Loperamide Hydrochloride

前言溶酶体是细胞内执行消化作用的主要细胞器，也是代谢信号的传递中枢，参与调控了细胞内的多种生理代谢过程。研究表明，多种非化疗药物（如抗疟疾药氯喹、抗抑郁药丙咪嗪、止咳药右美沙芬等）和抗癌药物（如阿霉素、尼达尼布、索拉菲尼等）分子均对溶酶体具有高亲和力。此类药物分子通常具有碱性或弱碱性，容易在溶酶体中发生大量滞留，导致治疗效果不佳，且长期服用也易于引发耐药性和一些不良反应。药物在溶酶体内蓄积会影响其药代动力学特性、有效性和安全性，因此，在药物研发的早期阶段，尽早明确候选药物是否会被溶酶体捕获，能够更好地预测药物在组织和亚细胞内的分布情况，为新药研发过程中的吸收（absorption）、分布（distribution）、代谢（metabolism）及排泄（excretion）性质预测以及早期安全性评估提供参考。本文将从溶酶体的结构与功能出发，综合阐述溶酶体捕获的机理与应用，并提供相应的体外研究策略。溶酶体的结构与功能1溶酶体的结构溶酶体是一种具有单层膜结构的囊泡状、异质化的细胞器（图1），广泛地存在于除成熟红细胞之外的所有动物细胞中。溶酶体膜上存在一种关键蛋白——H+‑ATPase质子泵（V-type ATPase），它能够利用ATP水解释放的能量，驱动H+进入溶酶体腔（pH值大致为4.5~5.0），从而形成溶酶体-细胞质的pH梯度差。V-type ATPase质子泵与膜上其它离子通道蛋白（如Cl-通道蛋白、Na+/K+通道蛋白等）协同作用，以维持腔体内环境的动态平衡。图1. 溶酶体的生理结构[1]2溶酶体的功能溶酶体主要执行消化作用。溶酶体内部含有丰富的酸性水解酶，包括蛋白酶、脂肪酶、磷酸酶等，这些酸性水解酶能够帮助溶酶体消化经自噬或内吞作用运输的多种内源性或外源性大分子物质，也可以消化衰老或损伤的其它细胞器。除了基础的消化功能外，溶酶体还可以通过自噬作用参与细胞的免疫反应。溶酶体膜上的mTOR（雷帕霉素靶蛋白复合体）能够帮助溶酶体感知细胞内营养物质的富集情况，从而调节细胞的能量代谢和信号转导过程[2]。溶酶体捕获的机理及对ADME的影响基于溶酶体内的酸性环境，药物在溶酶体中发生质子化电离，并大量滞留在溶酶体内的过程被称为“溶酶体捕获”。溶酶体捕获的发生需要两个前提条件：（1）药物具有一定的跨膜能力（脂溶性）；（2）药物具有碱性基团，在酸性环境中容易发生质子化。1溶酶体捕获的机理一般而言，油水分配系数ClogP＞2.0，且pKa在6.5~11的化合物极易发生溶酶体捕获。亲脂性的碱性药物在生理pH条件下，主要以非解离型的形式存在，能够自由地穿透生物膜，进入细胞质。当其进入溶酶体后，溶酶体腔的酸性环境会促进药物结构中的碱性基团发生质子化电离。离子型药物的跨膜能力差，从而被滞留在溶酶体中，由此形成了“溶酶体捕获”现象（图2）。图2. 溶酶体捕获的机理2溶酶体捕获与药物ADME药物在人体内的ADME过程会受到诸如给药途径（如口服给药、注射给药、呼吸道吸入给药等）、生理因素（如组织器官血流量、体液pH值、细胞膜转运蛋白表达量等）、药物的固有性质（如脂溶性、酸碱性、血浆蛋白结合率等）和组织成分等多重因素的共同调控。亲溶酶体药物一方面由于其具有良好的脂溶性，药物分子更倾向于分布在脂肪丰富的组织，如脂肪、肝脏、肾脏等；另一方面因其易被溶酶体、高尔基体等酸性细胞器捕获，因此亲溶酶体药物容易在溶酶体丰富的组织器官（如肺、肾脏、肝脏、脾脏、脑和肠道等）中表现出极高的组织分布。药物的表观分布容积越大，相应的药物消除半衰期延长，在体内的存留时间越长。此外，对于口服制剂药物，溶酶体捕获作用可能会降低药物的吸收程度和吸收速率，从而影响药效。例如，右美沙芬在生物药剂学分类系统（Biopharmaceutics Classification System，BCS）中属于BCS I类化合物，在胃肠道中具有高溶解性和高渗透性，但是由于肠细胞的溶酶体捕获作用，使得其口服制剂中药物成分的达峰时间（约2.5小时）明显晚于其他典型的BCS I类药物（如普伐他汀的达峰时间为1~1.5小时）[3]。溶酶体捕获的应用溶酶体通透化介导的肿瘤细胞死亡正常情况下，溶酶体膜高度糖基化，溶酶体内的酸性水解酶被充分隔绝在溶酶体腔中。当溶酶体膜的通透性（Lysosomal membrane permeabilization，LMP）发生改变时，可溶性溶酶体内容物（如组织蛋白酶B、组织蛋白酶D等）释放到细胞质中，会激活细胞内的级联反应和炎症小体，促进细胞凋亡或坏死，这一过程被称为“溶酶体膜通透化介导的细胞死亡”。一般而言，与正常细胞相比，肿瘤细胞中的溶酶体数量增多，体腔变大，且溶酶体内水解酶的水平升高。因此，肿瘤细胞对亲溶酶体药物的毒性作用更敏感。当阳离子两亲性药物（cationic amphiphilic drugs，CADs）在溶酶体中大量蓄积时，会促进酸性鞘磷脂酶从溶酶体膜上分离，溶酶体膜通透化，组织蛋白酶释放增加，从而引起肿瘤细胞死亡（图3）。例如，抗组胺药特非那定（Terfenadine）可诱导前列腺癌细胞死亡；阿司咪唑（Astemizole）可抑制乳腺癌细胞和淋巴癌细胞的增殖[4]。图3. 溶酶体膜通透化介导的细胞死亡基于溶酶体内药物相互作用的联合用药多种抗肿瘤、抗疟疾、抗心律失常以及抗抑郁等中枢神经系统类药物均存在溶酶体捕获现象。当药物的作用靶点位于细胞核/质时，溶酶体捕获会降低靶位点的药物浓度，因此亲溶酶体药物作为单一药物进行治疗时，往往治疗效果有限，可以通过联合用药的方式来改善治疗效果。以索拉菲尼（Sorafenib，SF）和维替泊芬（Verteporfin，VP）的合用为例（图4），索拉菲尼是肝癌治疗的一线用药，但其容易发生溶酶体捕获，无法充分发挥药效。维替泊芬是一种亲溶酶体的自噬抑制剂，采用维替泊芬处理肝癌细胞会导致溶酶体pH值升高，溶酶体膜的通透性发生改变，当二者联合用药时，能够有效地抑制肝癌细胞的生长和增殖[5]。图4. 索拉菲尼联合维替泊芬治疗肝癌的示意图药物性诱导的磷脂沉积研究表明，亲溶酶体药物在细胞内的大量蓄积，容易诱导磷脂沉积症的发生。可能的机制有两种：第一种：药物与溶酶体内的脂质结合，形成难以被脂肪酶降解的药物-脂质复合物；第二种：药物抑制溶酶体脂肪酶的活性，导致磷脂大量蓄积。2021年，Science期刊发表的一篇关于SARS-CoV-2和其它病毒的药物再利用筛选报告指出[6]，近34%的抗病毒“老”药均为CAD药物，此类药物具有亲溶酶体性，而药物的抗病毒活性则与药物性磷脂沉积密切相关，提示溶酶体捕获诱导的药物性磷脂沉积在药物的抗病毒活性中可能发挥一定的作用。尽管如此，更多的研究证据表明药物和磷脂的大量蓄积会损伤溶酶体正常的生理功能，导致巨噬细胞和多种实质细胞出现空泡化，同时引起包括神经系统、心血管系统在内的肝脏、肾脏等多器官功能损伤[7]。因此，提前对药物进行早期磷脂沉积安全性风险评估，能够为先导化合物的筛选和结构优化提供参考，并增加候选药物进入临床试验的可行性。溶酶体捕获的体外研究策略目前，有关溶酶体捕获的体外研究方法主要有两种（表1）：第一种是基于液相色谱‑联质谱（LC-MS/MS）技术的生物分析；第二种是溶酶体特异性荧光探针的细胞蓄积实验。01基于LC-MS/MS技术的直接检测法V-type ATPase抑制剂能够抑制溶酶体酸化，进而降低药物在溶酶体内的蓄积。通过对比加与不加抑制剂处理后，药物在细胞/溶酶体内的浓度差异，可反映出药物在细胞/溶酶体内的蓄积情况。目前，科学家们采用MDCK II细胞、大鼠心肌细胞H9C2和人肝癌细胞Hep G2等多种细胞模型已经成功构建出一套快捷、准确、高通量的溶酶体捕获体外筛选体系[8, 9]。02溶酶体荧光探针蓄积实验（间接检测法）亲溶酶体药物在溶酶体中蓄积，会导致溶酶体腔内的pH值升高，从而降低pH依赖性的溶酶体特异性荧光探针的摄入。加与不加药物处理后，采用高内涵荧光显微镜进行成像，通过对比荧光探针在溶酶体内的荧光强度，能够预测化合物是否存在溶酶体捕获[10]。表1. 溶酶体捕获的体外研究方法溶酶体捕获评估模型的建立由于直接检测法能够更直接、准确地反映药物在溶酶体内的蓄积程度，同时对化合物的测试浓度要求较低，因此，药明康德DMPK团队采用直接检测法，基于MDCK II细胞模型成功建立了评估溶酶体捕获的两种筛选模型：Transwell模型和孔板模型。Transwell模型将MDCK II细胞接种至Transwell板，待细胞形成完整的单层膜结构后开始渗透性实验。化合物在含有或不含抑制剂的条件下，顶端到基底端（A‑B）方向给药。采用LC-MS/MS技术，检测化合物在未知样品中的浓度，通过对比加与不加抑制剂时，化合物在A-B方向的溶液回收率的改变，从而评估其是否被溶酶体捕获。药明康德DMPK挑选了6种性质已知的模型药物（表2）开展验证实验。在测试条件下，加入抑制剂能够显著提高亲溶酶体药物（氯丙嗪、洛哌丁胺、伊马替尼、普萘洛尔和右美沙芬）在A-B方向的溶液回收率（p<0.05），而酸性化合物双氯芬酸的溶液回收率则无明显差异（p>0.05）（图5），这一结果充分证明了该MDCK II细胞Transwell实验模型体系的可行性。表 2. 溶酶体捕获的模型药物信息图5. MDCK II细胞模型药物验证（Transwell模型）（*p<0.05，即有显著性差异）随后，采用MDCK II细胞Transwell实验模型探究化合物A与化合物B是否受溶酶体捕获，如图6所示，加入抑制剂后，化合物A在MDCK II细胞中A-B方向的溶液回收率显著提高，而化合物B的溶液回收率则无明显差异。提示化合物A极可能被MDCK II细胞内的溶酶体捕获，而化合物B不易发生溶酶体捕获。图6. MDCK II细胞测试化合物验证（Transwell模型）（*p<0.05，即有显著性差异）孔板模型将MDCK II细胞接种至96孔板中，培养过夜且达到80-90%融合度后，先将细胞置于含有或不含抑制剂的预孵育液中进行预孵育，随后与测试化合物进行共孵育。孵育结束后，采用LC-MS/MS技术，检测细胞裂解样品中化合物的浓度。最后，通过对比加与不加抑制剂时，化合物在细胞内蓄积量的差异，以评估化合物被溶酶体捕获的程度。为了验证模型的可靠性，采用与Transwell模型相同的模型药物进行验证实验。在测试条件下，加入抑制剂能够明显降低亲溶酶体药物（氯丙嗪、洛哌丁胺、伊马替尼、普萘洛尔和右美沙芬）在胞内的蓄积，而酸性化合物双氯芬酸在胞内的蓄积量则无明显差异（图7），这一结果也充分证明了MDCK II细胞孔板模型实验体系的可行性。图7. MDCK II细胞模型药物验证（孔板模型）随后，采用MDCK II细胞孔板模型同时探究化合物A与化合物B是否受溶酶体捕获，如图8所示，在测试条件下，加入抑制剂后，化合物A在MDCK II细胞内的蓄积量明显降低，而化合物B在胞内的蓄积则无明显差异。表明化合物A极可能被MDCK II细胞内的溶酶体捕获，而化合物B不易发生溶酶体捕获，这与MDCK II细胞Transwell实验模型的结论一致。图8. MDCK II细胞测试化合物验证（孔板模型）两种模型的差异MDCK II细胞Transwell模型与MDCK II细胞孔板模型均可用于体外溶酶体捕获评估的高通量分析。其中，MDCK II细胞Transwell模型可在评估测试化合物被溶酶体捕获程度的同时，对化合物进行渗透性的预测，并可探究溶酶体捕获效应对该测试化合物渗透性的影响。相对于MDCK II细胞Transwell模型而言，MDCK II细胞孔板模型实验周期短、通量高且成本低，更适用于药物研发早期阶段的高通量筛选。结语溶酶体的捕获效应存在于多种已知的上市药物以及在研的候选药物中。药物在溶酶体内蓄积会影响药物的药代动力学特征、有效性和安全性。亲溶酶体药物还可以通过改变溶酶体腔内的pH值、稳态体积以及酶结合位点，从而引起药物相互作用，进一步影响药效或产生毒副作用。因此，尽早明确候选药物是否会被溶酶体捕获，能够为药物的早期研发提供更全面的指导与帮助。参考文献：[1] Trivedi PC, Bartlett JJ, Pulinilkunnil T. Cells. 2020 May 4;9(5):1131.[2] Zhang Z, Yue P, Lu T, Wang Y, Wei Y, Wei X. Role of lysosomes in physiological activities, diseases, and therapy. J Hematol Oncol. 2021 May 14;14(1):79.[3] Bolger MB, Macwan JS, Sarfraz M, Almukainzi M, Löbenberg R. The Irrelevance of In Vitro Dissolution in Setting Product Specifications for Drugs Like Dextromethorphan That are Subject to Lysosomal Trapping. J Pharm Sci. 2019 Jan;108(1):268-278.[4] Serrano-Puebla, A., and Boya, P. (2018). Lysosomal Membrane Permeabilization as a Cell Death Mechanism in Cancer Cells. Biochem. Soc. T 46, 207–215.[5] Gavini J, Dommann N, Jakob MO, Keogh A, Bouchez LC, Karkampouna S, Julio MK, Medova M, Zimmer Y, Schläfli AM, Tschan MP, Candinas D, Stroka D, Banz V. Verteporfin-induced lysosomal compartment dysregulation potentiates the effect of sorafenib in hepatocellular carcinoma. Cell Death Dis. 2019 Oct 3;10(10):749.[6] Tummino TA, Rezelj VV, Fischer B, Fischer A, O'Meara MJ, Monel B, Vallet T, White KM, Zhang Z, Alon A, Schadt H, O'Donnell HR, Lyu J, Rosales R, McGovern BL, Rathnasinghe R, Jangra S, Schotsaert M, Galarneau JR, Krogan NJ, Urban L, Shokat KM, Kruse AC, García-Sastre A, Schwartz O, Moretti F, Vignuzzi M, Pognan F, Shoichet BK. Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV. Science. 2021 Jul 30;373(6554):541-547[7] Breiden B, Sandhoff K. Emerging mechanisms of drug-induced phospholipidosis. Biol Chem. 2019 Dec 18;401(1):31-46.[8] Bednarczyk D, Sanghvi MV. The impact of assay recovery on the apparent permeability, a function of lysosomal trapping. Xenobiotica. 2020 Jul;50(7):753-760.[9] Nadanaciva S, Lu S, Gebhard DF, Jessen BA, Pennie WD, Will Y. A high content screening assay for identifying lysosomotropic compounds. Toxicol In Vitro. 2011 Apr; 25(3):715-23.[10] Schmitt MV, Lienau P, Fricker G, Reichel A. Quantitation of Lysosomal Trapping of Basic Lipophilic Compounds Using In Vitro Assays and In Silico Predictions Based on the Determination of the Full pH Profile of the Endo-/Lysosomal System in Rat Hepatocytes. Drug Metab Dispos. 2019 Jan;47(1):49-57. （下滑查看更多）作者：张喻，刘青，熊涛，陈根富编辑：钱卉娟设计：倪德伟，张莹莹免责声明“药渡”公众号所转载该篇文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片、文章版权均属于原作者所有，如有侵权，请及时告知，我们会在24小时内删除相关信息。微信公众号的推送规则又双叒叕改啦，如果您不点个“在看”或者没设为"星标"，我们可能就消散在茫茫文海之中~点这里，千万不要错过药渡的最新消息哦！👇👇

FY’23: Net Sales Increased 3.3% to $15.4 billion with Organic Growth1 of 5.0% FY’23: Diluted Earnings per Share of $0.90; Adjusted Diluted Earnings per Share1 of $1.29 Q4’23: Net Sales Decreased (2.7)% to $3.7 billion with Organic Growth1 of (2.4)% Q4’23: Diluted Earnings per Share of $0.17; Adjusted Diluted Earnings per Share1 of $0.31 SKILLMAN, N.J.--(BUSINESS WIRE)-- Kenvue Inc. (NYSE: KVUE) (“Kenvue”), the world’s largest pure-play consumer health company by revenue, today announced financial results for the fiscal full year and fourth quarter ended December 31, 2023. “2023 was a transformational year for Kenvue as we began delivering on our long-term value creation algorithm centered around profitable growth, durable cash flow generation and disciplined capital allocation,” said Thibaut Mongon, Chief Executive Officer. “We enter 2024 with clear strategic priorities as an independent Kenvue, including strengthened plans in our U.S. Skin Health and Beauty business. Looking ahead we’re focused on reaching more consumers, reinventing our ways of working to invest more in our brands, and fostering a culture that rewards performance and impact in our organization.” Full Year and Fourth Quarter 2023 Financial Results Net Sales & Organic Growth Full year Net sales increased 3.3% vs a (0.7)% decrease in the prior year period. Organic growth1 increased 5.0% vs a 3.8% increase in the prior year. Increases in Net sales and Organic growth were comprised of 7.7% value realization (defined as price including mix), and 2.7% volume declines. Volume performance includes the impacts of non-recurring product discontinuations, including portfolio rationalization initiatives in 2022 and the suspension of personal care products in Russia. Excluding these non-recurring items, volume was down slightly vs the prior year. Fourth quarter Net sales decreased 2.7% vs a 0.9% increase in the prior year period. Organic growth declined 2.4% vs a 6.2% increase in the prior year. Net sales and Organic growth were comprised of 5.8% value realization and 8.2% volume declines. Approximately five points of the volume performance are attributable to unique dynamics within the fourth quarter 2023 including lapping an early and strong start to the cold, cough, and flu season last year, 2022 product discontinuations, and customer inventory reductions. The remaining approximately three points of volume performance are mainly due to softer than anticipated performance in the U.S. Skin Health and Beauty business and continued softness in China. Gross Profit Margin & Adjusted Operating Income Margin Full year Gross profit margin was 56.0% vs 55.4% in the prior year period, on a reported basis. Adjusted gross profit margin1 was 58.4% vs 58.1% in the prior year period. Margin expansion was driven by favorable value realization and continued global supply chain efficiency initiatives partially offset by the impact of sustained higher cost inflation and approximately 110 basis points of foreign currency headwinds. Fourth quarter Gross profit margin was 55.7% vs 54.3% in the prior year period. Adjusted gross profit margin was 59.5% vs 57.3% in the prior year period. Margin expansion was driven by favorable value realization, non-recurring separation-related benefits, and continued global supply chain efficiency initiatives, partially offset by approximately 70 basis point of foreign currency headwinds. Full year Operating income margin was 16.3% vs 17.9% in the prior year period and fourth quarter operating income margin was 12.5% vs 14.1% in the prior year period. For both full year and fourth quarter, Operating income margin decrease vs prior year period was driven by Separation-related costs. Full year Adjusted operating income margin1 was 22.4% in the current and prior year period as strong Adjusted gross profit margin performance offset incremental ongoing public company costs not incurred last year and the impact of foreign currency headwinds. Fourth quarter Adjusted operating income margin was 21.8% vs 19.9% in the prior year period as strong Adjusted gross profit margin performance and non-recurring separation-related benefits was partially offset by the absorption of public company costs and the impact of foreign currency headwinds. Interest expense, net & Taxes Interest expense, net was $250 million for the year on a reported basis, and $96 million for fourth quarter 2023. Adjusted interest expense, net1 was $283 million for the year. The full year 2023 Effective tax rate was 24.0% vs 21.7% in the prior year on a reported basis. The increase in the reported Effective tax rate is the result of higher U.S. tax on foreign sourced income and limitations on the Company’s ability to utilize its foreign tax credits in the full year period 2023. The Adjusted effective tax rate1 was 23.4% vs 23.9% in the prior year period. The decrease in the Adjusted effective tax rate is due primarily to tax reserve releases due to statute of limitations expiring. The fourth quarter Effective tax rate was 8.4% vs 29.5% in the prior year period. The Adjusted effective tax rate was 15.8% vs 31.4% in the prior year period. The decrease in reported Effective tax rate and Adjusted effective tax rate is primarily the result of lapping tax law changes negatively impacting the prior year, tax reserve releases due to statute of limitations expiring, and the benefits from effective tax planning. Net income per share (“Earnings per share”) Full year Diluted earnings per share was $0.90 on a reported basis. Adjusted diluted earnings per share1 was $1.29. Fourth quarter Diluted earnings per share was $0.17. Adjusted diluted earnings per share was $0.31. 2024 Outlook Based on current spot rates, Kenvue introduced its outlook for 2024 as follows: Net sales & Organic growth Kenvue expects full year 2024 reported Net sales growth to be in the range of 1.0% to 3.0%. Foreign exchange is expected to be a headwind of approximately one percentage point to reported Net sales growth. The Company expects full year 2024 Organic growth in the range of 2.0% to 4.0% with Organic growth sequentially improving as the year progresses as prior year comparisons ease and the impact of 2024 strategic priorities take hold. “Our 2024 priorities are clear,” said Paul Ruh, Chief Financial Officer. “As we accelerate investment behind our brands, particularly focused on in-store presence and prominence, enhancing consumer engagement, and amplify innovation, we expect our operating model optimization initiatives to generate impact in the second half of the year. While we are confident in our plans, our guidance prudently reflects the potential for a continued challenging macro-back drop and the possibility for unknowns in our seasonal businesses.” Adjusted operating income margin and Earnings per share Kenvue expects full year 2024 Adjusted operating income margin to be slightly below 2023 as strong gross margin progression is offset by the impact of absorbing a full year of public company costs and 50 basis points of foreign currency headwinds. Kenvue expects full year 2024 Adjusted diluted earnings per share to be in the range of $1.10 - $1.20. This range assumes a full year 2024 diluted weighted average share count of 1.92 billion. Reported Interest expense, net For full year 2024, Kenvue expects reported Interest expense, net to be approximately $400 million. Reported and Adjusted effective tax rate For full year 2024, Kenvue expects an Effective tax rate between 26.5% to 27.5%, and an Adjusted effective tax rate between 25.5% to 26.5%. Kenvue is not able to provide the most directly comparable GAAP measures or reconcile Adjusted operating income margin or Adjusted diluted earnings per share to comparable GAAP measures on a forward-looking basis without unreasonable efforts given the unpredictability of the timing and amounts of discrete items such as acquisitions or divestitures. Webcast Information As previously announced, Kenvue will host a conference call with investors to discuss its fourth quarter results at 8:30 a.m. Eastern Time. The conference call can be accessed by dialing 888-660-5501 from the United States or 646-960-0416 from international locations. The conference ID for all callers is 1558006. A simultaneous webcast of the call for investors and other interested parties may be accessed by visiting the Investors section of the Company’s website. A replay will be available approximately two hours after the live event. About Kenvue Kenvue is the world’s largest pure-play consumer health company by revenue. Built on more than a century of heritage, our iconic brands, including Aveeno®, BAND-AID® Brand Adhesive Bandages, Johnson’s®, Listerine®, Neutrogena®, and Tylenol®, are science-backed and recommended by healthcare professionals around the world. At Kenvue, we believe in the extraordinary power of everyday care and our teams work every day to put that power in consumers’ hands and earn a place in their hearts and homes. Learn more at . 1Non-GAAP Financial Measures The Company uses certain non-GAAP financial measures to supplement the financial measures prepared in accordance with U.S. GAAP. There are limitations to the use of the non-GAAP financial measures presented herein. These non-GAAP financial measures are not prepared in accordance with U.S. GAAP nor do they have any standardized meaning under U.S. GAAP. In addition, other companies may use similarly titled non-GAAP financial measures that are calculated differently from the way the Company calculates such measures. Accordingly, the non-GAAP financial measures may not be comparable to such similarly titled non-GAAP financial measures used by other companies. The Company cautions you not to place undue reliance on these non-GAAP financial measures, but instead to consider them with the most directly comparable U.S. GAAP measure. These non-GAAP financial measures have limitations as analytical tools and should not be considered in isolation. These non-GAAP financial measures should be considered supplements to, not substitutes for, or superior to, the corresponding financial measures calculated in accordance with U.S. GAAP. The Company believes the presentation of these measures is relevant and useful for investors because it allows investors to view performance in a manner similar to the method used by management. The Company believes these measures help improve investors’ ability to understand the Company’s operating performance and makes it easier to compare the Company’s results with other companies. In addition, the Company believes these measures are also among the primary measures used externally by the Company’s investors, analysts, and peers in its industry for purposes of valuation and comparing the operating performance of the Company to other companies in our industry. Below are definitions and the reconciliation to the most closely related GAAP measures for the non-GAAP measures used in this press release and the related prepared materials and webcast. Adjusted diluted earnings per share: We define Adjusted diluted earnings per share as Adjusted net income divided by the weighted average number of diluted shares outstanding. Management views this non-GAAP measure as useful to investors as it provides a supplemental measure of the Company’s performance over time. Adjusted EBITDA margin: We define the non-GAAP measure EBITDA as U.S. GAAP Net income adjusted for interest, provision for taxes, and depreciation and amortization. We define Adjusted EBITDA, another non-GAAP financial measure, as EBITDA adjusted for costs incurred in connection with our establishment as a standalone public company (“Separation-related costs”), operating model optimization initiatives and restructuring expense, conversion of stock-based awards, stock-based awards granted to individuals employed by Kenvue as of October 2, 2023 (“Founders stock-based awards”), litigation expense, the impact of the deferred transfer of certain assets and liabilities from Johnson & Johnson in certain jurisdictions (the “Deferred Markets”), impairment of intangible assets, and unrealized gain on securities. We define Adjusted EBITDA margin as Adjusted EBITDA as a percentage of Net sales. Management believes this non-GAAP measure is useful to investors as it provides a supplemental perspective to the Company’s operating efficiency over time. Adjusted effective tax rate: We define Adjusted effective tax rate as U.S. GAAP Effective tax rate adjusted for tax effects of Separation-related costs, operating model optimization initiatives and restructuring expense, amortization and impairment of intangible assets, conversion of stock-based awards, litigation expense, interest income earned on the related party note receivable from Johnson & Johnson (i.e., special items) and taxes related to the Deferred Markets. We also exclude certain one-time tax only adjustments which include the removal of tax effects from the carve-out methodology, the impact of the interest expense from the debt issuance, which reduced the Company’s capacity to utilize foreign tax credits against U.S. foreign source income and other one-time items. Management believes this non-GAAP measure is useful to investors as it provides a supplemental measure of the Company’s performance over time. Adjusted gross profit margin: We define Adjusted gross profit margin as U.S. GAAP Gross profit margin adjusted for amortization of intangible assets, operating model optimization initiatives and restructuring expense, conversion of stock-based awards, and Founders stock-based awards. Management believes this non-GAAP measure is useful to investors as it provides a supplemental perspective to the Company’s operating efficiency over time. Adjusted interest expense, net: We define Adjusted interest expense, net as U.S. GAAP interest expense, net, adjusted to exclude the interest income earned on the related party note receivable from Johnson & Johnson. Management believes this non-GAAP measure is useful to investors in providing period-to-period comparisons of the results of the Company’s ongoing operational performance. Adjusted net income: We define Adjusted net income as U.S. GAAP Net income adjusted for amortization and impairment of intangible assets, Separation-related costs, operating model optimization initiatives and restructuring expense, conversion of stock-based awards, Founders stock-based awards, unrealized gain on securities, litigation expense, the impact of the Deferred Markets, interest income earned on the related party note receivable from Johnson & Johnson, and their related tax impacts (i.e. special items). Adjusted net income excludes the impact of items that may obscure trends in our underlying performance. Management believes this non-GAAP measure is useful to investors as the Company uses Adjusted net income for strategic decision making, forecasting future results, and evaluating current performance. Adjusted operating income: We define Adjusted operating income as U.S. GAAP Operating income adjusted for amortization and impairment of intangible assets, Separation-related costs, operating model optimization initiatives and restructuring expenses, conversion of stock-based awards, Founders stock-based awards, litigation expense, and the impact of the Deferred Markets. Management believes this non-GAAP measure is useful to investors as management uses Adjusted operating income to assess the Company’s financial performance. In the third quarter of 2023, the Company adjusted its definition of Adjusted operating income in order to align more closely with the financial measures used to evaluate performance by the Company’s peers. Adjusted operating income margin: We define Adjusted operating income margin as Adjusted operating income as a percentage of Net sales. Management believes this non-GAAP measure is useful to investors as it provides a supplemental perspective to the Company’s operating efficiency over time. Free cash flow: We define Free cash flow as U.S. GAAP Net cash flows from operating activities adjusted for Purchases of property, plant, and equipment. Management believes this non-GAAP measure is useful to investors as it provides a view of the Company’s liquidity after deducting capital expenditures, which are considered a necessary component of our ongoing operations. Organic growth: We define Organic growth as the period-over-period change in U.S. GAAP Net sales excluding the impact of changes in foreign currency exchange rates and the impact of acquisitions and divestitures. Management believes Organic growth provides investors with additional, supplemental information that is useful in assessing the Company’s results of operations by excluding the impact of certain items that we believe do not directly reflect our underlying operations. The non-GAAP measures as presented herein have been prepared as if our operations had been conducted independently from Johnson & Johnson prior to May 4, 2023, the date Kenvue’s common stock began trading on the New York Stock Exchange, and therefore they include certain Johnson & Johnson corporate and shared costs allocated to us. Management believes the cost allocations are a reasonable reflection of the utilization of services provided to, or the benefit derived by, us during the periods presented, though the allocations may not be indicative of the actual costs that would have been incurred if we had been operating as a standalone company. Cautions Concerning Forward-Looking Statements This press release contains “forward-looking statements” as defined in the Private Securities Litigation Reform Act of 1995 regarding, among other things, statements about management’s expectations of Kenvue’s future operating and financial performance, product development, market position and business strategy. Forward-looking statements may be identified by the use of words such as “plans,” “expects,” “will,” “anticipates,” “estimates” and other words of similar meaning. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Kenvue and its affiliates. Risks and uncertainties include, but are not limited to: the inability to execute on Kenvue’s business development strategy or realize the benefits of the separation from Johnson & Johnson; the risk of disruption or unanticipated costs in connection with the separation; Kenvue’s ability to succeed as a standalone publicly traded company; economic factors, such as interest rate and currency exchange rate fluctuations; the ability to successfully manage local, regional or global economic volatility, including reduced market growth rates, and to generate sufficient income and cash flow to allow Kenvue to effect any expected share repurchases and dividend payments; Kenvue’s ability to maintain satisfactory credit ratings, which could adversely affect its liquidity, capital position, borrowing costs and access to capital markets; competition, including technological advances, new products and intellectual property attained by competitors; challenges inherent in new product research and development; uncertainty of commercial success for new and existing products and digital capabilities; challenges to intellectual property protections including counterfeiting; the ability of Kenvue to successfully execute strategic plans, including operating model optimization and restructuring initiatives; the impact of business combinations and divestitures, including any ongoing or future transactions; manufacturing difficulties or delays, internally or within the supply chain; product efficacy or safety concerns resulting in product recalls or regulatory action; significant adverse litigation or government action, including related to product liability claims; changes to applicable laws and regulations and other requirements imposed by stakeholders; challenges to intellectual property; changes in behavior and spending patterns of consumers; natural disasters, acts of war or terrorism, catastrophes, or epidemics, pandemics, or other disease outbreaks; and financial instability of international economies and legal systems and sovereign risk. A further list and descriptions of these risks, uncertainties and other factors can be found in Kenvue’s filings with the Securities and Exchange Commission, including its registration statement on Form S-1 and subsequent Quarterly Reports on Form 10-Q and other filings, available at or on request from Kenvue. Any forward-looking statement made in this release speaks only as of the date of this release. Kenvue undertakes no obligation to update any forward-looking statements, whether as a result of new information, future events or developments or otherwise. Kenvue Inc. Condensed Consolidated Statement of Operations (Unaudited; Millions Except Per Share Data) Fiscal Three Months Ended Fiscal Twelve Months Ended December 31, 2023 January 1, 2023 December 31, 2023 January 1, 2023 Net sales $ 3,666 $ 3,767 $ 15,444 $ 14,950 Cost of sales 1,623 1,721 6,801 6,665 Gross profit 2,043 2,046 8,643 8,285 Selling, general and administrative expenses 1,586 1,532 6,141 5,633 Other operating income, net (3 ) (17 ) (10 ) (23 ) Operating income 460 531 2,512 2,675 Other expense, net 7 19 72 38 Interest expense, net 96 — 250 — Income before taxes 357 512 2,190 2,637 Provision for taxes 30 151 526 573 Net income $ 327 $ 361 $ 1,664 $ 2,064 Net income per share Basic $ 0.17 $ 0.21 $ 0.90 $ 1.20 Diluted $ 0.17 $ 0.21 0.90 $ 1.20 Weighted average common stock Basic 1,915 1,716 1,846 1,716 Diluted 1,919 1,716 1,850 1,716 Non-GAAP Financial Information Organic Growth The following tables present a reconciliation of the change in Net sales, as reported, to Organic growth for the periods presented: Fiscal Three Months Ended December 31, 2023 vs January 1, 2023(1) Reported Net Sales change Impact of foreign currency Organic growth(2) (Unaudited; Dollars in Millions) Amount Percent Amount Amount Percent Self Care $ (31 ) (2.0 )% $ — $ (31 ) (2.0 )% Skin Health and Beauty (87 ) (8.0 ) — (87 ) (8.0 ) Essential Health 17 1.5 (11 ) 28 2.5 Total $ (101 ) (2.7 )% $ (11 ) $ (90 ) (2.4 )% Fiscal Three Months Ended December 31, 2023 vs January 1, 2023(1) (Unaudited) Reported Net Sales change Impact of foreign currency Organic growth(2) Price/Mix(3) Volume Self Care (2.0 )% — % 4.3 % (6.3 )% Skin Health and Beauty (8.0 ) — 4.8 (12.8 ) Essential Health 1.5 (1.0 ) 8.8 (6.3 ) Total (2.7 )% (0.3 )% 5.8 % (8.2 )% Fiscal Three Months Ended January 1, 2023 vs January 2, 2022(1) Reported Net Sales change Impact of foreign currency Organic growth(2) (Unaudited; Dollars in Millions) Amount Percent Amount Amount Percent Self Care $ 120 8.3 % $ (73 ) $ 193 13.3 % Skin Health and Beauty 4 0.4 (54 ) 58 5.4 Essential Health (90 ) (7.5 ) (71 ) (19 ) (1.6 ) Total $ 34 0.9 % $ (198 ) $ 232 6.2 % Fiscal Three Months Ended January 1, 2023 vs January 2, 2022(1) (Unaudited) Reported Net Sales change Impact of foreign currency Organic growth(2) Price/Mix(3) Volume Self Care 8.3 % (5.0 )% 8.3 % 5.0 % Skin Health and Beauty 0.4 (5.0 ) 3.7 1.7 Essential Health (7.5 ) (5.9 ) 7.2 (8.8 ) Total 0.9 % (5.3 )% 6.6 % (0.4 )% Fiscal Twelve Months Ended December 31, 2023 vs January 1, 2023(1) Reported Net Sales change Impact of foreign currency Organic growth(2) (Unaudited; Dollars in Millions) Amount Percent Amount Amount Percent Self Care $ 421 7.0 % $ (84 ) $ 505 8.4 % Skin Health and Beauty 28 0.6 (52 ) 80 1.8 Essential Health 45 1.0 (117 ) 162 3.6 Total $ 494 3.3 % $ (253 ) $ 747 5.0 % Fiscal Twelve Months Ended December 31, 2023 vs January 1, 2023(1) (Unaudited) Reported Net Sales change Impact of foreign currency Organic growth(2) Price/Mix(3) Volume Self Care 7.0 % (1.4 )% 7.1 % 1.3 % Skin Health and Beauty 0.6 (1.2 ) 6.6 (4.8 ) Essential Health 1.0 (2.6 ) 9.6 (6.0 ) Total 3.3 % (1.7 )% 7.7 % (2.7 )% Fiscal Twelve Months Ended January 1, 2023 vs January 2, 2022 Reported Net Sales change Impact of foreign currency Acquisitions and divestitures Organic growth(2) (Unaudited; Dollars in Millions) Amount Percent Amount Amount Amount Percent Self Care $ 387 6.9 % $ (226 ) $ — $ 613 10.9 % Skin Health and Beauty (191 ) (4.2 ) (173 ) (39 ) 21 0.5 Essential Health (300 ) (6.2 ) (218 ) (14 ) (68 ) (1.4 ) Total $ (104 ) (0.7 )% $ (617 ) $ (53 ) $ 566 3.8 % Fiscal Twelve Months Ended January 1, 2023 vs January 2, 2022 (Unaudited) Reported Net Sales change Impact of foreign currency Acquisitions and divestitures Organic growth(2) Price/Mix(3) Volume Self Care 6.9 % (4.0 )% — % 4.2 % 6.7 % Skin Health and Beauty (4.2 ) (3.8 ) (0.9 ) 2.8 (2.3 ) Essential Health (6.2 ) (4.5 ) (0.3 ) 4.8 (6.2 ) Total (0.7 )% (4.1 )% (0.4 )% 4.0 % (0.2 )% (1) Acquisitions and divestitures did not materially impact the reported Net sales change. (2) Non-GAAP financial measure. Excludes the impact of foreign currency exchange and the impact of Acquisitions and divestitures. (3) Price/Mix reflects value realization. Full Year Organic Growth by Segment Self Care: Organic growth of 8.4% was comprised of 7.1% value realization and 1.3% volume growth. Self Care had another strong year of performance with all product categories growing mid-single digits to low double digits, and healthy growth across all regions. Innovation, supply recovery and brand activation across product categories and brands such as Motrin®, Tylenol®, Nicorette®, and Imodium® fueled growth for the segment and created expanded opportunities for our consumers to take care of their health. Skin Health and Beauty: Organic growth increased 1.8%, comprised of 6.6% value realization, partially offset by 4.8% volume declines. Sun Care had robust growth across key markets in full year 2023, growing share from successful innovation launches and strong in store presence. This was offset by underperformance in commercial U.S. in-store execution, particularly in the fourth quarter. Essential Health: Organic growth of 3.6% was comprised of 9.6% value realization, partially offset by 6.0% volume decrease. Value realization and strong performance in Oral Care driven by product innovation such as Listerine® Gum Therapy and clinical claims resulting in increased healthcare professional endorsements. Women’s Health growth in the year was led by value realization and brand activation. Total Segment Net Sales and Adjusted Operating Income Segment Net sales and Adjusted operating income for the periods presented were as follows: Net Sales Net Sales Fiscal Three Months Ended Fiscal Twelve Months Ended (Unaudited; Dollars in Millions) December 31, 2023 January 1, 2023 December 31, 2023 January 1, 2023 Self Care $ 1,537 $ 1,568 $ 6,451 $ 6,030 Skin Health and Beauty 1,001 1,088 4,378 4,350 Essential Health 1,128 1,111 4,615 4,570 Total segment net sales $ 3,666 $ 3,767 $ 15,444 $ 14,950 Adjusted Operating Income Adjusted Operating Income Fiscal Three Months Ended Fiscal Twelve Months Ended (Unaudited; Dollars in Millions) December 31, 2023 January 1, 2023 December 31, 2023 January 1, 2023 Self Care Adjusted operating income $ 558 $ 534 $ 2,299 $ 2,088 Skin Health and Beauty Adjusted operating income 162 92 679 708 Essential Health Adjusted operating income 241 290 1,011 1,111 Total $ 961 $ 916 $ 3,989 $ 3,907 Depreciation (94 ) (83 ) (305 ) (296 ) General corporate/unallocated expenses (77 ) (101 ) (296 ) (298 ) Other operating income, net 3 17 10 23 Other - impact of deferred markets(1) 1 — 34 — Litigation expense 5 — 25 — Impairment of intangible assets — — — 12 Adjusted operating income (non-GAAP) $ 799 $ 749 $ 3,457 $ 3,348 Reconciliation to Income before taxes: Amortization 80 83 322 348 Separation-related costs(2) 135 104 468 213 Operating model optimization initiatives and restructuring expense 29 31 32 100 Conversion of stock-based awards 80 — 55 — Other - impact of deferred markets(1) 1 — 34 — Litigation expense 5 — 25 — Founders stock-based awards 9 — 9 — Impairment of intangible assets — — — 12 Operating income $ 460 $ 531 $ 2,512 $ 2,675 Other expense, net 7 19 72 38 Interest expense, net 96 — 250 — Income before taxes $ 357 $ 512 $ 2,190 $ 2,637 (1) Includes tax expense and minority interest expense related to Deferred Markets recognized within Other operating income, net, which are payable to Johnson & Johnson through interim related-party agreements until these Deferred Markets can be transferred to the Company. Deferred Markets are local businesses in certain non-U.S. jurisdictions in which the transfer from Johnson & Johnson of certain assets and liabilities were deferred in order to ensure compliance with applicable law, to obtain necessary governmental approvals and other consents and for other business reasons. (2) Costs incurred in connection with our establishment as a standalone public company are defined as “Separation-related costs.” The following tables present reconciliations of GAAP to Non-GAAP for the periods presented: Fiscal Three Months Ended December 31, 2023 (Unaudited; Dollars in Millions) As Reported Adjustments Reference As Adjusted Net sales $ 3,666 $ — $ 3,666 Gross profit $ 2,043 $ 139 (a),(b),(c),(d) $ 2,182 Gross profit margin 55.7 % 59.5 % Operating income $ 460 $ 339 (a)-(j) $ 799 Operating income margin 12.5 % 21.8 % Net Income $ 327 $ 259 (a)-(h),(j-k) $ 586 Net income margin 8.9 % 16.0 % Interest expense, net $ 96 Provision for taxes $ 30 Depreciation and amortization $ 174 EBITDA (non-GAAP) $ 627 $ 259 (b)-(j) $ 886 EBITDA margin 17.1 % 24.2 % Detail of Adjustments (a) Amortization (COGS) $ 80 (b) Operating model optimization initiatives and restructuring expense (COGS) $ 20 (c) Conversion of stock-based awards (COGS) $ 35 (d) Founders stock-based awards (COGS) $ 4 (e) Separation-related costs (SG&A) $ 135 (f) Operating model optimization initiatives and restructuring expense (SG&A) $ 9 (g) Conversion of stock-based awards (SG&A) $ 45 (h) Founders stock-based awards (SG&A) $ 5 (i) Other - Impact of deferred markets (tax expense) (OOI&E) $ 1 (j) Litigation expense (OOI&E) $ 5 (k) Tax impact on special item adjustments $ (79 ) Fiscal Three Months Ended January 1, 2023 (Unaudited; Dollars in Millions) As Reported Adjustments Reference As Adjusted Net sales $ 3,767 $ — $ 3,767 Gross profit $ 2,046 $ 111 (a),(b) $ 2,157 Gross profit margin 54.3 % 57.3 % Operating income $ 531 $ 218 (a)-(d) $ 749 Operating income margin 14.1 % 19.9 % Net Income $ 361 $ 140 (a)-(e) $ 501 Net income margin 9.6 % 13.3 % Provision for taxes $ 151 Depreciation and amortization $ 166 EBITDA (non-GAAP) $ 678 $ 135 (b)-(d) $ 813 EBITDA margin 18.0 % 21.6 % Detail of Adjustments (a) Amortization (COGS) $ 83 (b) Operating model optimization initiatives and restructuring expense (COGS) $ 28 (c) Separation-related costs (SG&A) $ 104 (d) Operating model optimization initiatives and restructuring expense (SG&A) $ 3 (e) Tax impact on special item adjustments $ (78 ) Fiscal Twelve Months Ended December 31, 2023 (Unaudited; Dollars in Millions) As Reported Adjustments Reference As Adjusted Net sales $ 15,444 $ — $ 15,444 Gross profit $ 8,643 $ 375 (a),(b),(c),(d) $ 9,018 Gross profit margin 56.0 % 58.4 % Operating income $ 2,512 $ 945 (a)-(k) $ 3,457 Operating income margin 16.3 % 22.4 % Net Income $ 1,664 $ 719 (a)-(i),(k)-(n) $ 2,383 Net income margin 10.8 % 15.4 % Interest expense, net $ 250 Provision for taxes $ 526 Depreciation and amortization $ 627 EBITDA (non-GAAP) $ 3,067 $ 630 (b)-(l) $ 3,697 EBITDA margin 19.9 % 23.9 % Detail of Adjustments (a) Amortization (COGS) $ 322 (b) Operating model optimization initiatives and restructuring expense (COGS) $ 21 (c) Conversion of stock-based awards (COGS) $ 28 (d) Founders stock-based awards (COGS) $ 4 (e) Separation-related costs (SG&A) $ 468 (f) Operating model optimization initiatives and restructuring expense (SG&A) $ 11 (g) Conversion of stock-based awards (SG&A) $ 27 (h) Founders stock-based awards (SG&A) $ 5 (i) Other - Impact of deferred markets (minority interest expense) (OOI&E) $ 10 (j) Other - Impact of deferred markets (tax expense) (OOI&E) $ 24 (k) Litigation expense (OOI&E) $ 25 (l) Unrealized gain on securities (OI&E) $ 7 (m) Interest income from related party note (Interest expense, net) $ (33 ) (n) Tax impact on special item adjustments $ (176 ) Fiscal Twelve Months Ended January 1, 2023 (Unaudited; Dollars in Millions) As Reported Adjustments Reference As Adjusted Net sales $ 14,950 $ — $ 14,950 Gross profit $ 8,285 $ 403 (a),(b) $ 8,688 Gross profit margin 55.4 % 58.1 % Operating income $ 2,675 $ 673 (a)-(e) $ 3,348 Operating income margin 17.9 % 22.4 % Net Income $ 2,064 $ 456 (a)-(f) $ 2,520 Net income margin 13.8 % 16.9 % Provision for taxes $ 573 Depreciation and amortization $ 644 EBITDA (non-GAAP) $ 3,281 $ 325 (b)-(e) $ 3,606 EBITDA margin 21.9 % 24.1 % Detail of Adjustments (a) Amortization (COGS) $ 348 (b) Operating model optimization initiatives and restructuring expense (COGS) $ 55 (c) Separation-related costs (SG&A) $ 213 (d) Operating model optimization initiatives and restructuring expense (SG&A) $ 45 (e) Impairment of intangible assets (OOI&E) $ 12 (f) Tax impact on special item adjustments $ (217 ) The following table presents a reconciliation of Interest expense, net, as reported, to Adjusted interest expense, net: Fiscal Twelve Months Ended (Unaudited; Dollars in Millions) December 31, 2023 Interest expense, net $ 250 Adjustment: Interest income from related party note (33 ) Adjusted interest expense, net (non-GAAP) $ 283 The following tables present reconciliations of the Effective tax rate, as reported, to Adjusted effective tax rate for the periods presented: Fiscal Three Months Ended Fiscal Twelve Months Ended (Unaudited) December 31, 2023 January 1, 2023 December 31, 2023 January 1, 2023 Effective tax rate 8.4 % 29.5 % 24.0 % 21.7 % Adjustments: Tax-effect on special item adjustments 7.9 1.3 (1.0 ) 1.6 Removal of tax benefits from carve out methodology — — 2.0 — Taxes related to Deferred Markets 0.5 — 0.5 — Valuation allowance on foreign tax credits due to interest expense (0.6 ) — (2.4 ) — Other (0.4 ) 0.6 0.3 0.6 Adjusted Effective tax rate (non-GAAP) 15.8 % 31.4 % 23.4 % 23.9 % The following table presents a reconciliation of Effective tax rate, as forecasted on a U.S. GAAP basis, to forecasted Adjusted effective tax rate for fiscal year 2024: Fiscal Year 2024 (Unaudited) Forecast Effective tax rate 26.5% - 27.5% Adjustments: Tax-effect on special item adjustments (1.2 ) Taxes related to Deferred Markets 0.5 Other (0.3 ) Adjusted Effective tax rate (non-GAAP) 25.5% - 26.5% The following table presents a reconciliation of Diluted earnings per share, as reported, to Adjusted diluted earnings per share: Fiscal Three Months Ended Fiscal Twelve Months Ended (Unaudited) December 31, 2023 December 31, 2023 Diluted earnings per share $ 0.17 $ 0.90 Adjustments: Separation-related costs 0.07 0.25 Operating model optimization initiatives and restructuring expense 0.02 0.02 Amortization and impairment of intangible assets 0.04 0.17 Conversion of stock-based awards 0.04 0.03 Interest income from related party note — (0.02 ) Tax impact on special item adjustments (0.04 ) (0.10 ) Other 0.01 0.04 Adjusted diluted earnings per share (non-GAAP) $ 0.31 $ 1.29 The following table presents a reconciliation of Net cash flows from operating activities, as reported, and Purchases of property, plant, and equipment, as reported, to Free cash flow: Fiscal Twelve Months Ended (Unaudited; Dollars in Billions) December 31, 2023 Net cash flows from operating activities $ 3.2 Purchases of property, plant, and equipment (0.5 ) Free cash flow (non-GAAP) $ 2.7 Other Supplemental Financial Information The following table presents the Company’s Net sales by Geographic Region for the periods presented: Fiscal Three Months Ended Fiscal Twelve Months Ended (Unaudited; Dollars in Millions) December 31, 2023 January 1, 2023 December 31, 2023 January 1, 2023 Net sales by geographic region North America $ 1,762 $ 1,906 $ 7,610 $ 7,418 Europe, Middle East and Africa 822 796 3,388 3,188 Latin America 332 310 1,339 1,198 Asia Pacific 750 755 3,107 3,146 Total Net sales by geographic region $ 3,666 $ 3,767 $ 15,444 $ 14,950 The following table presents the Company’s Cash and cash equivalents, Total debt and Net debt balance as of December 31, 2023: (Unaudited; Dollars in Billions) December 31, 2023 Cash and cash equivalents $ 1.4 Total debt 8.3 Net debt $ 6.9