Impact of Nrf2 Activation on Macrovascular Function, Microvascular Function, Leg Function, and Walking Capacity in Patients With Peripheral Artery Disease

Purpose: Peripheral artery disease (PAD) is associated with elevated oxidative stress, and oxidative stress has been implicated as the cause of reduced endothelial reactivity in individuals with PAD. Endothelial function is important because the endothelium contributes to the dilation of arteries during exercise, thereby implicating impaired endothelial function as a mechanism contributing to exacerbated exercise-induced ischemia. Therefore, the purpose of this study is to test the hypothesis that acute exogenous diroximel fumarate (Vumerity) intake will improve antioxidant capacity, thereby reducing oxidative stress and improving vascular function and walking capacity in those with PAD. Eligibility: Individuals with PAD will be deemed eligible for this study if they 1) are 50-75 years old and postmenopausal, 2) have a positive history of exercise-limiting claudication (Fontaine II or III), 3) do not have renal impairments, 4) do not have Fontaine stage IV PAD, and 5) are not currently pregnant or nursing. Age-matched controls will be deemed eligible for this study if they 1) are 50-75 years old and postmenopausal, 2) have an ABI greater than 0.9 (no PAD), 3) do not have exercise-limiting diseases or injuries, 4) do not have renal impairments, and 5) are not currently pregnant or nursing. Intervention and Evaluation: During this study, participants will be administered diroximel fumarate or a placebo, and the acute effects of diroximel fumarate on vascular function and walking capacity will be assessed. Vascular function and walking capacity will be assessed with flow-mediated dilation, arterial stiffness, head-up tilt test, blood biomarkers, near-infrared spectroscopy, and a treadmill test. Follow-up: There will be a follow-up visit to assess blood work after diroximel fumarate.

开始日期2024-12-01

申办/合作机构

University of Nebraska

NCT05767736 / Active, not recruitingN/A

An Observational Study Utilising Data From Big MS Data Registries to Evaluate the Long-Term Safety of Vumerity and Tecfidera

The primary objective of the study is to estimate the incidence rate of serious adverse events (SAEs), including but not limited to malignancies and serious and opportunistic infections, among participants with MS treated with Vumerity, Tecfidera, other selected disease modifying therapies (DMTs [teriflunomide, beta interferons, or glatiramer acetate]), or Vumerity after switching from Tecfidera. The secondary objective of the study is to compare the incidence rate of SAEs, including but not limited to malignancies and serious and opportunistic infections, among MS participants treated with Vumerity, Tecfidera, and Vumerity after switching from Tecfidera with the incidence rate of MS participants treated with other selected DMTs (teriflunomide, beta-interferons, or glatiramer acetate), if the sample size allows.

开始日期2024-06-08

申办/合作机构

Biogen, Inc.

NCT05658497 / RecruitingN/A

Vumerity (Diroximel Fumarate) Prospective MS Pregnancy Exposure Registry

The primary objectives of the study are to estimate the risk of major congenital malformations (MCMs) in infants born to women with multiple sclerosis (MS) who were exposed to diroximel fumarate (DRF) at any time from 2 weeks after the first day of their last menstrual period (LMP) up through the first trimester of pregnancy and to comparatively evaluate pregnancy outcomes with MCMs in women with MS who were exposed to DRF at any time from 2 weeks after the first day of their LMP through the first trimester of pregnancy with the following: i) women with MS who were unexposed to disease modifying therapies (DMTs) and, ii) women with MS who were exposed to other DMTs (e.g., Avonex and Tysabri Pregnancy Registries).
The secondary objective of the study is to evaluate pregnancy outcomes in women with DRF exposure at any time from 2 weeks after the first day of their LMP through the end of pregnancy compared with the following: i) women with MS who were unexposed to DMTs, ii) women with dimethyl fumarate (DMF) exposure, iii) women with MS who were exposed to other DMTs (e.g., Avonex and Tysabri Pregnancy Registries), and iv) women without MS (e.g., women from external, general population comparators).

开始日期2023-10-27

申办/合作机构

Biogen, Inc.

100 项与富马酸地罗西美相关的临床结果

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100 项与富马酸地罗西美相关的转化医学

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100 项与富马酸地罗西美相关的专利（医药）

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项与富马酸地罗西美相关的文献（医药）

2025-01-01·COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY

Time-restricted feeding modulates gene expression related with rhythm and inflammation in Mongolian gerbils

Article

作者: Yang, Lin ; Wang, Chen-Zhu ; Zhang, Xue-Ying ; Wang, Xi-Zhi ; Wang, De-Hua ; Wang, Zhen-Shan

Time-restricted feeding (TRF) has the potential to modulate circadian rhythm and widely studied in humans and laboratory mice. However, less is known about the physiological responses to TRF in wild mammals. Here, we used Mongolian gerbils, Meriones unguiculatus, to explore the effect of 6-week TRF on gene expression related with circadian rhythm and inflammation. The TRF gerbils had higher cumulative food intake than the ad libitum (AL) group, but body mass, feeding frequency/time and metabolic rate did not differ between groups. In the hypothalamus, downregulation of rhythm-related genes Per3, Cry1 and Dbp was detected in the daytime-restricted feeding (DRF) group and Cry1 was downregulated in the nighttime-restricted feeding (NRF) group. In the liver, the expression of Per1/3, Rev-erbα/β and Dbp was lower, and Bmal1 was higher in the DRF than in AL group, while NRF gerbils showed no changes. In the colon, the expression of Bmal1 and Cry1 was higher but Per3, Rev-erbα/β and Dbp were lower in the DRF than in AL group. Further, the expression of inflammation-related genes such as NF-κB, IL-1β, IL-18 and Nlrp3 was lower in the liver of DRF gerbils, and IL-1β was lower both in the hypothalamus and liver of NRF gerbils. Moreover, the genes related with inflammation such as NF-κB, Nlrp3, IL-10/18/1β and Tnf-α were positively or negatively correlated with multiple rhythm-related genes in the central and peripheral organs. In conclusion, TRF, particularly DRF, could modulate rhythm-related genes in the central and peripheral tissues and reduce hepatic expression of inflammation-related genes in gerbils.

2025-01-01·BRAIN BEHAVIOR AND IMMUNITY

18 kDa Translocator protein (TSPO) is upregulated in rat brain after peripheral nerve injury and downregulated by diroximel fumarate

Article

作者: Avery, Thomas D. ; Zagrai, Sever M ; Avery, Thomas D ; Zagrai, Sever M. ; Grieco, Anamaria R. ; Grace, Peter M ; Loggia, Marco L ; Cazuza, Rafael A ; Grieco, Anamaria R ; Abell, Andrew D. ; Abell, Andrew D ; Loggia, Marco L. ; Wey, Hsiao-Ying ; Cazuza, Rafael A. ; Grace, Peter M.

Neuroimmune signaling is a key process underlying neuropathic pain. Clinical studies have demonstrated that 18 kDa translocator protein (TSPO), a putative marker of neuroinflammation, is upregulated in discrete brain regions of patients with chronic pain. However, no preclinical studies have investigated TSPO dynamics in the brain in the context of neuropathic pain and in response to analgesic treatments. We used positron emission tomography-computed tomography (PET-CT) and [¹⁸F]-PBR06 radioligand to measure TSPO levels in the brain across time after chronic constriction injury (CCI) of the sciatic nerve in both male and female rats. Up to 10 weeks post-CCI, TSPO expression was increased in discrete brain regions, including medial prefrontal cortex, somatosensory cortex, insular cortex, anterior cingulate cortex, motor cortex, ventral tegmental area, amygdala, midbrain, pons, medulla, and nucleus accumbens. TSPO was broadly upregulated across these regions at 4 weeks post CCI in males, and 10 weeks in females, though there were regional differences between the sexes. Using immunohistochemistry, we confirmed TSPO expression in these regions. We further demonstrated that TSPO was upregulated principally in microglia in the nucleus accumbens core, and astrocytes and endothelial cells in the nucleus accumbens shell. Finally, we tested whether TSPO upregulation was sensitive to diroximel fumarate, a drug that induces endogenous antioxidants via nuclear factor E2-related factor 2 (Nrf2). Diroximel fumarate alleviated neuropathic pain and reduced TSPO upregulation. Our findings indicate that TSPO is upregulated over the course of neuropathic pain development and is resolved by an antinociceptive intervention in animals with peripheral nerve injury.

2024-11-01·Multiple Sclerosis and Related Disorders

Safety, tolerability, and efficacy of diroximel fumarate in a cohort of Black patients with multiple sclerosis from the phase 3 EVOLVE-MS-1 study

Article

作者: Antezana, Ariel ; Schreiber, Bethany ; Branco, Filipe ; Levin, Seth ; Hunter, Samuel F ; Lindsey, John W. ; Scaramozza, Matthew ; Osborne, Benjamin ; Tian, Zhe ; Hunter, Samuel F. ; Lindsey, John W ; Lewin, James B ; Lewin, James B.

BACKGROUND:

Multiple sclerosis (MS) has not been well studied in racial and ethnic minorities, as these populations are typically underrepresented in clinical trials. Black or African Americans comprise ∼13 % of the US population, yet are represented by as little as 5 % in clinical trials. Differences in disease course and progression have been reported between races and ethnicities, so there is a need to understand the safety and efficacy of disease-modifying therapies (DMTs) in Black patients, to inform evidence-based approaches to treatment in this population.

METHODS:

EVOLVE-MS-1 (NCT0234307) was an open-label, single-arm, phase 3 study assessing the long-term safety, tolerability, and efficacy of diroximel fumarate (DRF) over 96 weeks in adults with relapsing-remitting multiple sclerosis (RRMS). Patients were either newly initiated to DRF or rolled over from completing EVOLVE-MS-2 (NCT03093324). In this post-hoc analysis of the phase 3 EVOLVE-MS-1 study, we evaluate the safety and exploratory efficacy outcomes for DRF in Black and non-Black patient subgroups.

RESULTS:

Of 1057 patients enrolled, 72 (6.8 %) were Black. In Black vs non-Black patients, mean age was 42 vs 43 years and 75 % vs 72 % were female, respectively. In both groups, median (range) duration of DRF exposure was 1.8 (0.0-2.0) years and mean Expanded Disability Status Scale (EDSS) was 2.7. The most common prior DMTs for both Black vs non-Black patients were interferons (47 % vs 37 %) and glatiramer acetate (36 % vs 24 %). DRF treatment was discontinued in 33 (46 %) Black and 224 (23 %) non-Black patients; most common reasons for discontinuation were withdrawal by patient (n = 11, 15.3 %), adverse events (AEs; n = 7, 9.7 %), and lost to follow-up (n = 7, 9.7 %) in Black patients; AEs (8.2 %) and withdrawal by patient (7.0 %) in non-Black patients. AEs were reported in 90 % Black and 89 % non-Black patients; most AEs were mild or moderate in both groups. Gastrointestinal (GI) AEs were reported in 36 % Black and 32 % non-Black patients; no Black patients discontinued due to GI AEs, vs 7 (0.7 %) non-Black patients. The most commonly reported AE was flushing (18 % Black and 28 % non-Black patients). No AEs of lymphopenia were reported in Black patients compared with 13 % of non-Black patients. Mean absolute lymphocyte count declined from baseline to week 48 by 15 % in Black patients and 29 % in non-Black patients, then plateaued and remained above the lower limit of normal (LLN; 0.91 × 10⁹/L). Adjusted annualized relapse rate (95 % confidence interval) was reduced by 78.2 % (54.6 - 89.5; p < 0.0001) in Black patients, from 12 months before to 96 weeks after DRF treatment; similar to 81.7 % (78.5 - 84.5 %; p < 0.0001) reduction in non-Black patients. Mean number of patients free from confirmed disability progression was 93.4 % by week 48, then 86.2 % vs 90.4 % by week 96 in Black vs non-Black patients, respectively.

CONCLUSION:

This study presents the first analysis of safety and efficacy of DRF in Black patients. Relapse rates remained low in Black patients on DRF, consistent with non-Black patients, and there were no new safety signals identified in the Black patient subgroup in EVOLVE-MS-1. Together, these outcomes support DRF as an effective treatment option in Black patients with RRMS.

项与富马酸地罗西美相关的新闻（医药）

2024-10-31

·Insight数据库

渤健 2024Q3：仑卡奈单抗卖了 6700 万美元，环比增长 66%

10 月 30 日，渤健发布 2024Q3 业绩，前三季度总营收 72.21 亿美元（-3%），其中产品收入 53.81 亿美元；第三季度营收 24.66 亿美元（-2.5%）。其中，用于阿尔兹海默病的 LEQEMBI（仑卡奈单抗）第三季度全球销售额约 6700 万美元，较上一季度增长 66%，其中美国市场销售额约 3900 万美元。截图来源：渤健财报仑卡奈单抗是全球首个获 FDA 完全批准的 AD 新药，今年三季度取得的进展如下： • 2024 年 7 月，卫材公布了 LEQEMBI 的 CLARITY AD 研究开放标签扩展的新临床数据，表明连续三年的 LEQEMBI 治疗减少了临床衰退，对早期阿尔茨海默病患者有临床意义的益处。 • 2024 年 6 月，FDA 接受了审查 LEQEMBI 每月静脉维持剂量治疗早期阿尔茨海默病的补充 BLA，PDUFA 行动日期定为 2025 年 1 月 25 日。 • 2024 年 5 月，在获得 FDA 快速通道资格后，卫材开始向 FDA 滚动提交 LEQEMBI 皮下自动注射的 BLA，用于每周维持剂量。多发性硬化症领域第三季度实现营收 10.54 亿美元同比 -9%。（主要产品包括 TECFIDERA, VUMERITY, AVONEX, PLEGRIDY, TYSABRI, 和 FAMPYRA）罕见病领域实现营收 4.95 亿美元，同比+10%。（主要产品包括SPINRAZA, SKYCLARYS 和 QALSODY）产后抑郁药物 ZURZUVAE（舒拉诺龙）第三季度收入约为 2200 万美元。截图来源：渤健财报渤健提高了 2024 年全年财务指引：截图来源：渤健财报维持 2024 年全年总收入较 2023 年全年下降个位数百分比的预期，核心药品收入预计与 2023 年全年大致持平；与 2023 年全年相比，目前预计营业收入将以较高的百分比增长，营业利润率将保持中等个位数的增长。重点产品前三季度销售额：截图来源：渤健财报封面来源：企业 Logo 免责声明：本文仅作信息分享，不代表 Insight 立场和观点，也不作治疗方案推荐和介绍。如有需求，请咨询和联系正规医疗机构。编辑：vvy PR 稿对接：微信 insightxb 投稿：微信 insightxb；邮箱 insight@dxy.cn 多样化功能、可溯源数据…… Insight 数据库网页版等你体验点击阅读原文，立刻解锁！

财报

2024-10-24

·PRNewswire

Alkermes plc Reports Third Quarter 2024 Financial Results

— Third Quarter Revenues of $378.1 Million — — Net Sales of Proprietary Products Increased Approximately 18% Year-Over-Year — — GAAP Net Income from Continuing Operations of $92.8 Million and Diluted GAAP Earnings per Share from Continuing Operations of $0.56 — — Company Reiterates 2024 Financial Expectations — DUBLIN, Oct. 24, 2024 /PRNewswire/ -- Alkermes plc (Nasdaq: ALKS) today reported financial results for the third quarter of 2024. "Our third quarter financial results reflect strong year-over-year growth of our portfolio of proprietary commercial products and position us well to meet our strategic, operational and financial priorities for the year. Looking ahead, we believe growing our proprietary commercial products and advancing our pipeline, particularly ALKS 2680, our novel, investigational, orexin 2 receptor agonist, and additional orexin development candidates, will serve as the key drivers of shareholder value. We plan to manage the business to deliver significant profitability and cash flow while investing in these strategic initiatives," said Richard Pops, Chief Executive Officer of Alkermes. "2025 has the potential to be a transformational year for Alkermes as we expect to complete the ongoing phase 2 studies in narcolepsy type 1 and narcolepsy type 2, and prepare for potential registrational studies for ALKS 2680. With the potential to transform the treatment of hypersomnolence disorders, and with broad potential applicability across other symptomatic domains, orexin 2 receptor agonists represent one of the most exciting new therapeutic categories in development and we believe a significant opportunity for Alkermes and our shareholders." Key Financial Highlights *As a result of the successful resolution of the arbitration with Janssen Pharmaceutica N.V., the nine months ended September 30, 2023 included approximately $195.4 million of back royalties (and related interest) related to U.S. net sales of long-acting INVEGA® products that would ordinarily have been recognized in prior periods. Revenue Highlights LYBALVI Revenues for the quarter were $74.7 million. Revenues and total prescriptions for the quarter grew 47% and 37%, respectively, compared to the third quarter of 2023. ARISTADAi Revenues for the quarter were $84.7 million. VIVITROL Revenues for the quarter were $113.7 million. Revenues for the quarter grew 14% compared to the third quarter of 2023, driven by the alcohol dependence indication. Manufacturing & Royalty Revenues Royalty revenues from INVEGA SUSTENNA®/XEPLION®, INVEGA TRINZA®/TREVICTA® and INVEGA HAFYERA®/BYANNLI® for the quarter were $58.4 million. VUMERITY® manufacturing and royalty revenues for the quarter were $32.6 million. Key Operating Expenses Please see Note 1 below for details regarding discontinued operations. Balance Sheet At Sept. 30, 2024, the company recorded cash, cash equivalents and total investments of $927.8 million, compared to $962.5 million at June 30, 2024. The company's total debt outstanding as of Sept. 30, 2024 was $288.8 million. Share Repurchase Program During the third quarter of 2024, the company repurchased approximately 4.4 million of the company's ordinary shares under the share repurchase program authorized in February 2024, at a total purchase price of $115.6 million. As of Sept. 30, 2024, the company had $200 million (exclusive of any fees, commissions or other related expenses) remaining under the program. Financial Expectations for 2024 Alkermes reiterates its financial expectations for 2024, as set forth in its press release dated Feb. 15, 2024. Recent Events In October 2024, the company hosted an investor event to review its portfolio of orexin 2 receptor agonists and development strategy. The company presented data from its ALKS 2680 phase 1b study in patients with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH), and discussed the study design for its ongoing phase 2 studies in NT1 and NT2. The company also announced its plans to initiate a phase 2 study in patients with IH in 2025. In September 2024, the company presented positive clinical data from its phase 1b study of ALKS 2680 in patients with NT2 and IH at the European Sleep Research Society's 27th Congress, Sleep Europe 2024. In August 2024, the company announced the initiation of its Vibrance-2 phase 2 study of ALKS 2680 in patients with NT2. In August 2024, the company published its latest Corporate Responsibility Report, which details how the company integrates environmental, social and governance considerations into its business. A copy of the report is available on the Responsibility section of Alkermes' website. Notes and Explanations 1. The company determined that upon the separation of its oncology business, completed on Nov. 15, 2023, the oncology business met the criteria for discontinued operations in accordance with Financial Accounting Standards Board Accounting Standards Codification 205, Discontinued Operations. Accordingly, the accompanying selected financial information has been updated to present the results of the oncology business as discontinued operations for the three and nine months ended Sept. 30, 2023. Conference Call Alkermes will host a conference call and webcast presentation with accompanying slides at 8:00 a.m. ET (1:00 p.m. BST) on Thursday, Oct. 24, 2024, to discuss these financial results and provide an update on the company. The webcast may be accessed on the Investors section of Alkermes' website at . The conference call may be accessed by dialing +1 877 407 2988 for U.S. callers and +1 201 389 0923 for international callers. In addition, a replay of the conference call may be accessed by visiting Alkermes' website. About Alkermes plc Alkermes plc is a global biopharmaceutical company that seeks to develop innovative medicines in the field of neuroscience. The company has a portfolio of proprietary commercial products for the treatment of alcohol dependence, opioid dependence, schizophrenia and bipolar I disorder, and a pipeline of clinical and preclinical candidates in development for neurological disorders, including narcolepsy and idiopathic hypersomnia. Headquartered in Ireland, Alkermes also has a corporate office and research and development center in Massachusetts and a manufacturing facility in Ohio. For more information, please visit Alkermes' website at . Non-GAAP Financial Measures This press release includes information about certain financial measures that are not prepared in accordance with generally accepted accounting principles in the U.S. (GAAP), including non-GAAP net income and EBITDA. These non-GAAP measures are not based on any standardized methodology prescribed by GAAP and are not necessarily comparable to similar measures presented by other companies. Non-GAAP net income adjusts for certain one-time and non-cash charges by excluding from GAAP results: share-based compensation expense; amortization; depreciation; non-cash net interest expense; change in the fair value of contingent consideration; certain other one-time or non-cash items; and the income tax effect of these reconciling items. EBITDA represents earnings before interest, tax, depreciation and amortization; earnings include share-based compensation expense. The company's management and board of directors utilize these non-GAAP financial measures to evaluate the company's performance. The company provides these non-GAAP financial measures of the company's performance to investors because management believes that these non-GAAP financial measures, when viewed with the company's results under GAAP and the accompanying reconciliations, are useful in identifying underlying trends in ongoing operations. However, non-GAAP net income and EBITDA are not measures of financial performance under GAAP and, accordingly, should not be considered as alternatives to GAAP measures as indicators of operating performance. Further, non-GAAP net income and EBITDA should not be considered measures of the company's liquidity. A reconciliation of GAAP to non-GAAP financial measures has been provided in the tables included in this press release. Note Regarding Forward-Looking Statements Certain statements set forth in this press release constitute “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, but not limited to, statements concerning: the company’s expectations concerning its future financial and operating performance, business plans or prospects, including drivers of shareholder value and profitability; and the company’s expectations regarding development plans, activities and timelines for, and the potential therapeutic and commercial value of, ALKS 2680 and the company’s other orexin portfolio candidates. The company cautions that forward-looking statements are inherently uncertain. The forward-looking statements are neither promises nor guarantees and they are necessarily subject to a high degree of uncertainty and risk. Actual performance and results may differ materially from those expressed or implied in the forward-looking statements due to various risks and uncertainties. These risks and uncertainties include, among others: whether the company is able to achieve its financial expectations, including those related to profitability; the unfavorable outcome of arbitration or litigation, including so-called “Paragraph IV” litigation and other patent litigation which may lead to competition from generic drug manufacturers, or other disputes related to the company’s products or products using the company’s proprietary technologies; clinical development activities may not be completed on time or at all; the results of the company’s development activities may not be positive, or predictive of final results from such activities, results of future development activities or real-world results; the U.S. Food and Drug Administration (FDA) or regulatory authorities outside the U.S. may make adverse decisions regarding the company’s products; the company and its licensees may not be able to continue to successfully commercialize their products or support revenue growth from such products; there may be a reduction in payment rate or reimbursement for the company’s products or an increase in the company’s financial obligations to government payers; the company’s products may prove difficult to manufacture, be precluded from commercialization by the proprietary rights of third parties, or have unintended side effects, adverse reactions or incidents of misuse; and those risks and uncertainties described under the heading “Risk Factors” in the company’s Annual Report on Form 10-K for the year ended Dec. 31, 2023 and in subsequent filings made by the company with the U.S. Securities and Exchange Commission (SEC), which are available on the SEC’s website at . Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. Except as required by law, the company disclaims any intention or responsibility for updating or revising any forward-looking statements contained in this press release. VIVITROL® is a registered trademark of Alkermes, Inc.; ARISTADA®, ARISTADA INITIO® and LYBALVI® are registered trademarks of Alkermes Pharma Ireland Limited, used by Alkermes, Inc. under license; BYANNLI®, INVEGA®, INVEGA HAFYERA®, INVEGA SUSTENNA®, INVEGA TRINZA®, TREVICTA® and XEPLION® are registered trademarks of Johnson & Johnson or its affiliated companies; and VUMERITY® is a registered trademark of Biogen MA Inc., used by Alkermes under license. i The term "ARISTADA" as used in this press release refers to ARISTADA and ARISTADA INITIO®, unless the context indicates otherwise. SOURCE Alkermes plc WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

财报临床1期临床2期临床结果

2024-09-28

·药事纵横

九月，多家制药巨头的“多事之秋”

声明：因水平有限，错误不可避免，或有些信息非最及时，欢迎留言指出。本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及）;本文不构成任何投资建议。九月原本应该秋高气爽，但今年的九月却成为了很多制药巨头的多事之秋，行业内一系列挑战接连而至，给这些公司带来了不小的压力。诺和诺德面临着药物定价的激烈辩论，辉瑞则因撤回加速批准的药物而遭受了重大投资失败，默沙东的药王Keytruda在临床研究中面临不小的挑战与挫折，BMS的CAR-T资产终端了临床研究，渤健则遭到了巴尔的摩市的起诉，同样可能面临起诉的还有胰岛素三巨头。这些事件交织在一起，揭示了制药行业在复杂环境下的脆弱与挑战，使得九月成为了反思与调整的时刻。 01 诺和诺德：药物价格机锋辩论与挑战近期最令诺和诺德头疼的问题在于他们的当家花魁Wegovy和Ozempic因为价格问题被美国参议员Bernie Sanders“咬定青山不放松”。诺和CEO Lars Fruergaard Jorgensen还因此在9月24日坐上了参议院听证会的证人席接受了Sanders询问。后者长期倡导降低美国医疗成本，也是参议院卫生、教育、劳工和养老金委员会主席。Sanders一遍又一遍地问Jorgensen 一个问题。为什么诺和的GLP-1 减肥药Wegovy 在美国的价格比世界其他地方高得多？ Jorgensen试图将问题归咎于美国复杂的医疗保健系统，尤其是制药行业的中间商（PBM，药品福利管理者），并指出这些中间商是导致患者承担高昂自付费用的主要原因。他还提到，如果药品价格大幅下降，PBM可能会将相关药物从其首选处方集中剔除，这会对患者产生不利影响。然而，Sanders显然已经对此有所准备，并表示他已收到所有主要PBM的书面承诺，称如果诺和诺德降低Ozempic和Wegovy的标价，PBM不会限制其在处方集中地位。 Sanders进一步对诺和诺德的利润提出质疑，指出其GLP-1药物的销售额即将超过该公司过去三十年的研发投入总和，进而抛出一个尖锐的道德问题：“如果你不采取行动，每年可能有4万人死亡，你能接受吗？”这一灵魂质问直击药品价格与患者生命之间的伦理冲突。Sanders还处心积虑地在身后悬挂着一张海报，上面明心见性地显示，在英国，每月服用一剂Wegovy 的费用为92 美元，在德国为137 美元，在丹麦为186 美元，在加拿大为265 美元，在美国为1349 美元。尽管Jorgensen并没有做出是否降价的明确表示，但无疑的是，诺和诺德正面临着来自美国立法者的巨大压力，尤其是在药品定价问题上，他们不仅要应对参议员Bernie Sanders对Wegovy和Ozempic高价的强烈质疑，还需平衡降低价格可能引发的市场和中间商的复杂反应，面临如何在利润与公众健康之间做出道德抉择的艰难挑战。诺和诺德是否放弃一部分利润，已成为其当前面临的关键抉择。降低Wegovy和Ozempic的价格或许能够缓解来自立法者的压力，并改善公众对其定价政策的看法，但这可能会削减公司的利润，尤其是在美国市场。诺和诺德正处于在保持利润与满足社会责任之间艰难权衡的十字路口。 02 辉瑞：重大投资失败，药物撤回辉瑞日前宣布了将自愿在全球范围内撤回其镰状细胞病（SCD）药物Oxbryta的公告，这次撤回宣告了辉瑞54亿美元收购交易的重大投资失败。 Oxbryta是辉瑞2022年以54亿美元收购Global Blood Therapeutics (GBT)时的核心资产，这笔收购发生在新冠疫情后的并购浪潮中。辉瑞当时预测，Oxbryta及GBT的SCD管线具有实现全球年峰值销售额超过30亿美元的潜力。Oxbryta于2019年底获得了FDA的加速批准，当时数据显示，与安慰剂相比，患者的血红蛋白水平有统计学显著改善。这款SCD口服疗法彼时被宣传为首个直接解决SCD根本原因的治疗方案。然而上市后验证性研究结果的出炉却给出了不利于Oxbryta的数据。新临床数据显示，“在目前批准的SCD适应症中，Oxbryta的整体收益已不再超过风险”。具体而言，数据提示了“血管阻塞性危象和死亡率的不平衡”，辉瑞称这些问题“需要进一步评估”。对此辉瑞表示，将停止分销Oxbryta，召回所有已生产的批次，并停止该药物的全部现有的临床试验和扩展使用项目。这并不是辉瑞SCD管线的首次失败，今年早些时候，辉瑞因患者招募困难终止了两个晚期SCD试验中的一个，该项目是辉瑞当年收购GBT获得的P-选择素抑制剂inclacumab。 Oxbryta在2023年的全球销售额达到了3.28亿美元。辉瑞表示，Oxbryta的撤市不会影响其2024年财务目标的实现。辉瑞已通知监管机构该药物的市场撤回。辉瑞表示，公司仍在调查新的临床发现，但建议患者联系其医生讨论替代治疗方案。巧合的是，Oxbryta的撤市恰好与FDA对两款SCD基因疗法，Vertex与CRISPR Therapeutics的Casgevy和bluebird bio的Lyfgenia药物的批准时间吻合。这两款基因疗法适应症的扩展能够减少或消除SCD患者的血管阻塞性危象。 03 默沙东：药王挑战不断默沙东的药王Keytruda在商业领域高歌猛进的同时，临床研究方面却在近期遭遇了不少挑战。先是Summit Therapeutics和Akeso Inc.的双特异性抗体ivonescimab在PD-L1阳性患者中将疾病进展或死亡的风险降低了49%，实现了Keytruda竞争对手在治疗晚期非小细胞肺癌的一线治疗中的首次超越。尽管默沙东风轻云淡地以ivonescimab上市之时Keytruda已经失去专利保护为由用“化骨绵掌”回避了对手的挑战，但药王的地位无疑遭到了严峻的威胁。 Keytruda的挑战接踵而来。9月25日，默沙东宣布了Keytruda与在研抗LAG-3抗体favezelimab联合疗法针对转移性结直肠癌患者的III期KEYFORM-007研究中未能显著改善总生存期。KEYFORM-007是一项随机开放标签研究，入组了超过440名微卫星稳定型（MSS）转移性结直肠癌（mCRC）患者，这些患者均为PD-L1阳性，并接受过多轮标准治疗。该研究使用固定剂量的联合疗法（favezelimab 800 mg和Keytruda 200 mg）与标准治疗进行比较。尽管Keytruda单药已获批用于结直肠癌治疗，但针对的不可切除或转移性微卫星不稳定性高（MSI-H）或错配修复缺陷型（dMMR）结直肠癌，Keytruda仅针对这些特定亚型的结直肠癌适应症。KEYFORM-007试验的受挫延缓了Keytruda在MSS结直肠癌领域的推进，这是一个难以攻克的治疗领域。2023年12月，BMS的Opdualag（nivolumab和relatlimab的联合疗法）在针对相同适应症的III期RELATIVITY-123研究中未能改善总生存期，BMS旋即宣布终止该项目。 04 BMS CAR-T临床研究无果而终同样是在9月25日，百时美施贵宝的CAR-T疗法Abecma遭遇了重大挫折。BMS及其合作伙伴2seventy bio决定终止Abecma的III期KarMMa-9试验。这项研究评估Abecma作为一线维持治疗的效果，研究对象为接受干细胞移植后疗效不理想的新诊断多发性骨髓瘤患者。 BMS将这一决定归因于入组困难。尽管该研究已在18个国家开展超过一年，但只完成了目标入组人数的10%。据clinicaltrials.gov的数据显示，该试验计划招募618名受试者。BMS认为，这种现象反映出了新诊断多发性骨髓瘤患者在移植后能够达到完全缓解或更好的疗效，因此适合KarMMa-9试验的患者已显著减少，远低于试验设计时的预期。 KarMMa-9终止后，Abecma在一线治疗中的III期试验项目将不复存在。一线治疗是骨髓瘤CAR-T疗法的主要市场。百时美施贵宝和2seventy在美国共同开发和商业化Abecma，而百时美施贵宝负责美国以外的市场。 05 渤健遭到巴尔的摩市起诉，胰岛素巨头可能面临诉讼在最新一起地方政府对制药公司的诉讼中，巴尔的摩市起诉渤健，指控其与最大的药品福利管理公司（PBM）达成非法协议，阻碍其多发性硬化症治疗药物的仿制药进入市场。诉讼称，渤健因为其新一代多发性硬化症药物Vumerity（替代其老药Tecfidera）的市场占有率不佳（仅1%的Tecfidera患者转用Vumerity），转而与美国三大PBM：CVS Caremark、OptumRx和Express Scripts达成反竞争协议，支付费用以确保这些PBM的处方集（formulary）上优先推荐Tecfidera和Vumerity，而不是价格更低的仿制药。诉讼指出，渤健向PBM支付可观的回扣，保护Tecfidera和Vumerity免受仿制药的竞争。这种操作使得仿制药的市场竞争大幅减弱，从而为渤健赢得了时间，将更多患者从Tecfidera转换到Vumerity。此外，一些PBM还将Tecfidera仿制药归为“特种药物”行列（实际上它们仅是普通片剂），这使得患者面临更高的自付费用，进一步抑制了对仿制药的需求。同时，特种药房抬高了仿制药的价格，更加削弱这些仿制药的竞争力。从2013年到2019年，渤健都会定期提高Tecfidera的价格，从每片72美元上涨到124.67美元，年治疗费用从52500美元涨至9万美元，涨幅达73.5%。而同期美国消费者价格指数仅上涨9.7%。诉讼估计，如果没有与PBM的这些小动作，到2021年，约90%的Tecfidera处方应已被廉价仿制药替代，渤健将几乎无法实现把Tecfidera患者转移至Vumerity的目标。巴尔的摩市因此声称遭受了巨大的经济损失。这起诉讼是近年来地方政府针对制药公司发起的一系列诉讼之一，焦点仍然集中在药品定价和市场竞争问题上。几乎与巴尔的摩市对渤健的起诉同时发生，美国联邦贸易委员会（FTC）也起诉了Optum Rx、CVS Caremark和Express Scripts这三家PBM，指控他们“勾结”胰岛素制造商赛诺菲、礼来和诺和诺德共同人为地提高了患者成本。FTC表示，未来可能会建议对礼来、赛诺菲和诺和诺德提起诉讼，指控它们在抬高胰岛素产品定价中所起的作用。 FTC的诉讼称，这三家PBM创造了一种“扭曲的”药品折扣体系，优先考虑药品制造商提供的高折扣，导致“人为抬高胰岛素的标价”。诉讼还声称，即使有价格更低的胰岛素可供选择，这些PBM仍倾向于支持那些标价较高的胰岛素。据FTC称，大约800万糖尿病患者依赖胰岛素生存，许多人因为高价而不得不定量使用治疗。FTC表示，胰岛素制造商在抬高标价中的角色“深感担忧”，认为他们在应对PBM高折扣要求时抬高了价格。礼来、赛诺菲和诺和诺德控制了美国约90%的胰岛素市场。例如，礼来的Humalog胰岛素在2017年的标价为274美元，相比1999年的21美元标价增长了1200%以上。 Ref. Griffin, R. Bernie Sanders’ Surprise for Novo’s CEO in the Ozempic Cost Hearing. Bloomberg. 25. 09. 2024. Manalac, T. Pfizer issues global market withdrawal of sickle cell disease therapy Oxbryta. Biospace. 25. 09. 2024. Liu, A. Citing enrollment challenges, Bristol Myers and 2seventy scrap Abecma trial in first-line myeloma. Fierce Pharma. 25. 09. 2024. Silverman, E. Baltimore claims Biogen ‘bribed’ PBMs to favor its pricey MS drug over generics. 24. 09. 2024. FTC Sues Prescription Drug Middlemen for Artificially Inflating Insulin Drug Prices. FTC Press Release. 20. 09. 2024. -END- 2025CMC-CHINA药博会 • 展位火热预定中！

细胞疗法免疫疗法加速审批医药出海

100 项与富马酸地罗西美相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11154	富马酸地罗西美	L03	DB14783

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
复发-缓解型多发性硬化	欧盟	Biogen Netherlands BV	2021-11-15
复发-缓解型多发性硬化	冰岛	Biogen Netherlands BV	2021-11-15
复发-缓解型多发性硬化	列支敦士登	Biogen Netherlands BV	2021-11-15
复发-缓解型多发性硬化	挪威	Biogen Netherlands BV	2021-11-15
多发性硬化症	瑞士	Biogen, Inc.	2021-09-20
复发性多发性硬化	美国	Biogen, Inc.	2019-10-29

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
GM1神经节苷脂贮积病	临床3期	美国	Alkermes, Inc.	2015-12-10
GM1神经节苷脂贮积病	临床3期	美国	Biogen, Inc.	2015-12-10
GM1神经节苷脂贮积病	临床3期	比利时	Alkermes, Inc.	2015-12-10
GM1神经节苷脂贮积病	临床3期	比利时	Biogen, Inc.	2015-12-10
GM1神经节苷脂贮积病	临床3期	保加利亚	Alkermes, Inc.	2015-12-10
GM1神经节苷脂贮积病	临床3期	保加利亚	Biogen, Inc.	2015-12-10
GM1神经节苷脂贮积病	临床3期	加拿大	Alkermes, Inc.	2015-12-10
GM1神经节苷脂贮积病	临床3期	加拿大	Biogen, Inc.	2015-12-10
GM1神经节苷脂贮积病	临床3期	德国	Biogen, Inc.	2015-12-10
GM1神经节苷脂贮积病	临床3期	德国	Alkermes, Inc.	2015-12-10

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临床结果

适应症

分期

评价

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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


NCT02634307 (EVOLVE-MS-1, Pubmed)	临床3期	复发-缓解型多发性硬化 lymphopenia \| ALC decline	-	Diroximel Fumarate	窪範夢淵鬱積鑰糧夢簾(構艱構願鹹壓繭壓願範) = 膚醖淵鏇構艱憲製糧糧壓範願顧膚壓餘鹽繭獵 (築窪簾憲淵積願廠繭遞 )	积极	2024-06-27
NCT02634307 (EVOLVE-MS-1, Pubmed)	临床3期	复发-缓解型多发性硬化	1,057	Diroximel fumarate	膚衊簾積憲衊膚遞淵齋(憲積夢鹽憲鬱夢築鏇獵) = 夢鹽構夢醖製鹹夢製糧鑰築鏇鑰淵淵製範積壓 (憲範顧襯選艱壓觸衊糧 )	积极	2024-06-15
				Dimethyl fumarate	膚衊簾積憲衊膚遞淵齋(憲積夢鹽憲鬱夢築鏇獵) = 願鹽廠範窪願夢鏇糧願鑰築鏇鑰淵淵製範積壓 (憲範顧襯選艱壓觸衊糧 )
ECTRIMS2023	N/A	多发性硬化症	29	Dimethyl Fumarate (DMF)	膚夢構顧觸鑰願窪鹽顧(廠淵顧顧餘蓋鹹齋觸醖) = The incidence of lymphopenia (ALC <910) in this cohort of PwMS who transitioned from DMF to DRF increased from 24% at baseline to 52% 12 months after treatment change. 鹽選製艱選鏇願鹽簾憲 (築鑰製顧鹽憲窪網顧窪 ) 更多	积极	2023-10-01
ECTRIMS2023	N/A	神经炎症	-	Diroximel fumarate (DRF)	鬱積壓襯襯壓餘鹹顧構(糧積壓蓋醖範膚糧構繭) = significantly reduced IFNγ secretion in splenocytes isolated from DRF treated mice 製鬱鏇艱鹽觸淵鏇構簾 (鹽醖選遞襯夢願製襯顧 ) 更多	积极	2023-09-30
				Vehicle (methocel)
ECTRIMS2023	N/A	淋巴细胞减少	72	Dimethyl Fumarate (DMF)	願壓齋廠膚蓋糧觸糧淵(餘夢餘築簾願簾網鹹餘) = 鹹構糧簾窪餘鹹襯糧蓋膚衊糧夢構憲觸齋網齋 (淵鑰廠範廠顧齋觸淵獵 )	-	2023-09-30
				Diroximel Fumarate (DRF)	願壓齋廠膚蓋糧觸糧淵(餘夢餘築簾願簾網鹹餘) = 鹽壓鹹壓膚窪範憲餘築膚衊糧夢構憲觸齋網齋 (淵鑰廠範廠顧齋觸淵獵 )
ACTRIMS2023	N/A	多发性硬化症	11	Diroximel Fumarate	鹹築鏇網簾遞顧獵窪齋(衊壓願製構齋壓選壓鬱) = 襯鬱製選簾鹹鬱艱鏇鑰獵廠鹽膚蓋願顧遞獵鏇 (醖積憲網窪窪製鹹醖積 ) 更多	积极	2023-05-30
				Dimethyl Fumarate	鹹築鏇網簾遞顧獵窪齋(衊壓願製構齋壓選壓鬱) = 糧積糧顧夢範網壓夢膚獵廠鹽膚蓋願顧遞獵鏇 (醖積憲網窪窪製鹹醖積 ) 更多
SUNBEAM (RPC01-301), RADIANCE phase 3 (RPC01-201B), EVOLVE-MS-1 (ACTRIMS2023)	临床3期	复发-缓解型多发性硬化	-	Ozanimod 1.0 mg	餘醖鏇繭膚築壓製築蓋(鬱餘簾遞襯鑰鏇蓋壓蓋): risk ratio = 0.924 (95% CI, 0.646 ~ 1.324) 更多	积极	2023-05-30
				Diroximel fumarate 462 mg
EVOLVE-MS-1, OPTIMUM (Pubmed)	临床3期	复发性多发性硬化	-	Diroximel fumarate	壓壓齋膚壓糧範蓋範築(鑰齋網窪製選憲膚膚願) = 鑰構蓋構鏇夢糧選餘簾獵壓糧醖顧製築衊顧選 (蓋簾顧壓獵構願鹹網範 )	-	2023-05-08
NCT02634307 (EVOLVE-MS-1, AAN2023)	临床3期	复发-缓解型多发性硬化	239	Diroximel Fumarate	顧積製願壓夢繭遞願繭(齋廠鹽築鏇範窪顧憲構) = 23 (9.6%) patients discontinued DRF due to adverse events 齋襯膚壓襯製鏇獵淵廠 (構餘膚繭鬱獵糧窪憲夢 ) 更多	积极	2023-04-25
NCT02634307 (EVOLVE-MS-1, AAN2023)	临床3期	多发性硬化症	1,057	Diroximel fumarate	鏇選網鹽醖膚鹹築齋製(鏇獵構鏇積鬱顧構鹹鬱) = 窪繭製簾選繭觸鏇蓋簾鏇顧顧範顧醖糧鹹選齋 (鹹廠夢簾簾壓衊鹹積觸 ) 更多	积极	2023-04-25
				Placebo	鏇選網鹽醖膚鹹築齋製(鏇獵構鏇積鬱顧構鹹鬱) = 鹹淵觸構鹹糧繭醖觸餘鏇顧顧範顧醖糧鹹選齋 (鹹廠夢簾簾壓衊鹹積觸 ) 更多