Somatrogon(OPKO Health, Inc.)

With the multinational pharma corporation (MNCs) annual reporting season for 2023 recently completed, GBI reviews company reports for performance highlights and trends, both globally and in the China market.The last 12 months saw the collapse of a mountain of COVID-19 vaccine sales, meaning that Pfizer lost its position as the leading pharma revenue generator globally to Johnson & Johnson. The lack of COVID competition allowed Merck, Sharp & Dohme’s PD-1 inhibitor Keytruda (pembrolizumab) to emerge as the world’s top-selling drug. However, the fact that more than half of the leading top - 20 blockbusters are either already off-patent or facing loss of exclusivity by 2028 underlines the urgency behind the recent surge in deal-making by Big Pharma. Meanwhile, in China, the success of one crucial product has seen Merck, Sharp & Dohme eclipse AstraZeneca as the market’s leading MNC pharma. J&JDisplaces Pfizer at Top of Revenue LeaderboardAfter underwhelming returns from its COVID-19 vaccine, the US giant Johnson & Johnson (J&J) returned to form in 2023. Focusing solely on pharmaceutical sales (as per all sales figures in this report), J&J generated USD 54.76 billion after growth of 4.8% year-on-year (YOY). J&J products occupied 4 of the top-20 selling drugs globally if co-development partnerships are included. The portfolio is led by auto-immune disease drug Stelara (ustekinumab), which hit USD 10.85 billion in 2023 sales, up 9% YOY, but faces its first biosimilar competitors in 2024, the first approved in Europe in January this year. Anti - CD38 antibody Darzalex (daratumumab), used to treat multiple myeloma (MM), hit USD 9.74 billion, up 22.2% YOY, and retains market exclusivity until 2029.Of the firm’s new launches, chimeric antigen receptor (CAR) T cell therapy Carvykti (ciltacabtagene autoleucel), in-licensed from China’s Legend Biotech, was a strong performer, with sales reaching USD 500 million during the year, up from USD 133 million in 2022. CEO Joaquin Duato underlined that “with more than 2,000 patients treated with Carvykti, it's already the fastest launched CAR-T in the market overall”. J&J is seeking approval for Carvykti as a second-line or later MM therapy, with a PDUFA date of April 4, 2024, and has taken steps to expand its lentivirus manufacturing capabilities in the US, as well as sites in the Netherlands and Switzerland, to meet expected growing demand for the therapy. An FDA investigation into the safety of CAR-Ts in general was also shrugged off by J&J, Duato noting: “We remain confident in ... both the risk-benefit of Carvykti in the indication that is being studied and at the same time on the potential of Carvykti to be a USD 5 billion plus asset at peak year sales”. Low-Key Deal-MakingAlthough J&J made no blockbuster multi-billion-dollar acquisitions during 2023, the firm has worked quietly to strongly expand its pipeline.“ CFO Wolk underlined the firm’s deal making during the year, when USD 3 billion was deployed for licensing and acquisitions. ”That included the purchases of antibody drug conjugate (ADC) specialist Ambrx for USD 2 billion and atrial fibrillation medtech firm Laminar for USD 400 million “as well as more than 50 smaller early stage licensing deals and partnerships that complement our current  Innovative Medicine and MedTech pipelines”. The firm expects another strong year of 5%-6% growth in 2024.PfizerRecord Year of Approvals Bodes Well for FutureHaving led the world for the last two years in revenue terms, Pfizer’s fall from its COVID pinnacle of USD 99 billion biopharmaceutical sales in 2022 was faster than had been predicted after sales targets were missed due to cancelled government contracts for COVID-19 therapy Paxlovid (nirmatrelvir/ritonavir) and vaccine Comirnaty. Revenues from pharma sales were down -45% YOY, however, excluding COVID-19 products, global sales were up a respectable 7% YOY.Pfizer had 3 products in the global top-20 rankings, including the anticoagulant Eliquis (apixaban), the Prevnar family of vaccines, and the Comirnaty COVID vaccine. However, both Eliquis and Prevnar face patent expiration in 2026, while Comirnaty is unlikely to feature heavily in 2024. Nevertheless, Pfizer’s in-house pipeline and recent acquisitions are expected to produce a soft landing. There were a record nine US FDA new drug approvals during 2023, for: migraine therapy Zavzpret (zavegepant), RSV vaccine Abrysvo, alopecia treatment Litfulo (ritlecitinib), growth hormone Ngenla (somatrogon), multiple myeloma drug Elrexfio (elranatamab), ulcerative colitis drug Velsipity (etrasimod), Neisseria meningitidis vaccine Penbraya, as well as Comirnaty and Paxlovid. Abrysvo and the 2022-acquired migraine therapy Nurtec ODT/Vydura (rimegepant) as well as sickle cell disease treatment Oxbryta (voxelotor) were among the recent launches to begin making meaningful commercial contributions. Seagen AcquisitionMuch of Pfizer’s COVID windfalls went towards the USD 43 billion acquisition of antibody drug conjugate (ADC) pioneer Seagen, a deal which closed in December 2023. Pfizer CEO Albert Bourla, speaking during the earnings conference call, underlined the importance of the acquisition to the company’s future, described as putting Pfizer “in a strong position... to achieve a world-class oncology leadership”. Pfizer’s oncology-focused R&D resources were immediately doubled thanks to the merger, as well as commercial network gains. The deal doubles Pfizer’s oncology pipeline and is expected to produce an immediate USD 3.1 billion positive impact on 2024 revenues, helping Pfizer to raise its 2024 financial guidance into a range between USD 58.5 billion and USD 61.5 billion total revenues.Seagen’s current lead product is Padcev (enfortumab vedotin), a treatment for bladder cancer being co-developed with Astellas. First approved in 2019, Pfizer/Astellas secured a significant new indication approval for the drug in December 2023, the US FDA giving the nod for Padcev’s use alongside Keytruda (pembrolizumab) in first-line urothelial carcinoma. Wall Street sales forecasts for Padcev average at around USD 2.8 billion by 2030.One of the motivations behind Pfizer’s recent cost-cutting drive has been to free up resources to support the commercial launch of so many new products. New molecular entities (NMEs) are forecast to potentially generate up to USD 20 billion in new revenues  by 2030, when a further USD 25 billion is forecast to be derived from the US giant’s licensing and acquisition deal-making. MSDKeytruda Claims its Rightful PlaceFor Merck, Sharp & Dohme (MSD), the programmed death-1 (PD-1) inhibitor Keytruda (pembrolizumab) took its place at the top of the global drug sales charts for the first time in 2023. The molecule generated USD 25 billion of MSD’s total USD 60.1 billion in revenues during 2023 after 21% YOY growth. Human papillomavirus (HPV) vaccine family Gardasil/Gardail-9 also enjoyed  a strong year with 29% YOY expansion to be just outside the  top-10 best-selling drugs globally in 2023 with USD 8.9 billion in sales.That means that Keytruda and Gardasil sales combined accounted for over 63% of MSD’s total pharma sales. First approved by the US FDA in 2014, Keytruda’s core patent in the US runs out in 2028. Gardasil was first approved in 2006 and is already off-patent, while Gardasil-9 was first approved in 2017 and is also set to lose exclusivity in 2028.However, Gardasil already faces competition in China – among the vaccine’s most significant markets globally – from locally developed innovative HPV vaccines, including 9-valent products.Like many of MSD’s peer companies, stocking the pipeline with the next generation of products to replace Keytruda and Gardasil is clearly a priority. Of note, 14 of the top-20 drugs by global sales are either already patent-expired or face loss of exclusivity within the next 4 years or less. MSD’s response was to put around USD 30 billion into R&D investments during 2023. That included the USD 10.8 billion acquisition of US biotech Prometheus Biosciences which closed in June 2023, mainly targeting PRA023, a tumor necrosis factor (TNF)-like ligand 1A (TL1A)-targeted antibody in late-stage development for autoimmune diseases including ulcerative colitis and Crohn’s  disease. And in October, Merck paid USD 4 billion upfront as part of a potential USD 22 billion partnership with Daiichi Sankyo, taking ex-Japan development rights to three antibody drug conjugates (ADCs). That deepened MSD’s involvement in the ADC space, following three significant deals with China’s Sichuan Kelun Pharmaceutical signed in 2022, cumulatively worth north of USD 10 billion in total commitments. MSD’s BD activity over the last three years means it has built a formidable pipeline covering three core therapeutic areas of oncology, cardiometabolic diseases, and immunology, with a potential USD 15 billion in forecast potential sales for the pipeline added by deal-making during 2023. Over 20 Phase III trials were initiated during 2023, and an even greater number is expected for 2024. Potential market is untapped70% of Gardasil’s potential market in China still untapped: Finally, MSD’s China performance is worthy of note. The region produced sales growth of 20% during Q4 to USD 1.5 billion, and rose 32% YOY over the 12 months to USD 6.71 billion in sales – over 12% of MSD’s global pharma total – meaning that MSD cemented its place as currently the leading pharma company in China.Gardasil remains the key driver, and during the earnings conference call investors questioned whether the locally approved innovative HPV vaccines pose a threat to future growth, particularly considering that one domestic firm recently received approval for a two-dose regimen.CEO Rob Davis voiced his confidence in MSD’s ability to maintain “a vast majority of share in the private market”. The US firm continues to mainly target urban females in Tier 1 to Tier 3 cities, a population of about 200 million, of which, Davis noted, “probably about 30% have actually received vaccination. So, you are still looking at 120 million, 130 million eligible population”. With most of the local competitors targeting lower-tier cities and a different population, MSD remains bullish on its prospects in China. MSD also submitted data for Gardasil in male subjects late last year, and could gain approval later this year for that new market segment.

关注并星标CPHI制药在线3月8日，维昇药业（VISEN Pharmaceuticals）宣布中国国家药品监督管理局（NMPA）已受理隆培促生长素（lonapegsomatropin，Skytrofa）的上市许可申请（BLA）。隆培促生长素是第一个在欧美获批上市的长效生长激素，每周注射一次，用于治疗儿童生长激素缺乏症。       隆培促生长素是采用全球极具创新性的TransConTM（Transient Conjugation, 暂时连接）专利技术平台设计的人生长激素前药，能够以可控的方式在体内缓慢释放未经修饰的生长激素，血浆半衰期可达30.7（±12.7）小时，支持每周一次给药。       已公布的隆培促生长素针对中国生长激素缺乏症（GHD）儿童患者的3期临床试验数据显示：治疗52周时，隆培促生长素治疗组儿童生长激素缺乏症患者的年化生长速率（AHV）显著高于生长激素日制剂组（10.66厘米/年Vs 9.75厘米/年），达到研究主要终点。       此外，在52周治疗期间，隆培促生长素治疗组和生长激素日制剂组患者的平均胰岛素样生长因子-1（IGF -1）标准差积分(SDS)均增加至正常范围内，且隆培促生长素组相对较高。IGF -1是肝脏对生长激素反应时产生的一种多肽，可刺激软骨细胞增殖、分化和胶原的合成。而且，隆培促生长素耐受性良好，安全性与生长激素日制剂相当。       隆培促生长素由Ascendis Pharma开发，维昇药业拥有其在大中华区的独家开发、制造和商业化权益。2021年8月，该药被FDA用于治疗年龄在一岁及以上、体重至少11.5公斤、因内源性生长激素分泌不足而导致生长迟缓的儿童患者。2022年1月，该药在欧盟被批准用于治疗因内源性生长激素分泌不足而导致的3-18岁儿童和青少年生长迟缓。据公司财报，隆培促生长素2022年、2023年销售额分别为35百万欧元和179百万欧元，预计2024年将达到320-340百万欧元。       生长激素药物的发展迭代       生长激素缺乏症（GHD），又称垂体性侏儒，因下丘脑-垂体轴的器质性病变或是功能性异常导致生长激素缺乏引起，患者不仅表现为身材矮小，还存在代谢异常、心理社会挑战、认知缺陷和生活质量差等问题。据公开资料，我国儿童患矮小症的比例约为3%，其中GHD最为常见，占比约三分之一。补充生长激素是目前公认治疗儿童GHD最有效方法之一。       生长激素是人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，在人体生长发育过程中发挥重要作用。       根据制备技术的迭代，生长激素药物的研发经历了五代更替。其中第一代生长激素从人脑垂体中提取，存在来源受限、传递传染性疾病的风险，且会引起慢性脑部海绵样变性导致死亡，世界各国已相继停用。第二代生长激素是利用大肠杆菌包涵体技术合成的基因重组人生长激素（rhGH），与天然生长激素结构不同，由192个氨基酸组成，但容易产生抗体影响疗效，目前已淘汰。第三代生长激素是利用普通大肠杆菌以及哺乳动物真核表达系统，表达合成的含有191个氨基酸的 rhGH ，结构与hGH还有差异，存在易产生抗体、成本高和易污染等缺点。第四代生长激素是利用哺乳动物细胞重组DNA技术合成的含有191个氨基酸的生长激素，其结构和天然的生长激素结构更为接近，目前仅被极少数生产厂家沿用。第五代生长激素是利用分泌型大肠杆菌表达技术合成，其氨基酸含量、序列和蛋白质结构与人垂体生长激素完全一致，因此生物活性高、免疫原性低、副作用少。       剂型上，目前市面上的生长激素产品包括短效粉针、短效水针和长效水针，其中粉针粉针和短效水针在疗效上没有显著差异，但针粉临床使用繁琐，注射前需抽取抑菌水注入冻干粉容器中重新配制，不过其稳定性较水针好。       金赛药业领跑，国内多款生长激素产品获批上市       目前，国内已批准多款生长激素产品，详见下表。整体来看，国内生长激素持有企业比较集中，主要为金赛药业、安科生物等。其中金赛药业是国内生长激素的领军企业，且是国内唯一实现短效粉针、短效水针、长效水针三种剂型全部上市的企业。       据米内网数据，2022年中国城市公立医院、县级公立医院、城市社区中心以及乡镇卫生院（简称中国公立医疗机构）终端生长激素销售规模约为67亿元，其中金赛药业是行业老大，市场占比超80%：在粉针剂市场，金赛药业市场份额占比超50%；在水针剂市场，金赛药业市场份额高达99%；金赛增是国内唯一获批的长效水针，2022年销售额超7亿元。       对比国外，国内批准的长效生长激素水针有限，仅金赛药业的金赛增。目前，国外已批准多款长效生长激素水针，即Ascendis Pharma的Skytrofa、诺和诺德的Sogroya和辉瑞的Ngenla。       上述四款长效生长激素的长效作用机制还不太一样。其中Skytrofa是凭借TransCon技术，该技术可使其给药后以可控方式在一周内缓慢释放未经修饰的活性生长激素，从而发挥作用。Sogroya是一种hGH的长效类似物，由天然的hGH经过修饰以增强其与血浆白蛋白的结合，使其适合每周一次给药。Ngenla也是一种长效hGH类似物，利用OPKO专有的C末端肽段（CTP）长效技术在一段天然生长激素序列的C和N末端分别加上了2个和1个来自人类绒毛膜促性腺激素（HCG）β亚基的CTP拷贝，使其半衰期得以延长。金赛增是全球首支上市的聚乙二醇（PEG）化长效生长激素注射液，其利用天然肽键连接了惰性PEG和天然结构的生长激素，从而降低其被肾脏过滤的速度和蛋白酶对它的降解作用，进而提高其在人体内的稳定性。       此外，微球技术也被开发用长效生长激素领域，如基因泰克的Nutropin Depot、韩国LG Life Sciences的 Declage。其中Nutropin Depot是全球第一个上市的长效生长激素，其采用PLGA缓释微球技术，缓释效果显著，1999年获批上市，但后续因注射局部疼痛，4年后退市。Declage采用的是透明质酸技术，2007年在韩国上市。       长效生长激素有哪些后备军       长效生长激素是儿童GHD生长激素替代疗法研发的热门方向，目前全球药企已研发出多款在研长效生长激素，详见下表。我国药企也积极布局长效生长激素，其中特宝生物的怡培生长激素已于今年1月在国内报产。       怡培生长激素由特宝生物自主研发，其采用40kD Y型分支聚乙二醇（YPEG）分子对rhGH进行单分子修饰，优选高生物学活性、非N-末端位点为主的修饰组分，在保证疗效的同时，旨在降低给药剂量，获得更佳的长期药物安全性。已公布的2/3期研究数据显示：儿童GHD患者接受12周治疗后，怡培生长激素100、120、140μg/kg/周组和重组人生长激素35μg/kg/天组（对照组）的身高增长速度分别为7.07、10.39、12.27厘米/年和11.58厘米/年。       天境生物的伊坦生长激素进展也相对较快，其治疗儿童GHD的3期研究已达到非劣效性主要终点，今年将递交上市申请。该药是基于Genexine的专利hyFc®技术开发，hyFc部分由人 免疫球蛋白D（IgD）和G4（IgG4）的一部分组成。前者包含一个柔性铰链，后者可通过新生儿Fc受体（FcRn）介导的代谢调控延长半衰期。已公布的3期临床试验结果显示：伊坦生长激素组患者的年化身高生长速率（AHV）为10.76厘米/年，而Norditropin（诺泽）组患者的AHV为10.28厘米/年。       值得一提的是，围绕伊坦生长激素药企间达成数项交易。该药由Genexine开发，2015年10月天士力子公司Tasgen（被天境生物收购）与Genexine达成协议，获得伊坦生长激素的中国权益。2021年11月，天境生物将伊坦生长激素的商业化权益授权给济川药业。       安科生物、优诺金的长效生长激素处于2期临床，其中AK2017通过采用Fc融合蛋白结合技术延长半衰期，是重组人GH同源二聚体与通过突变的人IgG4-Fc的融合蛋白。       此外，除了皮下注射生长激素，儿童GHD患者还有望迎来口服疗法。2023年11月，Lumos Pharma生长激素促分泌素受体（GHSR）激动剂LUM-201治疗儿童GHD的两项2期研究（OraGrowtH210研究和OraGrowtH212研究）达到了所有主要终点及次要终点。       总结       生长激素药物的问世给儿童生长激素缺乏症（GHD）患者带来了希望。历经60多年的发展，生长激素药物的研发取得巨大成功，已从每日一次给药实现每周一次给药的跨越。全球儿童GHD的治疗规模也随之扩大，Frost & Sullivan数据显示其2030年有望达到60亿美元。目前，我国也已批准多款生长激素药物，但长效制剂相对国外较少，而且生长激素药物的市场渗透率也比较低。不过随着生长激素纳入集采，我国将有更多的儿童GHD患者接受生长激素治疗。期待未来有更多的新型生长激素药物获批上市，造福众多儿童GHD患者。       参考资料：       1.《生长激素行业深度：长效剂型快速放量，产品出海未来可期》.青山医药笔记.2024-02-07       2.《洞察o创新｜慎思而笃行：生长激素发展历程带来的挑战与风险》.全球健康产业创新观察.2023-07-20       3.《临床需求决定研发方向：生长激素的不断进步史》.医学界儿科频道.2022-10-14       【智药研习社近期直播预告】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~