即便研發(fā)出效果很好的疫苗,全球范圍內(nèi)的新冠肺炎病例仍然有增無(wú)減。近期國(guó)內(nèi)出現(xiàn)了零星確診病例,而在國(guó)外,印度疫情依舊水深火熱,美國(guó)的情況也不容樂(lè)觀,根據(jù)約翰斯?霍普金斯大學(xué)的7日平均數(shù)據(jù),每天有超過(guò)4萬(wàn)多人感染。
很多人依然對(duì)注射疫苗猶豫不決,已經(jīng)接種疫苗的人偶爾也會(huì)出現(xiàn)感染的情況。與此同時(shí),一些國(guó)家依舊面臨著疫苗劑量不夠的困境。至少在可預(yù)見的未來(lái),新冠病毒將繼續(xù)存在。
藥物研發(fā)人員和公共衛(wèi)生專家表示,現(xiàn)在需要方便操作的治療新冠病毒的方法。只要服用類似達(dá)菲(Tamiflu,治療季節(jié)性流感的抗病毒藥)的藥,就能夠防止癥狀惡化以及住院。雖然抗體藥看起來(lái)可以滿足要求,但很多藥需要靜脈注射,很難迅速大范圍普及。而如果只是吃藥就方便得多。
“除非能夠說(shuō)服足夠多的人同意接種疫苗,否則就得采取第二種方法,也就是口服抗病毒藥物。”佐治亞州立大學(xué)的分子病毒學(xué)家和生化學(xué)家理查德?普倫珀表示。
針對(duì)新冠的抗病毒藥作用類似于一個(gè)療程的抗生素。醫(yī)生開一盒藥,之后患者在家一天吃一兩片,持續(xù)五到七天。目標(biāo)是希望通過(guò)吃藥緩解癥狀,幫人們更快恢復(fù)。但是作為針對(duì)流感病毒的抗病毒藥物,達(dá)菲只能緩解新冠患者的癥狀,但對(duì)“殺死”新冠病毒無(wú)效,并不能用來(lái)治愈患者。
目前,新冠藥物的研發(fā)明顯滯后于光速研發(fā)的疫苗,部分原因是抗病毒藥物沒(méi)有像新冠疫苗一樣獲得聯(lián)邦政府的資金支持。
目前一些實(shí)驗(yàn)性藥物正進(jìn)行臨床試驗(yàn),未來(lái)幾個(gè)月就能夠看出療效如何。最前沿的藥名為莫那比拉韋,由默沙東和Ridgeback Biotherapeutics公司研發(fā)。根據(jù)今年3月已經(jīng)公布的初步結(jié)果,公司表示新藥很安全,可以顯著降低未住院病人體內(nèi)的病毒含量。預(yù)計(jì)不久之后公司將公布更多數(shù)據(jù)。
輝瑞不僅開發(fā)了針對(duì)新冠的mRNA疫苗,也在測(cè)試抗病毒藥。首席執(zhí)行官艾伯樂(lè)最近告訴美國(guó)消費(fèi)者新聞與商業(yè)頻道,今年年底可能推向市場(chǎng)。
抗擊病毒
除了達(dá)菲,還有一些抗病毒藥能夠用于治療艾滋病毒、皰疹、乙肝和丙肝等感染,但與市場(chǎng)上眾多治療細(xì)菌感染的抗生素相比,可以應(yīng)付病毒的藥物還很少。
藥物研發(fā)人員表示,這主要是因?yàn)榘踩行У目共《舅幈瓤股馗y制造。病毒跟細(xì)菌不一樣,細(xì)菌是獨(dú)立有機(jī)體,能夠自行繁殖,而病毒要找到宿主才可以傳播。一旦病毒粒子進(jìn)入宿主細(xì)胞,就會(huì)劫持細(xì)胞運(yùn)轉(zhuǎn)并開始大量復(fù)制。隨后新復(fù)制的病毒傳遍全身,感染更多細(xì)胞。
病毒要不斷復(fù)制才能夠繼續(xù)感染,如果可以阻止復(fù)制過(guò)程中的某個(gè)步驟,就能夠停止感染。而抗病毒藥物不能完全殺死病毒,只是阻止病毒復(fù)制。
最棘手的是,讓藥物在抗病毒過(guò)程中只針對(duì)病毒,不能同時(shí)殺死病毒所在的細(xì)胞。抗生素就只殺死細(xì)菌細(xì)胞,不會(huì)傷害人類細(xì)胞。在開發(fā)抗病毒藥物時(shí),毒性始終是關(guān)注焦點(diǎn)。
“要找到病毒獨(dú)特的致命弱點(diǎn),在不影響宿主的情況下加以利用,確實(shí)是抗病毒治療的主要挑戰(zhàn)。”普倫珀稱。有些抗病毒藥物是直接針對(duì)病毒上的某個(gè)點(diǎn)進(jìn)行攻克,另一些則是針對(duì)在病毒復(fù)制過(guò)程中被占用的人類蛋白進(jìn)行突破。
另一個(gè)導(dǎo)致抗病毒藥物開發(fā)挑戰(zhàn)巨大的因素是用藥的時(shí)機(jī)。“抗病毒藥物需要盡早用藥,確診后就要盡快吃藥。”北卡羅來(lái)納大學(xué)教堂山分校的流行病學(xué)助理教授麗莎?格拉林斯基說(shuō),他參與了莫那比拉韋實(shí)驗(yàn)室測(cè)試。
如果病毒已經(jīng)在全身大范圍傳播,就可能造成嚴(yán)重傷害。抗病毒藥可以抗擊病毒,但不能夠逆轉(zhuǎn)對(duì)組織造成的損害。病人必須在出現(xiàn)癥狀幾天內(nèi)迅速確診,這導(dǎo)致招募患者參加臨床試驗(yàn)很困難。因?yàn)楹芏嘈鹿诓±际禽p癥,如果患者的癥狀不太嚴(yán)重,他們就可能沒(méi)有動(dòng)力自愿參加新藥試驗(yàn)。
目前,吉利德的瑞德西韋是唯一獲批治療新冠肺炎的抗病毒藥,主要通過(guò)輸液治療住院患者。不過(guò)還沒(méi)有證據(jù)顯示該藥能夠救命,但確實(shí)縮短了康復(fù)者的好轉(zhuǎn)時(shí)間。由于療效不明,世界衛(wèi)生組織建議不要使用該藥常規(guī)治療。吉利德正研發(fā)吸入式或藥片式瑞德西韋,供患者在家服用。
如果確實(shí)有效,抗病毒藥甚至可以作為預(yù)防措施,提供給有感染新冠病毒風(fēng)險(xiǎn)的高危人群。
蓄勢(shì)待發(fā)
莫那比拉韋最初由埃默里大學(xué)發(fā)現(xiàn),在這場(chǎng)抗病毒競(jìng)賽中一馬當(dāng)先,因?yàn)檠芯咳藛T已經(jīng)在實(shí)驗(yàn)室研究其對(duì)抗多種病毒的效用。
在疫情爆發(fā)之前,普倫珀發(fā)現(xiàn)該藥能夠抑制流感病毒,而且北卡羅來(lái)納大學(xué)教堂山分校的研究人員發(fā)現(xiàn),它也可以有效抑制其他冠狀病毒,例如中東綜合呼吸癥病毒(MERS)和非典肺炎(SARS)病毒。
格拉林斯基稱:“我們強(qiáng)烈地感覺到,這種藥物也能夠?qū)?SARS-CoV-2病毒,因?yàn)槲覀円呀?jīng)知道其顯效機(jī)理。”
莫那比拉韋是一種核糖核苷類似物藥物。其工作原理是引誘病毒的基因在復(fù)制時(shí)產(chǎn)生大量錯(cuò)誤或發(fā)生變異。當(dāng)變異達(dá)到一定數(shù)量之后,病毒便無(wú)法繼續(xù)存活。
去年,總部位于邁阿密的Ridgeback Biotherapeutics公司授權(quán)使用莫那比拉韋——當(dāng)時(shí)名為 EIDD-2801——進(jìn)行人體安全性初步實(shí)驗(yàn)。公司如今正在與默沙東合作,開展大規(guī)模研究,并將其用于住院和門診新冠患者。上個(gè)月,公司停止了莫那比拉韋的人體實(shí)驗(yàn),稱這些患者不大可能從該藥受益。
與此同時(shí),Atea Pharmaceuticals還對(duì)一款抗病毒藥進(jìn)行了重新定位。這款名為AT-527的藥物最初是針對(duì)丙肝病患開發(fā)的。上個(gè)月,公司啟動(dòng)了三期實(shí)驗(yàn),在1400名輕中度門診新冠肺炎患者的身上測(cè)試該藥。
輝瑞在其藥物方面采取了更具針對(duì)性的做法。輝瑞的藥物設(shè)計(jì)負(fù)責(zé)人夏洛特?阿勒頓稱,去年3月,公司成立了一支團(tuán)隊(duì),設(shè)計(jì)了一種專門用于對(duì)抗SARS-CoV-2病毒的分子。7月,該團(tuán)隊(duì)發(fā)現(xiàn)另一種潛在的分子,并將其命名為PF-07321332。
該藥物能夠與名為蛋白酶的病毒酶結(jié)合,從而阻止病毒復(fù)制。作為蛋白酶抑制劑,這些藥物在治療其他病毒方面一直十分有效,例如艾滋病和丙肝,既可以單獨(dú)使用,也能夠與其他抗病毒藥聯(lián)合使用。
本月,輝瑞啟動(dòng)了初期實(shí)驗(yàn),在健康成年人身上測(cè)試藥物的安全性。阿勒頓稱,公司計(jì)劃在夏季之前招募新冠肺炎患者參加藥物療效研究。
由于該藥物可以直接作用于病毒,因此人們對(duì)蛋白酶抑制劑的一個(gè)顧慮在于,如果病毒的靶向部分發(fā)生變異,SARS-CoV-2就可能會(huì)對(duì)該藥產(chǎn)生抗藥性。阿勒頓稱,她的團(tuán)隊(duì)將跟蹤SARS-CoV-2變種,以尋找可能會(huì)導(dǎo)致藥物療效降低的蛋白酶變異點(diǎn)。
她說(shuō):“由于報(bào)道的變異程度很低,因此我們當(dāng)前并不認(rèn)為它們會(huì)引發(fā)公司抗病毒藥物的療效問(wèn)題。”
小型生物科技公司Selva Therapeutics與Clear Creek Bio正在開發(fā)或許能夠避免抗藥性的藥物,因?yàn)檫@種藥物針對(duì)的是宿主,并非病毒。Selva的藥物由加州大學(xué)圣迭戈分校授權(quán),可以抑制在人類肺部和其他細(xì)胞中發(fā)現(xiàn)的一種酶,從而阻礙病毒的入侵。
Clear Creek的藥物布喹那于數(shù)年前購(gòu)于百時(shí)美施貴寶公司,也是一種酶的抑制劑,能夠讓病毒無(wú)法從宿主細(xì)胞盜取復(fù)制所需的遺傳物質(zhì)。
位于馬薩諸塞州劍橋市的Clear Creek Bio公司的聯(lián)合創(chuàng)始人與首席執(zhí)行官維克拉姆?希爾?庫(kù)瑪說(shuō):“疫情爆發(fā)后,令我們感到震驚的想法是,該藥可能具有應(yīng)對(duì)抗藥性的特性。”公司于去年11月開始了門診患者的布喹那中期實(shí)驗(yàn)。
不止于新冠病毒
大多數(shù)現(xiàn)有藥物僅針對(duì)特定病毒。然而,諸如莫那比拉韋這類擁有廣譜抗病毒特性的實(shí)驗(yàn)藥物依然有望被用于對(duì)抗多種病毒。科學(xué)家將這些藥物看作是抵抗病毒的殺手锏,因?yàn)樗鼈兓蛟S能夠治療未來(lái)出現(xiàn)的病毒。畢竟,SARS-CoV-2病毒是過(guò)去20年中第三種爆發(fā)的冠狀病毒,而在蝙蝠和其他動(dòng)物中傳播的已知冠狀病毒多達(dá)數(shù)百種。
格拉林斯基稱:“我們不敢去想第四種病毒到來(lái)之時(shí)會(huì)發(fā)生什么事情,但提前做好準(zhǔn)備和謀劃不失為一種明智的做法。如果我們擁有這些具有廣譜抗病毒特性的藥物,即便只是那些完成了開發(fā)并準(zhǔn)備進(jìn)行測(cè)試的藥物,那么我們也有希望避免另一場(chǎng)大規(guī)模疫情。”
新冠疫情爆發(fā)后沒(méi)有抗病毒藥物可用的一個(gè)主要原因在于,業(yè)界并未研制出應(yīng)對(duì)非典肺炎或中東綜合呼吸癥的藥物。當(dāng)這些疫情得到迅速控制后,藥物和疫苗開發(fā)基本上處于停滯狀態(tài)。
新冠病毒抗病毒藥物最終是否會(huì)投放大眾市場(chǎng),取決于聯(lián)邦政府和私人領(lǐng)域的投資。“曲速行動(dòng)”向疫情醫(yī)療防護(hù)領(lǐng)域注入了180億美元的資金,然而絕大多數(shù)資金流向了疫苗開發(fā)。特朗普政府的計(jì)劃并未投資新的抗病毒藥物。
2020年 4月,美國(guó)國(guó)立衛(wèi)生研究院推出了一個(gè)名為“加速新冠病毒治療干預(yù)和疫苗”(ACTIV)的舉措,然而,該項(xiàng)目主要專注于重新定位現(xiàn)有抗病毒藥物,而不是發(fā)現(xiàn)新藥。
位于圣迭戈的Selva Therapeutics公司的首席執(zhí)行官及聯(lián)合創(chuàng)始人泰德?達(dá)利稱,需要投入更多的資金來(lái)加速藥物的上市過(guò)程。
他說(shuō):“對(duì)于那些不僅能夠解決當(dāng)前人們所面臨的公共衛(wèi)生危機(jī),而且還可以作為武器應(yīng)對(duì)未來(lái)新涌現(xiàn)病毒的藥物,公共衛(wèi)生領(lǐng)域當(dāng)然會(huì)對(duì)其開發(fā)舉措表示支持。”
然而在開發(fā)艾滋病這類慢性感染的抗病毒藥物方面,大型制藥公司的積極性并不高。大多數(shù)呼吸道病毒會(huì)引發(fā)輕癥,而且感染會(huì)在數(shù)天內(nèi)恢復(fù)。這種短期感染的抗病毒藥物沒(méi)有任何經(jīng)濟(jì)效益可言。
位于西雅圖的哈欽森癌癥研究中心負(fù)責(zé)莫那比拉韋實(shí)驗(yàn)的感染病醫(yī)師與研究人員伊麗莎白?杜克說(shuō):“他們希望為糖尿病、高血壓研發(fā)藥物,他們希望研發(fā)出人們長(zhǎng)期需要的藥物,而不是僅使用5天的藥物。”
然而杜克認(rèn)為,新冠病毒可能成為醫(yī)藥行業(yè)的一個(gè)轉(zhuǎn)折點(diǎn)。疫情顯示,呼吸系統(tǒng)病毒可能比流感或普通感冒更致命。即便擁有有效的疫苗,SARS-CoV-2病毒依然可能留存于世。然而,抗病毒可以幫助把病毒引發(fā)的致命威脅,降低為能夠居家治療的可控感染。(財(cái)富中文網(wǎng))
譯者:馮豐
審校:夏林
即便研發(fā)出效果很好的疫苗,全球范圍內(nèi)的新冠肺炎病例仍然有增無(wú)減。近期國(guó)內(nèi)出現(xiàn)了零星確診病例,而在國(guó)外,印度疫情依舊水深火熱,美國(guó)的情況也不容樂(lè)觀,根據(jù)約翰斯?霍普金斯大學(xué)的7日平均數(shù)據(jù),每天有超過(guò)4萬(wàn)多人感染。
很多人依然對(duì)注射疫苗猶豫不決,已經(jīng)接種疫苗的人偶爾也會(huì)出現(xiàn)感染的情況。與此同時(shí),一些國(guó)家依舊面臨著疫苗劑量不夠的困境。至少在可預(yù)見的未來(lái),新冠病毒將繼續(xù)存在。
藥物研發(fā)人員和公共衛(wèi)生專家表示,現(xiàn)在需要方便操作的治療新冠病毒的方法。只要服用類似達(dá)菲(Tamiflu,治療季節(jié)性流感的抗病毒藥)的藥,就能夠防止癥狀惡化以及住院。雖然抗體藥看起來(lái)可以滿足要求,但很多藥需要靜脈注射,很難迅速大范圍普及。而如果只是吃藥就方便得多。
“除非能夠說(shuō)服足夠多的人同意接種疫苗,否則就得采取第二種方法,也就是口服抗病毒藥物。”佐治亞州立大學(xué)的分子病毒學(xué)家和生化學(xué)家理查德?普倫珀表示。
針對(duì)新冠的抗病毒藥作用類似于一個(gè)療程的抗生素。醫(yī)生開一盒藥,之后患者在家一天吃一兩片,持續(xù)五到七天。目標(biāo)是希望通過(guò)吃藥緩解癥狀,幫人們更快恢復(fù)。但是作為針對(duì)流感病毒的抗病毒藥物,達(dá)菲只能緩解新冠患者的癥狀,但對(duì)“殺死”新冠病毒無(wú)效,并不能用來(lái)治愈患者。
目前,新冠藥物的研發(fā)明顯滯后于光速研發(fā)的疫苗,部分原因是抗病毒藥物沒(méi)有像新冠疫苗一樣獲得聯(lián)邦政府的資金支持。
目前一些實(shí)驗(yàn)性藥物正進(jìn)行臨床試驗(yàn),未來(lái)幾個(gè)月就能夠看出療效如何。最前沿的藥名為莫那比拉韋,由默沙東和Ridgeback Biotherapeutics公司研發(fā)。根據(jù)今年3月已經(jīng)公布的初步結(jié)果,公司表示新藥很安全,可以顯著降低未住院病人體內(nèi)的病毒含量。預(yù)計(jì)不久之后公司將公布更多數(shù)據(jù)。
輝瑞不僅開發(fā)了針對(duì)新冠的mRNA疫苗,也在測(cè)試抗病毒藥。首席執(zhí)行官艾伯樂(lè)最近告訴美國(guó)消費(fèi)者新聞與商業(yè)頻道,今年年底可能推向市場(chǎng)。
抗擊病毒
除了達(dá)菲,還有一些抗病毒藥能夠用于治療艾滋病毒、皰疹、乙肝和丙肝等感染,但與市場(chǎng)上眾多治療細(xì)菌感染的抗生素相比,可以應(yīng)付病毒的藥物還很少。
藥物研發(fā)人員表示,這主要是因?yàn)榘踩行У目共《舅幈瓤股馗y制造。病毒跟細(xì)菌不一樣,細(xì)菌是獨(dú)立有機(jī)體,能夠自行繁殖,而病毒要找到宿主才可以傳播。一旦病毒粒子進(jìn)入宿主細(xì)胞,就會(huì)劫持細(xì)胞運(yùn)轉(zhuǎn)并開始大量復(fù)制。隨后新復(fù)制的病毒傳遍全身,感染更多細(xì)胞。
病毒要不斷復(fù)制才能夠繼續(xù)感染,如果可以阻止復(fù)制過(guò)程中的某個(gè)步驟,就能夠停止感染。而抗病毒藥物不能完全殺死病毒,只是阻止病毒復(fù)制。
最棘手的是,讓藥物在抗病毒過(guò)程中只針對(duì)病毒,不能同時(shí)殺死病毒所在的細(xì)胞。抗生素就只殺死細(xì)菌細(xì)胞,不會(huì)傷害人類細(xì)胞。在開發(fā)抗病毒藥物時(shí),毒性始終是關(guān)注焦點(diǎn)。
“要找到病毒獨(dú)特的致命弱點(diǎn),在不影響宿主的情況下加以利用,確實(shí)是抗病毒治療的主要挑戰(zhàn)。”普倫珀稱。有些抗病毒藥物是直接針對(duì)病毒上的某個(gè)點(diǎn)進(jìn)行攻克,另一些則是針對(duì)在病毒復(fù)制過(guò)程中被占用的人類蛋白進(jìn)行突破。
另一個(gè)導(dǎo)致抗病毒藥物開發(fā)挑戰(zhàn)巨大的因素是用藥的時(shí)機(jī)。“抗病毒藥物需要盡早用藥,確診后就要盡快吃藥。”北卡羅來(lái)納大學(xué)教堂山分校的流行病學(xué)助理教授麗莎?格拉林斯基說(shuō),他參與了莫那比拉韋實(shí)驗(yàn)室測(cè)試。
如果病毒已經(jīng)在全身大范圍傳播,就可能造成嚴(yán)重傷害。抗病毒藥可以抗擊病毒,但不能夠逆轉(zhuǎn)對(duì)組織造成的損害。病人必須在出現(xiàn)癥狀幾天內(nèi)迅速確診,這導(dǎo)致招募患者參加臨床試驗(yàn)很困難。因?yàn)楹芏嘈鹿诓±际禽p癥,如果患者的癥狀不太嚴(yán)重,他們就可能沒(méi)有動(dòng)力自愿參加新藥試驗(yàn)。
目前,吉利德的瑞德西韋是唯一獲批治療新冠肺炎的抗病毒藥,主要通過(guò)輸液治療住院患者。不過(guò)還沒(méi)有證據(jù)顯示該藥能夠救命,但確實(shí)縮短了康復(fù)者的好轉(zhuǎn)時(shí)間。由于療效不明,世界衛(wèi)生組織建議不要使用該藥常規(guī)治療。吉利德正研發(fā)吸入式或藥片式瑞德西韋,供患者在家服用。
如果確實(shí)有效,抗病毒藥甚至可以作為預(yù)防措施,提供給有感染新冠病毒風(fēng)險(xiǎn)的高危人群。
蓄勢(shì)待發(fā)
莫那比拉韋最初由埃默里大學(xué)發(fā)現(xiàn),在這場(chǎng)抗病毒競(jìng)賽中一馬當(dāng)先,因?yàn)檠芯咳藛T已經(jīng)在實(shí)驗(yàn)室研究其對(duì)抗多種病毒的效用。
在疫情爆發(fā)之前,普倫珀發(fā)現(xiàn)該藥能夠抑制流感病毒,而且北卡羅來(lái)納大學(xué)教堂山分校的研究人員發(fā)現(xiàn),它也可以有效抑制其他冠狀病毒,例如中東綜合呼吸癥病毒(MERS)和非典肺炎(SARS)病毒。
格拉林斯基稱:“我們強(qiáng)烈地感覺到,這種藥物也能夠?qū)?SARS-CoV-2病毒,因?yàn)槲覀円呀?jīng)知道其顯效機(jī)理。”
莫那比拉韋是一種核糖核苷類似物藥物。其工作原理是引誘病毒的基因在復(fù)制時(shí)產(chǎn)生大量錯(cuò)誤或發(fā)生變異。當(dāng)變異達(dá)到一定數(shù)量之后,病毒便無(wú)法繼續(xù)存活。
去年,總部位于邁阿密的Ridgeback Biotherapeutics公司授權(quán)使用莫那比拉韋——當(dāng)時(shí)名為 EIDD-2801——進(jìn)行人體安全性初步實(shí)驗(yàn)。公司如今正在與默沙東合作,開展大規(guī)模研究,并將其用于住院和門診新冠患者。上個(gè)月,公司停止了莫那比拉韋的人體實(shí)驗(yàn),稱這些患者不大可能從該藥受益。
與此同時(shí),Atea Pharmaceuticals還對(duì)一款抗病毒藥進(jìn)行了重新定位。這款名為AT-527的藥物最初是針對(duì)丙肝病患開發(fā)的。上個(gè)月,公司啟動(dòng)了三期實(shí)驗(yàn),在1400名輕中度門診新冠肺炎患者的身上測(cè)試該藥。
輝瑞在其藥物方面采取了更具針對(duì)性的做法。輝瑞的藥物設(shè)計(jì)負(fù)責(zé)人夏洛特?阿勒頓稱,去年3月,公司成立了一支團(tuán)隊(duì),設(shè)計(jì)了一種專門用于對(duì)抗SARS-CoV-2病毒的分子。7月,該團(tuán)隊(duì)發(fā)現(xiàn)另一種潛在的分子,并將其命名為PF-07321332。
該藥物能夠與名為蛋白酶的病毒酶結(jié)合,從而阻止病毒復(fù)制。作為蛋白酶抑制劑,這些藥物在治療其他病毒方面一直十分有效,例如艾滋病和丙肝,既可以單獨(dú)使用,也能夠與其他抗病毒藥聯(lián)合使用。
本月,輝瑞啟動(dòng)了初期實(shí)驗(yàn),在健康成年人身上測(cè)試藥物的安全性。阿勒頓稱,公司計(jì)劃在夏季之前招募新冠肺炎患者參加藥物療效研究。
由于該藥物可以直接作用于病毒,因此人們對(duì)蛋白酶抑制劑的一個(gè)顧慮在于,如果病毒的靶向部分發(fā)生變異,SARS-CoV-2就可能會(huì)對(duì)該藥產(chǎn)生抗藥性。阿勒頓稱,她的團(tuán)隊(duì)將跟蹤SARS-CoV-2變種,以尋找可能會(huì)導(dǎo)致藥物療效降低的蛋白酶變異點(diǎn)。
她說(shuō):“由于報(bào)道的變異程度很低,因此我們當(dāng)前并不認(rèn)為它們會(huì)引發(fā)公司抗病毒藥物的療效問(wèn)題。”
小型生物科技公司Selva Therapeutics與Clear Creek Bio正在開發(fā)或許能夠避免抗藥性的藥物,因?yàn)檫@種藥物針對(duì)的是宿主,并非病毒。Selva的藥物由加州大學(xué)圣迭戈分校授權(quán),可以抑制在人類肺部和其他細(xì)胞中發(fā)現(xiàn)的一種酶,從而阻礙病毒的入侵。
Clear Creek的藥物布喹那于數(shù)年前購(gòu)于百時(shí)美施貴寶公司,也是一種酶的抑制劑,能夠讓病毒無(wú)法從宿主細(xì)胞盜取復(fù)制所需的遺傳物質(zhì)。
位于馬薩諸塞州劍橋市的Clear Creek Bio公司的聯(lián)合創(chuàng)始人與首席執(zhí)行官維克拉姆?希爾?庫(kù)瑪說(shuō):“疫情爆發(fā)后,令我們感到震驚的想法是,該藥可能具有應(yīng)對(duì)抗藥性的特性。”公司于去年11月開始了門診患者的布喹那中期實(shí)驗(yàn)。
不止于新冠病毒
大多數(shù)現(xiàn)有藥物僅針對(duì)特定病毒。然而,諸如莫那比拉韋這類擁有廣譜抗病毒特性的實(shí)驗(yàn)藥物依然有望被用于對(duì)抗多種病毒。科學(xué)家將這些藥物看作是抵抗病毒的殺手锏,因?yàn)樗鼈兓蛟S能夠治療未來(lái)出現(xiàn)的病毒。畢竟,SARS-CoV-2病毒是過(guò)去20年中第三種爆發(fā)的冠狀病毒,而在蝙蝠和其他動(dòng)物中傳播的已知冠狀病毒多達(dá)數(shù)百種。
格拉林斯基稱:“我們不敢去想第四種病毒到來(lái)之時(shí)會(huì)發(fā)生什么事情,但提前做好準(zhǔn)備和謀劃不失為一種明智的做法。如果我們擁有這些具有廣譜抗病毒特性的藥物,即便只是那些完成了開發(fā)并準(zhǔn)備進(jìn)行測(cè)試的藥物,那么我們也有希望避免另一場(chǎng)大規(guī)模疫情。”
新冠疫情爆發(fā)后沒(méi)有抗病毒藥物可用的一個(gè)主要原因在于,業(yè)界并未研制出應(yīng)對(duì)非典肺炎或中東綜合呼吸癥的藥物。當(dāng)這些疫情得到迅速控制后,藥物和疫苗開發(fā)基本上處于停滯狀態(tài)。
新冠病毒抗病毒藥物最終是否會(huì)投放大眾市場(chǎng),取決于聯(lián)邦政府和私人領(lǐng)域的投資。“曲速行動(dòng)”向疫情醫(yī)療防護(hù)領(lǐng)域注入了180億美元的資金,然而絕大多數(shù)資金流向了疫苗開發(fā)。特朗普政府的計(jì)劃并未投資新的抗病毒藥物。
2020年 4月,美國(guó)國(guó)立衛(wèi)生研究院推出了一個(gè)名為“加速新冠病毒治療干預(yù)和疫苗”(ACTIV)的舉措,然而,該項(xiàng)目主要專注于重新定位現(xiàn)有抗病毒藥物,而不是發(fā)現(xiàn)新藥。
位于圣迭戈的Selva Therapeutics公司的首席執(zhí)行官及聯(lián)合創(chuàng)始人泰德?達(dá)利稱,需要投入更多的資金來(lái)加速藥物的上市過(guò)程。
他說(shuō):“對(duì)于那些不僅能夠解決當(dāng)前人們所面臨的公共衛(wèi)生危機(jī),而且還可以作為武器應(yīng)對(duì)未來(lái)新涌現(xiàn)病毒的藥物,公共衛(wèi)生領(lǐng)域當(dāng)然會(huì)對(duì)其開發(fā)舉措表示支持。”
然而在開發(fā)艾滋病這類慢性感染的抗病毒藥物方面,大型制藥公司的積極性并不高。大多數(shù)呼吸道病毒會(huì)引發(fā)輕癥,而且感染會(huì)在數(shù)天內(nèi)恢復(fù)。這種短期感染的抗病毒藥物沒(méi)有任何經(jīng)濟(jì)效益可言。
位于西雅圖的哈欽森癌癥研究中心負(fù)責(zé)莫那比拉韋實(shí)驗(yàn)的感染病醫(yī)師與研究人員伊麗莎白?杜克說(shuō):“他們希望為糖尿病、高血壓研發(fā)藥物,他們希望研發(fā)出人們長(zhǎng)期需要的藥物,而不是僅使用5天的藥物。”
然而杜克認(rèn)為,新冠病毒可能成為醫(yī)藥行業(yè)的一個(gè)轉(zhuǎn)折點(diǎn)。疫情顯示,呼吸系統(tǒng)病毒可能比流感或普通感冒更致命。即便擁有有效的疫苗,SARS-CoV-2病毒依然可能留存于世。然而,抗病毒可以幫助把病毒引發(fā)的致命威脅,降低為能夠居家治療的可控感染。(財(cái)富中文網(wǎng))
譯者:馮豐
審校:夏林
Even with highly effective vaccines, cases of COVID-19 are still happening in the U.S. More than 40,000 people a day are being diagnosed with the disease, based on a seven-day average of Johns Hopkins University data.
Many people remain hesitant about getting the shot, and breakthrough infections can occasionally occur in those who are vaccinated. Meanwhile, some countries don’t have enough vaccine doses. COVID-19 is likely here to stay—at least for the foreseeable future.
Drug developers and public health experts say what’s needed now is an easy-to-take treatment for COVID-19. A pill akin to Tamiflu—an antiviral for seasonal influenza—could prevent people with symptoms from getting worse and ending up in the hospital. Antibody drugs have been shown to do just that, but these drugs need to be given via an IV, making them difficult to deploy quickly to a large number of people. A pill would be far more convenient.
“Unless we can persuade enough people to agree to vaccination, we are going to need a second approach, and oral antivirals can give us that,” says Richard Plemper, a molecular virologist and biochemist at Georgia State University.
An antiviral pill for COVID-19 would work similarly to a course of antibiotics. Your doctor would prescribe a pack of pills, and you’d take one or two a day for five to seven days while you stay at home. The hope is that a pill would alleviate symptoms and help people bounce back from the infection faster. When Tamiflu is taken within 48 hours, it speeds recovery time by a day.
The search for a coronavirus pill has lagged behind the light-speed development of vaccines in part because antivirals haven’t gotten the same influx of cash from the federal government that COVID-19 vaccines have.
A handful of experimental pills are now being tested in clinical trials, and the next few months will reveal whether any of them are effective. At the forefront is a drug called molnupiravir, developed by Merck and Ridgeback Biotherapeutics. In preliminary results announced in March, the company said the pill was safe and significantly reduced viral loads in nonhospitalized adults. The companies are expected to release more data soon.
Pfizer, which developed one of the mRNA vaccines for COVID-19, is also testing an antiviral pill. CEO Albert Bourla told CNBC recently that the drug could be available by the end of the year.
Thwarting the virus
Beyond Tamiflu, antivirals are available to treat infections like HIV, herpes, and hepatitis B and C, but that’s a short list compared to the numerous antibiotics on the market for bacterial infections.
Drug developers say it’s because safe and effective antivirals are just trickier to make than antibiotics. Unlike bacteria, which are independent organisms that can reproduce on their own, viruses need to find a host in order to spread. Once a virus particle slips inside a host cell, it hijacks the cell’s machinery and starts churning out copies of itself. The new copies then travel throughout the body, infecting more cells.
All viruses need to keep replicating to continue the infection, so if you can block one of the steps in this replication process, then you can halt the infection. Antivirals don’t kill viruses outright; they just prevent the virus from replicating.
What’s tricky is targeting the virus during this process without also killing the cells where the virus resides. Antibiotics kill only bacterial cells, not human ones. But when developing antivirals, toxicity is always a concern.
“Finding the unique Achilles’ heel of the virus that we can exploit without affecting the host, that is really the major challenge for antiviral therapy,” Plemper says. Some do this by directly targeting a site on the virus. Others target human proteins that get commandeered in the viral replication process.
Another factor that makes antiviral development challenging is the timing of the drug. “Antiviral drugs need to be given very early, very rapidly after someone's been diagnosed,” says Lisa Gralinski, an assistant professor of epidemiology at the University of North Carolina at Chapel Hill, who’s been involved in lab tests of molnupiravir.
If the virus has already spread widely throughout the body, it can start inflicting serious damage. An antiviral can stop the virus, but it can’t reverse the damage that it’s already done to tissue. Patients have to be diagnosed quickly—within a few days of developing symptoms—making enrolling participants for clinical trials difficult. Many cases of COVID-19 are mild, and if patients aren’t very sick yet, they may not be motivated to volunteer for an experimental drug trial.
Currently, Gilead’s remdesivir is the only antiviral approved for COVID-19, and it’s given as an infusion to hospitalized patients. The drug hasn’t been shown to save lives, but it does shorten the recovery time for those who get better. But because of the unclear benefits, the World Health Organization has recommended against its use as a routine treatment. Gilead is looking to create an inhaled or pill version of remdesivir that patients could take at home.
If they work, antivirals could even be prescribed as a preventive measure to high-risk individuals exposed to COVID-19.
In the pipeline
Molnupiravir—originally invented at Emory University—got a head start in the antiviral race because researchers were already studying it against several viruses in the lab. Before the pandemic hit, Plemper had discovered that the drug inhibited influenza viruses, and researchers at the University of North Carolina at Chapel Hill found that it was effective against other coronaviruses like MERS and SARS.
“We had a strong inkling that it would work against SARS-CoV-2 because we already knew its mechanism of action,” Gralinski says.
Molnupiravir is a type of drug known as a nucleoside analog. It works by tricking the virus into making lots of mistakes, or mutations, in its genome when it replicates. The virus accumulates so many mutations that it can’t survive.
Last year, Miami-based Ridgeback Biotherapeutics licensed molnupiravir—then called EIDD-2801—for initial human safety trials. The company is now collaborating with Merck on larger studies to test the pill in both hospitalized and nonhospitalized COVID-19 patients. Last month, the companies stopped the trial of molnupiravir in hospitalized patients, saying that those individuals are unlikely to benefit from the drug.
Meanwhile, Atea Pharmaceuticals is also repurposing an antiviral. Its pill, called AT-527, was originally developed for the hepatitis C virus. Last month the company launched a Phase III trial to test the drug in 1,400 nonhospitalized patients with mild to moderate COVID-19.
Pfizer is taking a more tailored approach with its pill. In March of last year, the company formed a team to design a molecule to specifically fight SARS-CoV-2, says Charlotte Allerton, head of medicinal design at Pfizer. By July, the team had identified a promising molecule that it dubbed PF-07321332.
The drug blocks viral replication by binding to a viral enzyme called a protease. Known as protease inhibitors, these drugs have been effective at treating other viruses, such as HIV and hepatitis C, both alone and in combination with other antivirals.
This March, Pfizer began an early-stage trial to test the safety of the drug in healthy adults. Allerton says the company plans to recruit COVID-19 patients for efficacy studies by summer.
Since it acts directly on the virus, one concern with a protease inhibitor is that SARS-CoV-2 could become resistant to the drug if the targeted part of the virus mutates. Allerton says her team is tracking SARS-CoV-2 variants to look for mutations in the protease that could potentially make the drug less effective.
“While there are low levels of mutations reported, we're not currently expecting them to cause any issue in terms of the antiviral efficacy of our molecule,” she says.
Small biotech firms Selva Therapeutics and Clear Creek Bio are developing pills that may be able to evade drug resistance because they act on host cells rather than the virus. Selva’s drug, which it licensed from the University of California, San Diego, inhibits an enzyme found in human lungs and other cells to block viral entry. Clear Creek’s drug brequinar, which it acquired a few years ago from Bristol Myers Squibb, inhibits an enzyme that starves the virus of its ability to steal genetic material from the host cell, which it needs for replication.
“What really struck us when the pandemic emerged was the idea that this could be resistance resistant,” says Vikram Sheel Kumar, cofounder and CEO of Clear Creek Bio, which is based in Cambridge, Mass. The company began a mid-stage trial of brequinar in nonhospitalized patients in November.
Beyond COVID-19
Most available antivirals work only against a specific virus. But there’s hope for experimental drugs known as broad-spectrum antivirals, like molnupiravir, to be used against a wide range of viruses. Scientists see these drugs as the holy grail of antivirals because of their potential to treat future viruses that emerge. After all, SARS-CoV-2 is the third coronavirus outbreak in the past 20 years, and hundreds more coronaviruses are known to be circulating in bats and other animals.
“We don't want to imagine that possible fourth one coming, but it would be smart to be prepared for it and plan in advance,” Gralinski says. “If we have these broadly acting drugs available, or even ones that are most of the way through development and are ready for future testing, hopefully we could avoid another pandemic.”
A major reason why there were no antivirals ready to go when the COVID-19 pandemic hit was because no drugs for SARS or MERS had ever been developed. When those outbreaks were contained quickly, drug and vaccine development came to a virtual halt.
Whether COVID-19 antivirals will ever make it to the masses will depend on investment from the federal government and private industry. Operation Warp Speed provided an infusion of $18 billion into medical countermeasures against the pandemic, but the vast majority of that money went toward vaccine development. The Trump administration program didn’t invest in new antivirals.
In April 2020, the National Institutes of Health did launch an effort called Accelerating COVID-19 Therapeutic Interventions and Vaccines, or ACTIV, but that program has mostly focused on repurposing existing antivirals, not discovering new ones.
Ted Daley, CEO and cofounder of Selva Therapeutics in San Diego, says more investment in antivirals is needed to speed these drugs to patients.
“There’s certainly a common public health interest in supporting the development efforts of drugs that not only address the current public health crisis that we're in but could also be a tool in the arsenal next time one of these viruses pops up,” he says.
And Big Pharma has had little interest in developing antivirals beyond chronic infections like HIV. Most respiratory viruses cause mild illness, and infections clear up within a few days. The economics of antivirals for short-lived infections didn’t make sense.
“They want to make drugs for diabetes. They want to make drugs for hypertension. They want to make things that you will need forever, not something that you need for five days,” says Elizabeth Duke, an infectious disease physician and researcher at the Fred Hutchinson Cancer Research Center in Seattle who’s overseeing a trial there of molnupiravir.
But Duke thinks COVID-19 could be a turning point for the pharmaceutical industry. The pandemic has shown that respiratory viruses can be far more deadly than the flu or common cold. Even with effective vaccines, SARS-CoV-2 is likely here to stay. But antivirals could help reduce the virus from a deadly menace to a manageable infection that we could largely fight at home.