-L1抑制劑atezolizumab治療晚期實體瘤患者的效果。Vilastobart是一種腫瘤激活、Fc增強、高親和力結合的抗CTLA-4抗體。

截至2024年10月7日，17名患者接受了vilastobart聯用atezolizumab的治療。觀察到兩名患有難以治療的、免疫學上爲“冷腫瘤”的患者達到了未確認的PR。在1名微衛星穩定型結直腸癌（MSS CRC）患者中觀察到轉移性肝臟病竈的完全消退。安全性數據顯示，該聯合治療總體上耐受良好，vilastobart有潛力成爲與PD-1/PD-L1抑制劑聯合使用的差異化下一代抗CTLA-4抗體。

VK2735：公佈早期臨牀試驗的新數據

Viking Therapeutics在肥胖協會年會肥胖周（ObesityWeek）上公佈了其在研減重療法胰高血糖素樣肽1（GLP-1）/葡萄糖依賴性胰島素促泌肽（GIP）受體聯合激動劑VK2735的 。分析顯示，接受每日VK2735口服片劑28天的受試者，其安慰劑調整後平均體重較基線減輕達6.8%。而接受每週VK2735皮下注射治療13周的肥胖患者的平均體重則較基線減輕達14.7%。值得一提的是，在試驗第一週時便觀察到接受皮下劑型患者顯著的體重減輕效果，近100%患者在停藥4周後其體重減輕的大部分效果仍然維持。目前該公司正在規劃VK2735注射劑型的3期研究，以及口服劑型的2期研究，詳細信息將在接近試驗啓動時間時公佈。

▲接受口服VK2735治療28天受試者的體重減輕效果（圖片來源：參考資料[1]）

▲接受VK2735皮下注射13周受試者的體重減輕效果（圖片來源：參考資料[1]）

▲接受VK2735皮下注射受試者在停藥後體重減輕效果持續維持（圖片來源：參考資料[1]）

AZD5004：公佈1期臨牀試驗數據

阿斯利康公司公佈了在研口服GLP-1療法AZD5004，在患有2型糖尿病的肥胖患者中進行的1期臨牀試驗的 。AZD5004是一款每日一次、低劑量的小分子GLP-1受體激動劑，該藥物在臨牀前研究中證明具有理想的療效和安全性。去年11月，阿斯利康與誠益生物（Eccogene）達成 ，以潛在18.25億美元的總額獲得小分子GLP-1受體激動劑ECC5004（即AZD5004），用於治療包括肥胖症、2型糖尿病和其他合併症在內的適應症。

此次公佈的數據顯示，接受劑量爲50 mg的AZD5004治療的患者中，4周後患者體重與基線相比降低5.8%，約爲9.4斤。同時，患者的空腹血糖等指標也有所下降。

▲AZD5004降低患者體重和血糖指標（圖片來源：阿斯利康官網）

CIN-109、CIN-110：公佈1期臨牀試驗數據

CinFina Pharma公司公佈了其CIN-110的單劑量遞增（SAD）研究的初步中期數據以及CIN-109的多劑量遞增（MAD）研究的最終數據。CIN-110是一種強效、高選擇性的肽YY（PYY3-36）類似物，具有延長的半衰期，旨在顯著減少其他PYY分子觀察到的噁心和嘔吐，同時促進有效的長期體重減輕。CIN-109是一種新型長效生長分化因子15（GDF-15）類似物，有可能減少食慾、維持能量消耗和促進體重減輕，同時保持瘦體重。

兩項研究均顯示這些候選療法具有良好的耐受性，並能導致顯著的體重減輕。CIN-110的1期研究共納入24名平均BMI爲34 kg/m²的肥胖受試者，在給藥一週內，他們的食物攝入量減少了28%，體重最多下降了1.8%。總共報告了3例輕度噁心，通常在給藥後12-48小時內出現，並在一天內緩解。在CIN-109的1期研究中，平均BMI爲35 kg/m²的肥胖受試者的食物攝入量呈劑量依賴性的減少，最高達50%，患者在1-2個月內體重減輕了多達3.7%。此外，每兩週給藥一次CIN-109的耐受性更好，大部分減輕的體重來自於脂肪，且未觀察到與治療相關的嚴重副作用。

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參考資料（可上下滑動查看）

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[2] AZN Meet the Management: Weight Management Virtual Event. Retrieved November 4, 2024, from https://www.astrazeneca.com/content/dam/az/Investor_Relations/events/Weight-Management-Virtual-Event-IR-presentation.pdf

[3] Tango Therapeutics Reports Positive TNG462 Clinical Data and Provides Update on PRMT5 Development Program. Retrieved November 6, 2024, from https://ir.tangotx.com/news-releases/news-release-details/tango-therapeutics-reports-positive-tng462-clinical-data-and

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[26] Aummune Announces Results from Phase 1 Trial of its Novel AM003 Immunotherapy for the Treatment of Solid Tumors. Retrieved November 8, 2024 from https://www.globenewswire.com/news-release/2024/11/07/2976844/0/en/Aummune-Announces-Results-from-Phase-1-Trial-of-its-Novel-AM003-Immunotherapy-for-the-Treatment-of-Solid-Tumors.html

[27] Cellenkos Announces Oral Presentation at ASH Annual Meeting 2024 Highlighting Phase 1b Clinical Data of CK0804 in Myelofibrosis. Retrieved November 8, 2024 from https://www.prnewswire.com/news-releases/cellenkos-announces-oral-presentation-at-ash-annual-meeting-2024-highlighting-phase-1b-clinical-data-of-ck0804-in-myelofibrosis-302298808.html

[28] Indaptus Therapeutics Presents Encouraging Interim Safety Data from Phase 1 Clinical Trial of Decoy20 at the Society for Immunotherapy of Cancer (SITC) 2024 Annual Meeting. Retrieved November 8, 2024 from https://www.globenewswire.com/news-release/2024/11/07/2976598/0/en/Indaptus-Therapeutics-Presents-Encouraging-Interim-Safety-Data-from-Phase-1-Clinical-Trial-of-Decoy20-at-the-Society-for-Immunotherapy-of-Cancer-SITC-2024-Annual-Meeting.html

[29] Nimbus Therapeutics Presents Positive Updated Data from Phase 1/2 Clinical Trial of HPK1 Inhibitor for Advanced Solid Tumors at SITC 39th Annual Meeting. Retrieved November 8, 2024 from https://www.businesswire.com/news/home/20241107226079/en/Nimbus-Therapeutics-Presents-Positive-Updated-Data-from-Phase-12-Clinical-Trial-of-HPK1-Inhibitor-for-Advanced-Solid-Tumors-at-SITC-39th-Annual-Meeting

[30] Indapta Therapeutics Presents Clinical and Preclinical Data of Allogenic Natural Killer Cell Therapy at Society for Immunotherapy of Cancer Meeting. Retrieved November 8, 2024 from https://www.businesswire.com/news/home/20241107081017/en/Indapta-Therapeutics-Presents-Clinical-and-Preclinical-Data-of-Allogenic-Natural-Killer-Cell-Therapy-at-Society-for-Immunotherapy-of-Cancer-Meeting

[31] Radella Pharmaceuticals Announces Topline Data from the Phase 1a Study of MD-18, a First-In-Class Peptide Targeting PTP1B for Obesity. Retrieved November 8, 2024 from https://www.businesswire.com/news/home/20241107046414/en/Radella-Pharmaceuticals-Announces-Topline-Data-from-the-Phase-1a-Study-of-MD-18-a-First-In-Class-Peptide-Targeting-PTP1B-for-Obesity#:~:text=Radella%20Pharmaceuticals%20Announces%20Topline%20Data%20from%20the%20Phase,its%20platform%20targeting%20cardiometabolic%20disease%20and%20its%20adjacencies

[32] Palisade Bio Announces First Subject Dosed in Phase 1 Clinical Study of PALI-2108 for the Treatment of Moderate-to-Severe Ulcerative Colitis (UC). Retrieved November 8, 2024 from https://palisadebio.com/palisade-bio-announces-first-subject-dosed-in-phase-1-clinical-study-of-pali-2108-for-the-treatment-of-moderate-to-severe-ulcerative-colitis-uc/

[33] SystImmune, Inc. Announces FDA Clearance of IND Application for BL-M17D1 in Advanced Solid Tumors. Retrieved November 8, 2024 from https://www.prnewswire.com/news-releases/systimmune-inc-announces-fda-clearance-of-ind-application-for-bl-m17d1-in-advanced-solid-tumors-302298993.html

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