Botulism

While AbbVie's Botox dominates the medical aesthetics field, some new rivals have emerged. Public Citizen wants the FDA to change its messaging around the products. The U.S. advocacy group Public Citizen is taking aim at AbbVie’s medical and cosmetic injection Botox, as well as its new rivals, over safety and promotional issues with the shots. In a petition sent to the FDA, Public Citizen asked the FDA to “remove misleading promotional statements from the labeling of Botox and Botox Cosmetic” and to "strengthen the black box warning in the labeling of all approved Botox and related drugs.” Botox is the market leader in the medical aesthetics field, having been around for 34 years and generating around $5 billion annually for AbbVie. The Illinois-based pharma giant picked up the blockbuster drug from its buyout of Allergan in 2019. While Botox dominates the field, Public Citizen also wants the same crackdown for the med's rivals. Those are Revance Therapeutics' Daxxify, Evolus' Jeuveau, Supernus Pharmaceuticals' Myobloc, Galderma's Dysport, and Merz Therapeutics’ Xeomin. All of these products contain a form of a highly potent neurotoxin that can be used to treat cosmetic conditions, such as smoothing out wrinkle lines or, as is the case with Botox, also have medical labels, such as for migraines and incontinence. But there can be serious safety risks when using these neurotoxins, and Public Citizen wants the FDA to shore up messaging around the products. The group has a long history with Botox and originally petitioned for the drug’s black-box warning back in 2008. It argues that the current warning, which was slapped on the drug by the FDA in 2009, still does not go far enough as it “fails to explicitly mention the risk of ‘systemic iatrogenic botulism.'" This is a potential complication of Botox treatment and related drugs that can cause muscle paralysis or weakness, the group said. The advocacy group also wants the removal of “misleading promotional statements” from the labeling of Botox and Botox Cosmetic. These promotional statements are also related to potential safety risks, with Public Citizen singling out the claim that “[n]o definitive serious adverse event reports of distant spread of toxin effect” were associated with the use of recommended doses of these drugs to treat four therapeutic indications (blepharospasm, chronic migraine, severe underarm sweating, and strabismus) and certain approved cosmetic uses. It points out that regulators in other countries, including Canada and the U.K., do not use this claim, and that, when combing through the FDA’s safety database, the group said it saw that “Botox was the primary suspect when used to treat one of the four therapeutic indications listed in the misleading claims,” and that “269 (42%) included adverse reactions that were suggestive of iatrogenic botulism.”

T-box核糖开关是一类位于革兰氏阳性细菌mRNA的 5’非翻译区的顺式作用RNA元件。革兰氏阳性菌是一大类包括可引起结核病、坏疽、肉毒中毒、炭疽热、心脏内壁炎症和其他疾病的病原体。T-box核糖开关长度通常在300核苷酸以下，可分为适配体结构域和表达平台结构域。T-box核糖开关通过其适配体结构域识别和结合特定的tRNA并感知其3’末端的氨酰化状态，引发下游RNA元件构象状态的转变进而在翻译水平或转录水平调控下游基因的表达，这些下游基因通常与氨基酸的代谢密切相关。与其它核糖开关一般通过识别小分子代谢物或离子调控基因表达的机制不同，T-box核糖开关基因表达调控的功能主要是通过两个高度结构化的RNA（即T-box核糖开关和tRNA）之间的相互作用实现的。近年来多种T-box核糖开关与tRNA复合物的三维结构已被解析，但是分子内和分子间的RNA-RNA相互作用是如何促进T-box核糖开关折叠和发生结构转变进而形成特定构象状态以发挥生理功能的机制仍不清楚。2023年11月15日，中国科学院生物物理研究所方显杨研究组与清华大学生命学院陈春来课题组合作，在《自然通讯》（Nature communications）在线发表了题为“翻译调控型T-box核糖开关折叠与tRNA识别耦联的结构与动态机制”（Structural and dynamic mechanisms for coupled folding and tRNA recognition of a translational T-box riboswitch）的研究论文。在该项研究中，研究人员整合应用小角X射线散射（SAXS）技术、单分子荧光共振能量转移（smFRET）技术以及分子动力学模拟，探究了来自皮疽诺卡氏菌（Nocardia farcinica）的特异性识别异亮氨酸的ileS T-box核糖开关适配体结构域(包含stem I, stem II和stem IIA/B茎环元件)在溶液中的折叠与构象动态，揭示了由镁离子及ileS-tRNA结合调控的T-box核糖开关适配体结构域的折叠动态过程和相应的自由能面，为我们深入理解RNA-RNA相互作用对RNA折叠与识别的重要影响以及发展和理性设计靶向RNA的新型抗生素药物提供了理论依据。在该项研究中，为实现对T-box核糖开关适配体结构域的多对位点荧光探针标记(dense labeling)进而利用smFRET技术全面研究其构象动态，方显杨研究组设计并化学合成了碱基被炔基修饰的NaM非天然核苷酸NaM(NaMCO), 结合研究组此前设计合成的碱基被氨基修饰的TPT3非天然核苷酸 (TPT3A), 发展了基于非天然碱基系统（NaM-TPT3）的长链RNA位点特异性荧光探针正交标记技术（图1）。通过重叠延伸PCR以及体外转录，可向RNA的特定位点引入化学修饰的非天然碱基(NaMCO, rTPT3A)，随后通过点击化学以及NHS酯基与氨基的化学反应可将正交的荧光探针（如Cy3, Cy5）与非天然碱基相耦联，从而实现对RNA的位点特异性荧光标记。该方法突破了传统RNA位点特异性标记技术如化学合成等在RNA长度、标记位点、标记效率及对结构的干扰等方面的局限性，将极大推动和拓展smFRET技术在研究长链RNA构象动态以及解析其三维结构中的应用。图1 基于非天然碱基系统的RNA位点特异性荧光标记技术利用基于非天然碱基系统的位点特异性正交荧光标记策略，研究人员在T-box核糖开关适配体结构域上选择了七对标记位点，构建了一个密集的标记网络，得以全面的探究tRNA及镁离子诱导的T-box核糖开关适配体的构象动态。研究发现，镁离子可以稳定stem IIA/B假结结构，使其与stem II结构域共轴堆积，进而诱导stem I与stem II结构域的预对接，使T-box折叠为可以结合tRNA的活性构象，而tRNA的结合则进一步诱导了stem I与stem II结构域的对接。此外，研究者也利用SAXS技术结合分子动力学模拟建立了T-box核糖开关不同长度的转录中间产物(T77, T89)在不同镁离子条件下的溶液结构模型，并结合突变实验进一步证实了stem IIA/B假结结构以及S-turn结构基序在T-box识别tRNA过程中的重要作用。综合上述实验结果，研究者们提出了镁离子及tRNA介导的T-box核糖开关适配体的共转录折叠模型（图2），揭示了在转录过程中T-box核糖开关各个结构元件相互协同调控促进其折叠，最终保证其能高效、快速识别tRNA的分子机制。总的来说，该项工作揭示了镁离子以及分子内或分子间的RNA-RNA相互作用之间的微妙平衡在调控T-box核糖开关折叠以及功能中的作用。图2 镁离子及tRNA介导的翻译型T-box的折叠模型原文链接：https://doi.org/10.1038/s41467-023-43232-z本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

IRVINE, Calif., Feb. 10, 2023 (GLOBE NEWSWIRE) -- AEON Biopharma, Inc. (“AEON” or the “Company”), a clinical-stage biopharmaceutical company focused on developing a proprietary botulinum toxin complex for the treatment of multiple debilitating medical conditions, responded today to the recent ruling by the Seoul Central District Court in favor of Medytox, Inc. related to a long-standing trade secret dispute between Medytox and Daewoong Pharmaceutical Co. Ltd. AEON stated that it does not expect the ruling will affect its ongoing clinical development or planned commercialization strategy for ABP-450 (prabotulinumtoxinA) injection in target markets. As part of AEON’s global settlement with Medytox, which was entered into on June 21, 2021, all outstanding litigation relating to Medytox’s strain of C. botulinum between the two parties was fully resolved under confidential terms. The settlement contemplates that any Korean litigation between Medytox and Daewoong would not affect the supply of ABP-450 to AEON. The rights granted to AEON under the settlement include having ABP-450 manufactured and exported by Daewoong to AEON, and for AEON to continue its planned clinical development and, if approved by government regulators, commercialization of ABP-450. AEON is developing ABP-450 as a treatment for debilitating medical conditions, with an initial focus on the neurosciences market. “As previously announced, we have settled all litigation between AEON and Medytox, and we have a licensing agreement with Daewoong for ABP-450. As such, the ongoing litigation in Korea on trade secrets is between Medytox and Daewoong, and is not expected to have any impact on AEON’s clinical development and commercialization plans or timelines for ABP-450 in the U.S.,” said Marc Forth, AEON’s President and Chief Executive Officer. To learn more about AEON and the development of its uniquely positioned therapeutic neurotoxin, visit www.aeonbiopharma.com. About ABP-450 (prabotulinumtoxinA) Injection ABP-450 contains a 900 kDa botulinum toxin type-A complex produced by the bacterium Clostridium botulinum. The active part of the botulinum toxin is the 150 kDa component, and the remaining 750 kDa of the complex is made up of accessory proteins that the Company believes help with the function of the active portion of the botulinum toxin. When injected at therapeutic levels, ABP-450 blocks peripheral acetylcholine release at presynaptic cholinergic nerve terminals by cleaving SNAP-25, a protein integral to the successful docking and release of acetylcholine from vesicles situated within the nerve endings leading to denervation and relaxation of the muscle. AEON licenses ABP-450 from Daewoong Pharmaceutical Co., which provides AEON exclusive development and distribution rights for therapeutic indications in certain territories, including the United States, Canada and the EU, among other international territories. About AEON Biopharma AEON is a clinical stage biopharmaceutical company focused on developing its proprietary botulinum toxin complex, ABP-450 (prabotulinumtoxinA) injection, or ABP-450, for debilitating medical conditions, with an initial focus on the neurosciences market. AEON recently completed a Phase 2 study of ABP-450 for the treatment of cervical dystonia and has an ongoing Phase 2 study of ABP-450 for the treatment of both chronic and episodic migraine. ABP-450 is the same botulinum toxin complex that is currently approved and marketed for cosmetic indications by Evolus under the name Jeuveau. ABP-450 is manufactured by Daewoong in compliance with current Good Manufacturing Practice, or cGMP, in a facility that has been approved by the U.S. Food and Drug Administration, or the FDA, Health Canada and European Medicines Agency, or EMA. AEON has exclusive development and distribution rights for therapeutic indications of ABP-450 in the United States, Canada, the European Union, the United Kingdom, and certain other international territories. The company built a highly experienced management team with specific experience in biopharmaceutical and botulinum toxin development and commercialization. Proposed Transaction with Priveterra Acquisition Corp. On December 13, 2022, AEON and Priveterra announced entering into a definitive business combination agreement relating to a business combination that would result in AEON becoming a public company upon the closing of the proposed transaction. The Boards of Directors of both AEON and Priveterra have approved the proposed transaction, which is expected to close in the first half of 2023, subject to approval by Priveterra’s stockholders and the satisfaction or waiver of certain other customary closing conditions. In connection with the proposed transaction, Priveterra filed a registration statement on Form S-4 with the U.S. Securities and Exchange Commission (the “SEC”) on December 27, 2022. Forward-Looking Statements This press release contains certain forward-looking statements within the meaning of the federal securities laws with respect to the proposed transaction between AEON and Priveterra, including statements regarding the benefits of the proposed transaction, the anticipated timing of the proposed transaction, the products developed by AEON and the markets in which it operates, any statements about current or planned clinical trials or related milestones, any statements of expectation or belief regarding future events, potential markets, market size, or technology developments, AEON’s projected future results, and any statements of assumptions underlying any of the items mentioned. These forward-looking statements generally are identified by the words “believe,” “project,” “expect,” “anticipate,” “estimate,” “intend,” “strategy,” “future,” “opportunity,” “plan,” “may,” “should,” “will,” “would,” “will be,” “will continue,” “will likely result,” and similar expressions. Forward-looking statements are predictions and other statements about future events that are based on current expectations and assumptions and, as a result, are subject to risks and uncertainties. Many factors could cause actual future events to differ materially from the forward-looking statements in this document, including but not limited to: (i) the risk that the transaction may not be completed in a timely manner or at all, which may adversely affect the price of Priveterra’s securities, (ii) the risk that the transaction may not be completed by Priveterra’s business combination deadline and the potential failure to obtain an extension of the business combination deadline if sought by Priveterra, (iii) the failure to satisfy the conditions to the consummation of the transaction, including the adoption of the agreement and plan of merger by the shareholders of Priveterra and AEON, the satisfaction of the minimum trust account amount following redemptions by Priveterra’s public shareholders and the receipt of certain governmental and regulatory approvals, (iv) the lack of a third party valuation in determining whether or not to pursue the proposed transaction, (v) the occurrence of any event, change or other circumstance that could give rise to the termination of the business combination agreement, (vi) the effect of the announcement or pendency of the transaction on AEON’s business relationships, performance, and business generally, (vii) risks that the proposed transaction disrupts current plans of AEON and potential difficulties in AEON employee retention as a result of the proposed transaction, (viii) the outcome of any legal proceedings that may be instituted against AEON or against Priveterra related to the business combination agreement or the proposed transaction, (ix) the ability to maintain the listing of Priveterra’s securities on the NASDAQ Exchange, (x) volatility in the price of Priveterra’s securities due to a variety of factors, including changes in the competitive and highly regulated industries in which AEON plans to operate, variations in performance across competitors, changes in laws and regulations affecting AEON’s business and changes in the combined capital structure, (xi) the ability to implement business plans, forecasts, and other expectations after the completion of the proposed transaction, and identify and realize additional opportunities, and (xii) the risk of downturns in the highly competitive pharmaceutical industry. The foregoing list of factors is not exhaustive. You should carefully consider the foregoing factors and the other risks and uncertainties described in the “Risk Factors” section of the registration statement on Form S-4 and proxy statement/prospectus referenced above and other documents filed by Priveterra from time to time with the SEC. These filings identify and address other important risks and uncertainties that could cause actual events and results to differ materially from those contained in the forward-looking statements. Forward-looking statements speak only as of the date they are made. Readers are cautioned not to put undue reliance on forward-looking statements, and AEON and Priveterra assume no obligation and do not intend to update or revise these forward-looking statements, whether as a result of new information, future events, or otherwise. Neither AEON nor Priveterra gives any assurance that either AEON or Priveterra will achieve its expectations. Contacts Investor Contact: Corey Davis, Ph.D. LifeSci Advisors +1 212 915 2577 cdavis@lifesciadvisors.com Source: AEON Biopharma