瑞士巴塞爾2025年12月10日 /美通社/ -- 諾華近日宣布VAYHIT2三期臨床試驗(yàn)取得積極結(jié)果，該試驗(yàn)評(píng)估了ianalumab聯(lián)合艾曲泊帕在既往接受糖皮質(zhì)激素治療的原發(fā)性免疫性血小板減少癥（ITP）患者中的療效和安全性[1-3]。Ianalumab（9 mg/kg）聯(lián)合艾曲泊帕將ITP疾病控制延長了45%，該結(jié)果基于主要研究終點(diǎn)"至治療失敗時(shí)間（TTF, Time To Treatment Failure）"，即評(píng)估患者在治療期間及治療后維持安全血小板水平的時(shí)間[1,2]。接受ianalumab聯(lián)合艾曲泊帕治療的患者，其至治療失敗的中位時(shí)間是安慰劑聯(lián)合艾曲泊帕組的2.8倍（13.0個(gè)月 vs 4.7個(gè)月）[1,2]。
詳細(xì)數(shù)據(jù)于第67屆美國血液學(xué)會(huì)年會(huì)（ASH）的最新突破摘要（Late-Breaking Abstracts） 專場(chǎng)公布，并同步發(fā)表于《新英格蘭醫(yī)學(xué)雜志》[1,2]。
"ITP的治療一直以來側(cè)重于提升血小板計(jì)數(shù)，通常需要長期治療以控制疾病。這意味著許多患者需要長期用藥，持續(xù)承受疾病負(fù)擔(dān)和如疲勞等的癥狀，"麻總百瀚醫(yī)院（Mass General Brigham）血液學(xué)/腫瘤學(xué) Peggy S. Blitz 講席教授、哈佛醫(yī)學(xué)院醫(yī)學(xué)副教授Hanny Al-Samkari博士表示，"VAYHIT2試驗(yàn)結(jié)果令人鼓舞，顯示即使在患者停藥期間也能實(shí)現(xiàn)更好的疾病控制，為ITP患者帶來新的希望。"
接受ianalumab（9 mg/kg）聯(lián)合艾曲泊帕治療的患者，在第6個(gè)月時(shí)持續(xù)血小板計(jì)數(shù)改善的比例也顯著高于安慰劑聯(lián)合艾曲泊帕治療組（62% vs 39%），達(dá)到了關(guān)鍵次要終點(diǎn)[1,2]。疲勞改善方面，PROMIS疲勞評(píng)分顯示，ianalumab聯(lián)合艾曲泊帕組平均下降7.7分，安慰劑聯(lián)合艾曲泊帕治療組下降3.6分[1,2]。
"B細(xì)胞驅(qū)動(dòng)的自身免疫反應(yīng)導(dǎo)致ITP患者血小板破壞和出血風(fēng)險(xiǎn)增加。Ianalumab的創(chuàng)新雙重作用機(jī)制旨在清除B細(xì)胞并阻斷其存活信號(hào)。"諾華全球腫瘤開發(fā)負(fù)責(zé)人Mark Rutstein博士表示，"憑借我們?cè)贗TP領(lǐng)域多年的經(jīng)驗(yàn)，VAYHIT2結(jié)果進(jìn)一步證明ianalumab有望通過每月一次、共四次的靜脈輸注方案，實(shí)現(xiàn)持久疾病控制，讓患者無需長期持續(xù)治療。"
VAYHIT2評(píng)估了兩種劑量的ianalumab，其中9 mg/kg劑量在主要和關(guān)鍵次要終點(diǎn)均顯示出統(tǒng)計(jì)學(xué)顯著改善，3 mg/kg劑量在主要終點(diǎn)達(dá)到統(tǒng)計(jì)學(xué)顯著，關(guān)鍵次要終點(diǎn)有數(shù)值改善[1-3]。
Ianalumab 9 mg/kg + 艾曲泊帕 (N=50) |
Ianalumab 3 mg/kg + 艾曲泊帕 (N=51) |
安慰劑 + 艾曲泊帕 (N=51) |
|
主要終點(diǎn)： 至治療失敗時(shí)間（TTF） |
13.0個(gè)月 (HR 0.55; 95% CI: 0.32, 0.92; p=0.021a) |
尚無法估算 (HR 0.58; 95% CI: 0.34, 0.98; p=0.023a) |
4.7個(gè)月 |
關(guān)鍵次要終點(diǎn)： 6個(gè)月時(shí)持續(xù)應(yīng)答率（SR6） |
62.0% (p=0.023a) |
56.9% (p=0.035a) |
39.2 %
|
a. 統(tǒng)計(jì)學(xué)顯著性所需p值為單側(cè)<0.025
Ianalumab耐受性良好，未發(fā)現(xiàn)新的安全信號(hào)，安全性與既往研究一致[1,2]。Ianalumab組與安慰劑組的不良事件發(fā)生率相當(dāng)，最常見的不良事件為頭痛（9 mg/kg組14%，3 mg/kg組10%，安慰劑組8%）和輸注相關(guān)反應(yīng)（9 mg/kg組14%，3 mg/kg組8%，安慰劑組8%）[1,2]。中性粒細(xì)胞減少癥*在ianalumab組更常見（9 mg/kg組16%，3 mg/kg組12%，安慰劑組2%），大多數(shù)病例無需治療或劑量調(diào)整即可恢復(fù)[1,2]。未有因治療期間不良事件導(dǎo)致永久停藥的情況[1,2]。
VAYHIT2是ianalumab的第三項(xiàng)獲得陽性結(jié)果的III期臨床試驗(yàn)，此前在活動(dòng)性干燥綜合征成人患者中已有兩項(xiàng)陽性結(jié)果[1,4]。諾華計(jì)劃于2027年將VAYHIT2數(shù)據(jù)與正在進(jìn)行的一線ITP試驗(yàn)結(jié)果（VAYHIT1）一同提交。Ianalumab已獲得美國食品藥品監(jiān)督管理局（FDA）和歐洲藥品管理局（EMA）的孤兒藥資格認(rèn)定[5,6]。
*注：中性粒細(xì)胞減少癥為特別關(guān)注不良事件，包括多種與中性粒細(xì)胞、中性粒前體細(xì)胞及白細(xì)胞減少相關(guān)的術(shù)語。 |
關(guān)于ianalumab
Ianalumab（VAY736）是一種新型全人源單克隆抗體，正在開發(fā)用于治療多種B細(xì)胞介導(dǎo)的自身免疫性疾病，包括干燥綜合征、免疫性血小板減少癥（ITP）、系統(tǒng)性紅斑狼瘡（SLE）、狼瘡性腎炎（LN）、溫抗體型自身免疫性溶血性貧血（wAIHA）及彌漫性皮膚系統(tǒng)性硬化癥（dcSSc）[3,7-13]。其作用機(jī)制通過兩種途徑靶向B細(xì)胞：一方面通過抗體依賴性細(xì)胞毒作用（ADCC）耗竭B細(xì)胞，另一方面，阻斷BAFF-R介導(dǎo)的B細(xì)胞功能及存活信號(hào)[8]。臨床試驗(yàn)顯示，ianalumab在干燥綜合征、系統(tǒng)性紅斑狼瘡和免疫性血小板減少癥中具有良好的療效和安全性[4,14-16]。Ianalumab最初由MorphoSys AG公司與諾華早期合作開發(fā)，諾華于2024年收購了該公司[17]。
關(guān)于原發(fā)性免疫性血小板減少癥
原發(fā)性免疫性血小板減少癥（ITP）是一種罕見的自身免疫性疾病，患者的免疫系統(tǒng)錯(cuò)誤地攻擊并破壞血小板——血液凝固所必需的細(xì)胞[18]。這會(huì)導(dǎo)致出血時(shí)間延長、易瘀傷和慢性疲勞等癥狀，嚴(yán)重影響日常生活[18,19]。
盡管已有多種治療方法，許多ITP患者仍需多次更換治療方案，難以實(shí)現(xiàn)長期疾病控制[20]?，F(xiàn)有治療多以維持安全血小板水平和預(yù)防出血為主，往往需要長期用藥[20,21]。長期治療負(fù)擔(dān)和復(fù)發(fā)的不確定性嚴(yán)重影響患者生活質(zhì)量[19,22]。亟需能夠?qū)崿F(xiàn)持久反應(yīng)、減少長期治療負(fù)擔(dān)的新療法[23]。
關(guān)于VAYHIT2
VAYHIT2（NCT05653219）是一項(xiàng)III期、多中心、隨機(jī)、雙盲研究，評(píng)估兩種不同劑量的ianalumab與安慰劑（均聯(lián)合艾曲泊帕）在既往一線糖皮質(zhì)激素治療失敗的原發(fā)性免疫性血小板減少癥（ITP，血小板計(jì)數(shù)<30 G/L）成人患者中的療效和安全性[3]。所有患者均聯(lián)合艾曲泊帕，隨機(jī)分為1:1:1三組，分別接受每月一次、共四次的靜脈注射ianalumab 3 mg/kg、ianalumab 9 mg/kg或安慰劑[3]。主要終點(diǎn)為至治療失敗時(shí)間（TTF），定義為從隨機(jī)分組起至以下任一事件發(fā)生的時(shí)間：隨機(jī)分組8周后血小板計(jì)數(shù)<30 G/L；隨機(jī)分組8周后需救援治療；任何時(shí)間需新ITP治療；無法減/停艾曲泊帕；或死亡[3]。關(guān)鍵次要終點(diǎn)為第6個(gè)月時(shí)達(dá)到持續(xù)血小板計(jì)數(shù)應(yīng)答的患者比例[3]。其他次要終點(diǎn)包括血小板反應(yīng)深度和持續(xù)時(shí)間、患者報(bào)告的生活質(zhì)量和疲勞等[3]。
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參考文獻(xiàn)
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