Avid Radiopharmaceuticals, Inc.

Eli Lilly has shared positive results from a late-stage study of its amyloid plaque-targeting Alzheimer’s disease (AD) drug donanemab in adults with early symptomatic cases of the neurodegenerative disorder. The phase 3b TRAILBLAZER-ALZ 6 trial has been evaluating the impact of different dosing regimens of donanemab on the rates of amyloid-related imaging abnormalities with oedema/effusion (ARIA-E) and amyloid clearance in adults with early symptomatic AD, including those with mild cognitive impairment and the mild dementia stage of disease. An estimated 982,000 people are living with dementia in the UK, with AD accounting for up to 75% of cases. Donanemab, approved under the brand name Kisunla in countries including the US and Great Britain, is administered as an intravenous infusion every four weeks and is designed to help the body remove the excessive buildup of amyloid plaques in the brain associated with AD. The data presented at this year’s Clinical Trials on AD Conference showed a reduction of ARIA-E in patients receiving a slightly modified titration of donanemab, with an incidence of 14% compared to 24% for those being treated with the once-monthly standard dosing regimen. The largest ARIA-E reduction with the modified titration was seen in carriers of apolipoprotein E, a known genetic risk factor for developing AD. In these patients, 19% had ARIA-E on the modified titration compared to 57% on the standard dosing regimen. Patients on the modified titration also saw a reduction of amyloid plaque and P-tau217 comparable to those receiving the standard dosing regimen and, aside from the improvement in ARIA-E rates, safety profiles were comparable across the four arms. Lilly said it is discussing the results of the study with global regulators, with the intent to submit for a potential label update for the drug. Mark Mintun, group vice president neuroscience research and development, Eli Lilly, and president of Avid Radiopharmaceuticals, said: “We are confident in the benefits of Kisunla’s currently approved dosing regimen and are excited that these results reveal a path to potentially improving on Kisunla’s profile by reducing the risk of ARIA-E. “The modified titration could offer continued convenience of once-monthly dosing and limited duration treatment while also reducing ARIA-E and maintaining similar amyloid plaque removal.”

A change in the initiation of donanemab dosing, shifting one vial of donanemab from the first infusion to the third infusion, lowered ARIA-E to 14% compared to 24% in patients receiving the standard dosing regimen used in the pivotal Phase 3 clinical trialReduction of amyloid plaque and P-tau217 on this modified titration was comparable to patients receiving the standard dosing regimenLilly intends to submit this data to global regulators for a potential label update for Kisunla (donanemab-azbt) INDIANAPOLIS, Oct. 29, 2024 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) today announced positive results from the TRAILBLAZER-ALZ 6 Phase 3b study, showing a reduction in amyloid-related imaging abnormalities with edema/effusion (ARIA-E) at the 24-week primary endpoint for people receiving a slightly modified titration of donanemab in adults with early symptomatic Alzheimer's disease (AD).1 Donanemab is approved under the brand name Kisunla™ in the United States, Japan, Great Britain and other countries. These data were presented at the 17th Clinical Trials on Alzheimer's Disease (CTAD) Conference in Madrid, Spain. Continue Reading Modified Titration Differs from Standard Dosing by Shifting a Single Vial. TRAILBLAZER-ALZ 6 is a multicenter, randomized, double-blind, Phase 3b study to investigate the impact of different dosing regimens of donanemab on the rates of ARIA-E and amyloid clearance in adults with early symptomatic AD, which includes mild cognitive impairment (MCI) and the mild dementia stage of disease. "Lilly is committed to continuing research to optimize therapy for patients with Alzheimer's disease. We are confident in the benefits of Kisunla's currently approved dosing regimen and are excited that these results reveal a path to potentially improving on Kisunla's profile by reducing the risk of ARIA-E," said Mark Mintun, M.D., group vice president Neuroscience Research & Development, Eli Lilly and Company, and president of Avid Radiopharmaceuticals. "The modified titration could offer continued convenience of once-monthly dosing and limited duration treatment while also reducing ARIA-E and maintaining similar amyloid plaque removal." The study included four treatment arms. One arm was the once-monthly standard dosing regimen used in the Phase 3 TRAILBLAZER-ALZ 2 trial. The other three arms used alternative dosing regimens with the same total drug administered. The results at 24 weeks showed the once-monthly modified titration described below met the predefined study success criteria and demonstrated the greatest reduction of ARIA-E compared to the other dosing arms.1 Patients on the standard dosing regimen received two vials (700 mg) of donanemab for the first three infusions, then four vials (1400 mg) thereafter. Patients on the modified titration received 1 vial (350 mg) for the first infusion, two vials (700 mg) for the second infusion, three vials (1,050 mg) for the third infusion, and four vials (1400 mg) per infusion thereafter. The only difference between the modified titration and the standard dosing regimen is the shift of one vial from the first infusion to the third infusion. Pharmacokinetic (PK) analysis demonstrated equivalent cumulative exposure between modified titration and standard dosing regimen. The primary endpoint of the study was the proportion of participants with any occurrence of ARIA-E by week 24, and the results showed the incidence of ARIA-E was 14% in patients receiving the modified titration compared with 24% for those receiving the standard dosing regimen, a 41% lower relative risk. The largest ARIA-E reduction with the modified titration was seen in apolipoprotein E (APOE4) homozygotes, carriers of a known genetic risk factor for developing Alzheimer's disease. In these patients, 19% had ARIA-E on the modified titration as compared to 57% on the standard dosing regimen, resulting in a 67% lower relative risk. Patients on the modified titration of donanemab saw reduction of amyloid plaque and P-tau217 comparable to patients receiving the standard dosing regimen. As observed using amyloid PET at 24 weeks, amyloid plaque levels in patients on the modified titration of donanemab in TRAILBLAZER-ALZ 6 were reduced on average 67% from baseline compared to 69% for patients on the standard dosing regimen. The pathological relevance of beta-amyloid plaques in the development of Alzheimer's disease and the importance of removing plaques to slow disease progression has been well-established: both the Phase 3 TRAILBLAZER-ALZ 2 study and the Phase 2 TRAILBLAZER-ALZ study demonstrated that the removal of amyloid plaque from the brain can lead to statistically significant slowing of cognitive and functional decline in patients with early symptomatic Alzheimer's disease.2, 3 The TRAILBLAZER-ALZ 6 study is ongoing with data investigating the potential reduction of ARIA-E in adults with early symptomatic AD at week 52 expected early next year. Aside from the improvement in ARIA-E rates, safety profiles were comparable across arms, and no new safety signals were identified. The frequency of infusion-related reactions in the modified titration arm was similar to the standard dosing arm. One participant in the modified titration arm with an ongoing ARIA-E presented stroke-like symptoms, and after receiving tissue-type plasminogen activator treatment (tPA), subsequently died due to cerebral intraparenchymal hemorrhage. As noted in the FDA labeling for this class of medicines, caution should be exercised when considering the administration of agents such as thrombolytics (e.g. tPA) to patients already being treated with amyloid targeting therapies. Lilly is discussing the results of this study with global regulators, with the intent to submit for a potential label update for Kisunla. About TRAILBLAZER-ALZ 6 Study and the TRAILBLAZER-ALZ program TRAILBLAZER-ALZ 6 (NCT05738486) is a Phase 3b, multicenter, randomized, double-blind study to investigate different dosing regimens and their effect on ARIA-E in adults with early symptomatic Alzheimer's disease. The trial enrolled 843 participants ages 60-85 selected based on cognitive assessments in conjunction with amyloid plaque imaging by PET scan. Lilly continues to study donanemab in multiple clinical trials, including TRAILBLAZER-ALZ 3, focused on reducing risk of progression to symptomatic AD in participants with preclinical AD; and TRAILBLAZER-ALZ 5, a registration trial for early symptomatic AD currently enrolling in China, Korea, Taiwan, and other geographies. About Kisunla™ (donanemab) Kisunla™ (donanemab-azbt) (pronounced kih-SUHN-lah) is an amyloid-targeting treatment for people with mild cognitive impairment (MCI) as well as people with mild dementia stage of early symptomatic Alzheimer's disease, with confirmed amyloid pathology. Kisunla can cause serious side effects, including amyloid-related imaging abnormalities, or ARIA, and infusion-related reactions. Kisunla is a prescription medicine administered intravenously every four weeks, 700 mg for the first three doses and 1400 mg thereafter. INDICATION AND SAFETY SUMMARY WITH WARNINGS Kisunla™ (donanemab-azbt), pronounced kih-SUHN-lah, is used to treat adults with early symptomatic Alzheimer's disease (AD), which includes mild cognitive impairment (MCI) or mild dementia stage of disease. Warnings - Kisunla can cause Amyloid-Related Imaging Abnormalities or "ARIA." This is a common side effect that does not usually cause any symptoms, but serious symptoms can occur. ARIA can be fatal. ARIA is most commonly seen as temporary swelling in an area or areas of the brain that usually goes away over time. Some people may also have spots of bleeding on the surface of or in the brain and infrequently, larger areas of bleeding in the brain can occur. Although most people do not have symptoms, some people have headaches, dizziness, nausea, difficulty walking, confusion, vision changes and seizures. Some people have a genetic risk factor (homozygous apolipoprotein E ε4 gene carriers) that may cause an increased risk for ARIA. Talk to your healthcare provider about testing to see if you have this risk factor. You may be at higher risk of developing bleeding in the brain if you take medicines to reduce blood clots from forming (antithrombotic medicines) while receiving Kisunla. Talk to your healthcare provider to see if you are on any medicines that increase this risk. Your healthcare provider will do magnetic resonance imaging (MRI) brain scans before and during your treatment with Kisunla to check you for ARIA. You should carry information that you are receiving Kisunla, which can cause ARIA, and that ARIA symptoms can look like stroke symptoms. Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the symptoms listed above. There are registries that collect information on treatments for Alzheimer's disease. Your healthcare provider can help you become enrolled in these registries. Warnings - Kisunla can cause serious allergic and infusion-related reactions. Do not receive Kisunla if you have serious allergic reactions to donanemab-azbt or any of the ingredients in Kisunla. Symptoms may include swelling of the face, lips, mouth, or eyelids, problems breathing, hives, chills, irritation of skin, nausea, vomiting, sweating, headache, or chest pain. You will be monitored for at least 30 minutes after you receive Kisunla for any reaction. Tell your healthcare provider right away if you have these symptoms or any reaction during or after a Kisunla infusion. Other common side effects Headache Tell your healthcare provider right away if you have any side effects. These are not all of the possible side effects of Kisunla. You can report side effects at 1-800-FDA-1088 or . Before you receive Kisunla, tell your healthcare provider: About all medicines you take, including prescription and over-the-counter medicines, as well as vitamins and herbal supplements. Especially tell your healthcare provider if you have medicines to reduce blood clots from forming (antithrombotic medicines, including aspirin). About all of your medical conditions including if you are pregnant, breastfeeding, or plan to become pregnant or breastfeed. Kisunla has not been studied in people who were pregnant or breastfeeding. It is not known if Kisunla could harm your unborn or breastfeeding baby. How to receive Kisunla Kisunla is a prescription medicine given through an intravenous (IV) infusion using a needle inserted into a vein in your arm. Kisunla is given once every 4 weeks. Each infusion will last about 30 minutes. Learn more For more information about Kisunla, call 1-800-LillyRx (1-800-545-5979) or go to kisunla.lilly.com. This summary provides basic information about Kisunla. It does not include all information known about this medicine. Read the information given to you about Kisunla. This information does not take the place of talking with your healthcare provider. Be sure to talk to your healthcare provider about Kisunla. Your healthcare provider is the best person to help you decide if Kisunla is right for you. Please see full Prescribing Information including boxed warning for ARIA and Medication Guide for Kisunla. About Lilly Lilly is a medicine company turning science into healing to make life better for people around the world. We've been pioneering life-changing discoveries for nearly 150 years, and today our medicines help tens of millions of people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world's most significant health challenges: redefining diabetes care; treating obesity and curtailing its most devastating long-term effects; advancing the fight against Alzheimer's disease; providing solutions to some of the most debilitating immune system disorders; and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we're motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/news, or follow us on Facebook, Instagram and LinkedIn. P-LLY © Lilly USA, LLC 2024. ALL RIGHTS RESERVED. Cautionary Statement Regarding Forward-Looking Statements This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about Kisunla (donanemab-azbt) as a treatment for people with early symptomatic Alzheimer's disease, Kisunla dosing regimens and the prevalence of ARIA-E, and future readouts, presentations, and other milestones relating to Kisunla and reflects Lilly's current beliefs and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of drug research, development, and commercialization. Among other things, there is no guarantee that planned or ongoing studies will be completed as planned, that future study results will be consistent with study findings to date, that Kisunla will receive additional regulatory approvals or that Kisunla will be commercially successful. For further discussion of these and other risks and uncertainties, see Lilly's Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release. References Eli Lilly. A Study of Different Donanemab (LY3002813) Dosing Regimens in Adults With Early Alzheimer's Disease (TRAILBLAZER-ALZ 6). ClinicalTrials.gov identifier: NCT05738486. Updated July 24, 2024. Accessed September 30, 2024. . Kisunla (donanemab-azbt). Prescribing Information. Lilly USA, LLC. Data on File. Lilly USA, LLC. DOF-DN-US-0029. SOURCE Eli Lilly and Company WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

本次以“突破瓶颈 打造健康产业新引擎”为主题，设一场主论坛和八场主题论坛，从前沿创新突破、临床应用拓展、工艺技术优化、商业化开发等多个全新视角推动CGT技术开发与应用，成就健康产业未来。 凭借在降糖减重、AD市场“两开花”，礼来的市值可谓一骑绝尘，已达到8000亿美元水平。 8月，礼来发布的上半年财报超出预期，并将2024年的营收指引上调了30亿美元。随着Zepbound、Mounjaro等供应问题的解决，以及Kisunla逐步放量，这家巨头的跨过万亿美元市值门槛指日可待。 可从更大的视角来说，游戏还未终局。 一方面，作为GLP-1药物领导者，诺和诺德也正跑马圈地，缺货局面已大大缓解；而想要站稳于AD这块“新药坟场”，礼来得准备更多底牌，可惜近期，LY3372689传出失败的消息。 更重要的是另一方面。无论减肥抑或AD治疗，礼来眼下的享受都是长期努力探索后的果实。专利悬崖与“重磅炸弹”模式下，它还需要着眼未来。 放射性药物领域，正是礼来看中的下一片蓝海。去年，它以14亿美元的并购，正式涉足该市场。 GlobalData的报告称，2023年，放射性药物一跃成为备受追捧的项目，相关风险投资交易增长了722%，达到5.18亿美元。对比2017年的6300万美元，这是显著的提升。如果将礼来的收购算上，交易规模还会更大。 诺华旗下产品表现——其中，Pluvicto上市第二年，营收就达到9.8亿美元，同比增长261%——证明着放射性药物领域的可观机会。同时，这些竞争对手也是礼来得翻越的山头。 值得注意，礼来的打法背后，一张大网正徐徐张开。 1 高举高打买工厂 按照用途，放射性药物可分为诊断类、治疗类。前者用于获得人体器官组织的影像或功能参数，后者是将放射性核素输送到病变部位，进而产生杀伤作用。 早在2010年，礼来以3亿美元预付款，外加最高5亿美元的里程碑付款，将一家分子成像产品开发公司Avid Radiopharmaceuticals买下。此后，礼来手握Flortaucipir F-18（TAU）和Flortaucipir F-18（APP）两款诊断用放射性药物，它们可帮助评估AD等患者的脑部状况。 但是，对于治疗用放射性药物，即眼下投资关注的主要细分领域，巨头礼来就可谓是刚进“新手村”。 2023年9月，礼来参与了Mariana Oncology的B轮1.75亿美元融资，这是一家专注于开发新型靶向肽放射性药物的Biotech，彼时核心管线MC-339尚未进入临床。因此，礼来的动作更像是试水之举。 次月，通过一笔14亿美元的收购，该MNC才算真正下场。 “我们对这种新兴治疗方式的潜力感到非常兴奋。”礼来肿瘤学部门总裁Jacob Van Naarden称，他们并将收购Point Biopharma视为“投资开发多种治疗癌症的放射性药物的开始”。 Point管线进展情况 管线上，交易披露时，礼来获得两款处于III期临床的药物，以及几个处于早期阶段项目。 其中，PNT2002是一种前列腺特异性膜抗原靶向放射性配体疗法，用于二线治疗后的转移性去势抵抗性前列腺癌（mCRPC）。去年底，SPLASH研究显示，该药将未接受化疗的受试患者进展或死亡风险降低29%。 PNT2003属于生长抑素受体靶向放射性配体疗法，针对胃肠胰神经内分泌肿瘤患者。 这两款在研新药，与诺华的两款商业化产品适应症存在重合，意味着它们的上市和销售道路可能并不容易走。然而，这笔14亿美元巨额收购的更大价值，或许是让礼来拥有一个工厂平台。 Point是自带生产能力的Biotech，18万平方英尺的园区，属于世界上最大的放射性药物制造工厂之一。并且，陆空交通区位的优势，让货物可以快速进出，覆盖欧美等主要市场。 减肥药开发热潮和经验表明，供应若得不到保障，就是对创新产品生命周期的侵蚀。而众所周知，放射性药物产业链复杂且独特，每个环节都充满专业深度和技术壁垒，更需以终为始。Point在核素制造和供应链方面的专长，无疑有助于礼来解决放射性药物开发和商业化的瓶颈。 2 抢靶点，抓技术 礼来不打算将鸡蛋放在一个篮子里。相反，它要发挥自己的体量优势，多次下注，尤其是在靶点技术方面，以此提高成功概率。 2024年，礼来加快了进军放射性药物的步伐。 5月，它将向Aktis Oncology支付6000万美元预付款，引进后者的新型小蛋白技术平台生产放射性药物。Aktis负责发现阶段的工作，不过有机会获得高达11亿美元的临床前、临床、监管和商业化里程款。 Aktis的主要资产，是一种靶向Nectin-4的新型α放射疗法。Nectin-4作为不少恶性肿瘤过表达的肿瘤相关抗原，逐渐受到业界的关注，例如ADC开发领域。 “α放射疗法是放射性药物的未来，通过利用α粒子的力量——其效力是β粒子的近1000倍——我们相信，Aktis的方法有可能为患者提供改变游戏规则的结果。”Aktis肿瘤学总裁兼首席执行官Matthew Roden说。 疗效和便利性上，业界认为，α射线确实有显著优势。 Lutathera、Pluvicto都是利用Lu-177提供β辐射，接受治疗的患者在治疗后一周内必须远离孕妇和儿童，而α放射疗法则有望减少隔离要求，这对于患者和家庭来说是一个“大加分项”。 差异化让Aktis成为资本的宠儿。礼来之前，2021年，BMS和诺华都参与了这家Biotech的A轮7200万美元融资。次年，默沙东也向其注资8400万美元。 7月，礼来又跟另一家Biotech签署了投资协议，预付1.4亿美元以获得期权。如果礼来行使这项权利，Radionetics Oncology最终会以10亿美元的价格被收购，扩充前者在放射性药物上的布局。 Radionetics旗下建立了专有的发现平台，以及靶向GPCR的小分子放射性配体疗法管线。进展最快的，是2023年下半年开始的一项I期临床试验，针对罕见且具有侵袭性的肾上腺癌症。Radionetics透露，它还在开发其他项目，用于治疗乳腺癌、肺癌和其他尚未得到满足的癌症。 细胞外多巴胺与多巴胺受体结合，激活G蛋白 科学家已经证实，GPCR参与人体的多种生理过程。Radionetics在2021年被从Crinetics Pharmaceuticals分拆前，该团队致力于开发靶向GPCR的口服小分子药物，以治疗通常的内分泌疾病和相关肿瘤。 有意思的是，礼来之所以能搭上Radionetics这趟快车，离不开先前买下Point的交易推动。Radionetics首席执行官Paul Grayson暗示，Point的加盟很大程度充实了礼来这一领域的积累。 3 闭环关键：核素 关于Point并购案，前文尚未展开的一面，是核素布局。 放射性药物的作用机制决定了，它们离不开具有放射性的同位素。现阶段，诺华旗下的两款商业化产品，以及临床试验中的大多数疗法，都在使用Lu-177。 对于任何一家药企，获取临床级放射性同位素都面临不小挑战——它们需要在回旋加速器或核反应堆中产生。Pluvicto一度面临短缺的主要原因，就在于难以制造该药物的关键成分Lu-177。自两款放射性药物上市以来，诺华一直在解决核素的储备问题。 Point已与德国Lu-177生产商ITM Isotope Technologies Munich签订并扩大供应协议，一定程度减轻了礼来的压力。 此外，Point还对核素进行优化，在PNT2003中使用一种被称为非载体添加的Lu-177。这带来的好处是，避免像Lutathera那样担心引入杂质（Lu-177m，半衰期为5个月以上，增加使用过程中的管理开支）。 不过话说回来，光有Lu-177尚且不够。正如癌症是一种多种原因促成的疾病，放射性药物同样有赖于多种核素。 已有相当一部分药企在探索Ac-225、I-131、Cu-67等放射性同位素。其中，Ac-225的辐射强度大，半衰期只有约10天，很快从体内清除，这种特性让它成为不少药企的心头好。 Ac-225是一种理想的放射性同位素 8月，礼来通过可转换贷款方式，向一家名为Ionetix的同位素供应商投资了1000万美元。 Ionetix位于美国的工厂运行着一台回旋加速器，该机器通过用质子束轰击Ra-226来生产Ac-225。Ionetix正在安装另一台回旋加速器，估计到2025年底，每周将能够生产约1居里的Ac-225，每年可为约2.6万名患者提供治疗的剂量。 The Financial Times的文章认为，礼来对Ionetix的小额投资，是MNC进一步布局供应链上游以确保Ac-225供应的罕见例子。 由于Point此前已经向Ionetix发放了1000万美元的可转换贷款，因此，礼来总共拥有该公司2000万美元的债权。Ionetix还在推进新一轮融资，其估值将超过3亿美元——届时，礼来预计会把其贷款转换为股权。 问题是，由于Ac-225并非天然存在，礼来必须四处寻找可以提取同位素的材料。 被BMS以41亿美元收购的RayzeBio，不久前也因Ac-225短缺而被迫暂停其一款放射性药物III期试验的新患者招募。 Morgan Stanley分析师表示，放射性药物领域的增长因同位素供应不足而受到阻碍，预计到2032年，该领域的销售额为390亿美元。礼来想要在其中分一杯羹，不排除今年剩下的时间里，继续物色这方面的投资标的。 毕竟，对即将进入万亿美元市值俱乐部的礼来而言，手头最不差的就是钱。 参考资料： 1.Lilly bets on radiopharmaceuticals；C&EN 2.Intrigued by Novartis and Lilly deals, investors pour money into radiopharmaceuticals； 3.Fierce Pharma 4.Aktis Oncology enters into Strategic Collaboration with Lilly；Aktis 5.Eli Lilly Puts $1B on the Line to Expand its Cancer Radiopharmaceuticals Prospects；MedCity News 6.Eli Lilly inks another radiopharma deal, gaining option to buy startup；BioPharma Dive 7.IONETIX closes financing led by Tees River and Eli Lilly and Company；Ionetix 8.Eli Lilly enters nuclear isotope business to back cancer treatment；The Financial Times 9.POINT Pharma：核药新贵，靠实力推开巨头大门！；胖猫的生命医学札记 同写意媒体矩阵，欢迎关注↓↓↓