Moderna, Inc.

Pfizer says a new formulation of its Covid-19 vaccine boosted antibody levels by at least four-fold in adults ahead of the upcoming respiratory season. The biopharma and Comirnaty co-developer BioNTech released new data Monday on an updated version of the shot, targeting the LP.8.1 variant of the virus, in people 65 and older and at-risk people aged 18 to 64. The data come from the open-label portion of a Phase 3 study, and all participants were at least six months removed from receiving a dose of last year’s vaccine. The study enrolled 100 people, half of which were 65 and older and the other half were younger adults. The antibody levels were tested two weeks following vaccination, and Pfizer said the safety profile was consistent and no new concerns arose. Data were accrued in two months, after the trial launched in early July, according to a US clinical trial database . Patients were recruited across six sites in the US, and the study is expected to finish in January 2026. Pfizer teased the additional data last week when it defended Comirnaty, following a social media post from President Donald Trump claiming the company hadn’t publicly released data related to its Covid-19 shot. Pfizer CEO Albert Bourla said in a statement last week that Trump deserved a Nobel Prize for his role overseeing Operation Warp Speed, the US government’s effort to speed up the development of the Covid-19 vaccines during the pandemic. “We agree with President Trump about the role data and transparency play in helping to inform patients and providers about their decision to vaccinate,” Bourla said. Pfizer, Moderna and Novavax — makers of the three Covid-19 vaccines — each responded to Trump last week, even though the president only addressed Pfizer, and defended the data underpinning their vaccines. HHS Secretary Robert F. Kennedy Jr. has doubted whether the Covid-19 vaccines are safe and effective, and last month, he pulled back research and federal funding for new vaccines based on mRNA — the technology behind both Pfizer and Moderna’s shots. All three vaccine makers have agreed to run placebo-controlled, post-marketing studies of their shots in healthy adults. Pfizer also agreed to a post-marketing study assessing how long the virus’ spike protein antigens, mirrored via vaccination, circulate in the body. That study is not expected to be completed until April 2027.

摘要：FDA 近期经历了前所未有的领导层变动和大规模裁员，导致沟通瘫痪、不确定性弥漫，众多中小型生物制药公司在疗法审批道路上举步维艰。本文聚焦近六个月来五家与新 FDA 打交道的生物科技公司，解析它们在这一混乱局面中所遭遇的种种困境。FDA 动荡：药企前路迷雾重重 变革向来不易，尤其是当新一届政府热衷于彻底改革整个体系时。卫生部长罗伯特・F・肯尼迪 Jr. 下令削减卫生与公众服务部约 10,000 个工作岗位，并对高层领导进行大规模调整。在 FDA，专员马蒂・马卡里宣布了多项计划，包括通过专员国家优先券加快药物审查、通过尚未明确的 conditional approval 途径加快罕见病疗法审批，以及禁止制药代表参加某些咨询委员会。 这一系列动荡使得沟通系统崩溃，不确定性肆虐。曾在前总统乔・拜登任内担任白宫国家药物管制政策办公室主任、现任 AI/ML 公司 GATC Health 总裁的拉胡尔・古普塔指出，那些资金并不充裕、致力于研发罕见病治疗方法的公司，迫切需要一个清晰的框架，明确可接受与不可接受的范畴以及流程，而非在每次与 FDA 打交道时都感觉在用有限的资金赌博。五家药企的坎坷审批路赛雷普塔的夏日风波 马萨诸塞州的生物科技公司赛雷普塔 Therapeutics 无疑是这个夏天生物制药领域的焦点。春季，两名接受 Elevidys 治疗的非卧床青少年患者因急性肝损伤死亡，公司为此在 Elevidys 标签上添加了急性肝损伤和急性肝衰竭的黑框警告，以应对风险。 然而，第三名患者 —— 一名参与赛雷普塔 SRP - 9004 用于肢带型肌营养不良症（LGMD）I 期研究的 51 岁非卧床男性（该疗法与 Elevidys 采用相同基础技术）死亡后，FDA 采取行动，要求该公司停止在美国境内所有基因疗法的发货，并暂停所有 LGMD 临床试验，还撤销了此前授予该公司病毒载体技术的平台 designation。 起初，赛雷普塔坚决拒绝 FDA 的要求。其在 7 月 18 日的声明中称，当天早些时候通过媒体报道才首次得知这一潜在要求，而公司已于 7 月 3 日将死亡事件告知 FDA。FDA 随后证实了这一点，但向 STAT 新闻表示，该报告在官僚体系中丢失，实际上是在《生物世纪》报道时才与公众一同知晓，且该机构一直计划在出现第三例死亡时采取行动。 最终，赛雷普塔同意暂停 Elevidys 的发货，这引发了患者群体为期一周的行动，他们渴望重新获得该治疗。7 月 28 日，FDA 180 度大转弯，建议解除对能行走患者使用 Elevidys 的自愿暂停。次日，生物制品评价和研究中心（CBER）主任维奈・普拉萨德离职，多位消息人士称这与赛雷普塔事件有关。 BMO 资本市场的科斯塔斯・比利奥里斯在 7 月 30 日给投资者的信中写道，FDA “史无前例” 的泄密是 CBER 的 “失误”，给赛雷普塔和患者都造成了困惑。卡普里科的沟通纠纷 卡普里科 Therapeutics 也被卷入了 FDA 变革的漩涡。该公司首席执行官琳达・马班在 8 月 11 日的第二季度 earnings call 中表示，7 月其细胞疗法 deramiocel 被拒 “出乎意料，因为此前与 FDA 的互动态势积极”。 而在此次拒绝之前，就已出现戏剧性事件。马班在早些时候接受 BioSpace 采访时称，据一位 STAT 记者从机构内部人士处获得的消息，FDA 治疗产品办公室前主任妮可・Verdun 及其副手雷切尔・阿纳托尔因 “关于我们文件的争论” 被行政休假，普拉萨德想要拒绝他们的申请，而妮可则在为之抗争。 7 月 29 日普拉萨德离职后，马班对公司争取推翻拒绝结果抱有乐观态度。但在他不到 10 天就回归后，马班再次向 BioSpace 表示：“我的第一反应是非常惊讶。很明显他是被要求离开的…… 但我认为这表明马卡里对他极为信任。我们都明白其中的影响，除了普拉萨德这条线，没有太多其他途径可走。” 尽管如此，卡普里科仍在全力推进 deramiocel 的重新提交计划。该生物科技公司于 8 月 13 日与 FDA 举行了 A 型会议，讨论前进的道路，但马班表示希望能与未出席会议的普拉萨德会面，“我们从未与他有过任何直接沟通。我们非常希望能有这样的沟通，但目前还没有。”Ultragenyx 的未读回复 同样在 7 月 11 日，FDA 拒绝批准 Ultragenyx 的在研体内基因疗法 UX111，该疗法拟用于治疗 Sanfilippo 综合征 A 型，这是一种极其罕见的疾病，会导致包括语言和发育迟缓以及进行性智力障碍在内的神经系统症状。 在 7 月 17 日 STAT 新闻的播客《The Readout Loud》中，Ultragenyx 首席执行官埃米尔・卡基斯表示，在 CMC 检查过程中发现了一些问题，公司正在着手解决。卡基斯称，Ultragenyx 已向 FDA 发送了 “大量非常详尽的回复”。然而，在收到完整回复函（CRL）时，“他们实际上并未阅读或完成对我们最后四次回复的审查。他们在未充分审查这些回复的情况下就发出了 CRL。” 卡基斯在 7 月 11 日的一份事先准备好的声明中表示，Ultragenyx“认为这些（CMC）观察结果很容易解决，而且许多已经得到解决”。该公司计划重新提交审批申请，并预计 UX111 还需要六个月的审查期。Replimune 的意外拒绝 与名单上的其他三家公司不同，Replimune 的候选药物被拒显然要 “归功于” 一位资深 FDA 领导人。据多家新闻媒体报道，FDA 肿瘤卓越中心（OCE）主任兼肿瘤疾病办公室代理主任理查德・帕兹杜尔直接干预，对 Replimune 的晚期黑色素瘤药物 RP1 发出了 CRL。帕兹杜尔担任该机构首席癌症策略师已超过 25 年。 一位不愿具名的 FDA 官员在 8 月 4 日告诉 STAT 新闻，CBER “从一开始就对 RP1 的审查处理不当”，迫使帕兹杜尔及其团队介入。该人士补充说，CBER 内部的领导层动荡加剧了这种情况。 在 Replimune 宣布收到 CRL 时，首席执行官苏希尔・帕特尔对这一决定表示惊讶。他在一份事先准备好的声明中说：“CRL 中强调的问题在中期和后期审查中并未被机构提出。此外，我们在验证性研究的设计上也达成了一致。我们坚信，RP1 与纳武单抗（百时美施贵宝的 Opdivo）联合使用能为晚期黑色素瘤患者带来显著益处。” 8 月 5 日，22 位设计并开展 RP1 三期试验的专家发表公开信，回应了 CRL 中列出的几个问题，并敦促 FDA “重新审查” Replimune 的申请。 这一决定还产生了进一步的影响。上月末，Krystal Biotech 终止了其用于实体瘤的在研瘤内疗法 KB707 的 I/II 期研究。Krystal 公司企业发展副总裁斯特凡纳・帕奎特在接受 STAT 采访时表示，FDA 拒绝 RP1 后，KB707 “潜在加速审批途径的不确定性加剧”，这是该公司做出这一决定的原因之一。诺瓦瓦克斯的延迟 4 月 1 日，FDA 未能如期就诺瓦瓦克斯 2024 - 2025 配方的 COVID - 19 疫苗做出决定，这引发了人们对整个疫苗领域的担忧。这家总部位于马里兰州的公司最终勉强获得了 Nuvaxovid 的批准，但前 FDA 副专员彼得・卢里在 6 月告诉 BioSpace，这一审批过程可能是对 FDA integrity 构成威胁的 “预兆”。 4 月 2 日，Politico 报道称，FDA 副专员萨拉・布伦纳直接干预了诺瓦瓦克斯疫苗申请的审查。几天后，肯尼迪表示，这一延迟反映了卫生与公众服务部 “将优先事项转向多抗原疫苗”，导致该公司股价下跌 24%。卢里和其他三位前政府官员在 6 月发表于《美国医学会杂志》的一篇专栏文章中写道，布伦纳和肯尼迪的影响与正常程序存在显著偏差。 5 月 16 日，FDA 批准 Nuvaxovid 用于所有 65 岁及以上的老年人以及 12 至 64 岁有 COVID - 19 严重后果高风险的人群。根据 FDA 5 月推出的新的基于风险的 COVID - 19 疫苗接种方法，目前在美国销售的另外三种疫苗 —— 辉瑞和 BioNTech 的 Comirnaty、Moderna 的 Spikevax 和 mNEXSPIKE—— 也受到了类似限制。 FDA 的这场动荡给生物制药行业带来了巨大的不确定性，这些公司的遭遇只是冰山一角。未来，随着局势的发展，行业对 FDA 能尽快稳定下来、提供清晰监管框架的期待愈发强烈。 参考来源：https://www.biospace.com/fda/5-companies-caught-on-a-carousel-of-fda-confusion 识别微信二维码，添加抗体圈小编，符合条件者即可加入抗体圈微信群！ 请注明：姓名+研究方向！ 本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

iStock, mpalis Amid an unprecedented turnover in leadership at the FDA and mass layoffs of staff, communication has crumbled and uncertainty runs rampant, leaving small and medium biopharma companies without a clear path forward for their therapies. Change is hard—especially when a new administration comes in gung-ho to overhaul the entire system. For Health Secretary Robert F. Kennedy Jr., this has meant slashing some 10,000 jobs at the Department of Health and Human Services and overseeing an extensive turnover of leadership at the highest levels . At the FDA, Commissioner Marty Makary has announced plans to speed drug reviews through avenues such as the Commissioner’s National Priority Voucher , expedite rare disease therapies through a yet-to-be-defined conditional approval pathway and ban pharmaceutical representatives from some advisory committees. With all this upheaval, many biopharma companies have gotten caught up in the confusion. Ironically, many of them are seeking approval for rare disease therapies. Capricor Therapeutics, Ultragenyx and Replimune have expressed surprise at recent rejections in Duchenne muscular dystrophy (DMD) cardiomyopathy , Sanfilippo syndrome type A and melanoma , respectively. Meanwhile, three deaths stemming from Sarepta’s gene therapy platform—two of which were associated with its DMD therapy Elevidys—prompted the FDA to request the company halt all shipments of the approved therapy. Amidst these developments, Center for Biologics Evaluation and Research Director Vinay Prasad suddenly left his role , only to return less than two weeks later. With rumors swirling of his direct involvement in some regulatory decisions, his temporary ouster only adds to the uncertainty some biotechs are facing. “These companies who don’t have a lot of cash at hand, they’re actually looking to create these treatments for rare diseases,” Rahul Gupta, president of AI/ML company GATC Health, who served as head of the White House Office of National Drug Control Policy under former President Joe Biden, told BioSpace . “They need a very clear framework, a blueprint of what’s acceptable, what’s not acceptable, and how things will go so they’re not feeling like they’re gambling with their limited amount of funds every time they go up to the FDA.” Here, BioSpace unpacks the journeys of five biotechs that have tangled with the new FDA over the past six months. Sarepta’s Summer Saga Like it or not, the biopharma story of the summer belongs to Sarepta Therapeutics. The Massachusetts-based biotech had a difficult spring, with two nonambulatory teenage patients taking Elevidys succumbing to acute liver injury. It appeared that Sarepta was managing the risks, adding a black box warning to Elevidys’ label for acute liver injury and acute liver failure. But after the death of a third patient —a 51-year-old nonambultory man who had been participating in a Phase I study of Sarepta’s SRP-9004 for limb-girdle muscular dystrophy (LGMD), which used the same underlying technology as Elevidys—the FDA acted, requesting that Sarepta stop all shipments of the gene therapy in the U.S. and pause all LGMD clinical trials. The agency also revoked the platform designation the biotech had previously been granted for its viral vector technology. Initially, Sarepta stood its ground, refusing the FDA’s request. Notably, in its July 18 statement, the company said, “We first heard of this potential request earlier in the day at the same time the public and our patient communities did, through media reports.” The company noted in the same press release that it had alerted the FDA to the death on July 3. The agency later confirmed this to be true but told STAT News that the report had been lost in the bureaucracy and that it had, in fact, only learned of the death with the rest of the world when BioCentury reported it . The FDA further stated it had always planned to take action if a third death occurred. Sarepta ultimately relented to the FDA’s request to halt Elevidys shipments, setting off a week of action for patient groups eager to regain access to the treatment. That action apparently worked. On July 28, the FDA did a 180 and recommended that the voluntary hold on Elevidys be lifted for ambulatory patients. The following day, Prasad was out as CBER director —a development multiple sources suggested was connected to the Sarepta saga. The “unprecedented” FDA leaks were “missteps” on the part of CBER that sowed confusion for both Sarepta and patients, BMO Capital Markets’ Kostas Biliouris wrote to investors on July 30. Capricor Communication Kerfluffle Capricor has also reportedly been caught on the carousel of FDA change. The rejection of the company’s cell therapy deramiocel in July “was unexpected given the trajectory of positive [FDA] interactions,” CEO Linda Marbán said during the company’s second-quarter earnings call on Aug. 11. Drama reportedly predated the rejection, however. Nicole Verdun, the former director of the FDA’s Office of Therapeutic Products, and her deputy, Rachael Anatol, were allegedly “put on administrative leave because of an argument about our file, and that Prasad wanted to [reject] us and Nicole was fighting it,” Marbán told BioSpace in an earlier interview, attributing the information to a STAT reporter who’d contacted her after receiving a tip from an agency insider. After Prasad stepped aside from his role on July 29, Marbán expressed optimism about the company’s chances of fighting the rejection. Speaking again with BioSpace after his return less than 10 days later, she said: “My initial reaction was of great surprise. It was pretty clear that he was asked to leave . . . but I think what it showed is that Makary has tremendous faith in him. We all understand the ramifications of that, that there’s not a lot of ladders you can go up besides the Prasad ladder.” Nevertheless, Capricor is full speed ahead with its resubmission plans for deramiocel. The biotech met with the FDA on Aug. 13 for a type A meeting to discuss a path forward, but Marbán said she would appreciate an audience with Prasad, who did not attend the meeting. “We’ve never had any direct communication from or with him. We would like that very much, but nothing so far.” Ultragenyx’s Unread Responses Also on July 11, the FDA declined to approve Ultragenyx’s investigational in vivo gene therapy UX111, which the biotech is proposing for Sanfilippo syndrome type A—an ultrarare disease that leads to neurological symptoms including language and developmental delays and progressive intellectual disability. On the July 17 edition of STAT News ’ podcast, The Readout Loud , Ultragenyx CEO Emil Kakkis said that a number of issues were raised during the CMC inspection process, which the company was in the process of addressing. Ultragenyx had sent the FDA “a number of very large responses,” Kakkis said. However, at the time of the complete response letter (CRL), “they hadn’t actually read or completed review of the last four responses we had given them. They issued the CRL before they had fully reviewed those responses.” Ultragenyx “believes that these [CMC] observations are readily addressable and many have already been addressed,” Kakkis said in a prepared statement on July 11. Ultragenyx plans to resubmit an approval application and anticipates another six-month review period for UX111. Replimune’s Surprise Rejection In contrast to the other three companies on this list, Replimune can apparently thank a legacy FDA leader for the rejection of its candidate. According to reporting by multiple news outlets, Richard Pazdur , director of the FDA’s Oncology Center of Excellence (OCE) and acting director of the Office of Oncologic Diseases, directly intervened to issue the CRL for Replimune’s advanced melanoma drug, RP1. Pazdur has been the agency’s chief cancer strategist for more than 25 years . An unnamed FDA official told STAT News on Aug. 4 that CBER “mishandled the RP1 review from the beginning,” compelling Pazdur and his team to get involved. The situation was exacerbated, the individual added, by the leadership upheaval within CBER. In Replimune’s announcement of the CRL, CEO Sushil Patel expressed surprise with the decision. “The issues highlighted in the CRL were not raised by the agency during the mid- and late-cycle reviews,” he said in a prepared statement. “Additionally, we had also aligned on the design of the confirmatory study. We strongly believe that RP1 in combination with nivolumab [Bristol Myers Squibb’s Opdivo] can bring substantial benefit to advanced melanoma patients.” On Aug. 5, 22 experts who designed and ran RP1’s Phase III trial issued an open letter responding to several issues outlined in the CRL and urging the FDA to “re-review” Replimune’s application. This decision has had further reverberations as well. Late last month, Krystal Biotech discontinued a Phase I/II study of its investigational intratumoral therapy KB707, which it is developing for solid tumors. Speaking with STAT, Stéphane Paquette, Krystal’s vice president for corporate development, said “heightened uncertainty regarding potential accelerated approval pathways” for KB707 following the FDA’s rejection of RP1 contributed to the biotech’s decision. Novavax’s Delay When the FDA missed its deadline to issue a decision regarding the 2024–2025 formulation of Novavax’s COVID-19 vaccine on April 1, concern circulated about what it could mean for the broader vaccines space. While the Maryland-based company did ultimately secure a narrow nod for Nuvaxovid, the approval process represented a potential “harbinger” of a threat to the FDA’s integrity, former FDA associate commissioner Peter Lurie told BioSpace in June. On April 2, Politico reported that deputy FDA commissioner Sara Brenner directly intervened in the review of Novavax’s vaccine application. A few days later, Kennedy said the delay reflected HHS’ “shifting [its] priorities to multiple-antigen vaccines,” causing the company’s shares to drop by 24%. The influence of both Brenner and Kennedy is a significant deviation from normal protocols, Lurie and three other former government officials wrote in an op-ed published in the Journal of the American Medical Association in June. On May 16, the FDA approved Nuvaxovid for all seniors aged 65 years and older and people 12 through 64 years of age at high risk for severe outcomes from COVID-19. Similar restrictions have now also been applied to the three other vaccines marketed in the U.S.—Pfizer and BioNTech’s Comirnaty and Moderna’s Spikevax and mNEXSPIKE—in line with the FDA’s new risk-based approach to COVID-19 vaccination introduced in May.