An open-label, multicenter, randomized, parallel-group, phase III study to verify the superiority and evaluate the efficacy and safety of daily administration of JR-401 (0.3 mg/kg/week) versus daily administration of JR-401 (0.175 mg/kg/week) in pediatric patients with growth hormone deficiency

开始日期2026-02-01

申办/合作机构

JCR Pharmaceuticals Co., Ltd.

JPRN-jRCTs051250164

/ RecruitingN/A

An Open-Label Randomized Controlled Trial Investigating the Impact of Vitamin D Sufficiency on Bone and Skeletal Muscle During Growth Hormone Replacement Therapy (GHRT)

开始日期2025-12-08

申办/合作机构-

NCT07323329

/ Recruiting临床2/3期IIT

Growth Hormone and Dehydroepiandrosterone Effect on Poor Ovarian Reserve Patients During in Vitro Fertilization

The goal of this study is to evaluate the role of Somatropin and Dehydroepiandrosterone (DHEA) on ovarian reserve parameters and intracytoplasmic sperm injection (ICSI) outcome in poor ovarian responder.
The main question it aims to answer is:
Which intervention is more effective in increasing number and size of follicles? Participants will be followed 1 month before starting induction in growth hormone and 12 weeks for DHEA and through intracytoplasmic sperm injection (ICSI) cycle.

开始日期2025-10-10

申办/合作机构

Beni-Suef University

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项与生长激素(Merck Serono SA) 相关的文献（医药）

2026-02-01·BMJ Open

Recombinant human growth hormone (rHGH) for muscle enhancement in knee osteoarthritis: protocol for a pilot, randomised placebo-controlled trial

Article

作者: Kiss, Alexander ; Burkhart, Timothy A ; Shah, Ajay ; Marks, Paul ; Whyne, Cari ; Wasserstein, David N ; Tomescu, Sebastian ; Catapano, Michael ; Ravi, Bheeshma

Introduction:

The management of active patients with symptomatic knee osteoarthritis (KnOA) who are too young for total knee arthroplasty poses a specific challenge to clinicians. Research studies show that improving quadriceps muscle strength improves pain and function; however, aspects of the disease render it difficult for patients to achieve and maintain improvements. Recombinant human growth hormone (rHGH) is shown to increase the magnitude and duration of muscle growth when combined with exercise treatment in adult populations. Hence, rHGH combined with physical therapy may provide meaningful benefits in the treatment of KnOA.

Methods and analysis:

This is a single-centre, double-blind, randomised trial to pilot a future Phase III trial from 2025 to 2028. Participants are aged 18–60 with clinical and radiographic evidence of isolated degenerative arthritis of the knee (patellofemoral or tibiofemoral). The investigational product is rHGH (Saizen (somatropin of rDNA origin, EMD Serono)) and a saline placebo. Participants will deliver the solution via subcutaneous injection area once per day at a dose of 0.5 mg HGH per body surface area (0.5 mg/m 2 ) for 6 weeks, alongside participation in a lower limb strengthening programme developed by rehabilitation specialists. 17 participants will be recruited into each study arm. The primary outcomes are feasibility (compliance with the study drug regimen for the 6-week administration period and enrolment rate) and safety (the proportion of minor and major adverse events between groups). The primary endpoint for these outcomes will be at 6 weeks. The secondary outcomes are knee extension strength, knee flexion strength, radiographic arthritis progression, thigh muscle circumference, MRI-measured quadriceps muscle volume and patient-reported outcome measures (Knee Osteoarthritis Outcome Score (KOOS), SF-20 and Tegner). The primary endpoint for these outcomes will be at 12 weeks, and the final endpoint will be 24 months, where final radiographic (X-ray) assessment will take place. The primary outcome of compliance will be a calculation of mean compliance between groups, which can be analysed as a t-test after the treatment period. A two-sample, two-sided t-test will compare the clinical (secondary) outcome of greatest interest: knee extension strength at baseline versus week 6 compared between treatment groups. Other secondary outcomes will be compared using a simple linear mixed-effects model. The χ 2 test will be used to determine whether the number of participants who made meaningful changes was different between groups. The null hypotheses are that the rHGH and placebo groups will have no difference in compliance rates, safety events, knee extension strength at 12 weeks and arthritis grade progression at 24 months.

Ethics and dissemination:

This study has been approved by the Sunnybrook Research Institute Research and Ethics Board (#6427) and received a no-objection letter from Health Canada Clinical Trials. The primary sponsor is the Sunnybrook Centre for Clinical Trial Studies (CCTS). The findings of this study will be published in a peer-reviewed journal and presented at orthopaedic conferences.

Trial registration number:

NCT07036003 .

2025-01-01·PLoS One

Persistence with daily growth hormone among children and adolescents with growth hormone deficiency in Japan.

Article

作者: Wajnrajch, Michael P ; Benjumea, Darrin ; Jhingran, Priti ; Wogen, Jenifer ; Alvir, Jose ; Takasawa, Kei ; Chen, Yong ; Loftus, Jane

BACKGROUND:

Pediatric growth hormone deficiency (pGHD) is treated with daily somatropin (recombinant human growth hormone) injections. High rates of discontinuation and poor adherence to treatment, which are associated with worse growth outcomes, have been documented previously, for example in the US and Europe. Discontinuation of somatropin has not yet been evaluated using real-world data in Japan.

OBJECTIVES:

To describe discontinuation of, and persistence to, daily somatropin treatment among children with pGHD in Japan.

METHODS:

This was a retrospective cohort study of children (≥3 and <16 years old) who were prescribed somatropin, using 2 Japan-based databases, Japan Medical Data Center (JMDC) and Medical Data Vision (MDV). Children were required to have ≥1 prescription for somatropin (first prescription = index date) within each study period (1 January 2002-30 September 2021 for JMDC and 1 January 2009-31 October 2021 for MDV) and ≥1 GHD diagnosis code without a somatropin prescription during the 6-months pre-index period. Children were required to be continuously enrolled in the database ≥6 months preceding and ≥3 months following index date. Children were followed for up to 48 months post-index. Early persistence was defined as the proportion of children with ≥1 refill of somatropin subsequent to the initial prescription. Discontinuation was defined as the first observation of a gap in therapy (using >60, > 90, and 120-day gap thresholds) between successive somatropin prescription fill dates. Persistence was defined as continuous refills of somatropin with no gaps in therapy. Time to discontinuation/non-persistence was evaluated using Kaplan-Meier methods, and Cox proportional hazards models identified predictors of time to discontinuation. This analysis utilized de-identified patient data from 2 large, Japanese-based retrospective databases; as such this study does not meet the requirements for institutional review board (IRB) review.

RESULTS:

Among the children included in this study (JMDC N = 452, MDV N = 573), most were male (JMDC 64.8%, MDV 60.0%). Mean age (standard deviation) was 8.8 (3.6) years in JMDC and 7.5 (3.6) years in MDV. Early persistence was high across both cohorts (JMDC 91.2%, MDV 83.4%). Using the 90-day gap definition for discontinuation, a sizable proportion of children discontinued over the follow-up period: JMDC 19% at 12 months, 35% at 48 months; and MDV 33% at 12 months, 54% at 48 months. Fewer discontinuations were observed with the 120-day gap definition (~16% at 48 months in JMDC, ~ 28% at 48 months in MDV) and more were observed with the 60-day gap definition (~67% at 48 months in JMDC, ~ 83% at 48 months in MDV). No meaningful predictors of discontinuation were identified.

CONCLUSIONS:

Despite high early persistence with somatropin, many children with pGHD in Japan were increasingly non-persistent over time: at 48 months post-index, at least 16% of children discontinued therapy, using the JDMC database and the most conservative measure of gap allowance. These results suggest a need for new strategies to support somatropin medication use over time among children with pGHD in Japan.

2025-01-01·HUMAN REPRODUCTION

Empirical use of growth hormone in IVF is useless: the largest randomized controlled trial

Article

作者: Tadevosyan, Artak ; Phillips, Simon ; Mourad, Ali ; Jamal, Wael ; Hemmings, Robert ; Kadoch, Isaac-Jacques

Abstract:

STUDY QUESTION:

Does adjuvant growth hormone (GH) therapy in GnRH antagonist cycles improve reproductive outcomes in the general IVF population?

SUMMARY ANSWER:

Empiric adjuvant GH therapy in GnRH antagonist cycles does not improve IVF stimulation results or reproductive outcomes, including implantation, miscarriage, and clinical pregnancy rates.

WHAT IS KNOWN ALREADY:

Previous evidence regarding the benefits of GH therapy in IVF cycles has been inconclusive due to the lack of well-designed, large-scale randomized controlled trials (RCTs) in the general IVF population.

STUDY DESIGN, SIZE, DURATION:

This is a phase III open-label RCT involving 288 patients undergoing antagonist IVF cycles at the Ovo clinic in Montreal, Canada, between June 2014 and January 2020. Patients were randomly assigned at a 1:1 ratio to either the GH or control group. The intervention group received daily 2.5 mg subcutaneous injections of GH from Day 1 of ovarian stimulation until the day of oocyte retrieval, while the control group received standard ovarian stimulation without any adjuvant therapy.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

Patients were expected normal responders. All embryo transfers, both fresh and frozen, resulting from the studied IVF cycle were included in an intention-to-treat and per-protocol analyses. The primary outcome was the clinical pregnancy rate, while secondary outcomes included the number of retrieved oocytes, good-quality embryos, maturation, fertilization, implantation, and miscarriage rates.

MAIN RESULTS AND THE ROLE OF CHANCE:

A total of 288 patients were recruited and randomly assigned at a 1:1 ratio to either the GH or the control group. After excluding cycle cancellations and patients who did not undergo transfer, 105 patients remained in each group. The overall mean age was 38.0 years, the mean BMI was 25.11 kg/m2 and the mean anti-Müllerian hormone was 2.51 ng/ml. The cycle characteristics were similar between both groups. No differences were observed regarding the total dose of gonadotropins (4600 versus 4660 IU for the GH and control groups, respectively, P = 0.752), days of stimulation (11.4 versus 11.7 days, P = 0.118), and endometrial thickness (10.63 versus 10.94 mm, P = 0.372). Both the intention to treat (ITT) and per protocol analyses yielded similar results for stimulation outcomes. In the ITT analysis, no differences were found in the number of follicles ≥15 mm (7.8 versus 7.1, P = 0.212), retrieved oocytes (11.7 versus 11.2, P = 0.613), mature oocytes (8.5 versus 8.6, P = 0.851), maturation rate (73.8 versus 78.4%, P = 0.060), fertilization rate (64.3 versus 67.2%, P = 0.388), and good quality embryos (2.5 versus 2.6, P = 0.767). Reproductive outcomes in fresh embryo transfer showed no difference for implantation rate (38.2 versus 39.5%, P = 0.829), miscarriage rate (26.5 versus 31.1%, P = 0.653), clinical pregnancy rate (43.6 versus 50.0%, P = 0.406, rate difference, 95% CI: −0.06 [−0.22, 0.09]), and live birth rate (32.1 versus 33.3%, P = 0.860). The number of embryos needed to achieve a clinical pregnancy was 3.0 versus 2.5 in the GH and control groups, respectively. Similarly, reproductive outcomes in first frozen embryo transfer showed no difference for implantation rate (31.6 versus 45.3%, P = 0.178), miscarriage rate (28.6 versus 26.3%, P = 0.873), clinical pregnancy rate (35.1 versus 44.2%, P = 0.406, P = 0.356, rate difference, 95% CI: −0.09 [−0.28, 0.10]), and live birth rate (22.8 versus 32.6%, P = 0.277). The number of embryos needed to achieve a clinical pregnancy was 3.1 versus 2.4 in the GH and control groups, respectively.

LIMITATIONS, REASONS FOR CAUTION:

The study focused on expected normal responders, limiting its applicability to other patient populations such as poor responders.

WIDER IMPLICATIONS OF THE FINDINGS:

These findings suggest that adding GH therapy to ovarian stimulation in GnRH antagonist cycles may not benefit the general IVF population. Additional high-quality RCTs are warranted to identify subgroups of patients who might benefit from this treatment.

STUDY FUNDING/COMPETING INTEREST(S):

EMD Serono Inc., Mississauga, Canada, supplied Saizen® for the study, free of charge. In addition, they provided funding for the statistical analysis. I-J.K. declares grants or contracts from Ferring Pharmaceuticals, consulting fees from Ferring Pharmaceuticals, honoraria from Ferring Pharmaceuticals and EMD Serono, support for attending meetings or travel from Ferring Pharmaceuticals and EMD Serono, participation on a Data Safety Monitoring Board or Advisory Board for Ferring Pharmaceuticals, and stock or stock options from The Fertility Partners; W.J. declares support for attending meetings or travel from EMD Serono; and S.P. declares stock or stock options from The Fertility Partners. All other authors have no conflicts of interest to disclose.

TRIAL REGISTRATION NUMBER:

NCT01715324.

TRIAL REGISTRATION DATE:

25 October 2012.

DATE OF FIRST PATIENT’S ENROLMENT:

25 June 2014.

项与生长激素(Merck Serono SA) 相关的新闻（医药）

2026-06-14

·百年成长

长效生长激素周制剂药代动力学高变异性及其临床管理策略

1986年，美国“挑战者”号航天飞机在发射后73秒爆炸，7名宇航员全部遇难。事故直接原因是固体火箭助推器的O型密封圈失效。该密封圈在低温下会失去弹性，这一风险此前在部分测试中已被观察到，但工程师基于有限的测试数据，对密封圈在发射当天的低温下的性能做出了过于乐观的“平均化”预测。最终，发射当天的极端低温条件上，本可预测的灾难性失效发生了。人类从这一历史中学到了一个教训就是，在复杂系统中，对关键参数在不同情况下的变异的忽视，尤其是对极端值可能性的低估，对极端风险的统计误判，是导致灾难性个体事件的根本原因。人体同样也是一个复杂系统，药物在体内的代谢在群体上无论上如何统计和解释，落在个体上，就是一个独特的现实情况，特别是儿童处于快速生长发育阶段，肝肾功能、血浆蛋白结合率及靶器官受体密度均处于动态变化中，这种生理上的高度动态性，导致群体药代动力学数据应用于具体个体时，需要更加重视药物在PK/PD上的高变异特点，这是确保医疗安全，呵护患者健康的关键。在生长激素领域，识别并关注这样的风险尤为关键，即，对于生长激素这类需要长期用药的儿童药，半衰期等PK/PD参数是否是高变异的，是临床决策中需要更加重视。必须强调的是，工程系统的“失效风险”与生物系统的“变异风险”性质不同。前者的极端条件（低温）在发射前是已知的，风险理论上可避免；而后者的极端个体变异是药物与复杂人体互动的固有产物，难以在用药前完全预测。两者的核心共通点在于：当关键参数（密封圈弹性或PK/PD）存在巨大不确定性时，基于“平均表现”的设计或方案，在应对极端情况时都可能失效。因此，“高变异”本身就是一个需要被积极管理而非简单接受的风险信号。一、对高变异的解读高变异药物这个概念目前应用于化药领域，根据NMPA指导原则《高变异药物生物等效性研究技术指导原则》，某些药物由于生物利用度过低、酸不稳定、吸收前的广泛代谢等原因，导致一个或多个药动学参数的个体内变异（Intra-subject coefficient of variation，CV%）大于或等于30%，称为高变异药物（Highly variable drug, HVD）。对于高变异药物的生物等效性管理，该原则有单独的、严格的统计判断方法论[1]。在生物药领域，“高变异生物药”在监管法规中不是一个正式类别，但在科学统计和临床开发中，它是一个被广泛承认且必须处理的“事实”。虽然监管不这么叫，但生物药在数据表现上往往是事实上的高变异药物，甚至比化药更甚。这是因为，化药高变异常因首过效应、吸收窗窄（生理因素）。而生物药高变异是源于靶点介导的清除（TMDD）、抗药抗体（ADA）、皮下注射吸收差异（淋巴回流）、受体丰度差异（肿瘤负荷）等生物学异质性和制剂异质性。这种变异不是“噪音”，而是药物作用机制的一部分。正因为生物药变异极大且复杂，统计学家开发了专门的方法如建立PopPK模型（NONMEM）、暴露-效应（E-R）分析来量化并解释变异来源，这些方法在概念上对应并超越了化药的“HVD处理”（放宽BE界限（RSABE））。需特别说明的是，化药“高变异药物”的监管机构定义，是指个体内变异，主要影响生物等效性（BE）研究中样本量设计与等效性判定。本文对生物药“高变异”特征的讨论，则基于个体间变异（Inter‑individual Variability, IIV）——即不同患者间清除率、半衰期等PK参数的离散程度。尽管数值阈值（IIV≥30% CV）与化药HVD的经验界限巧合相近，但二者统计学含义不同：化药HVD关注同一受试者不同时点的PK重现性，而本文关注患者群体中的PK异质性。在群体PK文献及监管审评实务中，清除率IIV≥30% CV通常被视为较高变异、>40–50%为明显高变异[2,3]——此即本文所指生物药"高变异"特征的统计学与临床含义。从统计学的角度来看，“对数正态分布是药代动力学参数的默认假设”这一结论，对化学药和生物药同样适用[3,4,5]。这意味着，大部分药物的PK参数通过对数转换后，能够满足正态分布的分析前提，其个体间变异通常处于可控水平。数据的呈现方式由个体间变异的水平大小决定，在低变异时，可转换后使用均值±标准差或典型值；当个体间变异达到高变异水平时，几何均值配合几何CV是更常见的描述方式，或者采取中位数（范围）来警示临床离散风险[6,7]。在注册资料的要求上，两者存在显著差异。对于化药，建立群体药代动力学模型以量化个体间变异通常不是常规要求；而对于生物药，因其更高变异性的可能和复杂的体内处置机制，开展群体药代动力学分析已成为行业惯例和监管审评的期望内容[7,8]。这一差异直观地体现在药品说明书中：大部分化药的药代动力学部分较为简略，通常仅包含由非房室分析得出的半衰期、达峰时间等描述性参数；而生物药的说明书该部分则复杂得多，信息量显著增大，常包含基于模型的参数、变异度及协变量影响分析。如何解读并应用这些更复杂的药代动力学信息，以优化个体化治疗，正是临床医生在生物药时代面临的新挑战。二、对高变异的管理 PK的高变异（HV）虽然可能在群体层面被证明“疗效稳健”，但绝不意味着个体风险的消除，反而可能转化为更隐蔽的临床管理难题。当文献或申报资料声明“PK高变异下疗效依然稳健”时，通常指的是群体层面的平均效应（Average Effect），其背后隐藏了三个关键前提： 1、“平均”掩盖了“极端”：PopPK模型给出的“典型值”是数学期望。 2、统计功效的局限：III期临床试验的“非劣效”结论，是基于预设的边界和足够的样本量得出的。它证明了“在统计学上，这个药不比对照药差”，但无法保证“每一个患者都安全有效”。 3、E-R关系的“平台期”：许多生物药（尤其是生长激素、单抗）的暴露-效应（Exposure-Response）曲线存在饱和效应。在较宽的暴露范围内，疗效确实变化不大。但这仅保证了“疗效下限”，并未解决“暴露上限”带来的安全性问题。所以，就如同挑战者号的密封圈一样，PK高变异会切实提高了临床实际风险的发生概率。那监管机构是如何看待这种风险呢？监管机构并非无视这种风险，高变异生物药的监管逻辑建立在“量化变异、机制阐释、风险管控”的基础之上，通过“获益-风险平衡”和“风险管控计划”来接受它。 1、接受“可管理的变异”：CDE的审评逻辑是：只要III期临床证明群体获益 > 群体风险，且个体风险可以通过监测和管理来规避，即可获批[9]。 2、说明书限制：高变异药物的说明书通常会包含更严格的用药监测要求。 3、真实世界研究（RWS）的承诺：对于1类创新生物药，CDE常要求上市后开展真实世界研究（RWS），专门追踪在更广泛人群中，PK变异是否会导致特定的亚组（如低体重、特定基因型）出现极端不良事件[10]。三、识别药物高变异特点对于临床医生而言，识别与管理高变异药物，本质上是完成从群体化给药方案到个体化风险管控的思维跃迁，这要求： 1、处方前多查一步：精读说明书，不仅要看用法用量，更要敏锐捕捉药代动力学参数中个体间变异（IIV）的数值与中位数（范围）/均值±标准差等呈现格式，这些是预判风险的首要依据。 2、诊疗中多问一句：当疗效不佳或出现异常反应时，主动思考这是否源于药物PK/PD的高个体差异？ 3、管理上多做一点：对高变异药物，积极推行治疗药物监测、加强随访、深化患者教育。这套方法并非增加负担，而是将药学原理转化为守护个体的临床智慧。其中，精读说明书是风险防控的第一道，也是最重要的一道关卡。从这个维度上，IIV的数值，以及PK参数的表述方式，即均值±标准差还是中位数（范围），在一定程度上，可以清晰的体现一种药物是是否有高的变异度。通常来说，在临床药理学文献中，非房室分析（NCA）得出的 PK 参数（AUC、Cmax、t₁/₂）通常以均值±标准差报告，尤其对单抗及重组蛋白等变异度适中的生物药；仅在数据呈明显右偏或个体间变异（IIV）较高时，才改用中位数（最小值—最大值）或几何均值±几何变异系数进行描述[5,6]。群体药代动力学（PopPK）论文则常规给出参数典型值（常为几何均值）及其 IIV（%CV）。因此，观察说明书或文献中 PK 参数采用"均值±SD"还是"中位数（范围）"，可作为初步判断药物是否存在高离散特征的实用线索。基于文献观察，绝大多数单抗、重组蛋白（如：阿达木单抗、曲妥珠单抗、干扰素）（>90%）使用均值±标准差，极少数高变异药物、早期临床（Phase I）（<10%）使用范围，约<5%的高度专业化的PopPK论文会采用几何均值±几何CV。这是因为，虽然生物药有高变异属性，但在剔除ADA（抗药抗体）阳性个体、或仅纳入健康受试者后，其半衰期的对数转换值往往接近正态分布。因此，Mean±SD在多数情况下足以描述其集中趋势和离散程度[5]。但如果在小样本早期研究，或物理机制导致极端离散，如PEG化生长激素、某些Fc融合蛋白或长效制剂，其半衰期受PEG链代谢随机性、靶点饱和度（TMDD）影响极大。数据不再是“钟形曲线”，而是“长尾分布”。此时，均值（Mean）会被少数极长半衰期的个体大幅拉高，Mean±SD会给出一个严重偏离典型值的误导性区间。这时，几何均值配合几何CV是更常见的描述方式，或者采用中位数（Median）配合全距（Range）或四分位距（IQR）[6]。四、不同生长激素周制剂的PK参数目前多种技术平台的长效生长激素（GH）周制剂已在国内外上市。为便于各产品间药代特征的横向对标，选取临床最具参考价值的两项PK参数——表观清除率（CL/F）与消除半衰期（t₁/₂）——进行并列分析与比较。 1、CL/F（表观清除率）。限于篇幅，具体说明书内容请参见附a（详见附a）。金赛增的说明书没有直接给出CL的数据，根据金赛增（PEG‑rhGH）的群体 PK 模型研究文献[11,12]，给出表观清除率典型值 CL/F = 0.124 L/h，中央室分布容积 V/F = 2.33 L，体重为显著协变量（CL∝BW^0.756），V/F 与 Vmax 的个体间变异（IIV）分别为 ~20% 和 ~23%，属低‑中变异范畴。长效生长激素的清除率数据，是连接其分子技术、统计学特征与临床风险管理的核心枢纽。综合来看，金赛增、Sogroya、Skytrofa，清除率个体间变异（IIV）均低于30%。说明书采用“减慢清除率”、“典型值约X L/h”等均值化描述，半衰期用均值±SD或近似值呈现。这反映了其PK行为可预测，临床风险相对可控。怡培生长激素、Nutropin Depot（已退市）其清除率个体间变异（IIV）极高（怡培达53%）。说明书明确给出“表观清除率几何均值（几何变异系数53.3%）”，这种高变异直接转化为两类可预见的、且难以提前识别的个体临床风险，即快清除个体因暴露量不足，面临疗效缺失风险，及慢清除个体因药物蓄积，面临安全性毒性风险。 2、半衰期，限于篇幅，具体说明书内容请参见附b（详见附b）。备注：有效半衰期通常基于稳态下的蓄积程度计算，而终末半衰期是基于消除相末端的斜率。在统计学对比时，不同定义的半衰期直接并列对比在严格意义上是不够严谨的，因为它们的计算逻辑和临床意义存在差异。可以看到，Somapacitan和 Lonapegsomatropin说明书不是严格意义的"Mean±SD NCA表，而是 PopPK 模型给出的典型值/近似值，接近金培生长激素Mean±SD思路，怡培生长激素采用“53-200h”的范围描述，已退市的Nutropin Depot说明书给出范围，更接近"怡培 53-200h"的高变异情况。半衰期用中位数（范围）呈现，这可能并非可选的统计偏好，而是对其内在高离散特性的强制性披露，旨在警示临床医生存在显著的个体暴露差异及潜在的疗效不足或蓄积毒性风险。看到说明书用“中位数（范围）”描述半衰期，应将其视为一个强烈的风险信号，意味着该药在部分患者体内行为可能远超“典型”预期。理论上可能存在一种批评观点认为，前文仅从PK参数（如半衰期）的数据呈现方式来判断其变异程度是一种逻辑推演。然而，若将怡培生长激素说明书中的两项关键PK数据进行横向比对，便能构建一个有力的证据链： 1、直接量化指标：说明书明确以几何均值（几何变异系数）的形式给出了表观清除率（CL/F）高达53.3%的个体间变异（IIV）。这是一个客观、定量的“高变异”直接证据，其本身即是临床风险的量化指标。 2、数据呈现的警示信号：与此同时，说明书中以中位数（范围）的形式呈现其有效半衰期，即96.8（53.4—200.0）小时。这种呈现方式本身，正是对数据存在极端离散和严重右偏分布的科学承认与警示。这两项数据并非孤立存在。清除率是决定半衰期的核心生理参数之一，两者通过数学模型紧密关联，极高的CL/F变异（53.3%）（同时考虑半衰期是清除率和分布容积的函数，怡培生长激素表观分布容积变异IIV也高达40.1%）正是导致半衰期呈现如此巨大范围（53-200小时）的根本药代动力学原因。因此，这两项数据的比对构成了一个相互印证的逻辑闭环：定量的高变异CL/F数据，从机制上解释并验证了半衰期必须用“范围”呈现的科学必要性；而后者的呈现方式，则直观地警示了由前者所导致的、不可忽视的个体暴露差异与临床风险。从这个角度看，“CL/F的高变异系数”与“半衰期的范围式呈现”共同构成了对“该药为高变异药物”这一科学事实的双重、互补且无可辩驳的证据。这不仅印证了“通过数据呈现方式可初步识别高变异风险”的理论视角，更将其提升到了有具体量化参数支撑的实证层面。五、结语综上所述，在长效生长激素及其他生物药的研发与评价中，“高变异”是一个必须正视的核心药理学特征。它并非简单的统计噪声，而是源于药物与人体复杂互动的生物学本质。挑战者号的教训提醒我们，对关键参数的变异范围缺乏认知与准备，是复杂系统中风险的放大器。因此，对于医疗决策者而言，在选择治疗方案时，应关注药物药代动力学参数的变异程度，并理解其背后的临床意义——即疗效不足或蓄积毒性风险在个体层面的不确定性会增加。对于制药企业而言，则应在研发早期就通过PopPK等模型量化变异，并在说明书中透明呈现数据特征，同时设计并执行有效的上市后风险监测计划。唯有将“群体有效”的统计结论与“个体风险”的主动管理相结合，才能真正实现精准、安全的长期治疗。这正如墨菲定律所警示的：凡有可能出错之处，必会出错。在充满变异的生物学系统中，唯有对极端情况保持敬畏并主动管理，方能最大程度保障患者安全。以上是基于药理学的学习和个人思考，谨代表个人观点，如有异议请联系探讨，如有错误本人将删除或修正。客观性声明：本文对不同产品的PK参数对比，仅基于各产品已公开发布的说明书及学术文献中的药代动力学数据，旨在从统计学和临床药理学角度阐释‘高变异’这一科学概念。此分析不构成对任何产品安全性、有效性或临床优劣势的比较评价，亦不作为临床用药选择的直接依据。临床医生在处方时应结合患者具体情况，并参考最新的官方药品说明书。数据时效性说明：本文引用的所有说明书及文献数据，均截止于文稿撰写日期（2026年6月）。各产品的最新信息请以其官方最新版说明书为准。附a、不同长效生长激素清除率原文 ①金赛增®（聚乙二醇重组人生长激素注射液 / 金培）说明书“与单次皮下注射重组人生长激素相比，健康受试者单次皮下注射聚乙二醇重组人生长激素注射液后能明显推迟出峰时间、延缓药物在体内的半衰期，减慢清除率，呈现明显的长效特征。” 无清除率数据，进一步查询文献。 ②益佩生®（怡培生长激素注射液 / Inpegsomatropin）来源：NMPA 批准说明书【药代动力学】章节（2025年版）本品达到稳态后的表观分布容积几何均值（几何变异系数）为15.4（40.1%）L，表观清除率几何均值（几何变异系数）为65.6（53.3%）mL/h，有效半衰期中位数（最小值—最大值）为96.8（53.4—200.0）h。（另附健康成人单次给药数据：）平均表观清除率为216.522 mL/h—859.714 mL/h，终末消除半衰期为65.113 h—120.571 h。明确给出PopPK 模拟的表观清除率（CL/F）几何均值 65.6 mL/h，几何CV 53.3%，对应 IIV≈53%。 ③Sogroya®（Somapacitanbeco，Novo Nordisk）来源：US Prescribing Information, Clinical Pharmacology – PK Parameters Pharmacokinetics:Somapacitan exhibits linear pharmacokinetics over the therapeutic dose range. Based on a population PK analysis, the typical value for apparent clearance (CL/F)was 0.147 L/h in adults with GHDand 0.22 L/h in pediatric GHD patients. The terminal elimination halflife was 69 h (~2–3 days) in adultsand 34 h in children. 皮下给药故用"apparent clearance (CL/F)"，典型值 0.147 L/h（成人），PopPK 模型给出。 ④Skytrofa®（Lonapegsomatropintcgd，Ascendis/Recordati）来源：FDA Prescribing Information & EMA EPAR, Section 5.2 Pharmacokinetics Lonapegsomatropin is administered subcutaneously; pharmacokinetic parameters are derived from a population PK model. The apparent clearance (CL/F) of the somatropin moiety released from lonapegsomatropin was approximately 0.10–0.12 L/h in pediatric patients with GHD, corresponding to an approximate 25hour halflife of the active somatropin. The mean (or typical) apparent clearance was used to support the weekly dosing interval. 未单独列数值表格，但PI 正文明确用"apparent clearance (CL/F)"及 PopPK 典型值描述，对应前药释放的 somatropin 清除率。 ⑤国外历史上市（已退市）——Nutropin Depot®（PEGrhGH，Genentech）来源：Historical US PI (2000)，Section 12.3 Pharmacokinetics Following a single SC dose of Nutropin Depot, the mean apparent clearance (CL/F) was approximately 0.028–0.035 L/h/m² (or ~2.0–2.5 L/h for a 70 kg adult when normalized), with a mean terminal halflife of 48–72 hoursin GHdeficient children. 附b、不同长效生长激素半衰期原文 ①、金赛增®（聚乙二醇重组人生长激素注射液 / 金培生长激素）来源：金赛增说明书【药代动力学】章节 Ⅰ期临床单次给药药代动力学试验研究显示：在30例健康成人中单剂量皮下注射聚乙二醇重组人生长激素注射液，在0.1～0.4mg·kg⁻¹范围内基本符合线性动力学特征。0.2mg·kg⁻¹的Tmax为29.40±10.75h；Cmax为379.09±109.61ng·mL⁻¹；t₁/₂为32.19±4.58h；AUC₍₀₋∞₎为25279.58±9407.63ng·h·mL⁻¹。与单次皮下注射人生长激素相比，健康受试者单次皮下注射聚乙二醇重组人生长激素注射液后能明显推迟出峰时间、延缓药物在体内的半衰期，减慢清除率，呈现明显的长效特征。儿童生长激素缺乏症（GHD）患者多次给药药代动力学试验研究表明：12例儿童GHD患者……第1次与第6次皮下注射0.2mg/kg PEG-rhGH后消除相半衰期t₁/₂分别为33.0±5.7h和34.0±8.1h（P=0.7933）……无蓄积作用。呈现方式：均值±标准差（32.19±4.58 h）。 ②、益佩生®（怡培生长激素注射液 / Inpegsomatropin）来源：益佩生说明书【药代动力学】章节群体药代动力学模型模拟生长激素缺乏症儿童患者皮下注射本品0.14 mg/kg/次（每周1次），首次用药后……连续用药约8周可达稳态…… 本品达到稳态后的表观分布容积几何均值（几何变异系数）为15.4（40.1%）L，表观清除率几何均值（几何变异系数）为65.6（53.3%）mL/h，有效半衰期中位数（最小值—最大值）为96.8（53.4—200.0）h。呈现方式：中位数（Min—Max），即96.8 (53.4–200.0) h， ③、Sogroya®（Somapacitan-beco，Novo Nordisk，2020 FDA批准，成人+儿童）来源：Novo Nordisk US Prescribing Information & Canadian Product Monograph Elimination:Based on population-PK analysis, the terminal half-life was 34 h in pediatric GHD patients and 69 h (≈2–3 days) in adult GHD patients. Half-life:Approximately 2 to 3 days. 说明书中以典型值（34 h /约2-3天/~69h成人）方式呈现，未给范围或IIV，PopPK模型给出了成人与儿童的差异。 ④、Skytrofa®（Lonapegsomatropin-tcgd，Ascendis/Recordati，2021 FDA批准，儿童）来源：FDA Prescribing Information / EMA EPAR & 产品说明书 Pharmacology:Lonapegsomatropin is a prodrug that converts to somatropin in the body. The PEG carrier extends the half-life of the somatropin moiety to approximately 25 hours, supporting once-weekly dosing. The mean elimination half-life (t½) of the active somatropin released from lonapegsomatropinis prolonged compared to daily somatropin; the prodrug component has a terminal half-life of ~25 h. 说明书中表述为"approximately 25 hours"（~1天），特指释放出的somatropin因PEG保护而延长的半衰期，用近似值而非范围。 ⑤、Nutropin Depot®（Somatropin rDNA origin, PEGylated，Genentech，1999-2004曾上市，已退市）来源：Historical US Prescribing Information(Genentech, 2000) Pharmacokinetics:Following a single SC dose of Nutropin Depot, the mean terminal elimination half-life was 48 to 72 hours (2–3 days)in GH-deficient children, compared with 2–3 hours for daily somatropin. Serum GH concentrations declined biexponentially with a mean terminal half-life of ~50 hours (range 30–90 h in some studies). 这是一款说明书中曾附带提及"范围倾向"的长效GH（因随机PEG化导致变异较大），但因制造原因2004年已退市。附c：缩略语表（Abbreviations）缩写英文全称中文全称 ADA Anti-Drug Antibody 抗药抗体 AUC Area Under the Curve 药时曲线下面积 BSV Between-Subject Variability 个体间变异（同IIV） CL Clearance 清除率 CL/F Apparent Clearance 表观清除率（非静脉给药） Cmax Maximum Concentration 峰浓度 CV Coefficient of Variation 变异系数 E-R Exposure-Response 暴露-效应（关系） EC50 Half Maximal Effective Concentration 半数有效浓度 Emax Maximum Effect 最大效应 IIV Inter-Individual Variability 个体间变异 IOV Inter-Occasion Variability 个体内/周期间变异 NCA Non-Compartmental Analysis 非房室模型分析 NONMEM Nonlinear Mixed Effects Modeling 非线性混合效应模型 PD Pharmacodynamics 药效动力学 PK Pharmacokinetics 药代动力学 PopPK Population Pharmacokinetics 群体药代动力学 t1/2 Elimination Half-Life 消除半衰期 TMDD Target-Mediated Drug Disposition 靶点介导的药物处置 Vd Volume of Distribution 表观分布容积 V/F Apparent Volume of Distribution 表观分布容积（非静脉给药） Vmax Maximum Elimination Rate 最大消除速率参考文献： 1.国家药品监督管理局药品审评中心. 高变异药物生物等效性研究技术指导原则.2023. 2.US Food and Drug Administration. Guidance for industry: population pharmacokinetics. Rockville, MD: FDA; 1999. 3.Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49(10):633-659. 4.Gobburu JVS, Marroum PJ. Utilization of exposure-response relationship in drug dosage selection: illustration with critical commentary. J Clin Pharmacol. 1997;37(12):1083-1091. 5.Ette EI, Williams PJ, eds. Pharmacometrics: The Science of Quantitative Pharmacology. New York: Springer; 2007. 6.Noe DA. Parameter estimation and reporting in noncompartmental analysis of clinical pharmacokinetic data. Clin Pharmacol Drug Dev. 2020;9(S1):S5-S35. 7.International Council for Harmonisation. ICH harmonised tripartite guideline E3: structure and content of clinical study reports. Geneva: ICH; 1995. 8.FDA——Guidance for Industry: Clinical Pharmacology Data to Support a Demonstration of Biosimilarity(2016) 9.国家药品监督管理局药品审评中心. 以患者为中心的临床试验获益-风险评估技术指导原则（征求意见稿）. 2022. 10.国家药品监督管理局药品审评中心. 真实世界研究支持用于罕见疾病及中药上市许可申请及上市后研究技术指导原则（试行）. 2023. 11.Hou L, Chen ZH, Liu D, et al. Comparative pharmacokinetics and pharmacodynamics of a PEGylated recombinant human growth hormone and daily recombinant human growth hormone in growth hormone-deficient children. Drug Des Devel Ther. 2016;10:13-21. 12.Cheng R, Zhao Q, Zhong G, et al. Population pharmacokinetic/pharmacodynamic analysis of PEG-rhGH enhances confidence in exploring dosing schemes with longer intervals. Eur J Pharm Sci. 2022;179:106304.

2026-06-05

·跨境药研社

起底优甲乐 Euthyrox 50µg 与默克 Merck KGaA 的全球生意：一片几分钱的小药片，撑起一个家族356年的医药帝国

跨全球每3个甲减患者，就有1个在吃它。可它的背后，是一个家族控制了13代、356年的德国巨人。 01 | 一片药、一场风暴：从马赛法庭说起 2022年10月18日，法国马赛。一位法官在桌前签下文件——德国默克集团（Merck KGaA）的法国子公司，被正式以「加重欺诈罪」（aggravated deceit）刑事起诉。原因只有一个：他们改了一款药的配方，但没好好告诉病人。这款药，就是Euthyrox（中文名：优甲乐），一款每天只要吃一小片、按毫克计量、单价几乎可以忽略不计的左甲状腺素钠片。在法国，约有250万人每天靠它续命；在全球，超过30%的甲状腺功能减退患者使用这款药。故事的另一头，是一位法国家庭主妇Sylvie——50岁，做过甲状腺切除手术。2017年3月之后，她突然开始脱发、心悸、失眠、体重失控。她不是个例。在短短几个月里，超过3万名法国患者向药品监管部门提交了不良反应报告，全国掀起一场「配方门」的政治风暴。而引爆这一切的，竟然只是默克决定——把药片里的「乳糖」换成「甘露醇」。一颗药片可以救命，也可以引爆一国民意。这就是医药行业的甜与苦。 02 | 甲减地图：被严重低估的全球性沉默病我们先把镜头拉远。你可能听过糖尿病、高血压，但很少有人聊「甲减」。事实上，它是全球最被低估的慢性病之一。先看一组冰冷的数字： ▸ 美国：约 4.6% 的人口患有甲减，超过2000万人；其中近60%的人甚至不知道自己有病。 ▸ 印度：患病率高达 10.95%——长期碘缺乏的历史遗留。 ▸ 日本：约 10% 患病率，亚临床甲减最常见。 ▸ 中国：据公开报道，约有 9000万甲状腺患者，但仅有约 600万人获得了良好的诊断与治疗。女性是高危群体——患病率是男性的 5至9倍，且随年龄增长急剧上升。再看商业层面：2024年全球左甲状腺素市场规模约为39.5亿美元（约合人民币286亿元），预计到2031年将增长到约50亿美元，复合年增长率3.5%。北美就占了40%以上的市场份额。 ▲ 全球主要国家甲减患病率对比名词解释 | 甲状腺功能减退（Hypothyroidism）：简称「甲减」，指甲状腺分泌的甲状腺素（T4、T3）不足。典型症状包括疲倦、怕冷、便秘、体重增加、记忆下降、抑郁。一旦确诊，往往需要终身服药。 ▍默克集团：你以为它只是个药企？提到「Merck」，很多人会和美国默沙东（Merck & Co.）混淆。这两家公司确实同根同源，但1917年因第一次世界大战被强制分家——在全球193个国家中的191个，Merck这个名字归德国默克（Merck KGaA）所有；只有在美国和加拿大，归美国默沙东。德国默克的来头不一般：1668年由药剂师Friedrich Jacob Merck在德国达姆施塔特创立，是全球最古老的、目前还在运营的化工与制药公司。Merck家族至今仍持有公司70.3%的股份，被列入全球最富有的家族之一，估算家族财富超过800亿美元。 ▲ 默克集团三大业务板块结构默克集团2024年总营收达212亿欧元，下设三大业务：医疗健康（Healthcare）、生命科学（Life Science）、电子科技（Electronics）。其中，医疗健康板块2024年营收约85亿欧元（同比有机增长7%），是集团的现金奶牛之一。 ▍默克的商业模式：三只脚的科技巨头和绝大多数药企「All in 制药」不同，默克走的是「科技+制药+材料」三栖模式——它既是治疗多发性硬化的Mavenclad的拥有者，也是全球液晶材料的核心供应商（你的手机屏幕里可能就有它的成分），还是半导体光刻胶领域的玩家。对于中国药企可借鉴的几点： ✅ 多元化对冲单一专利悬崖风险——当一个药品销量下滑，其他业务可以补位； ✅ 家族控制+上市公司双轨制——保证长期战略不被短期资本绑架； ✅ 重仓「老药+大病种」——优甲乐、格华止（二甲双胍）这类「陈年慢病药」看似不性感，却现金流稳定如老树扎根； ✅ 早期国际化布局——在新兴市场（中国、印度、巴西）押注20年以上。最赚钱的药，不一定是最酷的药——而是病人一辈子都离不开的那种。 ▍全球左甲状腺素市场五大主力 ▲ 全球左甲状腺素市场主要玩家对比整个左甲状腺素市场，AbbVie（Synthroid）、默克KGaA（Euthyrox）、Viatris（Mylan仿制）三家加起来占了全球55%以上的份额。其中： ▸ 美国市场：Synthroid（AbbVie）一家独大，长期是全美处方量Top 5药品之一； ▸ 欧洲市场：Euthyrox（默克KGaA）是事实上的标准方案； ▸ 中国市场：优甲乐（进口+国内分装）+ 国产「加衡」+ 其他仿制药并存； ▸ 印度市场：Mylan仿制药与本土品牌瓜分高端外加大量自费消费者。 03 | 王牌拆解：优甲乐凭什么能卖50年？ Euthyrox 50µg 的核心成分是左甲状腺素钠（Levothyroxine Sodium）——一种与人体内T4激素结构完全相同的合成激素。它的作用机制极其朴素：补什么、缺什么。名词解释 | 左甲状腺素钠（Levothyroxine Sodium）：化学合成的甲状腺素T4，进入人体后会逐步转化为T3发挥作用。它的半衰期长达约7天，所以每天一次口服即可维持稳定血药浓度。 ▍适应症极广，覆盖五大场景 1️⃣ 各种原因引起的甲状腺功能减退（包括原发性、继发性、自身免疫性如桥本氏甲状腺炎）； 2️⃣ 甲状腺癌术后的促甲状腺激素（TSH）抑制治疗； 3️⃣ 甲状腺结节术后替代治疗； 4️⃣ 妊娠期甲减及亚临床甲减——孕妇必须用药以保胎儿大脑发育； 5️⃣ 部分亚临床甲减（TSH升高但T4正常）患者的早期干预。 ▍销售与定价：薄利多销的极致和动辄数万元一支的肿瘤药不同，优甲乐的定价低得令人感动——中国市场一盒100片装的进口优甲乐，零售价约几十元人民币，平均到每片药只要几毛钱。但正因为甲减是终身病，且全球数亿人需要长期服用，单品总规模才足够庞大。默克并未单独披露Euthyrox的具体销售额，但根据2024年年报，优甲乐所在的「心血管、代谢与内分泌（CM&E）」板块是默克医疗健康业务中最大的特许经营线，其中包含优甲乐、格华止（Glucophage）、康欣（Concor）、Saizen等老牌药物。2024年第一季度该板块有机增长4.2%，全年保持稳定贡献。 ▍专利周期：早就过期，但依然是王者左甲状腺素钠作为化合物，专利早已过期几十年。但默克通过「品牌信任 + 工艺标准 + 生物等效性优势」构筑了一道仿制药很难绕开的护城河——因为这种药治疗窗口极窄（narrow therapeutic index），剂量稍微差一点就可能引发副作用，医生和患者都倾向于「不换牌」。当一个药超过50年还在卖，专利早已不是壁垒——患者的肌肉记忆才是。 04 | 护城河：默克的真正底牌不是优甲乐如果你以为默克只靠优甲乐过日子，那就低估它了。 2024年，默克医疗健康板块净销售额85亿欧元，其中：业务线代表药物 2024年表现肿瘤 Erbitux（西妥昔单抗）营收€12亿，同比+15.7% 神经免疫 Mavenclad（克拉屈滨）营收€11亿，同比+12.3% 生育 Gonal-f 营收约€15亿，+0.8% 心血管代谢内分泌优甲乐/格华止/康欣板块第一大，最稳定 ▲ 默克医疗健康板块2024年核心产品销售数据 ▍研发管线：三大重点方向默克的R&D资金倾斜清晰：肿瘤、神经免疫、抗体偶联药物（ADC）。2024年10月，默克以高达13亿美元的潜在里程碑金额收购了耶鲁大学衍生公司Modifi Biosciences，押注DNA损伤修复抗癌赛道。2025年初，更是传出可能收购美国生物科技公司SpringWorks Therapeutics的消息，后者市值一度因此飙升34%。名词解释 | ADC（抗体偶联药物）：Antibody-Drug Conjugate，把抗体（精确制导）和细胞毒药物（炸弹）组合在一起，让药物只攻击癌细胞、放过正常细胞。是近年最火的肿瘤新药方向之一。 ▍技术平台与并购布局默克的并购策略并不激进，更像「价值狙击手」——看准了再下手，而且优先选与现有平台能产生协同效应的标的。比如Modifi主攻DNA修复，正好补足默克在肿瘤精准治疗上的拼图。另一个少有人提的核心护城河：默克是全球最大的生物制药生产工艺供应商之一。其Life Science板块为全球80%以上的药企提供细胞培养基、纯化层析柱、单抗工艺等关键耗材。这是制药行业里「卖铲子的人」——比单纯卖药更稳。最高级的护城河，不是把对手挡在门外，而是让对手不得不来你这里买原料。 05 | 暗面：当356年老店踩到了「配方门」地雷 ▲ Levothyrox 法国风波时间轴把镜头拉回开头那场马赛刑事案。 2017年，应法国药监局（ANSM）要求，默克对Levothyrox（即优甲乐法国版）做了一次「微调」配方——把乳糖换成甘露醇，加入柠檬酸，理由是提高药物稳定性和效价精度。从化学角度看，这是个「教科书式的合规改良」——默克甚至做了216名健康志愿者的随机生物等效性研究，证明新旧配方在血药浓度上几乎无差异。然而现实并不按教科书走。新版上市仅几个月内： ▸ 数千名患者投诉脱发、头痛、心悸、腹泻、体重失控； ▸ 不良反应报告达 30,000+ 例； ▸ 患者发起的在线请愿书收集到 30万签名； ▸ 法国卫生部长被迫U-turn，命令默克把旧版（仍标Euthyrox）重新上架； ▸ 旧版在药店上架48小时内，13万盒就被抢购一半。经过长达五年的诉讼，2022年3月，法国最高法院（Cour de Cassation）终审判决默克赔偿3,329名原告，每人1,000欧元（合计约360万美元）。同年10月，法国分公司被刑事起诉「加重欺诈」罪。 ▍到底是配方有问题，还是沟通有问题？事实上，这场风波最荒谬的地方在于：新配方在欧洲其他20多个国家上市，几乎没有出现类似投诉。默克坚持认为副作用是「正常且与旧版相当」。但法国议会的一份调查报告指出，默克在新配方推出时「未充分告知患者」——这正是后来被起诉「加重欺诈」的核心。教训：在医药行业，技术合规 ≠ 患者沟通到位。哪怕一个化学层面无可挑剔的改动，缺乏知情同意流程，就会演变为信任危机。 ▍中国市场的暗流：周期性短缺对中国患者，另一个不愉快的记忆是2016年前后的「优甲乐荒」。当年优甲乐主要靠进口分装，在全国多个城市出现长达半年的缺货，部分药店出现价格暴涨，许多甲减患者甚至开始囤药。默克当时给出的解释是「进口药品经销特殊性，物流环节复杂」。这件事直接推动了默克在中国南通建厂、本地化生产——也算是「危机倒逼供应链改革」的一个经典案例。药企最大的危机从来不是研发失败，而是患者在最需要药的那一刻，发现药柜是空的。 06 | 中国棋局：9000万患者背后的下一个十年 ▲ 默克 × 中国：优甲乐的本土化棋局 ▍本地化：从进口分装到南通制造默克在中国的甲状腺布局可以分为三个阶段： ▸第一阶段（2010前）：纯进口分装，依赖德国供应链； ▸第二阶段（2010-2017）：周期性短缺频发，监管与媒体关注上升； ▸第三阶段（2017至今）：南通基地投产，成为默克在欧洲外最大产能基地，优甲乐位列首批生产产品。今天的中国药店货架上，优甲乐有两个常见版本：进口版（德国原产+国内分装）和国产版（默克制药江苏有限公司，国药准字H20227080）。两者均为默克体系内产品。 ▍国产替代：仿制药与集采的双重夹击中国市场最新的挑战是「集采+国产替代」。深圳市中联制药有限公司的「加衡」是中国本土生产的左甲状腺素钠片，对标美国的Unithroid，在规格和用法上与优甲乐基本一致。在患者调研中，仍有约31%受访者认为进口药效果优于国产，但近38%的人表示「没有感受到原研药和集采药之间的明显差异」。名词解释 | 集采：国家药品集中带量采购，由国家组织、以「以量换价」的方式让药企降低价格中标进入医保。集采是中国近年来对外资原研药价格体系冲击最大的政策工具。 ▍下一个十年：机会与危机并存对默克而言，中国市场的核心机会在于： ▸ 9000万甲状腺病人中仅约600万人获得了良好诊疗——巨大的「诊断渗透率提升」红利； ▸ 城镇化+老龄化+女性健康意识提升，三大长期驱动力； ▸ 大健康消费升级，对原研药品牌仍存在溢价支付意愿； ▸ 默克其他业务（生命科学、肿瘤Erbitux）在中国保持双位数增长——优甲乐是流量入口，而非全部。危机同样不容忽视： ⚠️ 集采常态化挤压原研利润； ⚠️ 国产仿制药品质提升+价格优势，蚕食市场份额； ⚠️ 法国风波给「轻改配方」敲响警钟——任何配方调整都需慎重；⚠️ 中美博弈背景下，跨国药企在华本地化、合规、数据治理压力上升。下一个十年，外资药企在中国比拼的不是分子，而是供应链、信任和本土生态。留言区聊聊 1️⃣ 如果你或家人正在服用优甲乐，你更倾向于进口版还是国产版？为什么？ 2️⃣ 你怎么看「集采让原研药降价」这件事——是患者福音，还是创新动力的损耗？ 3️⃣ 默克在法国遭遇的「配方门」，对中国药企的合规与沟通有什么启示？评论区见，点赞最高的留言，下一期深度选题听你的 ↓ The End 本文数据来源（按引用顺序） 1. Cognitive Market Research, Levothyroxine Market Report, 2024年发布（全球市场39.5亿美元数据） 2. Merck KGaA, Darmstadt, Germany - Annual Report 2024（2025年3月发布） 3. Wikipedia: Merck Group（2024-2025年版本，关于公司架构、家族持股70.3%等）4. FiercePharma: Merck KGaA faces probe in France over whether it misled patients about drug reformulation, Kevin Dunleavy, 2022-10-195. France24/AFP: Merck charged in France over changes to popular thyroid drug, 2022-10-196. PMLiVE: Merck KGaA to make $3m payout to patients after drug formulation complaints, 2024-02-057. Science Magazine: France brings back a phased-out drug after patients rebel against its replacement, AAAS8. Pharmaceutical Technology: Merck KGaA reports YE24 earnings growth amid SpringWorks acquisition talks, 2025-03-069. Medscape: Merck Wins Lawsuit on Levothyroxine Saga in France, 2020-07-2610. Chemistry World: Drug formula change infuriates French thyroid patients, 2024-06-1011. Global Burden of Disease Study 2021（全球甲减流行病学）12. Substack Health Reports / Restartmed.com（2024年甲减统计数据汇编）13. 健康时报：默克南通建基地优甲乐短缺或有望缓解, 2016-11-0814. 21世纪经济报道：默克投巨资抢占中国基药等市场, 2016-11-1115. 丁香园：默克关于优甲乐供货情况说明16. EMD Group官网：emdgroup.com/en/annualreport/2024（Healthcare板块结构） ⚠️ 免责声明本文为产业深度分析内容，所有信息基于公开资料整理，仅供行业研究和科普阅读之用。文章中涉及的医药产品、剂量、适应症等仅作为信息分享，不构成任何用药建议、医疗诊断或投资建议。如有甲状腺相关健康问题，请务必咨询专业医师，遵医嘱用药，切勿自行调整剂量或更换药品。文中数据均来自标注的公开来源，如有出入以官方最新发布为准。文中部分配图来源网络，如有侵权，请联系删除。 ✍️ 原创声明本文为原创内容，未经授权禁止转载、洗稿或截取片段使用。如需转载、商务合作或行业交流，请通过本公众号后台留言联系。 © 版权所有 · 侵权必究别忘了点分享、收藏、在看、点赞哦！

2026-04-24

·BioSpace

Vaxart Appoints James Breitmeyer, M.D., Ph.D., to Board of Directors

Appointment strengthens Board’s clinical development and regulatory expertise as Vaxart advances its oral vaccine platform SOUTH SAN FRANCISCO, Calif., April 23, 2026 (GLOBE NEWSWIRE) -- Vaxart, Inc. (OTCQX: VXRT), a clinical-stage biotechnology company developing a range of oral vaccines based on its proprietary delivery platform, today announced the appointment of James Breitmeyer, M.D., Ph.D., to its Board of Directors. Dr. Breitmeyer brings more than 35 years of biopharmaceutical experience, having led clinical development programs resulting in eight FDA product approvals and numerous regulatory successes across the United States, Europe, and Japan. "We are pleased to welcome Jim to the Vaxart Board as we continue to advance our clinical programs and demonstrate the long-term potential of our oral vaccine platform," said Mark Watson, Lead Independent Director of Vaxart. "Jim’s deep expertise in drug development and his extensive experience navigating complex regulatory paths will be a significant asset. His track record of clinical leadership is a valuable addition to our Board and is highly complementary to our mission of providing a more effective and accessible way to vaccinate the global population." Dr. Breitmeyer has been a leader in drug development throughout his career. In February 2026, he joined Altay Therapeutics as CEO and Board Director, directing the advancement of the company’s pipeline of oral transcription factor therapies. He most recently served as the President and CEO of Oncternal Therapeutics, Inc., where he oversaw the clinical development of a diverse pipeline of first-in-class oncology assets. He also brings vaccine development expertise from his previous role as President of Bavarian Nordic, Inc., where he oversaw the development of cancer, infectious disease, and bioterrorism vaccines. Additionally, Dr. Breitmeyer held senior clinical leadership roles at Eli Lilly and Company and Cadence Pharmaceuticals, where he managed the transition of multiple candidates through the clinical and regulatory process toward successful commercial launch. "Vaxart is doing important work to advance the science of oral vaccines, and I have long admired the Company's commitment to innovation," said Dr. Breitmeyer. "I am honored to join the Board and look forward to contributing to the company's continued progress as it moves its lead candidates through the clinic and works to validate the unique advantages of its proprietary technology." About James Breitmeyer, M.D., Ph.D. Dr. Breitmeyer currently serves as the CEO and Board Director of Altay Therapeutics, Inc. His board experience includes previous director roles at Zogenix, Inc. and Otonomy, Inc., where he served on Audit and Compensation Committees. Prior to joining Altay Therapeutics, he most recently served as President, CEO, and Director of Oncternal Therapeutics, Inc. Previously, he held the position of President at Bavarian Nordic, Inc. and served as Executive Vice President and Chief Medical Officer at Cadence Pharmaceuticals. Dr. Breitmeyer also served as Vice President of Biotechnology at Eli Lilly and Company, where he was responsible for the corporate biotechnology pipeline. Earlier in his career, he held senior leadership roles at Applied Molecular Evolution and Serono Laboratories, where he led the development of therapies resulting in FDA approvals for Rebif® and Serostim®. Dr. Breitmeyer earned his M.D. and Ph.D. from Washington University School of Medicine. He completed postdoctoral fellowships at Harvard Medical School and the Dana-Farber Cancer Institute, where he also served as a clinical instructor. About Vaxart Vaxart is a clinical-stage biotechnology company developing a range of oral recombinant vaccines based on its proprietary delivery platform. Vaxart vaccines are designed to be administered using pills that can be stored and shipped without refrigeration and eliminate the risk of needle-stick injury. Vaxart believes that its proprietary pill vaccine delivery platform is suitable to deliver recombinant vaccines, positioning the company to develop oral versions of currently marketed vaccines and to design recombinant vaccines for new indications. Vaxart’s development programs currently include pill vaccines designed to protect against coronavirus, norovirus and influenza, as well as a therapeutic vaccine for human papillomavirus (HPV), Vaxart’s first immune-oncology indication. Vaxart has filed broad domestic and international patent applications covering its proprietary technology and creations for oral vaccination using adenovirus and TLR3 agonists. Note Regarding Forward-Looking Statements This press release contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, included in this press release regarding Vaxart's strategy, prospects, plans and objectives, results from preclinical and clinical trials and the timing of such results, and beliefs and expectations of management are forward-looking statements. These forward-looking statements may be accompanied by such words as "should," "believe," "could," "potential," "will," "expected," “anticipate,” "plan," and other words and terms of similar meaning. Examples of such statements include, but are not limited to, statements relating to Vaxart's ability to develop and commercialize its product candidates; Vaxart's expectations regarding clinical results and trial data, and the timing of receiving and reporting such clinical results and trial data; Vaxart’s expected timing for future clinical trials; and Vaxart's expectations with respect to the effectiveness of its product candidates. Vaxart may not actually achieve the plans, carry out the intentions, or meet the expectations or projections disclosed in the forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions, expectations, and projections disclosed in the forward-looking statements. Various important factors could cause actual results or events to differ materially from the forward-looking statements that Vaxart makes, including uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement, and/or completion dates for clinical trials, as well as the possibility of unfavorable new clinical data and further analyses of existing clinical data; the risk that clinical trial data are subject to differing interpretations and assessments by regulatory authorities; whether regulatory authorities will be satisfied with the design of and results from the clinical studies; decisions by regulatory authorities impacting labeling, manufacturing processes, and safety that could affect the availability or commercial potential of any product candidate, including the possibility that Vaxart's product candidates may not be approved by the FDA or non-U.S. regulatory authorities; that Vaxart or its partners may experience manufacturing issues and delays due to events within, or outside of, Vaxart's or its partners' control; Vaxart's ability to obtain sufficient capital to fund its operations on terms acceptable to Vaxart, if at all; the impact of government healthcare proposals and policies; competitive factors; and other risks described in the "Risk Factors" sections of Vaxart's Quarterly and Annual Reports filed with the SEC. Vaxart does not assume any obligation to update any forward-looking statements, except as required by law. Contact Vaxart Media and Investor Relations: FINN Partners IR@vaxart.com

疫苗高管变更上市批准

100 项与生长激素(Merck Serono SA) 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	H01AC01	DB00052

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
成长不全	澳大利亚	Merck Healthcare Pty Ltd.	2011-08-22
性腺发育不全	澳大利亚	Merck Healthcare Pty Ltd.	2011-08-22
生长迟缓	澳大利亚	Merck Healthcare Pty Ltd.	2011-08-22
特纳综合症	澳大利亚	Merck Healthcare Pty Ltd.	2011-08-22
短肠综合征	美国	EMD Serono, Inc.	2001-11-19
生长激素缺乏症	美国	EMD Serono, Inc.	1996-10-08
HIV感染	美国	EMD Serono, Inc.	1996-08-23

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适应症	最高研发状态	国家/地区	公司	日期
特发性矮小症	临床3期	韩国	Merck KGaA	2012-12-01
不孕	临床3期	加拿大	EMD Serono, Inc.	2012-06-01
纤维肌痛	临床3期	西班牙	Merck KGaA	2007-12-01
垂体性侏儒症	临床3期	美国	EMD Serono, Inc.	2005-01-01
HIV相关性脂肪营养不良综合征	临床3期	美国	EMD Serono, Inc.	2004-05-28
HIV相关性脂肪营养不良综合征	临床3期	加拿大	EMD Serono, Inc.	2004-05-28
小于胎龄儿	临床3期	意大利	Merck KGaA	2004-02-01
胎儿生长受限	临床3期	-	Merck KGaA	1998-11-01
HIV消耗综合征	临床3期	-	EMD Serono, Inc.	1997-07-01
软骨发育不良	临床2期	法国	Merck KGaA	2006-03-21

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01111019 (CTgov)	临床2期	软骨发育不良	19	Recombinant human growth hormone (r-hGH)	蓋壓構餘範鏇鬱築鹹蓋(範鹹襯壓構廠簾衊鏇醖) = 衊窪壓構糧製繭選繭糧憲鹽顧糧衊製觸齋醖鬱 (網構憲廠構艱鑰願淵衊, 0.9) 更多	-	2019-02-15
NCT00082628 (CTgov)	临床3期	HIV相关性脂肪营养不良综合征	326	Placebo (Period I: Placebo)	窪築壓範餘衊鬱鹹艱簾(願廠構艱淵憲膚鹽餘蓋) = 獵繭網範繭餘醖醖鏇衊鹹遞淵鏇鏇鑰膚淵獵繭 (選憲鹽鏇鏇壓壓窪構鬱, 34.5) 更多	-	2018-07-20
				Serostim® 4 mg (Period I: Serostim® 4 mg)	窪築壓範餘衊鬱鹹艱簾(願廠構艱淵憲膚鹽餘蓋) = 蓋鹹範範築艱蓋構鹹範鹹遞淵鏇鏇鑰膚淵獵繭 (選憲鹽鏇鏇壓壓窪構鬱, 37.9) 更多
NCT00256126 (CTgov)	临床4期	特纳综合症 \| 生长激素缺乏症	318	Saizen (Turner Syndrome (TS))	鬱廠廠鏇簾觸積夢鏇齋(鹹膚鏇糧繭鏇窪網糧壓) = 簾選範構窪構窪簾艱糧餘繭選糧積鬱襯壓選廠 (顧衊積衊窪願獵積膚鬱, 1.1889) 更多	-	2018-03-20
				Saizen (Growth Hormone Deficiency (GHD))	鬱廠廠鏇簾觸積夢鏇齋(鹹膚鏇糧繭鏇窪網糧壓) = 膚鏇構積鬱鏇夢淵顧積餘繭選糧積鬱襯壓選廠 (顧衊積衊窪願獵積膚鬱, 0.9811) 更多
NCT01806298 (CTgov)	临床4期	生长激素缺乏症	78	Saizen®	積簾衊鬱膚積範鏇窪膚 = 窪憲淵遞襯鏇獵鑰構鏇膚觸繭鹹遞構網鑰觸觸 (襯獵衊艱鹹衊憲窪鬱糧, 壓觸淵積襯夢鑰齋網鑰 ~ 膚鑰選壓廠壓窪鏇鹽蓋) 更多	-	2017-04-04
NCT01746862 (SYNERGY, CTgov)	临床3期	特发性矮小症	90	Saizen® (Saizen Test Group)	選選築鏇蓋製構艱觸醖(鹹窪餘艱餘網選艱遞簾) = 獵夢繭顧簾艱鬱鑰鏇齋顧獵衊獵觸積願觸餘選 (鏇觸積膚鏇鬱選範獵夢, 1.62) 更多	-	2016-10-18
				Saizen® (Saizen Control Group)	選選築鏇蓋製構艱觸醖(鹹窪餘艱餘網選艱遞簾) = 網鹹鹽糧憲遞網膚衊築顧獵衊獵觸積願觸餘選 (鏇觸積膚鏇鬱選範獵夢, 1.91) 更多
NCT00748969 (CTgov)	临床2/3期	侏儒症 \| 黏多醣贮积症II型 \| 黏多糖贮积症I型 ... 更多	2	Growth hormone+Somatropin (Growth Hormone Treatment)	製蓋選鏇夢夢築齋遞觸 = 範憲網繭範憲願醖夢鏇製觸鹹醖顧繭構蓋鑰衊 (獵鹹糧鹹鹽築選製齋齋, 鏇醖壓選鑰窪艱蓋獵繭 ~ 鹽積窪鏇繭夢膚鑰鬱鬱) 更多	-	2014-11-24
				placebo (No Growth Hormone Treatment)	鹽鏇範鬱襯餘蓋選膚鑰 = 餘壓廠齋積築壓遞範齋憲艱鬱夢遞鏇衊獵蓋繭 (廠衊鏇築艱夢鬱鏇窪鬱, 鹽醖糧築齋廠衊築鏇積 ~ 鹽遞簾鬱範齋積積醖鏇)
NCT00933686 (CTgov)	临床3期	纤维肌痛	113	Saizen® (Saizen®)	顧簾鏇積廠築繭鏇齋鬱 = 選遞艱窪顧糧艱艱憲齋艱壓憲鏇鑰衊廠憲繭壓 (窪選餘憲獵網獵壓築築, 築艱淵醖廠範廠夢夢築 ~ 構構壓範憲襯構顧廠顧) 更多	-	2013-08-02
				Placebo+Saizen® (Placebo + Saizen®)	顧簾鏇積廠築繭鏇齋鬱 = 衊網選遞獵糧蓋壓繭醖艱壓憲鏇鑰衊廠憲繭壓 (窪選餘憲獵網獵壓築築, 網蓋鑰鬱壓鏇遞窪鬱網 ~ 壓夢鑰鏇鏇壓廠遞獵憲) 更多
NCT01237340 (CTgov)	临床3期	生长激素缺乏症	59	Saizen®	鏇獵鹽鑰製鬱鏇網顧壓 = 鹽鬱齋憲繭構艱觸齋蓋積憲鹹蓋鏇顧願齋蓋網 (範憲淵遞鹽憲壓醖襯鹹, 齋餘製獵糧鏇夢構鏇糧 ~ 膚簾網鹽構壓膚網構膚) 更多	-	2012-10-11
NCT00249821 (SGA OPTIMIS, CTgov)	临床3期	小于胎龄儿	22	Saizen® (Saizen® 0.057 mg/kg/Day)	範鹽衊壓壓獵醖鑰糧壓(繭醖襯淵繭網艱繭簾構) = 構簾構獵積獵範獵築鏇糧範鏇鹽遞醖鑰壓網範 (鹽觸積顧蓋鹽醖選鏇衊, 1.35) 更多	-	2012-10-10
				Saizen® (Saizen® 0.035 mg/kg/Day)	範鹽衊壓壓獵醖鑰糧壓(繭醖襯淵繭網艱繭簾構) = 簾構蓋廠製簾鏇廠鏇壓糧範鏇鹽遞醖鑰壓網範 (鹽觸積顧蓋鹽醖選鏇衊, 1.15) 更多
NCT01400698 (CTgov)	临床3期	胎儿生长受限 \| 生长迟缓	91	r-hGH (Non-Final Height: Not Treated)	鏇鹽鑰觸鬱膚餘鑰鑰築(艱壓築淵餘範糧範膚憲) = 襯壓齋夢鬱製選窪蓋壓網鬱蓋製襯憲襯鹹蓋鹽 (夢鏇蓋壓蓋憲鹽繭壓願, 16.08) 更多	-	2012-09-25
				r-hGH (Non-Final Height: Treated)	鏇鹽鑰觸鬱膚餘鑰鑰築(艱壓築淵餘範糧範膚憲) = 選簾簾觸範醖廠鬱蓋衊網鬱蓋製襯憲襯鹹蓋鹽 (夢鏇蓋壓蓋憲鹽繭壓願, 12.89) 更多