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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.

康龙化成举办第四十三期“合成与药物化学前沿”名师线上讲座2024年2月29日，北京—加拿大多伦多大学Mark Lautens教授做客康龙化成第四十三期“合成与药物化学前沿”名师线上讲座，报告主题为“拨动开关：可逆催化反应”。在讲座中，Lautens教授介绍了他的团队运用可逆反应的策略合成多样的稠环以及多元并环结构并对反应机理进行了深入的探索。Catellani在1997年的一份报告概述了一种新的C-H官能化反应，其关键步骤是用降冰片烯进行可逆碳钯化，这激发了Lautens教授对可逆反应研究的兴趣。Lautens教授随后探索了Catellani反应的更优反应条件和合成潜力，包括其在天然产物合成中的应用。Lautens教授的小组在Catellani反应的基础上开发了一系列环化方法，合成了各种稠环以及多元并环结构。首先，Lautens教授介绍了使用2-氨基-1,1-二溴苯乙烯作为原料构建2-溴吲哚类衍生物。揭示了在2-溴吲哚的合成里面Pd催化剂对C(sp2)-Br键的氧化加成是可逆的。(DOI: 10.1021/ja1052335)此外，Lautens教授介绍了利用钯催化卤代烃与远程的端基烯烃发生分子内的Heck偶联反应形成新的碳碳键，从而形成烷基钯中间体，该中间体可以经可逆的消除过程得到具有碳卤键的稠环结构；该中间体也可以继续与亲核试剂反应，经还原消除得到含有季碳中心的稠环结构。(DOI: 10.1021/ja110377q) 同时，镍催化剂也可以有效催化这一反应类型，构建碳-碘代的吲哚酮类化合物。(DOI: 10.1021/jacs.8b06966)  通过调整底物结构，芳胺上用氯甲酰基取代时，以(S)-tBuPHOX作为配体可以以非常优秀的ee值获得预期的吲哚酮类化合物。(DOI: 10.1021/ACSCatal.0c00841)受此启发，他们继续探索了邻位由炔烃取代的氯甲酰苯胺类或氟甲酰胺类底物在钯和镍催化下的可逆反应。经过仔细的研究，他们发现，六氟异丙醇或三氟化硼乙醚就可以很好的促进这一反应进行，并用密度泛函理论计算对这一过程进行了详细解释。(DOI: 10.1021/jacs.3c03982)在报告的后半部分，Lautens教授详细阐述了他们合成异喹诺酮并环产物过程中的新发现。他们发现，钯和镍催化的碳碘化反应生成了碘代二氢异喹诺酮的顺式和反式非对映异构体产品。以这些底物为例，他们对钯催化形成C–C键的可逆性进行了广泛的研究。并用实验和计算研究相结合用于探讨其作用机制，探索可逆C–C键过程的关键，包括电子和空间位阻等参数对C–C键断裂步骤的影响。(DOI:10.1038/s41557-022-00898-0) 并且探索了光在碳碘化这一反应中的应用并对机理进行了详细解释。(DOI:10.1021/jacs.2c09716)Lautens教授的工作展示了在可逆催化反应方面的突破。总的来说，他们的合成策略为开发和利用新的化学转化提供了丰富的可能性。演讲结束后，Lautens教授在问答环节与观众进行了热烈的讨论。Frontiers in Synthetic and Medicinal Chemistry--The 43rd Pharmaron Virtual LectureBeijing China, February 29th, 2024 - Pharmaron held its 43rd virtual lecture in the Frontiers of Synthetic and Medicinal Chemistry series, which was delivered by Prof. Mark Lautens from University of Toronto, Ontario, Canada. The title of this presentation was “Flipping the Switch: Reversible Reactions in Catalysis.” During the lecture, Prof. Lautens introduced his group’s achievement of creating reversible reaction strategies for the synthesis of a variety of fused rings and multi cyclic structures and conducting in-depth exploration of reaction mechanisms.A 1997 report by Catellani outlining a novel C-H functionalization reaction stimulated Prof. Lautens’s interest in reversible reactions since a key step is reversible carbopalladation with norbornene. Prof. Lautens subsequently explored improved reaction conditions, and the synthetic potential of the Catellani reaction, including its application in the synthesis of natural products. Prof. Lautens’ group developed a series of cyclization methods based on the Catellani reaction, and synthesized a variety of heterocyclic structures with fused rings.Prof. Lautens introduced how to construct 2-bromoindole analogues using 2-amino-1,1-dibromobenzenes as starting materials, which revealed that the oxidative addition of C(sp2) - Br bond by Pd catalyst in the synthesis of 2-bromoindole is reversible. (DOI: 10.1021/ja1052335).Prof. Lautens then introduced the use of palladium catalyzed intramolecular Heck coupling reactions between halogenated substrates and remote terminal alkenes to form new C-C bonds, which formed alkyl palladium intermediates. This intermediate can be reversibly eliminated to obtain a fused ring structure with carbon halogen bonds. The intermediate can also undergo a nucleophilic reaction to give a fused ring structure containing a quaternary carbon center through reductive elimination. (DOI: 10.1021/ja110377q) At the same time, nickel catalysts can also effectively catalyze this reaction to construct iodinated indolinones. (DOI: 10.1021/jacs.8b06966) By adjusting the substrate structure, his group found that (S) - tBuPHOX can be used as a ligand to give the expected indoline with excellent ee values. (DOI: 10.1021/ACSCatal.0c00841)Inspired by this achievement, his group continued exploring the reversible reactions of chloroformamide or fluoroformamide containing substrates with alkynes at the ortho position under palladium and nickel catalysis. After careful research, they found that hexafluoroisopropanol or boron trifluoride ether can effectively promote this reaction. This process was explained in detail by using density functional theory calculations. (DOI: 10.1021/jacs.3c03982)In the second part of the lecture, Prof. Lautens presented their new findings in the synthesis of isoquinolone products. The development of palladium- and nickel-catalysed carboiodination reactions afforded access to the cis and trans diastereomers of the iodo-dihydroisoquinolone products. Taking these substrates as examples, they have extensively studied the reversibility of palladium catalyzed formation of C-C bonds. A combination of experimental and computational research is used to explore its mechanism. He presented a comprehensive investigation of reversible C–C bond formation using palladium catalysis employing diastereomeric neopentyl iodides as the starting point. (DOI: 10.1038/s41557-022-00898-0) and explored the application of light in the carbon iodization reaction and provided a detailed explanation of the mechanism. (DOI: 10.1021/jacs.2c09716)Prof. Lautens' work demonstrated a breakthrough in reversible catalytic reactions. Overall, their synthetic strategy brought a wealth of opportunities for developing and implementing new chemical transformations.Following the presentation, Prof. Lautens discussed key topics during the Q&A session with the audience.