由于龐大的需求和超過(guò)7000萬(wàn)美國(guó)人的市場(chǎng),沒(méi)有一家制藥公司不夢(mèng)想著開(kāi)發(fā)出一種有效的減肥藥。
再生元(Regeneron)是一家總部位于紐約塔里敦的生物技術(shù)公司,市值高達(dá)600億美元,新冠疫情期間,該公司因?yàn)槠湫鹿谥委熆贵w而聲名大噪。7月1日,該公司宣布自己發(fā)現(xiàn)了罕見(jiàn)的基因突變,或?qū)⒛軌蛞源藶榛A(chǔ)開(kāi)發(fā)出相關(guān)減肥藥物。
在再生元基因中心(Regeneron Genetics Center)對(duì)美國(guó)、英國(guó)、墨西哥的64.6萬(wàn)名志愿者開(kāi)展的一項(xiàng)研究中,每3000人中約有1人出現(xiàn)了這種突變。具有這種罕見(jiàn)突變的個(gè)體都有一條無(wú)活性的GPR75基因;整體來(lái)看,與沒(méi)有此種突變的人群相比,他們的身體質(zhì)量指數(shù)(BMI)、平均體重、肥胖風(fēng)險(xiǎn)都相對(duì)較低,其中體重平均低12磅(約合5.44千克),肥胖風(fēng)險(xiǎn)低54%。
該公司在其專有的VelocImmune小鼠(一種經(jīng)過(guò)基因改造的小鼠,具有人類免疫系統(tǒng),因而可以更準(zhǔn)確地反映人類疾病)身上驗(yàn)證了這一發(fā)現(xiàn)。在喂食高脂肪食物的情況下,擁有GPR75基因的小鼠的體重增長(zhǎng)相較普通小鼠少44%。
該團(tuán)隊(duì)的發(fā)現(xiàn)[7月2日發(fā)表于《科學(xué)》(Science)]進(jìn)一步加深了人們對(duì)基因在肥胖生物學(xué)中所起作用的認(rèn)識(shí)。“對(duì)此發(fā)現(xiàn)的重要性再怎么強(qiáng)調(diào)都不過(guò)分。”再生元基因中心的負(fù)責(zé)人、再生元的高級(jí)副總裁阿里斯?巴拉斯在接受《財(cái)富》雜志采訪時(shí)說(shuō),“這不只是一項(xiàng)科學(xué)發(fā)現(xiàn),更為相關(guān)藥物的研發(fā)打開(kāi)了一扇大門(mén)。”
巴拉斯之所以信心十足,是因?yàn)榇朔N保護(hù)性突變?yōu)橄嚓P(guān)藥物開(kāi)發(fā)提供了思路,通過(guò)模仿遺傳效應(yīng),其團(tuán)隊(duì)有可能開(kāi)發(fā)出有效防治肥胖癥的藥物。“在我們了解到這些突變(發(fā)揮作用的原因)是使相關(guān)基因失活之后,只需思考如何開(kāi)發(fā)出能夠發(fā)揮相同作用的藥物即可。現(xiàn)在,我們極有可能在人類肥胖問(wèn)題的解決方面取得重大進(jìn)展。”
對(duì)再生元而言,找到基因靶點(diǎn)、并以之指導(dǎo)藥物開(kāi)發(fā)已經(jīng)被證明是一種行之有效的藥物研發(fā)策略。(《財(cái)富》雜志在2018年曾經(jīng)報(bào)道過(guò)該公司的相關(guān)工作。)截至目前,再生元基因中心已經(jīng)對(duì)超過(guò)100萬(wàn)個(gè)外顯子(基因組的蛋白質(zhì)編碼部分)進(jìn)行了測(cè)序,使該公司的科學(xué)家可以在這一龐大數(shù)據(jù)中發(fā)現(xiàn)GPR75這樣非常罕見(jiàn)的保護(hù)性突變。巴拉斯表示,自八年前再生元基因中心成立以來(lái),其團(tuán)隊(duì)已經(jīng)找到的此類突變有數(shù)十種。其中一種突變的發(fā)現(xiàn)為膽固醇藥物Evkeeza的研發(fā)奠定了基礎(chǔ),該藥物已經(jīng)于今年早些時(shí)候通過(guò)了美國(guó)食品與藥品監(jiān)督管理局(FDA)的審批,該公司還在以另一發(fā)現(xiàn)為基礎(chǔ)開(kāi)發(fā)某種慢性阻塞性肺病候選藥物,該藥物目前正在進(jìn)行三期臨床試驗(yàn)。
再生元將基于本次發(fā)現(xiàn)的靶點(diǎn)基因同時(shí)推進(jìn)多種肥胖癥療法研發(fā)路線,包括抗體藥物(該公司成名之本)、RNA干擾療法(該公司與行業(yè)先驅(qū)Alnylam制藥合作研發(fā)的各類基因沉默藥物)和傳統(tǒng)的小分子藥物(與另一企業(yè)合作完成)。巴拉斯說(shuō):“我們(在藥物研發(fā)方面)很少有如此巨大的投入,由此能夠看出我們對(duì)相關(guān)發(fā)現(xiàn)的看好程度,以及我們?yōu)殚_(kāi)發(fā)安全、有效的藥物所付出的努力。”
(雖然再生元與Intellia的合作備受關(guān)注,但巴拉斯指出,再生元不會(huì)在其肥胖治療項(xiàng)目中嘗試使用基因編輯技術(shù)。他解釋稱,就當(dāng)前階段而言,基因編輯技術(shù)最適合的應(yīng)用場(chǎng)景仍然是罕見(jiàn)疾病的治療,而非涉及成千上百萬(wàn)人的慢性疾病。Intellia是一家使用Crispr技術(shù)研發(fā)藥物的生物技術(shù)公司。)
市場(chǎng)對(duì)有效肥胖治療方法的需求顯而易見(jiàn)。根據(jù)美國(guó)疾病控制與預(yù)防中心(Centers for Disease Control and Prevention)的數(shù)據(jù),肥胖癥每年給美國(guó)衛(wèi)生系統(tǒng)造成的損失高達(dá)1470億美元,有42%的美國(guó)成年人正在忍受肥胖癥的影響。而在全球范圍內(nèi),肥胖癥的影響范圍也在日益擴(kuò)大。在美國(guó),目前只有少數(shù)幾種藥物獲準(zhǔn)用于治療肥胖癥,其中包括Wegovy,這是一種可以幫助控制體重的注射劑,6月初剛通過(guò)美國(guó)食品與藥品監(jiān)督管理局的審批,這也是自2014年以來(lái)首次有肥胖癥治療藥物獲準(zhǔn)上市。
巴拉斯指出,目前還很難預(yù)測(cè)該藥的研發(fā)時(shí)間,在全速推進(jìn)相關(guān)研發(fā)工作的同時(shí),再生元還將對(duì)GPR75保護(hù)性突變進(jìn)行后續(xù)研究,包括對(duì)新陳代謝和食欲的進(jìn)一步研究等。該公司還與擁有該突變的228名受試志愿者保持著聯(lián)系。
至于該種預(yù)防肥胖突變是否會(huì)在其它方面給個(gè)體造成傷害,巴拉斯表示尚未看到任何相關(guān)證據(jù)。他說(shuō):“我們會(huì)非常仔細(xì)地觀察這些個(gè)體,評(píng)估其健康是否因?yàn)樵摶驔](méi)有活性而受到不利影響,但就目前來(lái)看,這些人的身體都比較健康,身材也比較苗條。”巴拉斯稱,這些人雖然人數(shù)不多,但代謝狀況都相對(duì)較好,糖尿病發(fā)病率也相對(duì)較低。他預(yù)計(jì),隨著研究的進(jìn)一步深入,數(shù)據(jù)的不斷增加,我們將會(huì)清楚看到這些人罹患其它與肥胖相關(guān)的慢性疾病(例如心血管疾病、脂肪肝)的概率也會(huì)相對(duì)較低。
蓋辛格醫(yī)學(xué)中心肥胖研究所(Geisinger Obesity Research Institute at Geisinger Medical Center)是再生元的合作伙伴之一,該中心的主任克里斯托弗?D?斯蒂爾說(shuō):“這一發(fā)現(xiàn)或?qū)⒏淖冋麄€(gè)行業(yè)的游戲規(guī)則,改善成百上千萬(wàn)肥胖癥患者的生活質(zhì)量和健康水平,讓他們能夠長(zhǎng)期保持較好身材,不再為體重反彈所困擾。”(財(cái)富中文網(wǎng))
譯者:梁宇
審校:夏林
由于龐大的需求和超過(guò)7000萬(wàn)美國(guó)人的市場(chǎng),沒(méi)有一家制藥公司不夢(mèng)想著開(kāi)發(fā)出一種有效的減肥藥。
再生元(Regeneron)是一家總部位于紐約塔里敦的生物技術(shù)公司,市值高達(dá)600億美元,新冠疫情期間,該公司因?yàn)槠湫鹿谥委熆贵w而聲名大噪。7月1日,該公司宣布自己發(fā)現(xiàn)了罕見(jiàn)的基因突變,或?qū)⒛軌蛞源藶榛A(chǔ)開(kāi)發(fā)出相關(guān)減肥藥物。
在再生元基因中心(Regeneron Genetics Center)對(duì)美國(guó)、英國(guó)、墨西哥的64.6萬(wàn)名志愿者開(kāi)展的一項(xiàng)研究中,每3000人中約有1人出現(xiàn)了這種突變。具有這種罕見(jiàn)突變的個(gè)體都有一條無(wú)活性的GPR75基因;整體來(lái)看,與沒(méi)有此種突變的人群相比,他們的身體質(zhì)量指數(shù)(BMI)、平均體重、肥胖風(fēng)險(xiǎn)都相對(duì)較低,其中體重平均低12磅(約合5.44千克),肥胖風(fēng)險(xiǎn)低54%。
該公司在其專有的VelocImmune小鼠(一種經(jīng)過(guò)基因改造的小鼠,具有人類免疫系統(tǒng),因而可以更準(zhǔn)確地反映人類疾病)身上驗(yàn)證了這一發(fā)現(xiàn)。在喂食高脂肪食物的情況下,擁有GPR75基因的小鼠的體重增長(zhǎng)相較普通小鼠少44%。
該團(tuán)隊(duì)的發(fā)現(xiàn)[7月2日發(fā)表于《科學(xué)》(Science)]進(jìn)一步加深了人們對(duì)基因在肥胖生物學(xué)中所起作用的認(rèn)識(shí)。“對(duì)此發(fā)現(xiàn)的重要性再怎么強(qiáng)調(diào)都不過(guò)分。”再生元基因中心的負(fù)責(zé)人、再生元的高級(jí)副總裁阿里斯?巴拉斯在接受《財(cái)富》雜志采訪時(shí)說(shuō),“這不只是一項(xiàng)科學(xué)發(fā)現(xiàn),更為相關(guān)藥物的研發(fā)打開(kāi)了一扇大門(mén)。”
巴拉斯之所以信心十足,是因?yàn)榇朔N保護(hù)性突變?yōu)橄嚓P(guān)藥物開(kāi)發(fā)提供了思路,通過(guò)模仿遺傳效應(yīng),其團(tuán)隊(duì)有可能開(kāi)發(fā)出有效防治肥胖癥的藥物。“在我們了解到這些突變(發(fā)揮作用的原因)是使相關(guān)基因失活之后,只需思考如何開(kāi)發(fā)出能夠發(fā)揮相同作用的藥物即可。現(xiàn)在,我們極有可能在人類肥胖問(wèn)題的解決方面取得重大進(jìn)展。”
對(duì)再生元而言,找到基因靶點(diǎn)、并以之指導(dǎo)藥物開(kāi)發(fā)已經(jīng)被證明是一種行之有效的藥物研發(fā)策略。(《財(cái)富》雜志在2018年曾經(jīng)報(bào)道過(guò)該公司的相關(guān)工作。)截至目前,再生元基因中心已經(jīng)對(duì)超過(guò)100萬(wàn)個(gè)外顯子(基因組的蛋白質(zhì)編碼部分)進(jìn)行了測(cè)序,使該公司的科學(xué)家可以在這一龐大數(shù)據(jù)中發(fā)現(xiàn)GPR75這樣非常罕見(jiàn)的保護(hù)性突變。巴拉斯表示,自八年前再生元基因中心成立以來(lái),其團(tuán)隊(duì)已經(jīng)找到的此類突變有數(shù)十種。其中一種突變的發(fā)現(xiàn)為膽固醇藥物Evkeeza的研發(fā)奠定了基礎(chǔ),該藥物已經(jīng)于今年早些時(shí)候通過(guò)了美國(guó)食品與藥品監(jiān)督管理局(FDA)的審批,該公司還在以另一發(fā)現(xiàn)為基礎(chǔ)開(kāi)發(fā)某種慢性阻塞性肺病候選藥物,該藥物目前正在進(jìn)行三期臨床試驗(yàn)。
再生元將基于本次發(fā)現(xiàn)的靶點(diǎn)基因同時(shí)推進(jìn)多種肥胖癥療法研發(fā)路線,包括抗體藥物(該公司成名之本)、RNA干擾療法(該公司與行業(yè)先驅(qū)Alnylam制藥合作研發(fā)的各類基因沉默藥物)和傳統(tǒng)的小分子藥物(與另一企業(yè)合作完成)。巴拉斯說(shuō):“我們(在藥物研發(fā)方面)很少有如此巨大的投入,由此能夠看出我們對(duì)相關(guān)發(fā)現(xiàn)的看好程度,以及我們?yōu)殚_(kāi)發(fā)安全、有效的藥物所付出的努力。”
(雖然再生元與Intellia的合作備受關(guān)注,但巴拉斯指出,再生元不會(huì)在其肥胖治療項(xiàng)目中嘗試使用基因編輯技術(shù)。他解釋稱,就當(dāng)前階段而言,基因編輯技術(shù)最適合的應(yīng)用場(chǎng)景仍然是罕見(jiàn)疾病的治療,而非涉及成千上百萬(wàn)人的慢性疾病。Intellia是一家使用Crispr技術(shù)研發(fā)藥物的生物技術(shù)公司。)
市場(chǎng)對(duì)有效肥胖治療方法的需求顯而易見(jiàn)。根據(jù)美國(guó)疾病控制與預(yù)防中心(Centers for Disease Control and Prevention)的數(shù)據(jù),肥胖癥每年給美國(guó)衛(wèi)生系統(tǒng)造成的損失高達(dá)1470億美元,有42%的美國(guó)成年人正在忍受肥胖癥的影響。而在全球范圍內(nèi),肥胖癥的影響范圍也在日益擴(kuò)大。在美國(guó),目前只有少數(shù)幾種藥物獲準(zhǔn)用于治療肥胖癥,其中包括Wegovy,這是一種可以幫助控制體重的注射劑,6月初剛通過(guò)美國(guó)食品與藥品監(jiān)督管理局的審批,這也是自2014年以來(lái)首次有肥胖癥治療藥物獲準(zhǔn)上市。
巴拉斯指出,目前還很難預(yù)測(cè)該藥的研發(fā)時(shí)間,在全速推進(jìn)相關(guān)研發(fā)工作的同時(shí),再生元還將對(duì)GPR75保護(hù)性突變進(jìn)行后續(xù)研究,包括對(duì)新陳代謝和食欲的進(jìn)一步研究等。該公司還與擁有該突變的228名受試志愿者保持著聯(lián)系。
至于該種預(yù)防肥胖突變是否會(huì)在其它方面給個(gè)體造成傷害,巴拉斯表示尚未看到任何相關(guān)證據(jù)。他說(shuō):“我們會(huì)非常仔細(xì)地觀察這些個(gè)體,評(píng)估其健康是否因?yàn)樵摶驔](méi)有活性而受到不利影響,但就目前來(lái)看,這些人的身體都比較健康,身材也比較苗條。”巴拉斯稱,這些人雖然人數(shù)不多,但代謝狀況都相對(duì)較好,糖尿病發(fā)病率也相對(duì)較低。他預(yù)計(jì),隨著研究的進(jìn)一步深入,數(shù)據(jù)的不斷增加,我們將會(huì)清楚看到這些人罹患其它與肥胖相關(guān)的慢性疾病(例如心血管疾病、脂肪肝)的概率也會(huì)相對(duì)較低。
蓋辛格醫(yī)學(xué)中心肥胖研究所(Geisinger Obesity Research Institute at Geisinger Medical Center)是再生元的合作伙伴之一,該中心的主任克里斯托弗?D?斯蒂爾說(shuō):“這一發(fā)現(xiàn)或?qū)⒏淖冋麄€(gè)行業(yè)的游戲規(guī)則,改善成百上千萬(wàn)肥胖癥患者的生活質(zhì)量和健康水平,讓他們能夠長(zhǎng)期保持較好身材,不再為體重反彈所困擾。”(財(cái)富中文網(wǎng))
譯者:梁宇
審校:夏林
With epidemic-level need and a market of more than 70 million Americans, what pharma company hasn’t dreamed of developing an effective obesity pill?
On July 1, Regeneron, the $60 billion Tarrytown, N.Y., biotech, perhaps best known for its COVID-treating antibody, announced its discovery of rare genetic mutations that it hopes will make such therapeutics possible.
The mutations, which appear to protect against obesity, occurred in about 1 out of 3,000 people in the Regeneron Genetics Center (RGC) study, which included 646,000 volunteers in the U.S., the U.K., and Mexico. Individuals with the rare mutations have one inactive copy of the GPR75 gene; as a group, they had lower weights (by an average of 12 pounds), lower body mass indexes (BMIs), and a 54% reduced risk of obesity compared with people without the mutation.
The company validated its findings in its proprietary VelocImmune mice (they are genetically modified to have human immune systems and so more accurately reflect human disease). When fed a high-fat diet, the animals with an inactivated GPR75 gene gained 44% less weight.
The team’s findings, which were published on July 2 in Science, adds to the still-forming understanding about the role genes play in the biology of obesity. “I can’t stress enough how significant the finding is,” said Aris Baras, head of the RGC and a senior vice president at Regeneron, in an interview with Fortune. “This is not just a science discovery story. This is a drug discovery and development story.”
That’s because the protective mutation also provides clues as to how one could develop effective obesity drugs: by mimicking the genetic effect. “Once we knew these mutations basically inactivate or knock out this gene, GPR75, we can think about how do we make medicines that inactivate that target. There’s a really high likelihood now we can have a big effect on people’s obesity.”
Identifying genetic targets to guide—and speed—drug development is at this point a tried-and-true strategy for Regeneron. (Fortune wrote about the effort in 2018.) The company’s RGC has sequenced more than a million exomes (the protein-encoding part of the genome), allowing its scientists to find in that vast data set very rare protective mutations, as with GPR75. Baras says his team has identified a couple dozen of them since the RGC was founded eight years ago. One led to the development of Evkeeza, a cholesterol drug that was approved by the FDA earlier this year; another was the basis for a drug candidate to treat chronic obstructive pulmonary disease, currently in Phase III trials.
For its most recently discovered target and obesity-treating therapeutics, Regeneron is pursuing multiple strategies, including antibody drugs (which the company is best known for); RNA interference therapeutics (drugs that silence genes, which the company has been pursuing in partnership with industry pioneer Alnylam), and traditional small-molecule drugs (through another partnership). “It’s pretty unusual for us to throw so much at this,” said Baras. “It gives you a sense of how excited we are about this, and the level of commitment we’re putting behind making a safe and effective therapeutic.”
(Though Regeneron also has a much-in-the-news collaboration with Intellia, a biotech using Crispr to develop drugs, Baras noted Regeneron will not be trying gene editing in its obesity program. That’s a still developing technology best for treating rare diseases—and not millions of people suffering from a chronic condition—at this stage, he explained.)
Certainly, effective treatments for obesity are sorely needed. According to the Centers for Disease Control and Prevention, the condition costs the U.S. health system $147 billion every year and affects 42% of American adults. It’s of course a fast-growing issue globally too. Only a handful of drugs are approved to treat obesity in the U.S. One of them, Wegovy, an injection to help with weight management, got the FDA’s nod early June, the first since 2014.
Baras says Regeneron’s development timeline is hard to predict at this point. As the company moves full speed ahead on development, it will also be doing follow-up studies prompted by its discovery of the GPR75 protective mutation, including more research on metabolism and appetite, said Baras. The company also has access to the 228 volunteers in its study who have the mutation.
As to the question of whether having the mutation that protects against obesity might harm individuals in another way, Baras hasn’t seen any evidence of that. “We look very carefully to see if there’s anything concerning that these individuals may have because of their inactive genes,” he said. “But these folks are just healthy lean.” Baras noted the population, though small, also had a better metabolic profile, with lower rates of diabetes. He expects that with additional study and data gathering it will become clear that these individuals have lower rates of other chronic disease associated with obesity, including cardiovascular and fatty liver diseases.
“This is a potentially game-changing discovery that could improve the lives and health of millions of people dealing with obesity, for whom lasting interventions have often been elusive,” said Christopher D. Still, director for the Geisinger Obesity Research Institute at Geisinger Medical Center, one of Regeneron’s partners in the study.