Clofazimine

抗生素与多重耐药性：我们需要新的抗生素吗？作者：Marc Maury，UNITHER制药公司科学总监翻译自《PHARMAnetwork》杂志第64期近年来，新闻报道多次强调了多重耐药细菌对公共卫生的巨大威胁，这些文章或会议论文均指出新型抗生素的发现速度缓慢，并通过两条曲线来展示新发现的抗生素数量与出现超级耐药细菌病例之间的尖锐对比。这两条曲线的交叉预示着严重的公共卫生问题，但这种令人担忧的情况需要放在更全面的背景下来分析，因为旧的抗生素仍然存在，并且抗生素的数量并没有减少。更科学的比较曲线应该使用所有可用的抗生素，而不仅仅是新的抗生素。尽管如此，我们仍旧有必要对这一主题进行盘点，从而评估抗生素耐药性对公共卫生的影响以及如何加以解决。要做到这一点，就必须了解这些多重耐药病原体出现的机制。可用性问题在实际生活中，如果仔细观察药房货架上可用的抗生素数量，就必须承认尽管偶尔有新的活性成分加入（但这种情况越来越少），抗生素的种类每年都在减少。实际上，许多抗生素的停用并非因为毒性问题或缺乏疗效，而是由于常见的盈利性问题。随着标准的变化，以及抗生素相较于慢性病药物价格低廉且销量有限，继续将其保留在市场上已不具备经济可行性。例如，硫氨苄青霉素（thioamphenicol）虽仍具临床治疗价值，但法国已停止供应；氯法齐明（clofazimine）原用于麻风病治疗，尽管其针对结核病可能具有显著疗效（因两种病原体存在高度相似性），但该药物同样在法国退市。多重耐药细菌的起源当多重耐药细菌出现时，人们会进行仔细调查、确定其来源并防止其扩散。细菌基因组分析方法的进步，以及诸如基质辅助激光解吸电离飞行时间质谱（MALDI-TOF）、聚合酶链式反应（PCR）和其他高通量测序技术的普及，使得研究深度和广度得以实现。古微生物学是理解抗生素耐药性的关键随着生物信息学的进步，研究古代沉积物或化石中许多细菌的基因组成为可能，这些技术甚至促成了微生物学研究新分支的诞生。古微生物学的一个重大发现是，在数千年历史的化石生物中找到了对现代抗生素具有耐药性的病原体，换言之，在人类使用抗生素之前，耐药基因就已经存在了。耐药性在抗生素的医学使用之前就已经存在。事实上，大多数人已经忘记了抗生素的真正起源及其作用。自地球上生命诞生以来，生物之间就一直在进行着生存竞争。在地质时间尺度上，真菌/酵母菌和细菌之间逐渐建立起了丰富的防御/攻击机制。实际上，目前使用的许多抗生素是从酵母或各种青霉菌中提取而来。通常，产生这些有毒成分的生物体必须有自己的防御系统，以避免自我杀伤。最著名的例子当属亚胺培南，它是一种由细菌产生的抗生素，具有高度活性，可以杀死宿主。这样一来，宿主菌存在并产生一种解毒剂以避免死亡。这种毒素-抗毒素系统在微生物群落中相当普遍。多重耐药细菌出现的主要原因是抗生素的医学使用导致了这些耐药能力的出现，并且大多数抗生素耐药基因在抗生素被分离之前就已经存在于自然界中。抗生素施加的选择压力使得耐药菌株通过消灭非耐药细菌而出现，亦即：通过基因转移机制，当一个耐药基因被选择时，它可以以一种不受控制的方式传播。埃博拉病毒的再次出现这个话题并不直接涉及多重耐药细菌的问题，但埃博拉病毒在非洲的周期性肆虐引发了诸多流行病学问题。人们做了大量工作来研究这种病毒的流行再次出现的原因，并且这些研究结果适用于解释多重耐药细菌的案例。病毒的宿主早就被确定为树栖蝙蝠，研究人员注意到流行病爆发系统地出现在森林砍伐行动后的两年。事实上，非洲的流行病学已经明白，森林砍伐后生态系统受到严重的破坏，蝙蝠在当地找不到食物，导致蝙蝠群落的四处传播，从而增加了蝙蝠与人类的接触，创造了新的污染源。大猩猩和白蚁尽管从未接受过抗生素治疗，大猩猩常携带多重耐药的肺炎克雷伯菌，经过调查发现这种耐药性来自它们食用的白蚁。白蚁在蚁丘中培养分解纤维素的真菌，这种行为持续了数百万年。在蚁丘中，数百万只跳虫 ”自然地” 分泌多种抗生素，包括青霉素和头孢菌素。在此情形下，蚁丘实际上对肺炎克雷伯菌施加了选择压力，筛选出了多重耐药细菌，而这些细菌随后被白蚁和大猩猩食用，有时也被人类食用。在非洲的一些村庄，“白蚁丘汤”是一种治疗扁桃体炎的传统偏方，因为白蚁丘提取物具有抗生素特性。这些例子表明，生态系统的破坏是新发多重耐药菌株传播的关键因素，即通过直接感染或预先存在的抗性基因对公共卫生造成威胁。集约化农业尽集约化农业实践中使用大量抗生素来避免病原菌感染，这也是多重耐药性问题的一个驱动因素。在许多国家，抗生素还被用作生长促进剂。万古霉素是治疗耐药感染的首选抗生素之一，但在人群中很快出现广泛的耐药性。事实上，一些耐药菌株是在使用阿伏霉素的火鸡养殖场中被分离出来的，而使用的原因是阿伏霉素可以使得火鸡体重增加30%。诸如此类的抗生素滥用间接导致了许多人类泌尿道感染的肠球菌耐药性问题，这些菌株对万古霉素均具有耐药性。多重耐药细菌在遇到 “可征服的” 环境时就会发展、壮大，停止使用阿伏霉素有助于减少对万古霉素的耐药性。实际上，两种抗生素在集约化农业中的使用量比在人类医疗中的用量高出好几个数量级。农药问题许多农药和除草剂具备抗生素特性，备受争议的草甘膦就是一个典型的例子。在其开发过程中，孟山都公司将草甘膦作为抗生素用途申请了专利。全球范围内使用千吨级草甘膦会摧毁农业用地的微小动物群落，并在土壤中施加巨大的选择压力，这将导致耐药菌株的出现。如何应对通过更好地理解多重耐药细菌的起源和动态，从而制定降低其出现风险的策略。我们需要认识到，耐药性基因并非由抗生素“产生”，而是被抗生素 “选择” 出来的。减轻选择压力为了避免多重耐药细菌的出现，必须对最重要的源头采取行动。在现代农业方面，我们必须重新思考其流程，大幅减少抗生素及具有抗生素特性的除草剂和农药的使用。了解耐药基因的动态多重耐药细菌在遇到 “生态真空” 时就会发展、壮大。譬如，当患者使用不合适、无获益的抗生素时，会破坏患者大部分的微生物群落，从而为耐药细菌留下发展空间，使其能够增加繁殖和致病的能力。在低收入国家，无症状患者的粪便中发现难缠的艰难梭菌并不少见；而在西方国家，该病原菌感染患者有相当高的死亡率。在众多细菌竞争的环境中，多重耐药病原体无法自由发展，数量保持在较低水平。多重耐药基因的生命周期当细菌的耐药性基因不再具有生存竞争优势时，它们可能会在连续的世代和突变中失去这个基因。因此，业已成为多重耐药菌可能会再次对某些抗生素敏感，这个 “参数" 很可能是调节流行病周期性的一个机制。优化剂量如何更有效地使用现有抗生素也是一个重要的研究领域。为了匹配最佳抗生素，对患者进行标准化抗菌谱检测是诊疗的一个标准。事实上，我们离个性化医疗还很远，大多数抗生素都是通过最小有效剂量来定义的，但对于特定抗生素则很少有针对特定患者感染的特定菌株的有效使用剂量数据。有时候改变剂量或治疗方案可以让病原菌的耐药性消失，意味着快捷的微生物学技术有助于我们在未来实施个性化治疗。总结超级耐药细菌对全球公共卫生构成重大风险，仅依靠研发新抗生素来制定反制策略同时也是不可接受的风险。我们应该尝试具有科学意义的、有效的措施，首先即要确定超级耐药细菌出现的根源。本文引用的所有例子都表明，研发新型抗生素并不是避免某些多重耐药细菌出现和引发流行病灾难的唯一解决方案。首先，也是紧急的措施，即大幅减少抗生素在畜牧业中用于生长因子或预防感染的惯例。巨量使用的抗生素不可避免地导致新的多重耐药菌株出现。另外，还有必要大幅减少具有抗生素活性的植物保护产品。事实上，这些产品中有很大一部分确实具有抗生素活性。这样做可以有两个直接的收益：●降低在畜牧场出现超级耐药细菌的风险；●由减产带来的抗生素生产厂的污染。由于这些抗生素工厂的反污染标准充其量是 “随机的”，意味着因大量排放废物从而引发超级耐药细菌风险较高； 显然，实施这两个策略需要彻底审查许多国家的农业模式，否则迟早会面临不易控制的流行性疾病爆发。我们必须控制这些超级细菌的出现，避免任何大规模的疫病流行，世界上大多数卫生系统已经采用了值得绝对保留和优化的良好实践。另一个显而易见的步骤，乃是重新学习如何通过优化抗生素剂量和实施有临床获益的治疗方案。我们需要充分利用这些在过去提供了巨大价值的“老的”化合物分子，优化其药代动力学和药效学特性。重新审视 “老” 的抗生素和曾经使用过的化合物（有色的衍生物），通过研究合理剂量、优化药代动力学以及不同抗生素联用或与相关耐药性酶的抑制剂进行组合来制定有效措施，这是至关重要的一环。近年来生物学基础研究的飞速发展，我们期待其开辟广阔的研究领域和提供新型解决方案。微生物多样性对人类有益的研究已经广为人知，我们必须认真考虑从“好细菌”那里获得帮助的可能性。这可能看起来违反公众的直觉，但在受到病原菌感染的情况下，人们完全可以考虑用活细菌 “鸡尾酒” 来对抗耐药细菌。这些 “鸡尾酒” 的成员在人体微生物群落中处于共生关系，如此可以避免让致病性细菌占据上风。同样，重新定义噬菌体是一个很有趣、前沿的治疗思路，它们在某些情况下对特定病原体十分有效。基因组分析的发展使得定义噬菌体 “鸡尾酒” 成为可能，在未来我们完全可以考虑发展相应的个性化医疗。最后，当然，我们必须继续努力寻找和研发新型抗生素。生物之间的斗争广泛存在于整个生命世界，它产生了丰富多样的剑和盾来保卫我们。通过广泛的寻觅，我们终会找到新的物质来增加抵抗病原菌的治疗武器库，而真正重要的是，我们需要在这些剑盾的普遍化并导致流行病之前找到正确的那一个，这是未来若干年的巨大挑战。文章来源● Do we need new antibiotics. 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Keita1, Jean-Christophe Lagier1, Martine Peeters2, Eric Delaporte2 & Didier Raoult1. SCIENTIFIC REPORTS 11/2014 | 4 : 7174● Antimicrobial resistant enteric bacteria are widely distributed amongst people, animals and the environment in Tanzania. Murugan Subbiah1,7, Mark A. Caudell1,2,7*, Colette Mair3,7, Margaret A. Davis1, Louise Matthews, Robert J. Quinla, Marsha B. Quinlan, Beatus Lyimo, Joram Buz, Julius Keyyu & Douglas R. Call. Nature communication (2020)11:228● The nexus between forest fragmentation in Africa and Ebola virus disease outbreaks. Maria Cristina Rulli, Monia Santini, David T S Hayman & Paolo D'Odorico. Scientific Reports 2017 | 7:41613● Enquête sur les usines d’antibiotiques indiennes, fabriques d’antibiorésistance. Le monde 11 décembre 2018● En Inde, la recette parfaite pour faire émerger des superbactéries. Le monde 10 décembre 2018● L’utilisation au Canada d’antimicrobiens chez les animaux destinés à l’alimentation : les conséquences pour la résistance et la santé humaine. Direction des médicaments vétérinaire du canada juin 2002. Diffusion du Rapport final du Comité consultatif d'experts sur l'utilisation d'antimicrobiens chez les animaux et les conséquences pour la résistance et la santé humaine - Canada.ca优尼特尔制药（Unither Pharmaceuticals）优尼特尔制药是一家全球领先的合同制药制造商，专注于液体剂型的开发与生产，包括无菌单剂量与多剂量眼药水、生理盐水、哮喘药物BFS单剂量包装以及口服液条剂。集团在法国、美国、巴西和中国共设有八家生产基地，并拥有一座研发中心，全球员工总数达2300人。2024年集团实现营业收入达5.22亿欧元。联系我们以获取更多信息!优尼特尔制药Single Best Way to Deliver

Conference call to provide corporate updates today at 9:00 am ET 1Q 2025 revenues of $78M, +18% v. 1Q 20241Q 2025 net income of $13M, + 24% v. 1Q 20241Q 2025 non-GAAP net income of $22M, +43% v. 1Q 2024Advanced pipeline: Expect to submit sBLA for Afrezza® in pediatric patients in mid-2025MNKD-101: NTM global Phase 3 trial enrollment on track for interim analysisMNKD-201: Expect to continue to next phase of global development in 2H 2025 DANBURY, Conn. and WESTLAKE VILLAGE, Calif., May 08, 2025 (GLOBE NEWSWIRE) -- MannKind Corporation (Nasdaq: MNKD) today reported financial results for the first quarter 2025 and provided a business update. “The first quarter was marked by strong year-over-year NRx growth in Afrezza, substantial Tyvaso DPI-related revenues and continued progress in our Phase 3 trial of MNKD-101 (clofazimine inhalation suspension) in NTM lung disease,” said Michael Castagna, PharmD, Chief Executive Officer of MannKind Corporation. “We expect to file for approval of Afrezza in the pediatric population this summer and to continue developing our MNKD-201 (nintedanib DPI) program in IPF.” 1Q 2025 Business Update and Upcoming Milestones Afrezza INHALE-1 Pediatric Phase 3 clinical trial Met with the FDA to obtain guidance on a supplemental Biologics License Application (sBLA) for the pediatric population expected to be filed in mid-2025Topline results from the full study pediatric data set with the safety extension expected in 2Q 2025 Clofazimine Inhalation Suspension (MNKD-101) Phase 3 global clinical trial (ICON-1) 85% of anticipated sites have been activated in five countries (U.S., Japan, Australia, South Korea, Taiwan)55 patients randomized in four countries (U.S., Japan, Australia, South Korea)Expect to meet the interim enrollment target of 100 patients by YE 2025 Nintedanib DPI (MNKD-201) Planning to advance into the next phase of global development in 2H 2025 Endocrine Business Unit Afrezza INHALE-3 Phase 4 30-week data published in two articles in Diabetes Technology & TherapeuticsLabel application to update initial Afrezza conversion dose submitted to FDA; currently under reviewAfrezza performance 1Q 2025 compared to 1Q 2024: 20% NRx growth; 14% TRx growth Corporate and Financial Cash, cash equivalents and investments as of March 31, 2025 totaled $198 millionMajority of revenue and future pipeline programs are derived from MannKind's U.S.-based manufacturing facility in Danbury, CT, mitigating potential tariff exposure First Quarter 2025 Financial Results Revenues Three MonthsEnded March 31, 2025 2024 $ Change % Change Revenues (Dollars in thousands) Royalties $30,005 $22,651 $7,354 32%Collaborations and services 29,376 24,848 $4,528 18%Afrezza 14,887 14,438 $449 3%V-Go 4,086 4,326 $(240) (6%)Total revenues $78,354 $66,263 $12,091 18% Total revenues increased $12.0 million, or 18%, in the first quarter of 2025 compared to the same period in the prior year. Revenue increases were driven by higher royalties primarily due to increased patient demand for Tyvaso DPI® and higher revenue from collaborations and services due to increased product sold to United Therapeutics Corporation. Commercial product revenue remained consistent with the prior year period due to an increase in net revenue for Afrezza, mainly due to higher demand and price, partially offset by a decrease in net revenue for V-Go® due to lower demand. Operating Expenses and Other Financial Highlights Research and development expenses were $11.0 million for the first quarter of 2025 compared to $10.0 million for the same period in 2024, an increase of 10%. The increase was primarily attributable to increased expenditures for development activities, including a Phase 3 clinical study for MNKD-101, clinical production scale up for MNKD-201, and personnel costs primarily due to additional headcount as a result of MannKind's transaction with Pulmatrix, Inc. in the third quarter of 2024, which bolstered our research capabilities and capacity.Selling, general and administrative expenses were $25.0 million for the first quarter of 2025 compared to $22.3 million for the same period in 2024, an increase of 12%. This increase was primarily attributable to increases in headcount, personnel costs and Afrezza promotional costs, partially offset by a loss of $1.2 million in the prior year period for estimated returns associated with sales of V-Go that pre-dated MannKind's acquisition of the product.For the first quarter of 2025, MannKind reported net income of $13.2 million, or $0.04 earnings per share – basic, compared to net income of $10.6 million, or $0.04 earnings per share – basic, for the same period in 2024, an increase in net income of $2.5 million, or 24%.For the first quarter of 2025, MannKind reported non-GAAP net income of $21.6 million, or $0.07 earnings per share – basic, compared to non-GAAP net income of $15.1 million, or $0.06 earnings per share – basic, for the same period in 2024, an increase in net income of $6.5 million, or 43%. For a reconciliation of GAAP reported net income and net income per share for basic weighted average shares to these non-GAAP measures, please see Non-GAAP Measures below. Conference Call MannKind will host a conference call and presentation webcast to discuss these results today at 9:00 a.m. Eastern Time. The webcast will be accessible via a link on MannKind’s website. A replay will also be available in the same location within 24 hours after the call and accessible for approximately 90 days. About MannKind MannKind Corporation (Nasdaq: MNKD) focuses on the development and commercialization of innovative inhaled therapeutic products and devices to address serious unmet medical needs for those living with endocrine and orphan lung diseases. We are committed to using our formulation capabilities and device engineering prowess to lessen the burden of diseases such as diabetes, nontuberculous mycobacterial (NTM) lung disease, pulmonary fibrosis, and pulmonary hypertension. Our signature technologies – dry-powder formulations and inhalation devices – offer rapid and convenient delivery of medicines to the deep lung where they can exert an effect locally or enter the systemic circulation, depending on the target indication. With a passionate team of Mannitarians collaborating nationwide, we are on a mission to give people control of their health and the freedom to live life. Please visit mannkindcorp.com to learn more, and follow us on LinkedIn, Facebook, X or Instagram. Forward-Looking Statements Statements in this press release that are not statements of historical fact are forward-looking statements that involve risks and uncertainties. These statements include, without limitation, statements regarding MannKind's expectations about the development of Afrezza for the pediatric population, MNKD-101 and MNKD-201, including the expected timing for regulatory filings and patient enrollment timelines. Words such as “believes,” “anticipates,” “plans,” “expects,” “intend,” “will,” “goal,” “potential” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon MannKind’s current expectations. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks associated with developing product candidates; risks and uncertainties related to unforeseen delays that may impact the timing of clinical trials and reporting data; risks associated with the regulatory review process; and other risks detailed in MannKind’s filings with the Securities and Exchange Commission (“SEC”), including under the “Risk Factors” heading of its Annual Report on Form 10-K for the year ended December 31, 2024, filed with the SEC on February 26, 2025, as updated by the "Risk Factors" in its Quarterly Report on Form 10-Q for the quarterly period ended March 31, 2025, being filed with the SEC later today. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this press release. All forward-looking statements are qualified in their entirety by this cautionary statement, and MannKind undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this press release. Tyvaso DPI is a trademark of United Therapeutics Corporation. AFREZZA, MANNKIND, and V-GO are registered trademarks of MannKind Corporation. MANNKIND CORPORATION AND SUBSIDIARIESCONSOLIDATED STATEMENTS OF OPERATIONS Three MonthsEnded March 31, 2025 2024 (In thousands except per share data) Revenues: Commercial product sales $18,973 $18,764 Collaborations and services 29,376 24,848 Royalties 30,005 22,651 Total revenues 78,354 66,263 Expenses: Cost of goods sold – commercial 3,768 3,819 Cost of revenue – collaborations and services 13,748 14,779 Research and development 11,022 10,013 Selling, general and administrative 25,014 22,329 Loss (gain) on foreign currency transaction 2,509 (1,399)Total expenses 56,061 49,541 Income from operations 22,293 16,722 Other income (expense): Interest income, net 1,956 3,434 Interest expense on liability for sale of future royalties (3,577) (4,248)Interest expense on financing liability (2,410) (2,447)Interest expense (4,645) (2,567)Total other expense (8,676) (5,828)Income before income tax expense 13,617 10,894 Income tax expense 459 264 Net income $13,158 $10,630 Net income per share – basic $0.04 $0.04 Weighted average shares used to compute net income per share – basic 303,481 270,356 Net income per share – diluted $0.04 $0.04 Weighted average shares used to compute net income per share – diluted 320,897 324,733 MANNKIND CORPORATION AND SUBSIDIARIESCONSOLIDATED BALANCE SHEETS March 31, 2025 December 31, 2024 (In thousands except share and per share data) ASSETS Current assets: Cash and cash equivalents $47,312 $46,339 Short-term investments 134,229 150,917 Accounts receivable, net 28,900 11,804 Inventory 28,892 27,886 Prepaid expenses and other current assets 34,404 31,360 Total current assets 273,737 268,306 Restricted cash 739 737 Long-term investments 16,681 5,482 Property and equipment, net 83,781 85,365 Goodwill 1,931 1,931 Other intangible assets 5,217 5,265 Other assets 28,055 26,757 Total assets $410,141 $393,843 LIABILITIES AND STOCKHOLDERS' DEFICIT Current liabilities: Accounts payable $5,041 $6,792 Accrued expenses and other current liabilities 40,103 40,293 Senior convertible notes – current 36,109 — Liability for sale of future royalties – current 12,802 12,283 Financing liability – current 10,125 10,062 Deferred revenue – current 11,757 12,407 Total current liabilities 115,937 81,837 Liability for sale of future royalties – long term 137,420 137,362 Financing liability – long term 93,665 93,877 Deferred revenue – long term 47,360 51,160 Recognized loss on purchase commitments – long term 60,713 58,204 Operating lease liability 11,141 11,645 Milestone liabilities 2,523 2,523 Senior convertible notes — 36,051 Total liabilities 468,759 472,659 Stockholders' deficit: Undesignated preferred stock, $0.01 par value – 10,000,000 shares authorized; no shares issued or outstanding as of March 31, 2025 or December 31, 2024 — — Common stock, $0.01 par value – 800,000,000 shares authorized; 303,918,969 and 302,959,782 shares issued and outstanding as of March 31, 2025 and December 31, 2024, respectively 3,039 3,029 Additional paid-in capital 3,125,830 3,118,865 Accumulated other comprehensive income 1,174 1,109 Accumulated deficit (3,188,661) (3,201,819)Total stockholders' deficit (58,618) (78,816)Total liabilities and stockholders' deficit $410,141 $393,843 Non-GAAP MeasuresTo supplement MannKind's condensed consolidated financial statements presented under GAAP, we are presenting non-GAAP financial measures for net income and net income per share – basic. We are providing these non-GAAP financial measures, which are among the indicators management uses as a basis for evaluating our financial performance, to disclose additional information to facilitate the comparison of past and present operations. We believe that these non-GAAP financial measures, when considered together with our GAAP financial results, provide management and investors with an additional understanding of our business operating results, including underlying trends.These non-GAAP financial measures are not meant to be considered in isolation or as a substitute for comparable GAAP measures; should be read in conjunction with our condensed consolidated financial statements prepared in accordance with GAAP; have no standardized meaning prescribed by GAAP; and are not prepared under any comprehensive set of accounting rules or principles. In addition, from time to time in the future, there may be other items that we may exclude for purposes of our non-GAAP financial measures; and we may cease to exclude items that we have historically excluded for purposes of our non-GAAP financial measures. Likewise, we may determine to modify the nature of its adjustments to arrive at our non-GAAP financial measures. Because of the non-standardized definitions of non-GAAP financial measures, the non-GAAP financial measures as used by us in this Quarterly Report on Form 10-Q have limits in their usefulness to investors and may be calculated differently from, and therefore may not be directly comparable to, similarly titled measures used by other companies.The following table reconciles our financial measures for net income and net income per share ("EPS") for basic weighted average shares as reported in our condensed consolidated statements of operations to a non-GAAP presentation: Three Months Ended March 31, 2025 2024 Net Income Basic EPS Net Income Basic EPS (In thousands except per share data) GAAP reported net income$13,158 $0.04 $10,630 $0.04 Non-GAAP adjustments: Sold portion of royalty revenue (1) (3,000) (0.01) (2,265) (0.01)Interest expense on liability for sale of future royalties 3,577 0.01 4,248 0.03 Stock compensation 5,385 0.02 3,885 0.01 Loss (gain) on foreign currency transaction 2,509 0.01 (1,399) (0.01)Non-GAAP adjusted net income$21,629 $0.07 $15,099 $0.06 Weighted average shares used to compute net income per share – basic 303,481 270,356 _________________ (1)Represents the non-cash portion of the 1% royalty on net sales of Tyvaso DPI which is remitted to the royalty purchaser and recognized as royalties from collaborations in our consolidated statements of operations. MannKind Contacts: Investor Relations Ana Kapor (818) 661-5000 Email: ir@mnkd.com Media Relations Christie Iacangelo (818) 292-3500 Email: media@mnkd.com