更新于：2024-05-01

Hutchinson-Gilford progeria syndrome

早衰

更新于：2024-05-01

基本信息

别名

Gilford's syndrome、Gilford-Hutchinson、HGPS

+ [37]

简介

An abnormal congenital condition, associated with defects in the LAMIN TYPE A gene, which is characterized by premature aging in children, where all the changes of cell senescence occur. It is manifested by premature graying; hair loss; hearing loss (DEAFNESS); cataracts (CATARACT); ARTHRITIS; OSTEOPOROSIS; DIABETES MELLITUS; atrophy of subcutaneous fat; skeletal hypoplasia; elevated urinary HYALURONIC ACID; and accelerated ATHEROSCLEROSIS. Many affected individuals develop malignant tumors, especially SARCOMA.

关联

项与早衰相关的药物

Lonafarnib

洛那法尼

靶点

Ftase

作用机制

Ftase抑制剂

在研机构

Eiger BioPharmaceuticals, Inc. [+5]

原研机构

Merck Sharp & Dohme Corp.

在研适应症

核纤层蛋白病 [+5]

非在研适应症

晚期乳腺癌 [+11]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2020-11-20

Progerinin

靶点-

作用机制

Nuclear proteins 抑制剂

在研机构

PRG Science & Technology Co., Ltd.

原研机构

PRG Science & Technology Co., Ltd.

在研适应症

代谢性骨病 [+1]

非在研适应症

早衰

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

PRG-S-1

靶点-

作用机制-

在研机构

PRG Science & Technology Co., Ltd.

原研机构

PRG Science & Technology Co., Ltd.

在研适应症

早衰

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

项与早衰相关的临床试验

NCT05978921 / Not yet recruitingN/AIIT

Effect of Physical Strength Exercise on Telomeric Length as a Marker of Aging and Early Death in Patients With Schizophrenia

Randomised clinical trial on a cohort of subjects with a diagnosis of schizophrenia of legal age, of both sexes, recruited in the mental health clinics of the Salamanca University Assistance Complex and who will be randomly distributed into two groups (intervention and control).
The main objective of the study is to determine the effect of physical exercise on telomere size in patients diagnosed with schizophrenia.
As secondary objectives in this group of patients we will try to:
Evaluate the influence of strength training on cognition and negative symptoms of schizophrenia.
To quantify the impact of strength training on frailty. To determine the effect of strength training on quality of life. To study the possible correlation between physical parameters (frailty) and telomere length.
To establish the importance of polymorphisms in telomerase genes, an enzyme involved in the maintenance of telomere length.

开始日期2024-03-01

申办/合作机构

University of Salamanca

ChiCTR2400080608 / SuspendedN/AIIT

Based on Spleen flourishing in four seasons is not affected by evil to explore the effectiveness and mechanism of modified Shenling baizhu powder in the prevention and treatment of senile weakness

开始日期2024-02-05

申办/合作机构-

NCT05953857 / Not yet recruitingN/AIIT

" Knowing & Treating Kosaki/Penttinen Syndromes " International Collaborative Consortium. A Real-life Observational Study on the Natural History of KOGS and PS and on the Efficacy and Safety Profile of TKIs in These Patients.

Kosaki overgrowth syndrome (KOGS) and Penttinen syndrome (PS) are extremely rare multisystem disorders caused by heterozygous activating variants of the PDGFRB gene. KOGS results in characteristic craniofacial, orthopedic, skin and neurological disorders. PS is a progeroid disease responsible for a prematurely aged appearance. Patients suffer significant morbidity and mortality due to various complications. Tyrosine Kinase Inhibitors (TKIs) targeting PGDFRB appear to be a potential treatment option, as evidenced by a few case reports showing clinical improvement in some patients, with modest and self-resolving side effects. The natural history of these two syndromes remains poorly understood as only case-reports have been published.
Therefore, an international consortium was created in December 2019 by Pr FAIVRE (CHU Dijon Bourgogne & ERN ITHACA) to follow treated and untreated patients in a real-life, multicentre, observational study, in order to expand our knowledge of these ultra-rare diseases. In the longer term, we believe that TKIs could bring clinical benefit to KOGS/PS patients.

开始日期2023-10-01

申办/合作机构

Centre Hospitalier Universitaire de Dijon

100 项与早衰相关的临床结果

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100 项与早衰相关的转化医学

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0 项与早衰相关的专利（医药）

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4,598

项与早衰相关的文献（医药）

2024-03-01·Clinics in chest medicine

Fibrotic Pulmonary Sarcoidosis.

Review

作者: Hilario Nunes ; Pierre-Yves Brillet ; Jean-François Bernaudin ; Thomas Gille ; Dominique Valeyre ; Florence Jeny

Fibrotic pulmonary sarcoidosis (fPS) affects about 20% of patients. fPS carries a significant morbidity and mortality. However, its prognosis is highly variable, depending mainly on fibrosis extent, functional impairment severity, and the development of pulmonary hypertension. Moreover, fPS outcomes are also influenced by several other complications, including acute exacerbations, and infections. fPS natural history is unknown, in particular regarding the risk of progressive self-sustaining fibrosis. The management of fPS is challenging, including anti-inflammatory treatment if granulomatous activity persists, rehabilitation, and in highly selected patients antifibrotic treatment and lung transplantation.

2024-02-21·The Journal of sports medicine and physical fitness

Prevalence of sunscreen use and sunburn in Greek athletes: a cross-sectional study.

Article

作者: Niki Tertipi ; Eleni Sfyri ; Vasiliki Kefala ; Efstathios Rallis

BACKGROUND:

Athletes participating in outdoor sports are in a high-risk category for prolonged sun exposure. This study investigates whether swimmers and beach volleyball athletes adopt appropriate measures to protect their skin from the sun. Sunscreens play a key role in protecting the skin from solar radiation and preventing premature aging. The study assesses the frequency of sunscreen use and the incidence of sunburn among athletes.

METHODS:

Athletes completed a self-administered questionnaire regarding their sun protection and exposure habits. Participants aged 9 to 60 years, engaged in swimming (N.=1047) and beach volleyball (N.=785), were included in this study.

RESULTS:

In the group of swimmers (N.=858), a notable percentage never used sunscreen, and among those who did, (N.=137), natural products were predominantly applied. Gender differences revealed a significantly higher sunscreen usage (P<0.001) among female swimmers compared to males. Among beach volleyball athletes, sunscreen use was notably higher (90%), with 55.6% applying natural sunscreen and 44.4% opting for non-natural alternatives. Regarding the incidence of sunburn, the occurrence among both male and female swimmers was observed to be very low. Among those with sunburn, females exhibited a significantly higher frequency than males (P<0.001). Conversely, in beach volleyball athletes, sunburn affected a higher percentage of males (49.8%) than females (43.9%).

CONCLUSIONS:

Sunscreen utilization is notably insufficient among athletes, reflecting a limited awareness of the potential risks associated with sun exposure, even though they frequently suffer from sunburn. This heightened susceptibility places them at an increased risk of developing skin lesions. Initiating and disseminating awareness campaigns that specifically emphasize the importance of sunscreen use within the outdoor sports community is imperative.

2024-02-19·Molecular biology reports

Alterations in leukocyte telomere length and mitochondrial DNA copy number in benzene poisoning patients.

Article

作者: Dianpeng Wang ; Dafeng Lin ; Xiangli Yang ; Dongpeng Wu ; Peimao Li ; Zhimin Zhang ; Wen Zhang ; Yan Guo ; Song Fu ; Naixing Zhang

OBJECTIVE:

The aim of this study is to examine and evaluate the impact of benzene poisoning on the relative content of the mitochondrial MT-ND1 gene and telomere length in individuals with occupational chronic benzene poisoning (CBP) compared to a control group. The study will analyze and gather data on the mitochondrial gene content and telomere length in cases of benzene poisoning, and investigate the relationship with blood routine parameters in order to contribute scientific experimental data for the prevention and treatment of CBP.

METHOD:

The case group comprised 30 individuals diagnosed with occupational chronic benzene poisoning, whereas the control group consisted of 60 healthy individuals who underwent physical examinations at our hospital concurrently. Blood routine indicators were detected and analyzed, and the PCR method was employed to measure changes in mitochondrial MT-ND1 content and telomere length. Subsequently, a comparison and analysis of the aforementioned indicators was conducted.

RESULT:

The case group exhibited a higher mitochondrial gene content (median 366.2, IQR 90.0 rate) compared to the control group (median 101.5, IQR 12.0 rate), with a statistically significant difference between the two groups (P < 0.05). Additionally, the case group demonstrated lower white blood cell levels (3.78 ± 1.387 × 10⁹/L) compared to the control group (5.74 ± 1.41 × 10⁹/L), with a significant difference between the two groups (P < 0.05). Furthermore, the case group displayed lower red blood cell levels (3.86 ± 0.65 × 10¹²/L) compared to the control group (4.89 ± 0.65 × 10¹²/L), with a significant difference between the two groups (P < 0.05). The hemoglobin level in the case group (113.33 ± 16.34 g/L) was lower than that in the control group (138.22 ± 13.22 g/L). There was a significant difference between the two groups (P < 0.05). Platelet levels in the case group (153.80 ± 58.31 × 10⁹/L) is smaller than the control group (244.92 ± 51.99 × 10⁹/L), there was a significant difference between the two groups (P < 0.05). The average telomere length of the normal control group was 1.451 ± 0.475 (rate); The mean telomere length of individuals in the case group diagnosed with benzene poisoning was determined to be 1.237 ± 0.457 (rate). No significant correlation was observed between telomere length and three blood routine parameters, namely white blood cells (WBC), hemoglobin (HB), and platelets (PLT). However, a significant correlation was found between telomere length and red blood cell count (RBC). Additionally, a negative correlation was observed between mitochondrial gene content and white blood cell count (r = - 0.314, P = 0.026), as well as between mitochondrial gene content and red blood cell count (r = - 0.226, P = 0.032). Furthermore, a negative correlation was identified between mitochondrial gene content and hemoglobin (r = - 0.314, P = 0.028), and platelets (r = - 0.445, P = 0.001).

CONCLUSION:

Individuals diagnosed with occupational chronic benzene poisoning exhibit a reduction in telomere length and an elevation in the relative content of the mitochondrial MT-ND1 gene. Moreover, a negative correlation is observed between the content of the mitochondrial MT-ND1 gene and four blood routine parameters, namely white blood cells (WBC), red blood cells (RBC), hemoglobin (HB), and platelets (PLT). Consequently, benzene exposure may potentially contribute to the onset of premature aging.

127

项与早衰相关的新闻（医药）

2024-04-02

·同写意

浅谈细胞衰老及治疗

大会由扬州市人民政府主办，同写意专业策划，以“打造生物医药新质生产力”为主题，邀请众多行业领袖和先锋人物一起取势明道，就如何打造中国医药新质生产力，面向未来创新药如何立项，资本寒冬下的创新药BD与出海，GLP-1&小核酸药物以及抗体药的质量与生产四大主题展开深度研讨，为行业发展提供方向性指引。细胞衰老就是人体衰老的开始？虽然细胞衰老并不等同于人类衰老，但由于其共同的特征，它长期以来一直被认为是生物年龄而非生理年龄的主要贡献者！1细胞衰老的定义细胞衰老是指细胞处于一种稳定的细胞周期停滞的状态，此时细胞无法正常增殖。细胞衰老只是衰老的标志性事件之一，并不能等同于衰老。随着年龄的增长，人体内的衰老细胞会日渐累积。1882年，德国生物学家Weismann曾预测“在细胞水平存在老化现象”。他推测：机体的寿命限制受控于体细胞的分裂能力；在遗传进化中，不同物种的体细胞获得了不同分裂的潜能，从而决定了不同物种的寿命长短。20世纪50年代，Swin和他的同事利用原代细胞体外培养试验证明了来源于不同物种的纤维细胞均不具备无限分裂的潜能。取得突破性进展的还是Hayflflick和Moorhead更系统更细致的观察和描述：对25株人成纤维细胞进行原代培养，在这个过程中发现，经过约50次传代之后，所有细胞出现功能退化，并且丧失分裂能力的现象。此后人们将这一现象称之为“Hayflflick极限”或者自发性老化。之后也有事实证明，细胞老化并不是体外培养所导致，细胞在体内也会随着年龄的增长，逐步走向老化。"由放射性标记小鼠细胞获得数据并将其同人类70岁的寿命相比较推测，人体细胞在一生中可以分裂500-5000次（具体次数取决于细胞类型），这些数值与体外观察到的20-70的群体倍增数之间存在极大差异。"鉴于其在生物活性中的重要性，细胞衰老现在正成为治疗几种与年龄相关的疾病的有前景的药物靶标！2细胞衰老原因内在因素：自然衰老、癌基因的激活，氧化应激、线粒体功能障碍等。外在因素：辐射和化疗药物。这些都可通过引起 DNA 损伤 (DNA damage)，激活 ATM/ATR 激酶和 p53/p21CIP1 信号轴，最终导致细胞周期阻滞，诱发衰老。3细胞衰老特征01细胞衰老特征细胞增殖变慢、细胞核体积异常及多核（4-8核）、表面分泌物增多、细胞体积增大、细胞扁平、细胞质中出现空泡等现象。衰老细胞的细胞核、细胞质和细胞膜等均有明显的变化：细胞内水分减少，体积变小，新陈代谢速度减慢；细胞内酶的活性降低；细胞内的色素会积累；细胞内呼吸速度减慢,细胞核体积增大，核膜内折，染色质收缩，颜色加深，线粒体数量减少，体积增大；细胞膜通透性功能改变，使物质运输功能降低。02细胞衰老形态总体来说老化细胞的各种结构呈退行性变化.衰老细胞的形态变化表现有：核：增大、染色深、核内有包含物染色质：凝聚、固缩、碎裂、溶解质膜：粘度增加、流动性降低细胞质：色素积聚、空泡形成线粒体：数目减少、体积增大高尔基体：碎裂尼氏体：消失包含物：糖原减少、脂肪积聚核膜：内陷03衰老细胞表型4细胞衰老的探索性治疗鉴于稳定的细胞周期停滞状态，细胞衰老主要因其阻止肿瘤生长的能力而闻名。然而，越来越多的证据表明，在多个过程中发挥相反的作用，可能对健康造成严重威胁，因此有必要采取对策！如图是可能的细胞衰老的治疗：衰老相关的改变和治疗策略。具有 SASP 的衰老细胞（中间）会经历一系列特定的属性和功能变化（左侧）。目前可用的治疗策略如右侧所示。SASP：衰老相关的分泌表型；ADC：抗体-药物偶联物；CAR-T：嵌合抗原受体（CAR）-T细胞疗法；CAR-NK：CAR-自然杀伤细胞疗法；SC：干细胞；EV：细胞外囊泡。举例：1. 韩国建国大学医学院和国立科学技术研究所的研究团队合作，在Journal of the American Chemical Society期刊发表了题为：Supramolecular Senolytics via Intracellular Oligomerization of Peptides in Response to Elevated Reactive Oxygen Species Levels in Aging Cells的研究论文。该研究开发了一种有前景的新技术，可以选择性的清除衰老细胞，而不损伤正常的健康细胞。2.免疫疗法：与衰老相关的免疫疗法多种多样。例如，senolytic 疫苗接种，即 senolytic 和免疫靶向性的结合，可以专门引导 SnCs被消除。最近报道的一个成功案例涉及在早衰小鼠模型中进行的研究。该方法采用 SnCs 中普遍表达的糖蛋白非转移性黑色素瘤蛋白 B（GPNMB）作为标靶。治疗结果令人鼓舞，显示雄性小鼠的正常和病理性年龄相关表型有所改善，寿命延长。至于免疫衰老本身，强烈推荐使用 CD153-胞嘧啶磷酸胍（CpG）疫苗来预防衰老T细胞的积累。此外，一种抗体药物偶联物（ADC），通过特异性 β-2-微球蛋白（B2M）识别将细胞毒性多卡霉素传递到 SnC 中，以特异性消除 SnC。免疫细胞是衰老相关免疫治疗的另一主力。经典的细胞衰老和免疫之间存在联系。p53和p21是两种著名的生长调节剂。它们在衰老相关免疫促进中的作用是增加免疫细胞的浸润和识别，并刺激巨噬细胞M1，最终诱导 SnC的清除。此外，基于特定的趋化因子分泌、组织特异性受体库和组织微环境，不同的免疫细胞亚群，如NK细胞、中性粒细胞、树突状细胞、单核细胞/巨噬细胞、B细胞和T细胞，可被招募进行SnC监视和清除。随着研究的进展，可以使用更先进的方法。例如，在CAR-T中，T细胞配备细胞特异性的CAR来精确攻击目标细胞。鉴于其独特的特性，一旦衰老特异性表面标记物可用，CAR-T就是消除SnC的有希望的候选者。— 总结 — 1）细胞衰老的表面标志物全部种类和特异性的类型还没有被确定；2）在衰老状态、单细胞水平以及细胞类型之间以及取决于诱导衰老的刺激，可能存在非常高度的异质性；3）细胞衰老是一个随时间演变的动态过程，其具体调控过程不明；4）鉴定出通用的衰老标志物以识别并区分不同类型的衰老细胞；5）目前所有的细胞衰老的治疗都是介于临床前试验，但是这个方向是所有科学家孜孜不倦的努力方向。参考文献（部分）：1.Yunzi ZHAO, Hui LI, Qinglong GUO, Hui HUI，Multiple characteristic alterations and available therapeutic strategies of cellular senescence，Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) 2023 24(2):101-1142.https://www-nature-com.libproxy1.nus.edu.sg/articles/s43587-023-00560-53.Chaleckis R, Murakami I, Takada J, et al., 2016. Individual vari‐ability in human blood metabolites identifies age-related differences. Proc Natl Acad Sci USA, 113(16):4252-4259.https://doi-org.libproxy1.nus.edu.sg/10.1073/pnas.1603023113 4.Chambers CR, Ritchie S, Pereira BA, et al., 2021. Overcoming the senescence-associated secretory phenotype (SASP): a complex mechanism of resistance in the treatment of cancer. Mol Oncol, 15(12):3242-3255. https://doi-org.libproxy1.nus.edu.sg/10.1002/1878-0261.13042 5.Chen F, Long QL, Fu D, et al., 2018. Targeting SPINK1 in the damaged tumour microenvironment alleviates therapeutic resistance. Nat Commun, 9:4315. 6.https://doi-org.libproxy1.nus.edu.sg/10.1038/s41467-018-06860-4更多优质内容，欢迎关注↓↓↓

核酸药物

2024-04-02

·BioSpace

Eiger Files for Bankruptcy, Plans to Shutter Operations After Difficult Year

Pictured: A U.S. federal bankruptcy courthouse building/iStock, GussWilder Eiger BioPharmaceuticals on Monday announced that it has voluntarily filed for bankruptcy and has kicked off the process of selling its assets and winding down the company’s operations. The California-based biotech has filed for Chapter 11 protection with the Bankruptcy Court for the Northern District of Texas, and has also submitted customary “first day” motions. If granted, the motion will provide Eiger some relief allowing it to transition into bankruptcy while it meets the company’s commitments to its stakeholders without “material disruptions” to its ordinary operations, according to the announcement. Eiger will sell all its assets during the bankruptcy case as it prepares for “an orderly wind down” of its operations. As part of the process, the biotech has inked a “stalking horse” agreement with rare disease player Sentynl Therapeutics which has agreed to purchase Zokinvy (lonafarnib), a farnesyltransferase inhibitor approved to treat the rare and progressive genetic disease Hutchinson-Gilford progeria syndrome. Sentynl will pay up to $26 million for Zokinvy, with the final price subject to other adjustments including per diem reductions. Zokinvy is an oral small molecule drug that blocks the farnesyltransferase protein. It is also approved for use in processing-deficient progeroid laminopathies with specific genetic mutations. The companies expect to close the sale by April 24, 2024. As part of its bankruptcy filing, other bidders can also submit competing offers for Eiger’s assets through a court-supervised process. Eiger’s bankruptcy filing on Monday caps off a difficult year for the biotech. In September 2023, it announced that it was discontinuing the Phase III LIMT-2 study of its candidate peginterferon lambda for chronic hepatitis delta. A quarterly review by a Data Safety Monitoring Board (DSMB) found concerning safety signals associated with peginterferon lambda. Four patients who received the investigational therapy developed hepatobiliary events, which led to liver compensation, leading the DSMB to recommend the study’s discontinuation. In September 2022, the FDA also rejected Eiger’s application for an Emergency Use Authorization for peginterferon lambda, which the biotech was proposing for the treatment of mild-to-moderate COVID-19. Following this rejection, Eiger in June 2023 laid off 25% of its workers in a sweeping reprioritization and savings program. The initiative also included a pivot to its GLP-1 receptor antagonist avexitide, which at the time was being developed for post-bariatric hypoglycemia and congenital hyperinsulinism. Eiger expected the cost-cutting measures to support its operations through the fourth quarter of 2024. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

临床3期上市批准并购优先审批加速审批

2024-03-31

·药时代

减肥神药成本5美元标价1000，药价与生产和研发成本是否相关？

药价是医药行业永恒的话题，而且越来越永恒地纠缠不清。药价辩论的双方，一边是付款者，以公共医疗健康保险计划和雇主保险计划，以及参保人为代表，他们是付款方；另一边是制药公司，他们代表收款方。站在中间的，是那些把控中间环节的代表，诸如左右通吃的PBM（药品福利管理者）。Bloomberg最近的一篇文章（图1）针对的是大热的减肥药物Wegovy的价格问题，他们的切入点很特别：生产成本。图1. Bloomberg文章截图生产成本是制药公司和CDMO的商业机密内容，外人基本上无从置喙，但也可以见微知著地估计一个大概。Bloomber援引JAMA Network Open的论文（图2），表明每月1000美元左右的四剂的GLP-1受体激动剂多肽Semaglutide，其每月剂量的生产成本在0.89-4.73美元之间。图2. JAMA文章截图对此，佛蒙特州参议员，美国参议院健康、教育、劳工和养老金 (HELP) 委员会主席Bernie Sanders在他的推特上发文，再度表明声讨制药公司制定过高药物价格的行为。Sanders就是前不久以强硬手腕要求默沙东、强生和BMS的首席执行官参加听证会的那位参议院。Sanders在他的推文中直言不讳地向诺和诺德发出灵魂质问，“除了贪婪”之外，还有什么理由可以将美元生产成本不足5美元的Ozempic标价近1000美元，而在德国人们只需为此支付59美元？并且强调，诺和诺德必须大幅度降低Ozempic在美价格（图3）。图3. Bernie Sanders推文截图药品生产成本往往属于保密内容，只有制药公司和CDMO清楚，外人几乎无法得到准确信息。但众所周知的是，drug product的成本（包括活性药物中间体）在很多情况下只占据药品标价的极小一部分，就像JAMA Network Open发表的论文中描述的那样，这个结论一点都不让人吃惊。有研究发现，Ozempic生产过程中的最大成本可能并不来自于semaglutide，而是用于注射的一次性注射笔。这支注射笔每月使用一支，成本大约在2.83美元左右。相比之下，Ozempic 中的活性药物的生产成本约为每月30美分（1 mg剂量而言）。Semaglutide的每公斤成本据称超过7万美元，相当于1 mg 7美分，一周注射一次的话相当于一个月注射4.29次（以30天计），那么一个月的成本大约就是30美分。Ozempic的其他成本包括他成本包括每支笔的灌装成本（每月剂量估计为 20 美分）和其他化学成分，包括excipient（估计每月剂量为 15 美分）。药品价格和生产成本之间是否具有关联性？如果我们接受Ozempic每月剂量的生产成本不超过5美元的这个事实，那么是否可以理直气壮地以此作为凭据挑战其在美国将近1000美元的标价？恐怕不能。在为其产品的高价格辩护的过程中，制药公司根本就没有将生产成本作为依据。药物（新药）标价与生产成本之间原本就没有显著性的关联，这是业内基本都接受的共识。以前工作中接触的一款药物，据称其API成本只占据了价格的1%。如果拿Ozempic来对比，后者1000美元的每月价格对应的API成本只有0.3美元，也就是0.03%的比例，1%已经算是较高的情况了。药品标价与生产成本无显著性关联的一个最好说明就是前不久刚刚经历临床失败的ALS药物Relyvrio。这款Amylyx Pharmaceuticals开发的肌萎缩侧索硬化症（俗称渐冻症）药物2022年9月获得了FDA的加速批准。这款药物包含两个简单的活性成分：苯丁酸钠sodium phenylbutyrate和牛磺酸二醇taurursodiol。在获得加速批准之后，Amylyx的III期验证性研究表明了Relyvrio的无效性。在主要终点上的得分与对照组比较的p值为0.67，远高于设定的显著性水平α （0.05）。这表明 Relyvrio从统计学的角度来看与安慰剂没有显著性区别。除了主要临床终点之外，Relyvrio上市后研究的次要终点，即患者报告的生活质量、呼吸功能或生存率的改善也都没有实现。就是这样一款接近安慰剂的药物，它的活性成分生产成本有多高？单看苯丁酸钠sodium phenylbutyrate和牛磺酸二醇taurursodiol这两款简单小分子的化学结构，即便没有详细信息，人们心中对其生产成本也应该有一杆秤。Taurursodiol是一种廉价的营养补充剂，属于牛磺酸类似物，通常被用作消化助剂和肝脏支持，有时作为营养补充剂出现。而苯丁酸钠看上去更像是一个合成其它复杂化合物的原材料。那么Relyvrio的标价几何呢？每年16.3万美元。2023年销售3.81 亿美元，获得 4900 万美元的利润。药物价格与研发成本之间存在关联吗？制药公司从来不会用生产成本作为依据维护药物的高价格，但很多制药公司会选择研发成本作为高药价的背书，包括同类药物中“壮志未酬”未能撞线的先驱者所产生的研发成本。那么药物价格和研发成本之间存在显著关联吗？JAMA Netw Open上发表的另一篇文献研究了药价与研发成本之间是否存在关联。研究者选取了2009 年至 2018 年FDA 批准的60种新药价格与研发投资之间的关系作为研究对象。结果发现，新药上市时的标价（R2 = 0.0005，p值=0.87）或上市后 1 年后的净价格（R2 = 0.007，p值 = 0.73) 与药物研发成本之间不存在相关性。线性回归模型（linear regression model）显示，研发投资与药物标价之间没有关联。这项研究的结果表明，研发投资并不能解释样本中 60 种药物的标价。如果制药公司继续利用“研发投资”作为论据来支持高药价的合理性，他们应该提供出更多的数据来作证这一论点。即便对于超罕见病的疗法，其高昂价格也不应该从研发成本的角度解释，而是从潜在的市场规模和药物价值出发。唯一能够解释药物价格的，是它们的价值。这听上去似乎有些像废话，但price和value是两个不同的概念。什么是价值呢？简单地说，就是体现在购买者为产品支付价格的意愿。例如刚获批的Orchard早发性异染性脑白质营养不良基因疗法Lenmeldy，其425万美元的价格超过了美国非营利组织临床与经济评论研究所建议的230 万美元至 390 万美元的区间，对此Orchard Therapeutics 在其声明中表示，Lenmeldy的价格“反映了其临床、经济和社会价值”。又如2019 年获批的脊髓性肌萎缩症基因疗法Zolgensma。诺华为每剂Zolgensma指定了210万美元的价格，并允许分期付款（5年）的方式支付费用，这使得Zolgensma的费用与第一款脊髓性肌萎缩症药物的成本Spinraza可比。诺华还认为，一次性治疗带来的变革性效益和长期价值为Zolgensma的高价提供了背书。也就是说，Spinraza疗法穷患者一生所产生的费用，与一次性的Zolgensma疗法相当，这就是用价值解释价格的案例之一。又如Bluebird Bio 针对β地中海贫血的基因疗法Zynteglo刚被开发出来时，Bluebird 将单次治疗的价格定为 150 万欧元（180 万美元），但市场表现欠佳，于是Bluebird将这款基因疗法退出了欧洲市场，转而专注于美国，同时将治疗成本上调到每剂280万美元。Bluebird Bio认为，Zynteglo的治疗可以帮助患者节省大量成本，因为此前针对地中海贫血的定期输血疗法或者干细胞移植，同样会造成高额的成本，因此参照这些疗法，Bluebird Bio对他们指定的280万美元的基因疗法给予了背书。以上都是基因疗法的案例，我们再举一个小分子疗法，就是刚刚获得FDA批准的第一款代谢功能障碍相关脂肪型肝炎（MASH）疗法，Madrigal的小分子口服制剂Rezdiffra（有效成分resmetirom）。其研发成本数据不得而知，但根据其结构来看，它的制造成本不应该高于产能非常有限的GLP-1多肽。然而ICER （临床与经济评估研究所）去年五月曾经估算过，如果resmetirom的价格定在每年在 3.96万美元到 5.01万美元之间，那么它就属于具有成本效益的药物。最终这款小分子药物的年标价被定在4.74万美元左右上，远高于semagltuide和tirzaptide。小分子药物中也不乏超过100万美元的天价药物。例如102万美元的Ipsen的进行性骨化性纤维发育不良（FOP）疗法Sohonos（Palovarotene）以及Eiger BioPharmaceuticals 100万美元的Hutchinson-Gilford 早衰综合症疗法Zokinvy（Lonafarnib）。如果说价格和研发成本和生产成本有什么关联的话，那么开发商为产品制定的价格，必须能确保他们收回研发成本和生产成本。但在覆盖这些成本的基础之上，究竟应该设定怎样的溢出值，这就是一个非常复杂的问题了，涉及到市场规模、同行竞争、中间环节的“盘剥”（回扣与折扣），专利时间和市场独占期的长短等众多因素了。例如诺和诺德曾经表示过，他们的semaglutide产品销售收入中，有75%用于回扣与折扣。无论这个“藉口”找的是否到位，这些“不透明”因素无疑使得价格成为了开发商最为倚重的工具。价格与成本之间并不存在人们头脑中的绝对关联，就连经济思想先驱亚当∙斯密早在18 世纪的著作《国富论》中都有阐述。这位苏格兰哲学家和经济学家指出，“生产成本与市场上实际购买商品价格无关。当买家来到市场时，他从不询问生产成本，以及卖方在生产商品时花费了多少费用。”因此说，开发商搬出高昂的研发成本来解释高药价，是站不住脚的，但似乎又攻不破。你说药物的价格远高于研发成本（如果你有研发成本的数据的话），他会说，那还有很多相关联的研发没有走到终点，因此它们的成本也要揉入这款产品之中。你又找出那些项目的投入，证明价格还是高。他会说，我这款产品就剩几年的市场独占期了，之后不仅要面临仿制药，FDA还要有可能在上市后九年（小分子药物）开启价格谈判，我的利润肯定会受影响。你说即便如此，药价和销售额也足够覆盖这些成功并产生利润了。他会说，那这中间还有大量回扣和折扣，卖药的钱只有一部分落入了开发商的腰包。你问，那折扣和回扣有多少？他会说，折扣付款人知道，回扣PMB不让说，这都是商业机密。辩论结束。药价当然必须覆盖开发和生产成本，没有人会做赔本而买卖。但标价多少，就不是成本决定的了。价格实际上是购买者支付意愿的函数，而不是产品投资的函数。举个例子，如果在一个寒风凛冽的冬天出现了供暖供电中断，那么此时煤炭的价格还与它的成本有关吗？或者说CBD的房价是否合理，有人要去质疑它的地皮价格和建造成本吗？这里并不是说制药公司等同于奸商，只是为了说明他们对于产品的定价与其研发成本之间并无关联性。这也在一定程度上解释了上文提到的Relyvrio为什么敢于标出16.3万美元的价格。这个看不见的力量实际上也在一定程度上对FDA的监管决策产生了影响。Relyvrio的II期研究CENTAUR给出了不令人乐观的结果。FDA 的第一个顾问小组于 2022 年 3 月以 6 比 4 的投票拒绝批准该药物，而第二个小组在六个月后却改弦更张，投票支持加速批准，但仍然对 Relyvrio 的功效保留了怀疑。据报道，FDA在审批Relyvrio的进程中得到了一份有 5 万人签名的请愿书。患者权益倡导者的意见显然对FDA的决定起到了一定作用。ALS（渐冻症）是一种罕见的、破坏性的进行性疾病，影响运动神经元功能，通常在症状出现后两到三年内致命。美国只有约 3万名 ALS 患者，但最终却搞到了一张五万人签名的请愿书。很难说FDA在做出加速批准Relyvrio时是否有投鼠忌器的掣肘。从这个角度不难看出ALS 患者为这款药物支付的意愿，尽管彼时Amylyx可能尚未对Relyvrio标出16.3万美元的“天价”。为什么ALS无效的16.3万药物没有引发轩然大波，而GLP-1减肥药的价格却成为众矢之的？背后的原因比较复杂，但还是离不开价值这一核心。作为一种罕见疾病，ALS面临着巨大的疗法未满足现状。行业领域内但凡出现一丝微小的进步力量，都会被视作希望，因此价格在其潜在的价值面前就有些不那么重要了。反观肥胖症，尽管越来越多的人已经将其视为一种疾病，但仍然有很多人怀疑其作为药物的价值（并非功效），尤其是考虑到这种药物可能需要终生服用，将会对公共健康保险计划和雇主保险计划带来沉重的负担，它的价格问题就成为了不可回避的论战焦点。这也解释了美国联邦政府选择十款药物作为IRA法案下的价格谈判的原因。它们都是为Medicare造成了极大经济负担的药物，因此它们的价格必然成为联邦政府终点关注的对象。结语Concluding Remark购买者应不应该为研发投入支付金钱？这件事情很难说清楚。就像那副价格昂贵的“拐”一样，背后可能的确有很多只“甩丢的鞋”，但是买拐的是否应该为鞋埋单？这可能就是仁者见仁智者见智的话题了。不过对于制药行业来说，确定的因素是，只有他们存在下去并且有意愿为各种疾病和适应症开发新的更好疗法，人类的健康才能得到更大的保障。Reference：Barber, M. J. Estimated Sustainable Cost-Based Prices for Diabetes Medicines. JAMA Netw Open. 2024;7(3):e243474. doi:10.1001/jamanetworkopen.2024.3474Wouters, O, J. et al. Association of Research and Development Investments With Treatment Costs for New Drugs Approved From 2009 to 2018. JAMA Netw Open. 2022;5(9):e2218623. doi:10.1001/jamanetworkopen.2022.18623.Smith, A. Stock Watch: Acadia And Amylyx Trial Failures Were No Shock. Scrip. 26. 03. 2024.Carroll, J. Do big R&D budgets justify US premium drug prices? No way, analysts scoff. Endpoints News. 08. 03. 2017.Cohen, J. Pharmaceutical Industry Ought To Justify Drug Prices On Value, Not R&D Costs. Forbes. 01. 06. 2023.Ozempic, Novo’s $1,000 Diabetes Shot, Can Be Made for Under $5 a Month. Bloomberg. 27. 03. 2024从 “皇帝新衣”撤市和历史首封特殊CRL看FDA加速批准单抗统治下的倔强，小分子阿尔茨海默病疗法Ferring首席科学家杨翼博士：肥胖症疫苗离我们还有多远？点击阅读原文，了解更多！