Somatrogon(OPKO Health, Inc.)

The FDA asserts that it released the complete response letters in a bid to “modernize and increase transparency.” When the FDA unexpectedly uploaded around 200 drug rejection letters this week, the regulator provided an in-depth view into the high-stakes discussions that decide whether a medicine will ever make it to market.  The FDA said it released the complete response letters (CRLs) on Thursday morning as part of an effort to “modernize and increase transparency” at the agency. We’ve typically had to rely on the companies themselves to communicate the FDA's rejection rationale in the immediate aftermath of the decisions—assuming they chose to go into any detail at all—so the FDA's document drop offered an opportunity to cross-reference agency records and public communications from pharmas.In addition, the haul of documents offers insight into not only the rationale the FDA employs during its reviews, but also the language the agency uses to communicate these decisions.If you don’t have a spare weekend to read through hundreds of pages of letters, then have no fear; The Fierce Biotech and Fierce Pharma teams have trawled through the documents ourselves and selected some of the examples that we found most enlightening. One caveat to note: Most drugmakers are reasonably transparent when hit with a CRL, and given that the products involved in the initial batch of published responses are all now approved, the FDA’s previous comments don’t reflect the current status of the drugs in question, analysts at Evercore ISI noted in a webinar Friday.“Good companies have no incentive to be tricksy,” given that the information will eventually come out if their drug passes muster at the FDA, Evercore’s Jonathan Miller said on the call.Still, while several companies' press releases “didn’t fully capture” what was disclosed in their respective FDA response letters, “those are absolutely the exception,” he stressed, adding that “the majority of CRLs are well reported.” Response letters are typically tucked into drug approval packages, so most of the information published by the FDA was previously accessible, albeit cumbersome to access. Consolidating the letters certainly makes it easier for the public to glean the FDA’s rationale, though releasing rejection notices for unapproved drugs would represent a greater step toward full transparency.A ‘concerning reduction’ in growth Pfizer’s rare disease strategy suffered an unexpected setback in 2022 when the FDA rejected Ngenla (somatrogon), a potential treatment for pediatric growth hormone deficiency. The CRL came as a surprise—given the drug had already been approved in Japan, Australia and Canada—and Pfizer’s announcement offered no insight into the agency’s decision. But the FDA’s letter now reveals that one of the key reasons for the agency’s decision was a single individual in a phase 3 open-label trial who developed a “concerning reduction” in annualized height velocity (AHV)—in other words, their growth had slowed.  “There are insufficient follow-up data to determine whether the reduction in AHV in this patient was caused by immunogenicity, and we consider attenuation of effectiveness due to immunogenicity to be a potential risk at this time,” the FDA explained in its letter.  The agency requested that Pfizer “provide reassurance that the anti-drug antibody formation caused by [somatrogon] is not expected to have an impact on long-term growth achieved with [somatrogon] and does not interfere with other recombinant human growth hormone formulations.” The FDA was presumably reassured by the data Pfizer included as part of its resubmission, as the pharma eventually secured approval of Ngenla the following year. In poor taste Sometimes, the reason for a drug’s rejection can leave a bad taste in the mouth—literally. When considering a request from Galephar Pharmaceutical to approve Legubeti as an oral solution for acetaminophen overdose, the FDA noted that Legubeti’s long-approved ingredient, N-acetylcysteine, “has an unpleasant odor that may affect the tolerability of oral ingestion.”“Because timely administration of acetylcysteine is essential to mitigate toxicity from acetaminophen overdose, uncertainty remains as to whether ingestion of the full Legubeti dose can be administered, either due to inadequate palatability or inadequate tolerability,” the FDA said in its May 2023 letter. Bad taste or not, Legubeti was later approved by the FDA in 2024.  Cardiovascular risk When Amgen and UCB’s application for Evenity (romosozumab) as a treatment for postmenopausal women with osteoporosis was knocked back by the FDA in 2017, it was no secret that one of the factors at play was an increase in cardiovascular risks identified in two studies. However, when Amgen described the feedback received in the CRL, the pharma was less clear-cut, only referring to the agency’s request to submit more efficacy and safety data from its various phase 3 studies. In fact, the CRL itself confirms that the FDA did indeed home in specifically on the cardiovascular risks when explaining the rational for the rejection, pointing explicitly to preliminary findings from the phase 3 Arch study, which it said showed “a higher incidence of cardiovascular serious adverse events with romosozumab compared to alendronate in women with postmenopausal osteoporosis.” A “similar signal” was seen in the Bridge study, the FDA also noted in the letter.  “These findings raise concerns that romosozumab may increase cardiovascular risk,” the FDA added. “Although [the Frame phase 3 study] did not appear to have a cardiovascular safety signal, these disparate findings across studies require detailed review once the completed final analyses have been submitted.” Evenity was eventually approved in 2019 with a boxed warning for the risk of stroke, heart attack, and cardiovascular death. ‘Weak and contradictory' evidence Sometimes it’s not what you say, but how you say it. That’s certainly one reason why the FDA’s letter to Orphazyme is interesting. When the Danish biopharma’s application for Miplyffa (arimoclomol) in the rare lysosomal storage disorder Niemann-Pick disease type C was rejected in 2021, Orphazyme was open about the fact that “additional qualitative and quantitative evidence” had been requested in a number of areas, including the validity and interpretation of its primary endpoint, along with additional data to support a benefit-risk assessment.  In its letter, we can now see that the FDA was even blunter in its own language. The agency branded the company’s submitted evidence for Miplyffa’s effectiveness as “weak and contradictory” a total of three times in the same letter and stressed that it had already identified various concerns with the primary endpoint measurement “at several time points during your [investigational new drug] development.”  The letter went on to list the various times the FDA had tried to hammer home its concerns, before noting that—“despite our advice”—the requested data had not been included in the final drug application. Orphazyme's CRL was "one of the ones where it got a little bit spicy," said Evercore's Miller, who noted that the rejection potentially offers "the first example here where I would say there's some suspect decision-making at the company." The FDA document can’t have been easy reading at Orphazyme’s Copenhagen HQ, and the company was eventually acquired in full by KemPharm. Luckily, Miplyffa’s story didn’t end there and KemPharm, which rebranded as Zevra Therapeutics, went on to see the med become the first approved treatment for Niemann-Pick disease type C. Third-party data concerns In other instances, the CRLs highlighted shortfalls by contract development and manufacturing organizations (CDMOs), which often go unnamed in FDA and company communications.  When Checkpoint Therapeutics received a rejection for its oncology asset cosibelimab in late 2023, the company attributed the FDA’s decision to issues uncovered during an inspection of a  “third-party contract manufacturing organization.”  That manufacturer, as the company’s CRL shows, was Samsung Biologics. Samsung Bio offered remediation solutions after the FDA uncovered problems during an inspection of one of its production facilities in Incheon, South Korea, but the FDA stated in its complete response letter to Checkpoint that “not all deficiencies have been satisfactorily resolved.”  Samsung Bio's response to the inspection findings didn’t sit right with the FDA, which asserted in the CRL that it had “identified concerns regarding the reliability of data generated at Samsung Biologics."“The concerns impact data that support drug substance and drug product manufacturing process validation and process characterization,” the FDA said in its rejection notice. “Therefore, the adequacy of the proposed cosibelimab manufacturing process and overall control strategy cannot be determined at this time to support the licensure of cosibelimab.”  Checkpoint’s PD-L1 inhibitor, cosibelimab, ultimately secured FDA approval last December as a new treatment option for certain types of cutaneous squamous cell carcinoma. 

关注并星标CPHI制药在线 3月21日，维昇药业在第四次向港交所递交IPO文件后，终于顺利“敲钟”，成为“港股生长发育第一股”。事实上，无论是运营模式还是管线产品，维昇药业都有值得业界学习的地方。　 反向Newco标杆 维昇药业成立于2018年，由丹麦药企Ascendis Pharma A/S（下称Ascendis）、维梧资本和Sofinnova Ventures共同在上海创立。其中Ascendis以产品入股，维梧资本和Sofinnova Ventures出资支持。 这一模式与近两年来国内涌现的NewCo模式不同。作为一种复杂的创新药资产交易模式，传统NewCo是指新公司由境外资本出资设立，在获得中国药企许可的管线权益后，向NewCo公司提供资金并负责经营管理，中国药企除了获得管线的授权许可费外，还可以获得NewCo公司的部分股权，NewCo公司今后独立在境外IPO或公司/管线被MNC并购。 而维昇药业这种借助海外药企技术+本土化运营的模式，与传统NewCo模式恰恰相反，这一新颖模式被形象地称为反向NewCo。　 专注内分泌领域，避开红海市场 根据维昇药业与Ascendis的达成独家许可协议，公司能够在相关地区开发、生产和商业化隆培促生长素（lonapegsomatropin）、那韦培肽（navepegritide）及帕罗培特立帕肽（palopegteriparatide）等内分泌领域的候选药物，这三款药物也是维昇药业的核心产品。与扎堆内卷PD-1、GLP-1等大赛道的药企不同，维昇药业从一开始就避开这些红海市场，专注内分泌疾病领域。据弗若斯特沙利文数据，预计到2026年，中国的非糖尿病类内分泌药物市场规模将增至68亿美元；到2030年将增至115亿美元。与此同时，目前至少有近一半的内分泌疾病缺乏有效的治疗手段。 以隆培促生长素为例，这是一款每周一次的长效生长激素替代疗法。已获FDA及欧盟EMA批准上市，用于治疗儿童生长激素缺乏症（PGHD）。 GHD是一种因下丘脑-垂体轴的器质性病变或功能性异常导致生长激素缺乏引起的疾病，患者表现为身材矮小、代谢异常、认知缺陷和生活质量差等问题。据相关媒体报道，我国4-15岁的人群矮小症发病人数有700万，但每年就诊人数预估不足30万人，接受规范治疗的患者渗透率仍然远远低于欧美国家。 对于PGHD来说，补充生长激素是目前公认的最有效方法之一。生长激素是由脑垂体前叶嗜酸性细胞分泌的一种长度为191个氨基酸的肽类 激素，通过刺激肝脏等组织产生胰岛素样生长因子（IGF -1）发挥生理功能，促进骨骼生长，促进蛋白质合成，调节脂肪、糖、矿物质代谢等。目前，国内已上市的生长激素产品，还是以短效类产品为主，高端的长效类产品仅获批一款——金赛增（金赛药业，长春高新子公司），患者的需求远没有得到充分满足。预计2030年，长效生长激素将是PGHD的主要疗法，市场份额占比可达74%。 隆培促生长素基于维昇药业的暂时连接技术（TransCon），被设计为每周一次给药方案，并在体内释放未经修饰的与人内源性生长激素相同的分子，保留了原始作用机制。 据国内III期临床试验数据显示，隆培促生长素的年化生长速率为10.66厘米/年，优于传统短效制剂的9.75厘米/年，达到研究主要终点。 基于该III期临床试验，2024年3月，隆培促生长素在国内的上市许可申请（BLA）获得中国国家药监局受理，预计于2025年在中国上市。 值得一提的是，隆培促生长素海外上市以来，销量一路攀升。2024年，其销售额达到2.02亿欧元（约14.7亿元人民币），同比增长高达84%。 另一款核心产品那韦培肽，是一款C型利钠肽的长效前药，每周一次给药，拟开发用于治疗2至10岁软骨发育不全患者，该患者群体在国内有超过5万人。据国内II期临床试验显示，在治疗第52周时，剂量为100μg/kg/周的队列的那韦培肽的AGV（5.939厘米/年）较安慰剂（4.760厘米/年）高。 帕罗培特立帕肽是一种甲状旁腺激素替代疗法，每日一次，拟开发用于治疗慢性甲状旁腺功能减退症，该病由于甲状旁腺激素分泌减少或功能缺陷，引起钙磷代谢异常。 在一项III期关键试验中，经过长达156周的治疗，77.6%（45/58）接受帕罗培特立帕肽治疗的患者达到了主要终点（界定为在治疗第26周时，符合下列要求的受试者比例：白蛋白校正血清钙浓度在正常范围内，停用骨化三醇或阿法骨化醇活性维生素D，且停用治疗剂量的钙，在26周随访前的4周内未增加研究药物的剂量），而对照组中0.0%（0/22）的患者达到了主要终点。 早在2023年9月，国家卫生健康委等6部门联合制定了《第二批罕见病目录》，软骨发育不全和遗传性甲状旁腺功能减退症均被纳入其中，意味着该类疾病将得到全方位的政策支持。 除了在内分泌蓝海市场布局产品管线外，维昇药业的TransCon（Transient Conjugation，暂时连接）平台深受药企关注。　 独一无二的技术平台，引诺和诺德押注 为了攻克肽类激素（如生长激素等）长效化的壁垒，维昇药业开发了TransCon（Transient Conjugation，暂时连接）技术平台，TransCon分子包括三个部分：未经修饰的原型药物，保护原型药物的惰性载体分子和将两者暂时连接起来的连接体。当3部分结合后，形成前药，其载体分子可以使得原型药物以无活性状态存在，不被机体清除。当前药注射至人体内，在生理条件的PH和体温下，有活性的、未经修饰的原型药物将以可控的方式释放出来，从而实现了从短效到长效的突破。 2024年11月，维昇药业宣布授予诺和诺德TransCon技术平台的全球独家许可，以开发、制造和商业化诺和诺德在代谢性疾病（包括肥胖和2型糖尿病）方面的产品等。维昇药业将有资格获得高达2.85亿美元的预付款、开发和监管里程碑付款，以及基于销售额的里程碑付款和全球净销售额的分层特许权使用费等。该合作的达成肯定了TransCon在长效化技术方面的优势。 维昇药业通过反向NewCo落地中国，如今凭借核心产品和技术平台在港股上市，未来公司将有望以全方位的优势，缔造内分泌赛道全新的传奇。 参考资料：　 1.维昇药业招股书 https://www1.hkexnews.hk/listedco/listconews/sehk/2025/0313/2025031300018_c.pdf. 2.https://www.hsppharma.com/news/pfizer-once-a-week-long-acting-drug-somatrogon-38750405.html. 3.Miller BS, Yuen KCJ. Spotlight on Lonapegsomatropin Once-Weekly Injection and Its Potential in the Treatment of Growth Hormone Deficiency in Pediatric Patients. Drug Des. END 2025金笔奖征文活动开启，来投稿吧！ 领取CPHI & PMEC China 2025展会门票 智药研习社直播预告 来源：CPHI制药在线 声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。 投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~