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前言 自免靶点药物是指针对自身免疫性疾病的药物，这些药物通过作用于相关的生物靶点来调节免疫系统的功能。近年来，随着对自身免疫疾病机制的深入理解，这一领域的药物开发取得了显著进展。 前有阿达木单抗登顶“药王”，现有度普利尤单抗强势增长，自免药物市场方兴未艾，药企纷纷加注潜力靶点，一场治愈自身免疫性疾病的竞赛正在热火朝天地开展。 自免赛道 千亿级蓝海市场 尽管肿瘤是第一大疾病领域，市场空间广阔，但由于抗肿瘤新药研发风险大、成本高，再加上全球药企的争相涌入、同质化问题凸显，早已是红海竞争。 事实上，仅次于肿瘤赛道的自身免疫赛道市场蛋糕也不小。根据弗若斯特沙利文数据，2022年全球自免药物市场规模约1323亿美元，预计至2030年全球市场规模将达到1767亿美元。 自免疾病领域不仅市场增速快，而且时常见证多个“百亿美元分子”重磅药物的诞生。2023年全球药品销售额TOP10中，3款为自免类药物，合计销售额达484亿美元，包括赛诺菲/再生元的Dupixent，艾伯维的Humira，强生的Stelara。 图：2023年全球药品销售额TOP10药物 自免疾病靶向制剂 自身免疫性疾病（AID）是由于机体免疫系统错误地攻击正常细胞而引起的一类疾病。常见的自身免疫性疾病包括类风湿关节炎、系统性红斑狼疮、多发性硬化症等。研究表明，炎症因子的异常表达在这些疾病的发生和发展中起着关键作用。 自身免疫疾病的治疗，过去主要是非甾体抗炎药、传统改善病情抗风湿药、糖皮质激素等传统的抗炎治疗。随着医学技术的持续发展，目前自免疾病领域常用的创新药已经转变为创新靶向制剂，也就是抗TNF（肿瘤坏死因子）制剂、抗IL（白介素）制剂和JAK1抑制剂等。 表：传统抗炎药和创新药针对自免疾病的治疗现状对比 实际上，在自免领域，无论是大分子还是小分子领域已经涌现出不少科学家持续探索，热门靶点更是有不少药企角逐亮相。一起来了解当下的热门药物靶点。 表：自身免疫疾病热门靶点 主要靶点及相关药物 01. TNF相关 TNF-α是一种主要的促炎细胞因子，靶向TNF-α的单克隆抗体，如英夫利昔单抗（Infliximab）和阿达木单抗（Adalimumab），已经在多种自身免疫疾病中取得了良好的临床效果。 TNF-α和TNFR结合，通过激活下游信号通路发挥调控作用。TNF-α不适当或过度激活与慢性炎症有关，并导致自身免疫性疾病如类风湿关节炎、炎症性肠病、银屑病和非感染性葡萄膜炎的发展。 目前，国内已有多款靶向TNF-α的药物获批上市(详见下表)，此外，还有一些TNF-α抑制剂药物正处于临床试验阶段。 OX40信号通路在多种免疫相关疾病中扮演了重要角色，OX40是一种属于肿瘤坏死因子受体（TNFR）超家族的共刺激分子，OX40通过与OX40L结合导致T细胞活化以及效应功能增强。OX40/OX40L阻断可改善自身抗原特异性T细胞反应并降低自身免疫性疾病中的免疫活性。因此，阻断 OX40/OX40L通路对于治疗自身免疫性疾病具有重要意义。 目前正在针对OX40或OX40L自免领域的临床试验中，进度较快的分别是安进/协和麒麟的rocatinlimab，及赛诺菲的amlitelimab。 此外，TNF家族成员TL1A/DR3信号在黏膜免疫中扮演关键角色，影响T细胞亚群如Th1、Th2、Th17和Th9，以及调节性淋巴细胞和ILC2、ILC3。而阻断TL1A可能对多种由不同T效应免疫表型主导的慢性炎症性疾病具有治疗价值。临床已验证其可用于炎症性肠病（IBD）治疗。 目前，全球正在研发的TL1A项目中临床开发进度最快的是罗氏TL1A抗体RVT-3101和默沙东以108亿美元现金收购Prometheus的MK-7240，均已进入临床Ⅲ期。 近两年，多家MNC巨头已完成针对TL1A靶点的交易。2024年6月，艾伯维宣布获得明济生物TL1A抗体FG-M701的全球开发、生产和商业化的独家许可权，交易额高达17.1亿美元。由此可见，TL1A靶点已成为自身免疫和IBD领域中的热门研究焦点。 吉满生物推出（☞点击靶点，了解更多产品详情）TNF-α/OX40/TL1A一系列工程化改造的稳定表达/功能检测细胞系、抗体及蛋白相关产品助力药物研发，详情咨询吉满客服联系同微信：18916119826！ 02. 白介素靶点 多个药物上市，研究前景广泛 自免行业的白介素靶点主要包括IL-17、IL-23、IL-2、IL-6等。白介素靶向药物最主要针对的适应症是银屑病，在银屑病领域头对头击败TNF-α单抗。自免药物包括靶向IL-6的托西利珠单抗、靶向IL-12/23的乌司奴单抗、靶向IL-17A的司库奇尤单抗和靶向IL-23的古塞奇尤单抗。 IL-17 IL-17细胞因子，包括IL-17A和IL-17F，在IBD的发病机制中发挥重要作用。目前，全球共上市5款靶向IL-17A/IL-17RA药物，即司库奇尤单抗、依奇珠单抗、尼塔奇单抗、布罗利尤单抗和比吉利珠单抗。其中，司库奇尤单抗、依奇珠单抗和布罗利尤单抗已在国内获批，比吉利珠单抗也已在国内申报上市。截至目前，国内IL-17靶点药物适应症以银屑病、强直性脊柱炎和中轴型脊柱关节炎为主。 近期，FDA刚批准IL-17A/IL-17F抑制剂Bimzelx用于治疗活动性银屑病关节炎（PsA）成人患者、有客观炎症症状的活动性非放射学中轴型脊柱关节炎（nr-axSpA）成人患者以及活动性强直性脊柱炎（AS）成人患者。该药物是第一个被批准用于治疗这三种适应症的IL-17A/IL-17F抑制剂（PsA、nr-axSpA、AS）。 IL-12/IL-23 由树突状细胞产生的IL-12和IL-23均属于IL-12家族，在慢性炎症性疾病的发病机制中发挥重要作用。IL-23和IL-12共用p40亚基，但IL-23更广泛地参与自身免疫性疾病的发病机制。通过靶向IL-12/IL-23p40或IL-23p19，可以阻断IL-23信号。IL-23的阻断可有效治疗银屑病和PsA。 目前全球有4种IL-23抗体药物获批，分别为乌司奴单抗、古塞奇尤单抗、替拉珠单抗及瑞莎珠单抗，其中前3款药物已在国内获批，瑞莎珠单抗在国内的上市申请已获批受理。 9月26日，CDE官网显示，信达生物自研的1类新药—重组抗白介素23p19亚基（IL-23p19）抗体匹康奇拜单抗申报上市，用于治疗中重度斑块状银屑病。该药物是首款递交上市申请的由中国企业自主研发的IL-23p19靶向药物。 IL-2 IL-2最早于1976年被发现，事实上已经是一个比较成熟的抗癌靶点。IL-2是对免疫系统具有多效作用的关键细胞因子之一。IL-2通过与其受体结合，发挥信号调节作用。IL-2与IL-2R亲和力的不同，决定了不同的下游信号传导，影响了最终塑造效应T细胞、Treg细胞，NK细胞等细胞的功能活性，这也为免疫相关疾病的治疗提供了重要思路。 图：IL-2在免疫反应中的作用 20世纪90年代，许多企业开始发力工程化IL-2，改变IL-2与不同受体亚单位的亲和力，从而增加活力，降低毒性，主要类型包括IL-2 muteins，聚乙二醇化IL-2，IL-2-抗IL-2免疫复合体和IL2-CD25融合蛋白。从工程化IL-2全球进展来看BMS、赛诺菲、罗氏等纷纷在这一领域布局。在国内，针对IL-2靶点的布局，以恒瑞医药（SHR-1916和RS2102）、信达生物IBI363、君实生物LTC002等为代表。 吉满生物推出（☞点击靶点，了解更多产品详情）IL-5/IL-12/IL-17/IL-2/IL-23一系列工程化改造的稳定表达/功能检测细胞系、抗体及蛋白相关产品助力药物研发，详情咨询吉满客服联系同微信：18916119826！ 03.B细胞相关 针对B细胞的靶点包括CD20、补体系统以及FcRn等。其中CD20蛋白位于B细胞质膜表面，针对CD20的抗体能直接诱导免疫系统对于B细胞的杀伤，在血液瘤和自身免疫病治疗中有广泛应用。FcRn位于内皮细胞表面，能够结合并延长引起自身免疫性疾病的抗体的半衰期。通过单抗靶向补体系统的蛋白，可以减少补体系统对自身组织细胞的杀伤。 CD3 CD3蛋白是一种存在于人类T细胞和B细胞表面的蛋白质。在T细胞识别和应答外来抗原的过程中起着重要作用，是T细胞免疫应答的关键组成部分。 图：TCR-CD3 蛋白复合物 CD3重磅交易 CD3 抗体以及相关的生物制剂在肿瘤免疫治疗方面展现出了良好的前景。另一方面，扩展到自免疾病这一更广大的市场。近期嘉和生物GB261、同润生物CN201纷纷出海也再次验证了这款靶点的巨大潜力。8月5日，嘉和生物就CD20/CD3双抗GB261与TRC 2004达成4.5亿美元加股权的海外授权协议，双方合作将主要集中探索GB261在自免疾病方面的潜力，嘉和当日涨幅便11.57%。 CD20 CD20属于跨膜4结构域家族A（MS4A）蛋白家族，分子量为33-37KDa的非糖基化蛋白。 CD20仅在pro-B细胞到记忆B细胞谱系中表达，不在浆细胞中表达。过去几十年，抗CD20疗法一直是B细胞耗竭的主要工具。 CD20因其治疗领域的广泛性，不仅拥有B细胞肿瘤治疗研发者的爱戴，又得到自体免疫开发者的青睐。自1997年利妥昔单抗上市以来，抗CD20单抗发展迅速，已经出现了大量相关靶点的新药及仿制药。目前以此为靶点的单抗包括利妥昔单抗（商品名：美罗华）、替伊莫单抗（商品名：泽娃灵）、托西莫单抗（商品名：BEXXAR）、奥法木单抗（商品名：Arzerra）、奥瑞珠单抗（商品名：Ocrevus）以及奥妥珠单抗（商品名：Gazyva）。治疗的领域包括淋巴瘤、白血病和某些自体免疫疾病等。 FcRn FcRn是一种位于细胞膜表面的IgG抗体受体，主要在内皮细胞中表达。FcRn通过结合IgG的Fc部分，阻止IgG在体内的自然代谢，延长了IgG的作用时间。通过靶向FcRn的药物可以促进IgG降解，起到治疗自身免疫疾病的效果。目前该类药物主要应用于重症肌无力治疗。 目前，全球已有两款FcRn单抗获得FDA批准上市：Argenx/再鼎的efgartigimod和优时比的rozanolixizumab，均已获批重症肌无力适应症。还有一些 FcRn 靶点抗体类药物也在临床试验进程中，据不完全统计，目前进展靠前的在研FcRn药物具体信息总结如下： 2024年7月25日，Argenx发布二季度财报，FcRn靶向Efgartigimod加速放量，二季度销售额4.78亿美元，同比增长78%，环比增长20%！ 吉满生物推出（☞点击靶点，了解更多产品详情）CD3/CD20/FcRn一系列工程化改造的稳定表达/功能检测细胞系、抗体及蛋白相关产品，充分满足药物研发需求，助力药物临床申报。（具体请咨询吉满客服联系同微信：18916119826） 04.激酶靶向 JAK家族的酪氨酸激酶（如JAK1、JAK2、JAK3及TYK2）在多种细胞因子信号传导中起关键作用，尤其是在自身免疫疾病中。JAK抑制剂（如托法替尼、巴瑞替尼等）已经被批准用于类风湿关节炎和其他多种自身免疫疾病的治疗。 截至2023年11月底，全球共有14款JAK抑制剂新药获批上市，乌帕替尼（JAK1）、托法替布（泛JAK）两大单品在AS/IBD/RA/PsA/JIA等自免类大适应症领域均有所布局，其余产品主要集中覆盖IBD、RA、皮炎、骨髓纤维化等领域。国内管线中，江苏恒瑞的艾玛昔替尼（JAK1）针对AS与RA的适应症已分别于2023年8及2023年11月申报NDA，泽璟生物的杰克替尼（JAK1/JAK2/ALK2）针对RA适应症的管线已进入III期临床，凌科药业、无锡福祈与杭州高光针对RA布局的管线也均进入III期临床。 除JAK抑制剂外，布鲁顿酪氨酸激酶（BTK）抑制剂也有望通过调节 B 细胞功能来改善自身免疫性炎症。目前正在研究BTK抑制剂在各种自身免疫性疾病中的应用，包括 RA、MS、pSS 和SLE。 总结 白介素与JAK逐渐替代TNF-α，成为新一代自免药品布局的热门靶点。2021年至今，有多款JAK抑制剂集中获批上市，自免药物领域延续高景气发展态势，靶点布局呈现明显代际。 图源：Insight、开源证券研究所 随着对自身免疫疾病机制的进一步理解，新的靶点和治疗策略不断涌现。未来的研究方向包括： 发现新的生物标志物以指导治疗 开发新型靶向药物，尤其是针对尚未有效治疗的疾病表型 结合多种治疗机制改善患者的治疗反应和生活质量 总之，自免靶点药物的研究与开发代表了自身免疫性疾病治疗领域的重要进展，期待未来将继续推动个体化治疗的发展和新的靶点发现，以改善患者的治疗效果和生活质量。 联系我们 吉满生物助力药物研发，紧随前沿靶点资讯，储备几百株现货细胞，覆盖GPCR、细胞因子、免疫检查点、TAA等多领域，截止当前已布局近300个热门靶向药靶点，1000余株细胞系，旨在助力、加速大分子早期研发，做到进口细胞的国产替代。同时可根据客户需求提供细胞系服务。自免热门代表性产品如下，具体请咨询吉满客服联系同微信：18916119826。 扫码咨询 扫码找现货

Dedicated to the memory of Natalie Grover, who co-created the Women in Biopharma R&D special report while she was a reporter at Endpoints from 2018-2020. Natalie passed away earlier this year, but part of her legacy lives on through this project. When Natalie Grover and Amber Tong launched Endpoints News’ Women in Biopharma R&D report in 2019, they set a few key ground rules. They decided to give equal airtime to honorees’ R&D accomplishments and their experience as women leaders; to not shy away from hard questions; and to try their best to bring these women the recognition they deserve. Natalie’s indignation at gender inequality, her passionate belief in change, and her love of a good story set the tone for what has become a beloved annual tradition. We have now celebrated more than 120 women breaking boundaries in biopharma R&D. Natalie and Amber’s vision has transformed into a newsroom-wide effort involving more than 17 reporters and editors. We’re pleased to introduce you to 20 women driving change in 2024. Thank you for continuing the tradition with us. — Amber Tong and Nicole DeFeudis Annaliesa Anderson helped steer Pfizer’s RSV vaccine efforts, setting the company up for success in a burgeoning market that’s caught a lot of attention. But she actually got her start in bacteria, not viruses. Growing up in England, Anderson said there wasn’t much to do during summers off from school. But as a 12-year-old at her cousin’s house, she watched a TV show describing how people could use yeast to make human growth hormone and it just hooked her. “I just thought that was the coolest thing,” Anderson said. “The fact that people think about bugs and organisms as things that are bad, but you could actually make them do things that were good. That was my first kind of, ‘Oh, this looks like something I’m interested in.’” While yeast is technically a fungus, the TV program started Anderson on a path down learning about the ins and outs of microbiology. Her sense of direction led to, eventually, becoming the head of vaccine R&D at Pfizer, whose RSV shot Abrysvo exceeded sales expectations in 2023 with $890 million in its first season. Originally interested in how bacteria and other microorganisms could help prevent pollution, Anderson shifted to biomedical research while doing her PhD, looking into how bacteria can make molecules that interact with other bacteria. The research helped lead to her first job at Merck, where she ran a lab tasked with finding new ways of making drugs from bacteria. As she continued working with bacteria, however, she began developing more interest in the biology of drug discovery. “What I noticed was, you’re there in your lab, making all these new molecules. But your molecule’s only interesting if it fits with a biological purpose,” Anderson said. Soon, Anderson was asked to join Merck’s vaccines organization and found it a natural pairing. Even though she didn’t know much about vaccines at the time, her colleagues needed her expertise to understand how bacteria were causing certain infections. She said the experience of pointing the team to the right target antigen helped her realize she enjoyed being able to apply her knowledge to a more hands-on environment. “It fit more with my sense of curiosity and problem solving, because ultimately, what is science?” Anderson said. “It’s solving problems, and that’s what I like to do.” Anderson stayed at Merck for nearly 10 years, mainly in the early-phase space, before moving to Pfizer, where she worked on the Prevnar pneumococcal, meningitis B and C. difficile vaccines. She didn’t move to viruses until the Covid-19 pandemic. When her boss who had recruited her to Pfizer, Kathrin Jansen, announced her retirement, Anderson inherited the vaccines leadership position and began overseeing RSV work. Following its strong first season, Abrysvo is expected to continue to compete with GSK’s Arexvy and Moderna’s mResvia as the companies look to expand their labels into younger populations and for use during pregnancy. When it comes to improving gender balance in the workplace, Anderson said the struggles biopharma faces are similar to most other industries. She began to notice it more, especially as she continued ascending through the ranks, noting that at universities, the gender split in biological science degrees is roughly 50-50. The same is true for many entry-level jobs at Pfizer, she said. But her biggest piece of advice for women who want to pursue careers in biopharma is to not let other people define who you are. “Most people, especially women, often bring more to the table than they realize. And so I think that that’s an important lesson,” Anderson said. — Max Gelman Allison August knew she wanted to make a difference. “I grew up in a household where the ethos was you had a responsibility in repairing the world a little,” she said. August carried that motto with her, from 20 years in gynecology and obstetrics to her work on Moderna’s Phase 3 trials for a Covid-19 vaccine during the global pandemic. Yet throughout her vast and varied career, one condition kept cropping up: preeclampsia, a form of high blood pressure in pregnant women that can lead to premature birth. Her interest was sparked during her medical studies at the University of Chicago. The school building has five plaques for physicians in women’s health. Four are filled, but the fifth is left blank and is dedicated to a future scientist who develops a cure for preeclampsia. During her work as a gynecologist, August routinely diagnosed women, in some cases who were 30 weeks pregnant or earlier. “Obstetrics and gynecology has been a field where there has been potentially less true innovation,” August said. “If you look at the way that preeclamptic patients are managed today, as compared with 100 years ago, it really hasn’t changed.” Fast forward two decades, and she is now fully focused on developing a treatment for preterm preeclampsia in her role at Comanche Biopharma. The company won the FDA’s fast track designation last August for its Phase 1 lead candidate, an siRNA investigational drug injected into patients. “That’s really what drew me to Comanche, is that we know that there are several approved siRNA-based therapeutics. But part of what’s unique here is that this asset is targeted and specifically delivered to the placenta,” August said. August also hopes Comanche will be a template and a model for how clinical studies should be conducted in pregnant women. She said researchers should be mindful of the pregnant individual as well as the fetus. It’s a major unmet need, August said. Globally, preeclampsia causes around 80,000 maternal and more than 500,000 fetal and newborn deaths each year. Mortality rates due to preeclampsia in maternal women are rising in the US, she said, in part due to rising rates of general hypertension and diabetes, which can go hand in hand with preeclampsia. August describes her work as a “full circle” moment after starting her career as an obstetrician gynecologist. “There’s no shortage of issues that need to be addressed. It really needs to be rooted in that basic science. I think that’s what differentiates Comanche; they get how powerful this potentially can be,” she said. — Anna Brown Sharon Barr always wanted her science to lead to new medicines. She kicked off her career as a postdoctoral fellow in molecular pharmacology at Stanford University, but later realized that she might be able to reach her goal faster in the pharmaceutical industry. “The timeline would be very compressed,” she told Endpoints News . In 2005, Barr landed her “dream job” as a research scientist at the biotech company OSI Pharmaceuticals, which had an EGFR kinase inhibitor on the market for non-small cell lung cancer dubbed Tarceva. The company didn’t know where to take the drug next, and it was up to Barr and a handful of other scientists to form a translational research team and find out. During this period, Barr said she was learning about how drugs are created, what questions have to be asked and answered during their development, and the unknowns that remain once they’re in the clinic. Astellas acquired OSI in 2010, and Barr remained at the company’s oncology unit for almost a decade. Then, in 2013, she found herself at a “career juncture,” with several job opportunities in oncology and one in a completely different area: rare diseases. “I thought, ‘If I go work in rare disease, I’m going to have to learn new modalities, build a new network, learn new pathways, completely reboot my understanding of biology,’” Barr said. “That sounds really hard, so I think I want to do it.” Barr joined Alexion Pharmaceuticals in July of that year, starting off as a director in translational medicine and cycling through various roles over a period of eight years. There, she gained a deeper understanding of how to tailor R&D to the needs of specific disease communities after meeting patients with fibrodysplasia ossificans progressiva, a debilitating neuromuscular condition in which muscle tissue and connective tissue gradually ossify to bone. “They might care more about upper body strength than they do about the six-minute walk test, because they want to be able to feed themselves more than they want to be able to walk downstairs,” Barr said. “It changed the way I think about creating new medicines.” In 2021, AstraZeneca snapped up Alexion for $39 billion, and Barr was heading up the UK drugmaker’s biopharmaceuticals R&D unit just two years later. Now, she applies the learnings from rare diseases to much larger, more chronic conditions, spanning therapeutic areas from cardiometabolic to immunology. She is one member of a team of senior executives who report to CEO Pascal Soriot, alongside executive vice president of oncology R&D Susan Galbraith. At AstraZeneca, Barr is keen on expanding the company’s capabilities in immunology with the help of its $1 billion acquisition of China-US cell therapy company Gracell Biotechnologies. The deal brought in a BCMA- and CD19-targeting CAR-T therapy called AZD-0120. In an investigator-initiated lupus trial, the candidate achieved “extremely” promising Systemic Lupus Erythematosus Disease Activity Index scores, returning patients’ scores to baseline, she said. Barr is also “super-excited” about an upcoming cardiomyopathy readout for the company’s Ionis-partnered ligand-conjugated antisense oligonucleotide drug Wainua, which is approved for polyneuropathy associated with hereditary transthyretin-mediated amyloidosis. “We have the chance to offer patients a medicine that changes the outcome of their disease, and I’m thrilled to pieces about that,” she said. — Ayisha Sharma In her years as a practicing oncologist and clinical trial investigator, Johanna Bendell has seen and cared for thousands of patients. But these days, she pushes herself to think of ones she has never met. “Who’s the cancer patient of the future? I say this to my folks all the time, especially in discovery,” she said. “Because when we start in discovery, we’re going to make a molecule for patients 10 years from now.” Discovery was a new area for Bendell when she joined Roche in 2021. Before joining the company to head up oncology for its pharma research and early development group, or pRED, Bendell spent 13 years at Sarah Cannon Research Institute in Tennessee, where she led hundreds of clinical trials while thinking of new ways to design them and bring them to patients. She believes that the experience of being in the room with patients gave her a unique perspective as she spearheaded a strategy revamp at one of the world’s largest cancer drugmakers — with the goal of diversifying the early-stage portfolio but also focusing on areas pRED is best positioned in. When Bendell first arrived at Roche, for instance, cancer immunotherapies took up 80% to 90% of the pipeline following the checkpoint boom. Today, she counts a 50/50 split between immunotherapies and what she calls “cancer cell dependencies” — treatments that hit cancers in vulnerable spots such as transcription factors and through synthetic lethality. Building on Roche’s historic expertise on T cell bispecifics, her team is “aggressively chasing down” a combination of the CD20-directed drug glofitamab with a targeted co-stimulator that showed early promise as an off-the-shelf replacement for CAR-T therapy. The group is also exploring new extracellular cancer cell surface targets, which could bolster the development of antibody-drug conjugates and radioligands down the road, she said. Those changes she spearheaded at pRED coincided with a broader prioritization exercise at Roche, including a separate decision by Bendell’s counterparts at gRED — the R&D unit at Roche’s Genentech — to dissolve its cancer immunology group and integrate it into the larger oncology unit. While stopping the development of molecules is always a tough decision, Bendell considers them necessary to maximize patient impact. That pursuit for efficiency, after all, was what pushed her to move from academia to a community-based research center before joining pharma. Being efficient, though, doesn’t mean never slowing down. Bendell recalls being scared of taking three months off when she was pregnant with her second child. It was Sarah Cannon’s president, Skip Burris, who reassured her that maternity leave will be “a blink in your professional timeline.” “That always made me feel so safe,” she said. At pRED, she is now a sponsor for the women’s network. “To be able to now say that to other women in the organization, ‘We’re going to be there. We’re going to help you through it […] that’s great.” There will always be more to do with Roche’s push for R&D excellence . For Bendell, that means also reflecting on how various groups are operating together. In oncology, she champions “seamless” drug development by ensuring that her team of 280 in discovery and early clinical development is in regular conversation with those in late-stage development. The former needs to know who the patients are and what options they already have, especially in a rapidly changing field; the latter could benefit from understanding how the science is evolving and what could be possible. “Being able to translate those two languages to each other [is] going to be key to coming up with what’s next and what’s best,” she said. — Amber Tong Behind one of the biggest names in biotech startup investing of the past quarter-century is Kristina Burow, a managing director at ARCH Venture Partners, a firm that’s seemingly attached to nearly every large bet in the fickle world of drug development. The former UC Berkeley swimmer quickly found her lane once entering the biopharma field, first working at the Genomics Institute at the Novartis Research Foundation, then moving over to the Swiss giant’s venture fund in San Diego around the turn of the millennium. A few years later, she took a role at ARCH, an investment apparatus in operation since its late-’80s founding in Chicago. “This will surprise no one who knows Bob Nelsen, but I had an open invitation to hang out and do cool shit at ARCH. So that’s what I did,” Burow told Endpoints News . She moved to Chicago, worked for ARCH while getting her MBA and then opened up the firm’s office in San Francisco, where she stayed until the pandemic. Burow has played a role in the firm’s go-big-or-go-home bets on infectious disease at Vir Biotechnology (that company is shape-shifting now), in neuroscience at Neumora Therapeutics (expect a crucial Phase 3 readout for a new type of major depression drug in the coming quarters) and now in obesity at Metsera (a partnership with former Medicines Company executives). Her imprint is also found in the dark genome at Rome Therapeutics, in RNA medicines at Orbital Therapeutics, in mitochondrial biology at Pretzel Therapeutics and in oncology at Boundless Bio, which was part of a small cohort of biotech startups to go public earlier this year. The list goes on. She said each new build starts with three key questions: What’s the mission? Who’s going to lead the daily grind? And what’s the likelihood of success? Each of those come with a laundry list of subquestions. When she entered the biotech investing world nearly 30 years ago, the pace of company creation paled in comparison to today’s momentum, at least at ARCH, which has some of the industry’s biggest pockets. “Every company seemed to take 15 years to build, and now I think the biotech industry has gotten much faster at taking innovation, putting it on the train tracks and creating therapeutics that drive patient outcomes but also tend to drive mergers and acquisitions and IPO outcomes,” Burow said. That longevity gives Burow little to no pause when thinking about the state of the biotech financing scene over the past few years. She and the ARCH team have seen it again and again. “We are not letting the external environment dictate what types of companies we’re going to build or what types of science or entrepreneurs we’re going to back,” she said. And creating biotech startups might not be as hard as helping start new Montessori schools in San Francisco, which the mother of three has also done. “They’re very similar. There is a lot of regulation in preschools in San Francisco. I can tell you that,” Burow said with a chuckle. “It requires a lot of capital, so there are some very distinct similarities. And it all comes down to the teacher, which is like the CEO.” Setting up schools and forming the blueprint for biotechs: It’s all one big experiment. And Burow said she has “enjoyed every single minute.” — Kyle LaHucik Karin Conde-Knape and Anna Windle watched Novo Nordisk’s weight loss drug Wegovy take off from two different perspectives: Conde-Knape from a global drug discovery role, and Windle from a clinical development and regulatory focus in North America. Now they’re interested in what the drug can do outside of weight loss and diabetes. Windle joined Novo Nordisk in 2011 in medical affairs, roughly six years before semaglutide won its first approval in diabetes as Ozempic. The company was already developing the GLP-1 receptor agonist at the time, and upon reviewing the data, the team realized they had something “pretty amazing.” Semaglutide was approved in 2017 as Ozempic for diabetes. In 2021, it became the first drug approved for chronic weight management, a landmark moment for the obesity field. The treatment, marketed as Wegovy, generated more than $915 million in 2022, its first full year on the market. “But I would say probably the big turning point was essentially when we actually got the readouts of the cardiovascular data,” Windle said. In the SELECT trial, Wegovy reduced patients’ risk of major adverse cardiovascular events by 20% compared to placebo, leading to a label expansion in March. “I was so proud of us, actually, for that trial,” Windle said. “People were leaving the obesity field, and Novo decided that we would commit to it and we would stay in it.” Windle’s current role involves leading clinical development for North America across all therapeutic areas, as well as leading regulatory interactions with the FDA. Her team spends a lot of time understanding what patients’ unmet needs are — and planning semaglutide’s next steps. The drug is in clinical trials for a variety of conditions, including Alzheimer’s and a liver disease called MASH. As senior vice president of global drug discovery, Conde-Knape also thinks about “continuing to build the journey around GLP-1.” Conde-Knape joined Novo in 2018, first focused on cardiovascular and liver diseases and then eventually diabetes and kidney disease as well as building a translational team. She said it was clear early on that the GLP-1 mechanism had “the potential to deliver more.” Looking to the future, Conde-Knape sees a saturated GLP-1 space, including double and triple agonists, similar to the PDL-1 space for cancer. She sees the next generation of molecules as “quite critical,” as well as considering subgroups of patients in the obesity community who have comorbidities. “What else do you bring in the understanding of disease and biology so that you can actually impact multiple organs that go beyond weight loss? That is, for me, what is going to be the change,” she said. — Katherine Lewin Susan Galbraith fell into oncology by chance. As a junior doctor, she had wanted to specialize in cardiology, but ended up on a rotation that included oncology at Addenbrooke’s Hospital in the UK. She found herself enjoying the long-term contact with cancer patients and their families, and nurtured a growing interest in the mechanisms behind cancer and its treatment. At the turn of the century, Galbraith followed that interest even further and pursued a PhD focused on a vascular-targeting agent for cancer owned by a small biotech company. The compound was later licensed by Bristol Myers Squibb, with a job opportunity at the US drugmaker following soon after. “It came at a convenient time in my career — I’d always been interested in working in a different country for a period of time and it was just before I would have been applying for consultant roles in the NHS,” she told Endpoints News . With her husband and two young children in tow, Galbraith made the trip across the Atlantic, only to learn two weeks after her arrival that Bristol Myers had killed the drug. “That was a lesson about burning bridges,” she said. “I had no choice but to make it work at that point.” After chatting with staff at Bristol Myers’ discovery lab, Galbraith became interested in the then-nascent field of immunotherapy. While attending a small conference in New York, she came across a presentation on Phase 1 data for a monoclonal antibody drug targeting CTLA-4. Impressed by the results, she initiated the in-licensing of that drug by Bristol Myers. Now better known by its brand name Yervoy, the drug generated $1.38 billion in sales last year. “I probably wouldn’t have been so focused on the potential of immuno-oncology if they hadn’t killed the drug I’d originally worked on,” Galbraith said. “It’s like one door closes and another opens, but you’ve got to be willing to take the risk and walk through that door.” Nine years into her time at Bristol Myers in the US, Galbraith got a call from AstraZeneca. “It was probably the only job back in the UK that I would have been interested in doing, with a company that had its discovery and early development group focused there,” she said. When Galbraith joined AstraZeneca in 2010, its PARP inhibitor olaparib was at a crossroads. The company had reformulated the drug from a capsule to a tablet, but was struggling to achieve bioequivalence. Olaparib had also completed a Phase 2 test in second-line platinum-sensitive relapsed ovarian cancer, showing improved progression-free survival, but there was “not yet a trend to overall survival,” Galbraith said. Galbraith, however, noticed a “remarkably large” effect size in a subset of patients with BRCA mutations. “We’re not even sure we’ve got a formulation that could go forward, and we’re wanting to spend more money to test biomarkers in this trial — somebody told me that I was proposing to throw good money after bad,” she said. But with the support of Pascal Soriot, who was named CEO in 2012, Galbraith managed to secure the funds to look further into olaparib’s potential. The drug’s approval in 2014 was a “turning point” for AstraZeneca’s oncology group and helped drive a change in its philosophy. Now marketed as Lynparza, olaparib made $2.81 billion in sales last year. Galbraith is now one member of a team of senior executives who report to Soriot, alongside executive vice president of biopharmaceuticals R&D Sharon Barr. In recent years, AstraZeneca has made a point of diversifying its oncology pipeline. In December, the drugmaker entered the CAR-T field with a $1 billion deal to acquire China-US cell therapy company Gracell Biotechnologies. In March, it struck a deal for $2 billion upfront to buy Fusion Pharmaceuticals, joining the increasingly popular radiopharmaceuticals field. These deals added to ongoing work on antibody-drug conjugates in collaboration with Japan’s Daiichi Sankyo. While some have questioned whether the company is spreading itself too thin, Galbraith said there’s a method to the approach. “The idea is we’ve got to have a diverse set of mechanisms that we can put together in effective combinations,” she said. For instance, radio conjugates could supplement or replace some parts of the way radiotherapy is given, while cell therapies could help broaden the potential reach of immunotherapies to areas where immune checkpoint inhibitors on their own haven’t been as effective, Galbraith said. That all comes along with the company’s efforts to boost early screening and diagnosis of cancer with the help of tools such as AI, and with its expansion into the digital health space. It builds on the lessons she learned at Bristol Myers — being receptive to other doors opening in case one closes. “I think we have something that’s differentiated from what many companies are offering,” Galbraith said. — Ayisha Sharma Quita Highsmith was putting together a summit in 2017 for Genentech employees to learn from patients who had participated in the company’s clinical research. But she was having a hard time finding Black or Hispanic patients to engage, because their representation was so disproportionate. The episode drove Highsmith and a co-worker to found the Advancing Inclusive Research initiative at Genentech to recruit more representative populations into clinical research. After narrowing down locations specific to certain diseases and research areas such as oncology, she would pick cities like Memphis, San Antonio, Los Angeles and others where the community around them has a population that’s representative of those most affected by each condition. Under the initiative, Genentech’s participating oncology sites enrolled 89% more Black and Hispanic patients than other sites on the same studies, the biotech said. Genentech also launched what it says was the first trial to assess disease activity and biomarkers in Black and Hispanic patients with relapsing multiple sclerosis, and submitted 20 diversity action plans out of a total of 76 plans turned in to the FDA across the biopharma industry last year. It was the perfect segue into her current role as Genentech’s first chief diversity officer in the 48-year history of the biotech. Highsmith reached out to HBCUs to fund schooling for underprivileged students who want to pursue PhDs to become scientists. She pushed for diversity in Genentech’s suppliers, seeking out businesses owned by veterans, individuals with disabilities or women. It’s rewarding but tough to have to wear so many hats in her role, Highsmith said. “Just to be a chief diversity officer, here’s what you are: You are a changemaker, you are an advocate, you are an advisor, you are an educator, you’re a truth teller, you bring in the data,” she said. “And lastly, you are a therapist to the entire company because everybody wants to talk about their issues.” — Ngai Yeung When Travere Therapeutics’ chief medical officer Jula Inrig came aboard in late 2016 to help develop and guide two rare disease kidney trials, she brought tons of experience with her, having already run more than 50 clinical trials across dozens of countries. That extensive experience has led her to stress the importance of collaboration. “Collaboration has been the biggest key driver to change and success,” Inrig told Endpoints News . “It often takes many years to move the field forward as it takes a village, and many stakeholders work in silos.” She offered one collaborative example with the Kidney Health Initiative, which is a partnership involving the FDA, the American Society of Nephrology, academics and industry that defined endpoints for diseases such as IGA nephropathy, a kidney disorder. Ten years ago, there were no FDA-approved drugs for IGA nephropathy, “and now we have three new FDA-approved therapies (including one we got approved) and 10+ in development,” Inrig, a former global head of the Renal Center of Excellence at IQVIA, noted. Regarding her experience as a woman in a male-dominant biotech world, Inrig said things have changed, particularly in the last five years as companies look to more diversity. “I was very intentional in where I worked, and I try to commit to gender equity and also working to ensure the next generation has a similar experience to me. That means mentoring and giving time to professional societies which focus on gender equality,” she said. As far as advice for women who are debating whether to move into the biopharma industry, Inrig said, “Do your research, make sure you are well informed at all levels about who you are working for (the science, the corporate priorities, the culture), and who your peers are as you will be in the trenches with them! Culture is critical and can make or break you.” On the benefits of moving from academia to industry, Inrig added that academia “can be very siloed and the ability to make an impact can sometimes be limited to n=1 or n=100,” whereas working on a collective goal such as a new drug approval “can be personally rewarding and impactful on a much larger scale,” she said. — Zachary Brennan Iya Khalil has a different perspective than most on Merck’s recent $10.8 billion purchase of Prometheus Biosciences. For many Wall Street analysts and investors, the deal looks like a move to replace revenue from Keytruda with a potential immunology blockbuster in a TL1A blocker now called MK-7240. But for Khalil, who joined Merck in 2023 as vice president and head of data, AI, and genome sciences, that TL1A program is just one example of an even bigger trend defining Merck’s future. Khalil’s team is building disease foundation models, hoping to uncover new therapeutic targets as well as finding precision biomarkers to help learn which patients are most likely to respond to a drug. Patients who enroll in Merck’s late-stage studies for MK-7240 will also have a mix of genetic and -omics profiling, both pre-treatment and post-treatment. All those data are fed into AI models her team is building to model and simulate diseases. The goal is these foundation models could then be fine-tuned to simulate specific scenarios to help researchers make decisions on what disease or types of patients may be most likely to benefit from a drug. Khalil has been working in the computational biology space since 2000, when she co-founded a startup called GNS (recently named Aitia). After two decades there, she left to run an AI lab at Novartis before jumping to Merck last year. “We are in build mode,” Khalil said. “As far as I can tell, it looks very promising.” Khalil’s team of over 100 people is helping turn ambitious ideas like foundation models of biology into reality across Merck’s research in immunology, neuroscience, oncology and cardiometabolic disease. “We’re at a point where we can now do this,” she said. “It was prohibitive a while back” for reasons like the quality of the biological data and challenges in capturing this data while maintaining the trial’s integrity. “We’re at the convergence of 2024, where these things can truly come together.” The work is early, but Khalil said there are multiple reasons to believe now is the opportune time for these models to be successful. Patient data have become cheaper and more detailed. New AI models allow better ways for computers to process different types of biological data. And compute power has gotten significantly better, allowing these models to be trained. “Instead of learning the language of words with ChatGPT, can it learn the language of genetics, genomics, proteomics, imaging and how that impacts a cell phenotype?” Khalil said. “It’s a massive effort, both in terms of the data we’re collecting and generating to train them, as well as the compute power.” — Andrew Dunn Theresa LaVallee is used to running projects that everybody says couldn’t be done — or wouldn’t think to do. She was the first translational medicine employee at AstraZeneca’s MedImmune, watching them take on the bold challenge of developing an antibody for RSV and exploring checkpoint inhibition before immuno-oncology took off. A couple of executive jobs later, she moved across the country to join “this wacky idea” that was the Parker Institute for Cancer Immunotherapy, where she led collaborative research projects to run experiments that pharma companies wouldn’t. “A couple of people asked me if I was having a life crisis,” she said. So when Coherus BioSciences, a company mostly known for its biosimilars, called about steering a made-in-China PD-1 drug to a historic FDA approval in the middle of a pandemic, she took the opportunity. When LaVallee first joined Coherus, the perception was that the agency had an open-arms attitude toward drugs tested and developed exclusively in China. But soon after, the agency made clear — through a rejection of Eli Lilly and Innovent’s drug — that China-only data are not going to cut it. But even with some confusion about the FDA’s viewpoint on China-only data, and after a manufacturing-related rejection, it happened: In October 2023, California-based Coherus and its partner Junshi brought the ninth PD-(L)1 inhibitor onto the US market. The FDA greenlit toripalimab — a particularly impressive feat for her “little teeny” regulatory team of six. “Getting toripalimab approved was by far the biggest hurdle — the hardest thing I’ve ever done,” said LaVallee, who’s now chief development officer at the biotech. “People really didn’t believe it was going to happen.” Coherus and Junshi managed to pull off the exception that proved the rule by focusing on nasopharyngeal carcinoma, a cancer type that’s particularly prevalent in East Asian populations and rare in the US. They were also successful because they were able to find solutions when China imposed severe travel restrictions related to Covid, physically barring FDA inspectors from reaching the contract research or manufacturing sites involved in producing the drug. By 2023, those inspections were the only thing holding up the approval. “We looked at some very creative approaches collaborating with other companies that were in similar situations,” LaVallee said, including asking the FDA to consider setting up a “bubble” for personnel, like in the Olympics. It didn’t come to that, and China eventually lifted all restrictions. And that “almost was a bigger problem,” she said, because the FDA now had an entire backlog to go through. But with her constant contact with the agency or even luck — LaVallee herself wasn’t quite sure which ended up the deciding factor — the drug ended up being the FDA’s second inspection once the agency entered China. With a PD-1 backbone in its portfolio, Coherus is exploring partnerships to fund combination studies while testing other early-stage candidates as it looks to establish itself in immuno-oncology. The company is still open to working with Chinese biotechs with scientific merits — it will just have to be vigilant about the evolving geopolitical concerns. “We are moving the manufacturing of toripalimab to the United States,” LaVallee said. “I don’t want to have to worry about traveling to China again.” — Amber Tong Jeanne Loring, who has been called the godmother of stem cells, is watching her decadeslong research reach a pivotal juncture. Her tenacity produced, perhaps most notably, a potential Parkinson’s treatment that started a clinical trial earlier this year. The milestone follows years of setbacks in the stem cell field, and more broadly, Parkinson’s drug development. “A plan I put in place a long time ago is working,” said Loring, founding director of the Center for Regenerative Medicine at Scripps Research. Her work with stem cells has run the gamut and extended to areas that might seem more science fiction than reality: from reviving the northern white rhinoceros population to studying cells in space. Her pursuits were the subject of an in-depth Endpoints News profile last year. Loring’s next big frontier: potentially treating brain conditions. She co-founded Aspen Biosciences in 2018 and helped raise $220 million to try a personalized approach to Parkinson’s. The company creates therapies using a patient’s own cells, which is known as an autologous therapy. The clinical trial is looking to see if, once injected, these cells can mature into dopamine-producing neurons. In patients with Parkinson’s, neurons die, causing stiffness, tremors and anxiety, among other symptoms. Patients currently have limited options. Longtime Parkinson’s treatment levodopa has limited effects and wears off over time. A competitor, BlueRock Therapeutics, is in clinical trials with a similar therapy, but one that’s based on donor cells. To prevent the body from rejecting the medicine, patients must take immunosuppressive drugs that can weaken the body’s defenses. Because of Aspen’s personalized approach, the industry is closely watching its clinical trial. But Loring doesn’t see it as an either/or. In June, Loring and co-authors wrote in the journal Stem Cells that competition shouldn’t take precedence over collaboration — one of her key philosophies. Aspen, BlueRock and other organizations are part of a global partnership called G-Force PD to share data on stem cell therapies. “This field is too challenging for competition to be the main goal; there are so many people suffering from Parkinson’s disease that there should be room for multiple approaches to succeed,” Loring and others wrote in the paper. Multiple companies pursuing stem cell treatment for Parkinson’s seemed like a far-off possibility early in Loring’s career. At that time, she ran into difficulties putting stem cells to work because she struggled to get funding. Her advice to women encountering similar barriers? “When funders say ‘no,’ ask them why, and then have them explain it, and then tell them why they’re wrong,” Loring said. But, she cautioned, not every investor welcomes such directness. “The path I’ve taken has probably alienated just as many people as I’ve won over because I’m very straightforward,” she said. Nonetheless, she’s learned how to speak the language of both academia and industry, moving back and forth between the two realms throughout her career. “You really do have to change the way you talk to people, the way you interact with people, and remarkably, it has been a lot of fun,” Loring said. — Jared Whitlock There’s a lot of behind-the-scenes work that goes into turning a promising antibody into a bona fide drug candidate. Jirong Lu is the chemist responsible for fine-tuning some of Eli Lilly’s biggest antibody medicines, including the psoriasis drug Taltz and the recently-approved Alzheimer’s disease therapy Kisunla. Lu grew up in rural China, where time spent outdoors fostered an appreciation for nature and a strong curiosity. Her parents never went to college, but a young high school chemistry teacher ignited her interest in the central science, which she then studied at Sichuan University. Later, as she was wrapping up her postdoctoral research on proteins at the University of Washington in 1997, Lilly began hiring scientists for a new biotechnology research unit. When Lu saw an advertisement for the Indianapolis drugmaker’s initiative while flipping through a science magazine, she immediately knew it was “like a dream job.” This was a big turning point for Lilly, best known then for making insulin and Prozac. Protein therapies were cutting-edge science, and Lu loved the group’s mantra that “your body doesn’t make the protein to be used as a therapeutic,” she said. Natural proteins needed to be engineered and optimized to do their job. It was chemistry, but with molecules whose size and complexity dwarfed the compounds found in pills. Lu became fast friends with biologist Ling Liu, another newcomer to Lilly who also studied at Sichuan University. The duo worked on a mysterious immune protein now known as IL-17. Liu discovered that it caused inflammation, and Lu created an antibody that could block it. Making antibodies was still a laborious task in the early 2000s. Lu had to immunize mice with the IL-17 protein, collect their antibodies, test them to find the best ones, rework the mouse antibodies to make them look like human ones, and then optimize those molecules to make sure they were soluble and stable. All told, it could take three to five years, Lu said. When antibody optimization fails, programs are often canned before investors ever hear about them. And when they succeed, the focus quickly shifts to clinical tests. The vital work that scientists like Lu do rarely reaches the public limelight. The IL-17 antibody was initially tested in rheumatoid arthritis, with lackluster results, but its ability to clear skin plaques in people with psoriasis was dramatic. The antibody was first approved in 2016 and is now marketed as Taltz. It’s among Lilly’s biggest sellers, earning the company more than $2.7 billion last year. Lu also played a key role in multiple Alzheimer’s programs, planting the seeds for Lilly’s eventual success after several failures . It all started when Lilly neuroscientist Ron DeMattos identified a particular part of the infamous amyloid plaques that he wanted to target. Antibody engineer Ying Tang worked nights and weekends to find an antibody that could do the job. After identifying a promising lead, Lu steered a full-blown effort to improve its affinity. Humanizing the antibody was tricky, and initially resulted in a weaker molecule that was quickly cleared from the body. But additional chemical tweaks saved the drug. That antibody, called donanemab, is now sold as Kisunla. It’s unclear if it will be the big blockbuster that Lilly and others always imagined an Alzheimer’s drug would be. But Lilly already has sequels in the works. Remternetug, another amyloid-busting antibody that Lu helped design, is given as a simple injection rather than a lengthy infusion. It’s being tested in Phase 3 trials now. More recently, Lu has helped push Lilly’s “10-year journey” to design antibody and protein therapies that penetrate the blood-brain barrier, the protective shield that keeps most drugs out of the brain — including most of donanemab. Lilly hasn’t talked much about this effort publicly, but Lu said the company is working toward testing it in the clinic. Over the past few years, Lu has stepped back from the lab bench and taken on management roles at the company to guide its antibody and protein drug strategies. She also devotes a lot of time mentoring the next generation of scientists. “I have really benefited from having great mentors at Lilly,” she said. “So I’m very passionate about trying to pay back, to give other scientists that opportunity.” — Ryan Cross Growing up east of the Iron Curtain in Hungary, Mariann Micsinai-Balan has always been comfortable with blending cultures, languages and ideas. That has led her to the cutting edge of R&D in pharma, tasked with bringing artificial intelligence technology to a legacy drug-making giant. Before joining Bristol Myers Squibb in 2020, where she is now head of data science, Micsinai-Balan worked on Wall Street at Lehman Brothers and in the tech world at a startup then called Greenplum Software. She’s picked up a few degrees along the way, including master’s degrees in computational biology, economics, international studies and international relations. She also earned a PhD in computational biology and is now completing an executive MBA program. That eclectic academic journey included an elective class in statistical genomics, which got her hooked on biopharma. “I’ve taken the long, nontraditional route to biopharma that ended up giving me a pretty good wealth of experience and an adaptive, flexible mindset,” Micsinai-Balan said. That journey across disciplines has shaped her perspective on bringing data science and computer science into the drug R&D world. Her team at Bristol Myers isn’t focused on applying AI to one particular R&D task, but rather thinking across the entire process. For instance, she said early discovery insights can be integrated into later-stage development plans. Data science is a team sport, Micsinai-Balan said, emphasizing the importance of getting buy-in across the company and working together, rather than operating as a siloed group. Micsinai-Balan’s team also has some diversity that is often lacking in AI circles. Two-thirds of her interns were women this year, she said, as are over a quarter of permanent team members. The team has a wide range of backgrounds, from astrophysics to computational biology to mathematics and more. Micsinai-Balan said she advises her interns to stop doubting themselves. As her own career shows, in moving from Wall Street to the tech startup world to a drug-making giant, some professional boundaries on what’s doable are self-imposed, she said. “Don’t be afraid of failing, because if you don’t explore, you close your chances of figuring out, ‘Hey, this might be a route,’” she said. — Andrew Dunn Growing up, Theo Ross says she had “no interest in science.” Instead, she wanted to be a concert violinist or maybe a stand-up comic. She dropped out of high school, went to music school and chased her dreams. Then she heard her brother, a renowned cellist, play in a recital. She came to a painfully clear realization: “‘Oh my God, I can never be this person, and this is who I want to be,’” she thought to herself. “So I quit.” Decades later, scores of patients can be grateful that Ross put down the violin for the lab coat. Ross, an academic and oncologist at heart, has forayed into industry for the latest chapter of her career. She’s now the vice president of oncology research & development at AbbVie after prior executive stints at Amgen and Merck. After switching from music to medicine, Ross landed at Brigham and Women’s Hospital, where she worked under the tutelage of Marshall Wolf, the internal medicine residency director. Wolf is colloquially known as the “dean of medical residency program directors” and helped train more than 2,000 doctors, including more than 1,000 who became full-time professors at leading medical institutions. Ross said that Wolf only allowed two people in the residency program from Harvard. The rest had to come from medical schools around the country. “He was a guy who believed in diversity before people believed in diversity,” she said. Wolf was at Ross’ wedding. And he stepped up for her in the clinic when she had to deal with a family emergency. His empathy became a blueprint for Ross who, despite her ascension, continues to see patients periodically, mainly for family or friends. She’s driven by the fact that just taking a moment out of her day to give some medical advice could extend someone’s life. The empathy — and the power of diversity — came to the forefront while Ross worked at the University of Michigan. When her soon-to-be-hired lab manager told her she was pregnant, Ross didn’t bat an eye. Only upon reflection did she realize how novel that may have been to someone like that lab manager who was concerned about taking maternity leave in a field where men dominate leadership roles. Ross next moved from Michigan to UT-Southwestern, where she led the Cancer Genetics Program and had a lab of her own. She investigated how certain genes impacted patients’ risk for cancer, including the relationship between BRCA1 and leukemia. In one of the early iterations of Ross’ lab, she went by “Snoop Dog,” because she was so hyper-vigilant of what everyone was working on that she’d check her researchers’ lab notebooks at night. When they’d come back to work the next day, Ross would be armed with questions. “I learned that I was a micromanager, and I needed to work on that, and I have been working on it ever since,” she conceded. Years later, a conversation with Roger Perlmutter, the former head of Merck Research Labs, inspired her jump to pharma. He offered her a job working in translational medicine — a sweet spot for physician-scientists — and Ross felt it was an opportunity she “had to take.” She spent almost two years at Merck before jumping to Amgen for a year. In November 2022, Ross joined AbbVie as the VP of oncology early development, veering the company toward solid tumors for the first time with the acquisition of ImmunoGen. She’s also been able to hire new leaders on her team and “clean up” some of the early portfolio. Ross said she’s not concerned about moving quickly. “We want to get our drugs to patients sooner,” she said. “And if we waste time on something that’s not working out, or it’s toxic or it’s not efficacious, that’s bad for patients.” — Max Bayer For three and a half years, Luisa Salter-Cid has been building out Flagship Pioneering’s in-house pipeline of new medicines. She leads the scientific charge at Pioneering Medicines , where she brings together the R&D engines of the Boston-area incubator’s 40-plus startups and corrals three big partners: Novo Nordisk, Pfizer and the Cystic Fibrosis Foundation. Salter-Cid is familiar with bridging teams. After working at the human genome research company Genset in the early 2000s, she moved to La Jolla Pharmaceutical and then spent about a dozen years at Bristol Myers Squibb. While at the large pharma, she helped integrate the Medarex team (which gave them what would become Yervoy), and eventually moved up to head of immuno-oncology small molecule work and scientific lead on Bristol Myers’ dealmaking. “BMS at that time was probably one of the best drug discovery companies,” Salter-Cid said. She is particularly fond of the company’s TYK2 work, which led to the plaque psoriasis pill Sotyktu. “One day we were told by high management, ‘Well, the IL-23 antibodies are already out there, so you need to come up with a small molecule that does the same thing,’” she recalled. She then went to Gossamer Bio for a few years before landing at Pioneering Medicines in early 2021. Her team is working on experimental drugs for MASH, obesity, cystic fibrosis and other areas being kept under wraps. She hopes to give cystic fibrosis patients better treatments, as there’s “still a lot of drawbacks from the current therapies,” she said. Salter-Cid enjoys overseeing a broad portfolio that goes beyond her longtime focus on immunology. “You cannot avoid metabolics these days,” she said. Cardiovascular has also become an area of interest for her lately. It’s probably the most different from immunology, she said. “It really blows my mind a little bit, to be honest. I like my cells in a Petri dish that we can put together and see stuff happening. That’s not going to happen in cardiovascular,” Salter-Cid said with a laugh. — Kyle LaHucik Nia Tatsis has been with Vertex Pharmaceuticals for seven years and was promoted to chief regulatory and quality officer in 2019. Tatsis is also a board member at cardiovascular disease gene editing company Verve Therapeutics. She was born in Athens, Greece, but immigrated with her family to the US outside of Philadelphia when she was a year old. This interview has been edited substantially for length and clarity. Lei Lei Wu: Part of your job involves working with the FDA, so I’m curious what your thoughts are on how the FDA is changing. Nia Tatsis: There’s CDER [Center for Drug Evaluation and Research] and there’s CBER [Center for Biologics Evaluation and Research]. CDER always felt, when I started, like the most regimented. They knew exactly how they wanted things done, and what they wanted. CBER, when I started at vaccine [at Wyeth], they were open to just meeting with us a lot. CBER now is a different beast altogether. Now, as we’ve all moved into biologics, they have to learn science very quickly. They have to make some really big decisions in the absence of having the ability to sit down with us and go through it, as much as I used to have the pleasure of doing, 10, 15, 20 years ago. They’ve become much more like CDER. It’s a little bit more regimented. Wu: You recently joined Verve’s board. How did that conversation come about, and what are your personal thoughts on what Verve is working on? I feel like people have very different opinions on doing gene editing for a very common disease. Tatsis: Before I joined [Vertex], I did the anti-PCSK9 that Sanofi was developing with Regeneron — Praluent. I remember sitting and talking and listening to the patients that came through the advisory committee [for Praluent], and these folks have heart attacks. Those folks who have hypercholesterolemia, many don’t know they have it. It’s a silent disease. And it’s a really important disease. I spoke to a recruiter like you normally do. Verve was one of the companies that kept coming up. For the rare diseases that we’ve been working on, maybe it’s an easier way to think about CRISPR gene therapy. But science is going to evolve. And the way it’s going to evolve is it’s not always going to be a small molecule, it’s not always going to be a pill, and maybe a one-and-done is the way to go. I think Verve has the right idea. I think their science is amazingly strong. I think their leadership is strong. Do you know Sek [Kathiresan]? Wu: I’ve met him a couple times. Tatsis: I think if you spend 10 minutes talking to Sek, you’re converted. It’s because of the passion he feels for what he’s doing and the deep knowledge that he has. So it wasn’t a hard decision at all. Wu: What is your perspective on how the position of women in the industry has evolved or changed, if at all, since you’ve joined? Tatsis: It’s evolved. First, I would say, Vertex does it so well: Reshma [Kewalramani] being the CEO. Before she was the CEO, she was prominently doing amazing work. [Former CEO] Jeff [Leiden] before Reshma was committed to ensuring that women are well-represented. If you look at our executive team, or if you look at our board, I think you’d see that. But there are different ways different companies think about it. One of the reasons I wanted to come to Vertex … There were women in leadership and everyone was treated pretty equally. I didn’t feel like I was a woman interviewing for a job. I just felt like I was another candidate — that really mattered. I don’t know that I always felt that way at other places. There wasn’t anything overt, but I felt like here it was not even a discussion. I don’t know that other companies have evolved. I’m not there. But if you look across senior leaders — if I look at Sanofi, and I’m not saying it in a bad way, I don’t know who they have now, but when I was there — there really weren’t senior leaders who were women. There were a few. Here, you can’t help but notice that we have a lot of strong and important women who have a lot to say and are really making changes. I get to learn watching them, and hopefully someone learns watching me. — Lei Lei Wu Scientists and clinicians didn’t quite understand the severity of a liver disease called nonalcoholic steatohepatitis (NASH) more than 20 years ago. But even then, Becky Taub knew it would be an important disease to treat. Up to 5% of Americans are estimated to have NASH, a disease also referred to as metabolic dysfunction-associated steatohepatitis (MASH) that can progress to severe scarring or cirrhosis of the liver. For years, the standard of care was diet and exercise. Taub led a team of scientists at Madrigal Pharmaceuticals to the field’s first drug approval in March, a crucial milestone for patients. The story starts with a shelved Roche candidate, an inopportune job offer and a valuable “going-away present.” Taub left a position at the University of Pennsylvania in 2000 to pursue a career in the pharmaceutical industry. She landed at Roche in 2004, where resmetirom was discovered as a potential metabolic candidate for clinical development. But scientists had already written it off because when they dosed animals, they didn’t see very high levels of the molecule circulating in the blood. “When I looked at it, I said, ‘Well, maybe that’s because it’s going to the liver,’” Taub said. “We had in the back of our minds that there was a fatty liver disease and it might be good for that.” They also hypothesized that it would be good at lowering cholesterol and other lipids that cause heart disease. Taub and her team revisited the candidate, working on it for four years until Roche reorganized. The new job Roche had for Taub was in Basel, Switzerland, which she said “wasn’t something I wanted to do at the time.” So for “not much money,” she licensed resmetirom and related molecules and eventually founded Madrigal in September 2011. “I called it a going-away present,” Taub jokes. Meanwhile, scientists chipped away at the vexing liver disease. Intercept Pharmaceuticals’ pioneering obeticholic acid stirred up a surge of interest around NASH in the investor and medical communities, but the therapy was rejected by the FDA last year over safety issues. Bill Sibold, now Madrigal’s CEO, would go on to call NASH a “veritable graveyard of drug development.” There was little recognition for the disease and no designated regulatory path. “The hardest things were early on,” Taub said. “We had a certain amount of money that was coming from a single fund, and you have to make that go a long way.” When Madrigal was first founded, Taub was essentially both CEO and chief medical officer. The company was still focused on resmetirom’s lipid-lowering effects at the time. Madrigal officially pivoted to NASH in 2014, when it had nonclinical, clinical and toxicology data to support a Phase 2 trial in NASH. Resmetirom was approved in March as Rezdiffra. Madrigal said on its most recent earnings call that it’s “making great progress” on the launch. Jefferies analysts predicted in March that Rezdiffra sales could reach $3.4 billion across the US and Europe. The focus now is expansion. “A lot of our prescribers are not aware of NASH and I think that that’s a big challenge,” Taub said. Looking back, Taub said she was always “super-interested in NASH,” even before the industry knew much about the disease. “It was a good direction for me.” — Nicole DeFeudis It was a PE teacher at a school in Stockholm who suggested that Michelle Werner and her husband bring their son to see a doctor once they moved back to the US. Werner, then an executive at AstraZeneca, was moving with her family to Maryland to take a new post heading the company’s hematology franchise. It was December 2019, and Werner’s son Caffrey, 9 at the time, was getting up off the floor in an unusual way. They now know that’s called the Gower maneuver — a result of muscle weakness and often a sign of Duchenne muscular dystrophy. In Washington, DC, the family went to Children’s National Hospital. “Right away, when we were in that appointment with the neurologist, she said, ‘I can tell you right now, Caffrey has muscular dystrophy,’” Werner said. She reflected back to the beginning of her son’s life, when he started missing gross motor skill milestones like rolling over and sitting at around six months old. At the time, he was diagnosed with hypotonia, or low muscle tone, but doctors said he would eventually catch up with his peers. On Caffrey’s 10th birthday, genetic test results confirmed he had Duchenne muscular dystrophy. Werner, having worked in the pharma industry for two decades, immediately went searching for clinical trials of investigational therapies for Duchenne. “Caffrey was eligible for zero of these clinical trials because he had the wrong mutation, or he was too old already at 10 years old, or he was too ambulatory,” she said. “It was an impossible idea to me that there was really nothing that was being done or could be done for my kid, and as somebody who has really dedicated their career to trying to address some very, very challenging diseases.” Werner and her husband fell into what she calls a “black hole period” for a few months. “You realize that everything that you thought about your kids’ future, your family’s future, might not be real anymore, and that we might be facing a completely different reality as a result of this diagnosis,” she said. It’s now been more than four years since Caffrey’s diagnosis. Combating rare disease has become both Werner’s personal mission and her career. In 2022, she became a CEO-partner at Flagship Pioneering, the venture firm behind Moderna, to lead a startup focused on harnessing transfer RNA, or tRNA for short. Known as Alltrna, the company’s chasing a holy grail therapy that can be used across a host of rare diseases to restore functional protein production. The company isn’t working specifically on Duchenne. Alltrna’s still in the early phases and has not yet said when it will have an experimental treatment ready for human studies. “In the 20 years that I’d dedicated to drug development so far, it had all been focused on oncology,” Werner said. “I wanted to spend the next 20 years of my career focusing on rare diseases.” For Caffrey, Werner’s family has been pursuing an n-of-1 treatment with Cure Rare Disease, a non-profit started by Rich Horgan, whose brother had Duchenne, to develop new treatments for rare and ultra-rare diseases. For a treatment for Caffrey’s Duchenne mutation, research in mice is being conducted with SickKids in Toronto. When the first Duchenne gene therapy from Sarepta Therapeutics was granted a broad label by the FDA in June (and not without controversy), Werner’s family had a decision to make. Caffrey’s mutation of Duchenne enables him to produce 1% to 2% of dystrophin on his own, which may be why he was diagnosed later than what’s typical for Duchenne, Werner said, and there are no answers around how natural dystrophin and microdystrophin — which is what is made with the gene therapy — interact. Caffrey, who recently started high school, also weighed in on the final decision, saying he did not want the gene therapy now. And after consulting with experts, Werner concluded that the family should not pursue Sarepta’s gene therapy Elevidys for Caffrey. “There is no right answer. There is maybe no wrong answer. There is only any person’s individual answer, and we just have to get comfortable with that,” Werner said. Meanwhile in her day job at Alltrna, Werner hopes to inject the urgency she feels as a rare disease parent into her team. “We need to take a ‘many diseases at a time’ strategy if we are going to be able to help as many patients as possible,” Werner said. “Otherwise, so many of these diseases would have no innovation whatsoever, because only a handful of them that are maybe the most prevalent would get the attention of, for example, the pharma companies that I had been working with in my career up until that point. “There are over 6,000 rare genetic diseases, and when we’re trying to tackle 6,000 diseases, one disease at a time, it will take thousands of years for us to make a dent in all of them,” she said. “This is something that I realized as a parent: the importance of time and making progress as quickly as possible is critical, because patients really do not have time to wait. It’s a race against the clock.” — Lei Lei Wu