NPRC

关注并星标CPHI制药在线 近日，Ascendis Pharma 披露了其在研疗法 TransCon CNP（navepegritide）于 ApproaCH 试验中的积极顶线数据情况。研究分析表明，该试验达成了主要终点，与安慰剂相比，TransCon CNP 显著提高了软骨发育不全儿童（年龄处于2 至11岁）患者的年化生长速度（AGV）。那韦培肽（navepegritide）属于一款长效的C 型利钠肽前药，被用于软骨发育不全的治疗。并且，此药已同时被美国食品和药品监督管理局以及欧盟委员会认定为孤儿药。 软骨发育不全属于人类最为常见的矮小症，是由编码成纤维细胞生长因子受体3(FGFR3)基因当中的一种常见致病突变所引发，这种突变会给骨骼生长的软骨内骨化过程带来影响。针对软骨发育不全发病机制的治疗手段始终是一项重大却尚未被满足的需求。针对 FGFR3基因变异的药物，当下仅有一款 CNP药物，即伏索利肽（Vosoritide)。C型利钠肽(CNP)在人体里自然存在，是骨骼生长的正向调控因子，是有效的软骨内骨化刺激物，能够和特定的受体相结合，启动能抑制过度活跃的 FGFR3通路的细胞内信号，进而阻止 FGFR3对软骨细胞造成干扰。 一、软骨发育不全（ACH）-先天性遗传性罕见骨病 骨发育不良属于先天性、遗传性的罕见病症，会对骨与软骨的组织结构及发育形成影响，为常染色体显性遗传病症。其在人群中的发病几率大概在 1/5000 至100,000之间，涵盖了与数以百计遗传缺陷相关的各种不同类型的骨和软骨发育不良，在临床上呈现的表型有差异，软骨发育不全（ACH）属于最为常见的类型，此外还包含假性软骨发育不良、多发骨骺发育不良（MED）、脊椎骨骺发育不良（SED）等等，其中的绝大多数已被全球范围内纳入罕见病的目录之中。 软骨发育不全（ACH）大概每17,000 至28,000名的活产婴儿中会有1 名出现（其中约20%是由父母遗传），我国的儿童软骨发育不全患儿大概有10000 人上下。儿童软骨发育不全也被称作胎儿型软骨营养障碍、软骨营养障碍性侏儒等，属于由于软骨内骨化存在缺陷所致的先天性发育异常情况，是一种儿童罕见病。软骨发育不全由成纤维细胞生长因子受体3(FGFR3)基因的功能增益突变所引发，属于常染色体显性遗传。FGFR3及其抑制性下游信号通路的激活会致使软骨内骨化的速度减缓。几乎所有软骨发育不全患者的 FGFR3 跨膜编码区均存在1138G→A(Gly380Arg)或者1138G→C(Gly380Arg)的致病突变。在过去的 20 年当中，针对这些致病突变下游通路的界定和认知为靶向治疗提供了基础。该疾病的特征为头部明显较大（大头畸形）、上臂较短（根状侏儒症）以及身材矮矮小小（女性的最终成人身高通常处于124cm 之间，男性则在132cm之间）。软骨发育不全通常不会致使智力受到损伤，倘若连接头颈部的骨头未对脑干或者上脊髓形成压迫，那么预期寿命和正常人接近。 软骨发育不全的最优治疗时机应当在生长板闭合之前进行用药，一旦错过这一生长发育的黄金时期，药物所能起到的帮助将会十分有限。 二、ApproaCH试验 鉴于CNP类似物在治疗软骨发育不全方面存在希望，Ascendis Pharma研发出了一种具有缓释且长效特性的 CNP（那韦培肽），期望能够为生长板提供更为平稳的CNP 水平。为此，他们把 CNP 和一种无活性的载体分子相联结，让 CNP避免被清除，并且有望延长其对于生长板发挥的作用。在完成动物机制验证研究之后，又在健康的成年男性中开展了 1期研究，结果表明这种长效的CNP 具备良好的耐受性，药代动力学特点契合每周给药一次的需求。 此次所公布的ApproaCH试验属于一项关键的双盲安慰剂对照试验，总计有 84名罹患软骨发育不全的儿童（年龄处于2 - 11 岁）参与进来，按照2 ：1 的比例被随机分配为接受每周一次的TransCon CNP或者安慰剂治疗。分析表明，试验达成了主要终点。在第52周的时候，接受TransCon CNP治疗的儿童（n =57）的最小二乘（LS）平均 AGV 为5.89厘米/年，然而安慰剂组（n =27）患者的 LS 平均AGV 为4.41 厘米/年，两组之间的 LS 平均差异是 1.49厘米/年（p<0.0001）。 进一步开展的亚组分析指出，接受TransCon CNP治疗的2 至5 岁儿童（n =21）在第 52周时的LS 平均 AGV 为6.07厘米/年，而安慰剂组（n =10）的LS 平均 AGV 为5.06厘米/年，LS 平均差异为 1.02厘米/年（p = 0.0084）。接受TransCon CNP治疗的5 - 11 岁儿童（n =36）在第 52周时的LS 平均 AGV 为5.79厘米/年，而安慰剂组（n =17）的LS 平均 AGV 为4.02厘米/年，LS 平均差异为 1.78厘米/年（p<0.0001）。 TransCon CNP一直保持着与安慰剂相似的安全性，并且总体耐受性优良，治疗过程中出现的不良事件（TEAE）大多数都是轻度的。 TransCon CNP属于一种处于研究阶段的 C型利钠肽（CNP）前体药物，每周给药一次，旨在给予患者活性CNP 的持续暴露。C型利钠肽能够通过阻挡 FGFR3 的活性，仿若松开抑制儿童生长的“刹车”。直接靶向软骨发育不全的潜在病理生理学，从而促进软骨内骨形成，让患儿的生长速率恢复正常。 三、其他临床疗法 伏索利肽 （Vosoritide) 欧洲药品管理局（EMA）在2021 年准许伏索利肽对 2岁及以上的软骨发育不全患儿（直至生长板闭合）展开治疗。基于针对3 个月至5 岁软骨发育不全患儿临床试验所有数据集合的评价，美国FDA 在 2023年 10月许可伏索利肽用于治疗全部生长板开启的软骨发育不全患儿（也就是从出生起始）。伏索利肽已经在46 个国家被批准用以治疗软骨发育不全儿童，于日本和澳大利亚，从出生到生长板闭合的这段时期都能够加以运用。 在II期临床探究中，经过 60个月的治疗，年化生长速度（AGV）提升了 1.35厘米/年，治疗 60个月时身高增加了 9.08厘米；在III期临床研究里，治疗 1年时年化生长速度（AGV）改良了1.57厘米/年，治疗 1年时身高增进了 0.28；最新的II期临床研究显示，观察到 3 -59个月年龄的患者接受 52周的治疗，除去身高的改变，身体比例、颅骨以及脑形态（涵盖枕骨大孔、脑室和脑实质的尺寸）的变动较为显著。 伏索利肽 （Vosoritide)具备良好的耐受性，副作用发生的几率不存在明显差异，5 岁以下和较大年龄的患者在安全性方面相近，III期临床研究未上报与治疗有关的严重不良情况。 英菲格拉替尼(Infigratinib) 英菲格拉替尼属于一种口服型且具备生物可利用性的 FGFR1 -3 选择性的抑制剂，在针对由 FGFR2突变所驱使的曾经接受过治疗或者转移性的肝内胆管癌的治疗中呈现出良好前景。鉴于这些数据以及英菲格拉替尼对软骨发育不全小鼠模型的骨表型（涵盖枕骨大孔和骨性椎管的尺寸）所发挥的改善作用，针对软骨发育不全儿童（年龄处于2.5- 16岁）的观察性生长与干预的临床试验已然开启，以此对该种口服疗法的安全性与有效性展开评估（PROPEL[NCT04035811]以及 PROPEL - 2[NCT04265651]）。2 期的剂量探寻研究（PROPEL- 2）表明，处于最高剂量组的英菲格拉替尼（0.25mg/kg/d）的患儿未曾出现和治疗相关的不良事件，并且相较于之前的观察性研究中的基线生长速度，平均每年能够多长3cm。这些数据相当振奋人心，特别是鉴于这种药物为口服的小药片，能够撒在幼儿的食物之中。一项重要的 3期试验已于2023 年12 月启动（NCT06164951）。 瑞夫明西普(Recifercept) 一种具备配体捕获作用的可溶性FGFR3分子（瑞夫明西普），能够优化软骨发育不全小鼠模型的骨表型。基于这一数据，Therachon Pharma 公司与辉瑞公司接连开发了此类潜在疗法，并针对0-10 岁的软骨发育不全儿童实施了观察性和干预性临床试验（NCT03794609以及 NCT04638153）。在 2022年，鉴于随机分配接受瑞夫明西普治疗的儿童相较安慰剂儿童来说，年生长速度没有上升，这些试验因疗效欠佳而被终止。 SAR-442501 2021 年，一种针对 FGFR3 的人单克隆抗体（SAR-442501）获取了欧洲医学管理局（EMA）所授予的孤儿药认定，目的是用于医治软骨发育不全的儿童。赛诺菲展开了一项观察研究，针对 0至 10岁软骨发育不全儿童实施纵向生长的测量数据收集工作，并对数字生物标志物（像是家庭睡眠监测仪器以及监控体力活动的可穿戴设备）的运用状况予以评估，以此当作该 FGFR3 抗体化合物 2期干预试验的序曲。到了2023 年10 月，SAR-442501 的开放标签2 期研究在 0至 12 岁的软骨发育不全儿童当中开启，每周进行两次皮下注射（NCT06067425）。 美克洛嗪(Meclizine) 美克洛嗪是一种现成的非处方口服抗组胺药，常用于治疗晕车，被认为是治疗软骨发育不全症的潜在方法，可促进软骨发育不全小鼠模型的纵向骨生长。这一发现促成了一项1a期试验，在12名5-11岁软骨发育不全日本儿童中每天给予一次或两次美克洛嗪，从而获取药代动力学数据。美克洛嗪的耐受性良好，没有出现严重的不良反应。 RBM-007 RBM-007 属于一种 RNA 适配体，能够和FGF2实现特异性结合，进而阻挡其与FGFR3相互接触。相关研究指出，RBM-007 能够挽回野生型小鼠胫骨里的 FGFR3 信号，让软骨发育不全患者诱导多能干细胞中的软骨细胞分化得以恢复，也能够让软骨发育不全小鼠模型里的非正常生长回归正常化。基于此，提出了它或许能有效治疗软骨发育不全的这一假设。当前，RBM-007 在日本正处于早期临床研发的阶段。 四、展望 在过去的十年期间，首个用于软骨发育不全儿童的精准疗法（伏索利肽）已得到批准，同时其他具有潜力的疗法也在临床研发的进程之中。接下来的十年，不但要明确哪些药物对于改善软骨发育不全的并发症效果最为显著，而且还得进一步明确这些新疗法的利弊得失。能够促进软骨发育不全婴儿颅面部骨骼非正常发育改善以及颅底孔（特别是枕骨大孔）生长的药物将会具有关键的潜在临床价值。长期的临床研究将会查明这些改善有无降低婴儿猝死、睡眠呼吸障碍的出现概率，还有减压和颅颌面手术的必要程度。未来的试验还会评判这些疗法的最佳起始时刻和剂量，以及是否能够联合运用来增强治疗效果。既然这些疗法是由制药公司研制开发的，所以一定要保证软骨发育不全患儿在全球范围之内都能够平等地获取这些疗法。此项工作需要国际方面以及政府与制药公司相互合作，同时也离不开软骨发育不全患者及其家人和支持组织的倡议与主动参与。 不管是当下还是未来，都会存在软骨发育不全患者以及他们的家人选择不去运用这些新药物，特别是倘若新药的主要作用是增多线性生长，就像临床试验的主要终点所体现的那样。针对这些人而言，身材娇小是其内在个人身份的一个重要构成部分，而并非是需要变更的特质——这类观点必须予以尊重。想要清楚这些新药是否还会改变软骨发育不全相关的基线发病概率和死亡概率，仍然需要长期的观察资料。这些新疗法永远没办法替代针对软骨发育不全患者及其家庭的全生命周期看护、宣扬、社区教育和政策扶持。 参考资料：        [1] Pivotal ApproaCH Trial of TransCon™ CNP (Navepegritide) Achieved Primary Objective, Demonstrated AGV Superior to Placebo. Retrieved September 17, 2024 from https://investors.ascendispharma.com/news-releases/news-release-details/pivotal-approach-trial-transcontm-cnp-navepegritide-achieved END 来源：CPHI制药在线 声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。 投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

BOSTON--( BUSINESS WIRE )-- Ironwood Pharmaceuticals, Inc. (Nasdaq: IRWD), a GI-focused healthcare company, today reported its second quarter 2024 results and recent business performance. “We continued to make progress across our portfolio in the second quarter,” said Tom McCourt, chief executive officer of Ironwood Pharmaceuticals. “LINZESS prescription demand and new-to-brand growth remain robust, increasing 11% and 15% year-over-year in Q2, respectively. While demand is up, LINZESS continues to experience pricing headwinds driven by higher-than-expected Medicaid utilization trends. Even with continued LINZESS pricing pressure, we believe we are in a fortunate position with meaningful cash flow generation from LINZESS and a capital structure to support the continued execution of our strategic priorities. Beyond LINZESS, we have continued to receive positive feedback from physicians, key opinion leaders, and patient advocacy partners on apraglutide’s clinical profile. This positive feedback supports our belief that, if approved, apraglutide would be the drug of choice among physicians to treat adult patients with short bowel syndrome who are dependent on parenteral support, based on its demonstrated efficacy, tolerability and once-weekly dosing convenience. In addition, we look forward to providing an update on CNP-104 later this quarter, which will inform a decision on our option to acquire an exclusive license from COUR for CNP-104 in the U.S.” Second Quarter 2024 Financial Highlights 1 (in thousands, except for per share amounts) Q2 2024 Q2 2023 Total revenue 2 $94,396 $107,382 Total costs and expenses 3 69,419 1,190,521 GAAP net loss 2,3 (860) (1,089,478) GAAP net loss attributable to Ironwood Pharmaceuticals, Inc. 2,3 (860) (1,062,187) GAAP net loss – per share basic 2,3 (0.01) (6.84) GAAP net loss – per share diluted 2,3 (0.01) (6.84) Adjusted EBITDA 2,3 27,909 (1,034,182) Non-GAAP net income (loss) 2,3 1,508 (1,041,325) Non-GAAP net income (loss) per share – basic 2,3 0.00 (6.71) Non-GAAP net income (loss) per share – diluted 2,3 0.00 (6.71) 1 Refer to the Reconciliation of GAAP Results to Non-GAAP Financial Measures table and to the Reconciliation of GAAP Net Loss to Adjusted EBITDA table at the end of this press release. Refer to Non-GAAP Financial Measures for additional information. 2 Figures presented for the second quarter of 2024 include a $17.0 million adjustment to collaborative arrangements revenue, driven by a $30.0 million increase to collaborative arrangements revenue as a result of a gross-to-net change in estimate related to the year ended December 31, 2023, previously recorded by Ironwood in the first quarter of 2024, which was reflected in LINZESS U.S. net sales as reported by AbbVie in the second quarter of 2024. This was partially offset by a $13.0 million reduction to collaborative arrangements revenue in the second quarter of 2024, to reflect Ironwood’s estimate of LINZESS gross-to-net reserves as of June 30, 2024. 3 Figures presented for the second quarter of 2023 include a one‐time charge of approximately $1.1 billion related to acquired in‐process research and development from the acquisition of VectivBio in the second quarter of 2023. Second Quarter 2024 Corporate Highlights U.S. LINZESS Prescription Demand : Total LINZESS prescription demand in the second quarter of 2024 was 52 million LINZESS capsules, an 11% increase compared to the second quarter of 2023, per IQVIA. U.S. Brand Collaboration : LINZESS U.S. net sales are provided to Ironwood by its U.S. partner, AbbVie Inc. (“AbbVie”). LINZESS U.S. net sales were $211.2 million in the second quarter of 2024, a 22% decrease compared to $269.7 million in the second quarter of 2023. Ironwood and AbbVie share equally in U.S. brand collaboration profits. LINZESS U.S. net sales as reported by AbbVie in the second quarter of 2024 reflected the gross-to-net change in estimate related to the year ended December 31, 2023, which Ironwood previously accounted for in the first quarter of 2024 by recording a $30.0 million reduction to collaborative arrangements revenue. LINZESS commercial margin, including the gross-to-net change in estimate, was 62% in the second quarter of 2024, compared to 71% in the second quarter of 2023. See the U.S. LINZESS Full Brand Collaboration table at the end of this press release. Net profit for the LINZESS U.S. brand collaboration, net of commercial and research and development (“R&D”) expenses, and including the gross-to-net change in estimate, was $120.5 million in the second quarter of 2024, a decrease compared to $180.3 million in the second quarter of 2023. See the U.S. LINZESS Full Brand Collaboration table at the end of this press release. Collaboration Revenue to Ironwood : Ironwood recorded $91.4 million in collaboration revenue in the second quarter of 2024 related to sales of LINZESS in the U.S., compared to $104.8 million for the second quarter of 2023. Second quarter of 2024 collaboration revenue to Ironwood includes a $17.0 million adjustment, driven by a $30.0 million increase to collaborative arrangements revenue as a result of a gross-to-net change in estimate related to the year ended December 31, 2023, previously recorded by Ironwood in the first quarter of 2024, which was reflected in LINZESS U.S. net sales as reported by AbbVie in the second quarter of 2024. This was partially offset by a $13.0 million reduction to collaborative arrangements revenue in the second quarter of 2024, to reflect Ironwood’s estimate of LINZESS gross-to-net reserves as of June 30, 2024. See the U.S. LINZESS Commercial Collaboration table at the end of the press release. Pipeline Updates Apraglutide Ironwood is advancing apraglutide, a next-generation, synthetic glucagon-like peptide-2 (“GLP-2”) analog for short bowel syndrome (“SBS”) patients dependent on parenteral support (“PS”), a severe chronic malabsorptive condition. Ironwood believes apraglutide has the potential to improve the standard of care for adult patients with SBS who are dependent on PS as the first and only GLP-2 with once-weekly administration, if approved. In May 2024, Ironwood presented late-breaking data during the 2024 Digestive Disease Week ® (DDW) meeting from its pivotal Phase III clinical trial, STARS, which evaluated the efficacy and safety of once-weekly subcutaneous apraglutide in adult patients with short bowel syndrome with intestinal failure (“SBS-IF”). These findings build on the positive topline data that Ironwood previously announced in February 2024. Additional details from the late-breaking presentation can be found here . Ironwood is working to submit a new drug application (“NDA”) to the U.S. Food and Drug Administration (“FDA”) and marketing applications to other regulatory agencies for apraglutide for the treatment of adult patients with SBS who are dependent on PS. CNP-104 Ironwood has a collaboration and license option agreement with COUR Pharmaceuticals Development Company, Inc. (“COUR”). This agreement grants Ironwood an option to acquire an exclusive license to research, develop, manufacture and commercialize, in the U.S., products containing CNP-104 (“CNP-104”), a tolerizing immune modifying nanoparticle, for the treatment of primary biliary cholangitis (“PBC”), a rare autoimmune disease targeting the liver. If successful, CNP-104 has the potential to be the first approved disease modifying therapy for PBC. COUR is currently conducting a clinical study with CNP-104 evaluating the safety, tolerability, pharmacodynamic effects and efficacy of CNP-104 in PBC patients. Topline data is expected in the third quarter of 2024. IW-3300 Ironwood is currently advancing IW-3300, a guanylate cyclase-C agonist being developed for the potential treatment of visceral pain conditions, such as interstitial cystitis / bladder pain syndrome (“IC/BPS”) and endometriosis. Ironwood is continuing the Phase II proof of concept study in IC/BPS. Second Quarter 2024 Financial Results Total Revenue. Total revenue in the second quarter of 2024 was $94.4 million, compared to $107.4 million in the second quarter of 2023. As noted above, revenue was lower year-over-year, primarily due to the decrease in collaborative arrangements revenue. Total revenue in the second quarter of 2024 consisted of $91.4 million associated with Ironwood’s share of the net profits from the sales of LINZESS in the U.S., and $3.0 million in royalties and other revenue. Total revenue in the second quarter of 2023 consisted of $104.8 million associated with Ironwood’s share of the net profits from the sales of LINZESS in the U.S. and $2.6 million in royalties and other revenue. Operating Expenses . Operating expenses in the second quarter of 2024 were $69.4 million, compared to $1,190.5 million in the second quarter of 2023, which included a one-time charge of $1,090.4 million of acquired in-process research and development (“IPR&D”) from the acquisition of VectivBio. Operating expenses in the second quarter of 2024 consisted of $37.0 million in selling, general and administrative (“SG&A”) expenses, $30.4 million in R&D expenses and $2.1 million in restructuring expenses. Operating expenses in the second quarter of 2023 consisted of $52.5 million in SG&A expenses and $34.6 million in R&D expenses, $13.0 million in restructuring expenses and approximately $1.1 billion in acquired IPR&D from the acquisition of VectivBio. Interest Expense. Interest expense was $7.5 million in the second quarter of 2024, primarily in connection with Ironwood’s convertible senior notes and revolving credit facility. Interest expense was $1.8 million in the second quarter of 2023, in connection with Ironwood’s convertible senior notes and revolving credit facility. Interest and Investment Income. Interest and investment income was $1.4 million in the second quarter of 2024. Interest and investment income was $8.8 million in the second quarter of 2023. Income Tax Expense. Ironwood recorded $19.7 million of income tax expense in the second quarter of 2024, the majority of which was non-cash, as Ironwood continues to utilize net operating losses to offset taxable income for federal purposes and in many states. Ironwood recorded $13.3 million of income tax expense in the second quarter of 2023, the majority of which was non-cash, as Ironwood continued to utilize net operating losses to offset taxable income for federal purposes and in many states. GAAP Net Loss Attributable to Ironwood. GAAP net loss attributable to Ironwood was ($0.9) million, or ($0.01) per share (basic and diluted) in the second quarter of 2024, compared to GAAP net loss attributable to Ironwood of ($1,062.2) million, or ($6.84) per share (basic and diluted) in the second quarter of 2023, which included a one-time charge of ($1,090.4) million of acquired IPR&D from the acquisition of VectivBio. Non-GAAP Net Income (Loss). Non-GAAP net income was $1.5 million, or $0.00 per share (basic and diluted), in the second quarter of 2024, compared to non-GAAP net loss of ($1,041.3) million, or ($6.71) per share (basic and diluted), in the second quarter of 2023, which included a one-time charge of ($1,090.4) million of acquired IPR&D from the acquisition of VectivBio. Non-GAAP net income (loss) excludes the impact of mark-to-market adjustments on the derivatives related to Ironwood’s 2022 Convertible Notes, amortization of acquired intangible assets, restructuring expenses and acquisition-related costs, all net of tax effect. See Non-GAAP Financial Measures below. Adjusted EBITDA . Adjusted EBITDA was $27.9 million in the second quarter of 2024, compared to ($1,034.2) million in the second quarter of 2023, which included a one-time charge of ($1,090.4) million of acquired IPR&D from the acquisition of VectivBio. Adjusted EBITDA is calculated by subtracting mark-to-market adjustments on derivatives related to Ironwood’s 2022 Convertible Notes, restructuring expenses, net interest expense, income taxes, depreciation and amortization, and acquisition-related costs, from GAAP net loss. See Non-GAAP Financial Measures below. Cash Flow Highlights. Ironwood ended the second quarter of 2024 with $105.5 million of cash and cash equivalents, compared to $92.2 million of cash and cash equivalents at the end of 2023. In the second quarter of 2024, Ironwood repaid the aggregate principal amount of the 2024 Convertible Notes of approximately $200.0 million upon maturity, using $50.0 million of cash on hand and drawing $150.0 million from its revolving credit facility. The outstanding principal balance on the revolving credit facility was $425.0 million as of June 30, 2024. Ironwood generated $33.5 million in cash from operations in the second quarter of 2024, compared to $35.0 million in cash from operations in the second quarter of 2023. Ironwood 2024 Financial Guidance. Ironwood has revised its FY 2024 financial guidance due to continued LINZESS pricing pressure as a result of higher-than-expected Medicaid utilization trends for FY 2024. Ironwood now expects: Prior 2024 Guidance (May 9, 2024) Revised 2024 Guidance (August 8, 2024) U.S. LINZESS Net Sales Mid-single digits % decline 2 $900 - $950 million Total Revenue $405 - $425 million $350 - $375 million Adjusted EBITDA 1 >$120 million Excludes potential CNP-104 option exercise >$75 million Excludes potential CNP-104 option exercise 1 Adjusted EBITDA is calculated by subtracting restructuring expenses, net interest expense, income taxes, depreciation and amortization, and acquisition-related costs from GAAP net loss. For purposes of the 2024 guidance, Ironwood has assumed it will not incur material expenses related to business development activities in 2024 and excludes any costs associated with potential CNP-104 option exercise. Ironwood does not provide guidance on GAAP net loss or a reconciliation of expected adjusted EBITDA to expected GAAP net loss because, without unreasonable efforts, it is unable to predict with reasonable certainty the non-GAAP adjustments used to calculate adjusted EBITDA. These adjustments are uncertain, depend on various factors and could have a material impact on GAAP net loss for the guidance period. Management believes this non-GAAP information is useful for investors, taken in conjunction with Ironwood’s GAAP financial statements, because it provides greater transparency and period-over-period comparability with respect to Ironwood’s operating performance. These measures are also used by management to assess the performance of the business. Investors should consider these non-GAAP measures only as a supplement to, not as a substitute for or as superior to, measures of financial performance prepared in accordance with GAAP. In addition, these non-GAAP financial measures are unlikely to be comparable with non-GAAP information provided by other companies. 2 2024 U.S. LINZESS Net Sales guidance presented as year-over-year change relative to 2023 U.S. LINZESS Net Sales as reported by AbbVie of $1,073.2 million. Non-GAAP Financial Measures Ironwood presents non-GAAP net income (loss) and non-GAAP net income (loss) per share to exclude the impact, net of tax effects, of net gains and losses on derivatives related to Ironwood’s 2022 Convertible Notes that are required to be marked-to-market, amortization of acquired intangible assets, restructuring expenses, and acquisition-related costs. Non-GAAP adjustments are further detailed below: The gains and losses on the derivatives related to Ironwood’s 2022 Convertible Notes were highly variable, difficult to predict and of a size that could have a substantial impact on the company’s reported results of operations in any given period. Amortization of acquired intangible assets are non-cash expenses arising in connection with the acquisition of VectivBio and are considered to be non-recurring. Restructuring expenses are considered to be a non-recurring event as they are associated with distinct operational decisions. Restructuring expenses include costs associated with exit and disposal activities. Acquisition-related costs in connection with the acquisition of VectivBio are considered to be non-recurring and include direct and incremental costs associated with the acquisition and integration of VectivBio to the extent such costs were not classified as capitalizable transaction costs attributed to the cost of net assets acquired through acquisition accounting. Ironwood also presents adjusted EBITDA, a non-GAAP measure, as well as guidance on adjusted EBITDA. Adjusted EBITDA is calculated by subtracting mark-to-market adjustments on derivatives related to Ironwood’s 2022 Convertible Notes, restructuring expenses, net interest expense, income taxes, depreciation and amortization, and acquisition-related costs from GAAP net loss. The adjustments are made on a similar basis as described above related to non-GAAP net income (loss), as applicable. Management believes this non-GAAP information is useful for investors, taken in conjunction with Ironwood’s GAAP financial statements, because it provides greater transparency and period-over-period comparability with respect to Ironwood’s operating performance. These measures are also used by management to assess the performance of the business. Investors should consider these non-GAAP measures only as a supplement to, not as a substitute for or as superior to, measures of financial performance prepared in accordance with GAAP. In addition, these non-GAAP financial measures are unlikely to be comparable with non-GAAP information provided by other companies. For a reconciliation of non-GAAP net income (loss) and non-GAAP net income (loss) per share to GAAP net loss and GAAP net loss per share, respectively, and for a reconciliation of adjusted EBITDA to GAAP net loss, please refer to the tables at the end of this press release. Ironwood does not provide guidance on GAAP net loss or a reconciliation of expected adjusted EBITDA to expected GAAP net loss because, without unreasonable efforts, it is unable to predict with reasonable certainty the non-GAAP adjustments used to calculate adjusted EBITDA. These adjustments are uncertain, depend on various factors and could have a material impact on GAAP net loss for the guidance period. Conference Call Information Ironwood will host a conference call and webcast at 8:30 a.m. Eastern Time on Thursday, August 8, 2024 to discuss its second quarter 2024 results and recent business activities. Individuals interested in participating in the call should dial (888) 596-4144 (U.S. and Canada) or (646) 968-2525 (international) using conference ID number and event passcode 2530602. To access the webcast, please visit the Investors section of Ironwood’s website at www.ironwoodpharma.com . The call will be available for replay via telephone starting at approximately 11:30 a.m. Eastern Time on August 8, 2024, running through 11:59 p.m. Eastern Time on August 22, 2024. To listen to the replay, dial (800) 770-2030 (U.S. and Canada) or (609) 800-9909 (international) using conference ID number 2530602. The archived webcast will be available on Ironwood’s website for 1 year beginning approximately one hour after the call has completed. About Ironwood Pharmaceuticals Ironwood Pharmaceuticals (Nasdaq: IRWD), an S&P SmallCap 600® company, is a leading gastrointestinal (GI) healthcare company on a mission to advance the treatment of GI diseases and redefine the standard of care for GI patients. We are pioneers in the development of LINZESS® (linaclotide), the U.S. branded prescription market leader for adults with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC). LINZESS is also approved for the treatment of functional constipation in pediatric patients ages 6-17 years-old. Ironwood is also advancing apraglutide, a next-generation, long-acting synthetic GLP-2 analog being developed for rare gastrointestinal diseases, including short bowel syndrome with intestinal failure (SBS-IF) as well as several earlier stage assets. Building upon our history of GI innovation, we keep patients at the heart of our R&D and commercialization efforts to reduce the burden of GI diseases and address significant unmet needs. Founded in 1998, Ironwood Pharmaceuticals is headquartered in Boston, Massachusetts, with a site in Basel, Switzerland. We routinely post information that may be important to investors on our website at www.ironwoodpharma.com . In addition, follow us on X and on LinkedIn . About LINZESS (Linaclotide) LINZESS® is the #1 prescribed brand in the U.S. for the treatment of adult patients with irritable bowel syndrome with constipation (“IBS-C”) or chronic idiopathic constipation (“CIC”), based on IQVIA data. LINZESS is a once-daily capsule that helps relieve the abdominal pain, constipation, and overall abdominal symptoms of bloating, discomfort and pain associated with IBS-C, as well as the constipation, infrequent stools, hard stools, straining, and incomplete evacuation associated with CIC. LINZESS relieves constipation in children and adolescents aged 6 to 17 years with functional constipation. The recommended dose is 290 mcg for IBS-C patients and 145 mcg for CIC patients, with a 72 mcg dose approved for use in CIC depending on individual patient presentation or tolerability. In children with functional constipation aged 6 to 17 years, the recommended dose is 72 mcg. LINZESS is not a laxative; it is the first medicine approved by the FDA in a class called GC-C agonists. LINZESS contains a peptide called linaclotide that activates the GC-C receptor in the intestine. Activation of GC-C is thought to result in increased intestinal fluid secretion and accelerated transit and a decrease in the activity of pain-sensing nerves in the intestine. The clinical relevance of the effect on pain fibers, which is based on nonclinical studies, has not been established. In the United States, Ironwood and AbbVie co-develop and co-commercialize LINZESS for the treatment of adults with IBS-C or CIC. In Europe, AbbVie markets linaclotide under the brand name CONSTELLA® for the treatment of adults with moderate to severe IBS-C. In Japan, Ironwood's partner, Astellas, markets linaclotide under the brand name LINZESS for the treatment of adults with IBS-C or CIC. Ironwood also has partnered with AstraZeneca for development and commercialization of LINZESS in China, and with AbbVie for development and commercialization of linaclotide in all other territories worldwide. LINZESS Important Safety Information INDICATIONS AND USAGE LINZESS® (linaclotide) is indicated for the treatment of both irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) in adults and functional constipation (FC) in children and adolescents 6 to 17 years of age. It is not known if LINZESS is safe and effective in children with FC less than 6 years of age or in children with IBS-C less than 18 years of age. IMPORTANT SAFETY INFORMATION WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS LESS THAN 2 YEARS OF AGE LINZESS is contraindicated in patients less than 2 years of age. In nonclinical studies in neonatal mice, administration of a single, clinically relevant adult oral dose of linaclotide caused deaths due to dehydration. Contraindications LINZESS is contraindicated in patients less than 2 years of age due to the risk of serious dehydration. LINZESS is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. Warnings and Precautions LINZESS is contraindicated in patients less than 2 years of age. In neonatal mice, linaclotide increased fluid secretion as a consequence of age-dependent elevated guanylate cyclase (GC-C) agonism, which was associated with increased mortality within the first 24 hours due to dehydration. There was no age dependent trend in GC-C intestinal expression in a clinical study of children 2 to less than 18 years of age; however, there are insufficient data available on GC-C intestinal expression in children less than 2 years of age to assess the risk of developing diarrhea and its potentially serious consequences in these patients. Diarrhea In adults, diarrhea was the most common adverse reaction in LINZESS-treated patients in the pooled IBS-C and CIC double-blind placebo-controlled trials. The incidence of diarrhea was similar in the IBS-C and CIC populations. Severe diarrhea was reported in 2% of 145 mcg and 290 mcg LINZESS-treated patients and in <1% of 72 mcg LINZESS-treated CIC patients. In children and adolescents 6 to 17 years of age, diarrhea was the most common adverse reaction in 72 mcg LINZESS-treated patients in the FC double-blind placebo-controlled trial. Severe diarrhea was reported in <1% of 72 mcg LINZESS treated patients. If severe diarrhea occurs, dosing should be suspended and the patient rehydrated. Common Adverse Reactions (incidence ≥2% and greater than placebo) In IBS-C or CIC adult patients: diarrhea, abdominal pain, flatulence, and abdominal distension. In FC pediatric patients: diarrhea. Please see full Prescribing Information including Boxed Warning: https://www.rxabbvie.com/pdf/linzess_pi.pdf LINZESS® and CONSTELLA® are registered trademarks of Ironwood Pharmaceuticals, Inc. Any other trademarks referred to in this press release are the property of their respective owners. All rights reserved. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Investors are cautioned not to place undue reliance on these forward-looking statements, including statements about Ironwood’s ability to execute on its mission; Ironwood’s strategy, business, financial position and operations; Ironwood’s ability to drive growth and profitability; the commercial potential of LINZESS; our financial performance and results, and guidance and expectations related thereto; LINZESS prescription demand growth, LINZESS U.S. net sales growth, total revenue and adjusted EBITDA in 2024; our plan to pursue apraglutide rolling NDA review and the expected timing to complete submission; our belief that our cash flow position supports the continued execution of strategic priorities; our belief that if apraglutide is approved, it would be the drug of choice among physicians to treat adult patients with SBS who are dependent on PS, based on its demonstrated efficacy, tolerability and once-weekly dosing convenience; our plan to submit an NDA and marketing applications to other regulatory agencies for apraglutide; apraglutide's potential, if approved, to be the first and only once-weekly GLP-2 analog for adult SBS patients who are dependent on PS; the timing of topline data for CNP-104, which will inform a decision on our option to acquire an exclusive license from COUR, and that, if successful, CNP-104 has the potential to be the first approved disease modifying therapy for PBC. These forward-looking statements speak only as of the date of this press release, and Ironwood undertakes no obligation to update these forward-looking statements. Each forward-looking statement is subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statement. Applicable risks and uncertainties include those related to the effectiveness of development and commercialization efforts by us and our partners; preclinical and clinical development, manufacturing and formulation development of linaclotide, apraglutide, CNP-104, IW-3300, and our other product candidates; the risk of uncertainty relating to pricing and reimbursement policies in the U.S., which, if not favorable for our products, could hinder or prevent our products’ commercial success; the risk that clinical programs and studies, including for linaclotide pediatric programs, apraglutide, CNP-104 and IW-3300, may not progress or develop as anticipated, including that studies are delayed or discontinued for any reason, such as safety, tolerability, enrollment, manufacturing, economic or other reasons; the risk that findings from our completed nonclinical studies and clinical trials may not be replicated in later trials and earlier-stage clinical trials may not be predictive of the results we may obtain in later-stage clinical trials or of the likelihood of regulatory approval; the risk that apraglutide will not be approved by the FDA or other regulatory agencies; the risk of competition or that new products may emerge that provide different or better alternatives for treatment of the conditions that our products are approved to treat; the risk that we are unable to execute on our strategy to in-license externally developed products or product candidates; the risk that we are unable to successfully partner with other companies to develop and commercialize products or product candidates; the risk that healthcare reform and other governmental and private payor initiatives may have an adverse effect upon or prevent our products’ or product candidates’ commercial success; the efficacy, safety and tolerability of linaclotide and our product candidates; the risk that the commercial and therapeutic opportunities for LINZESS, apraglutide or our other product candidates are not as we expect; decisions by regulatory and judicial authorities; the risk we may never get additional patent protection for linaclotide, apraglutide and other product candidates, that patents for linaclotide, apraglutide or other products may not provide adequate protection from competition, or that we are not able to successfully protect such patents; the risk that we are unable to manage our expenses or cash use, or are unable to commercialize our products as expected; the risk that the development of any of our linaclotide pediatric programs, apraglutide, CNP-104 and/or IW-3300 is not successful or that any of our product candidates does not receive regulatory approval or is not successfully commercialized; outcomes in legal proceedings to protect or enforce the patents relating to our products and product candidates, including abbreviated new drug application litigation; the risk that financial and operating results may differ from our projections; developments in the intellectual property landscape; challenges from and rights of competitors or potential competitors; the risk that our planned investments do not have the anticipated effect on our company revenues; developments in accounting guidance or practice; Ironwood’s or AbbVie’s accounting practices, including reporting and settlement practices as between Ironwood and AbbVie; the risk that our indebtedness could adversely affect our financial condition or restrict our future operations; and the risks listed under the heading “Risk Factors” and elsewhere in our Annual Report on Form 10-K for the year ended December 31, 2023, and in our subsequent Securities and Exchange Commission filings. Condensed Consolidated Balance Sheets (In thousands) (unaudited) June 30, 2024 December 31, 2023 Assets Cash and cash equivalents $ 105,524 $ 92,154 Accounts receivable, net 58,108 129,122 Prepaid expenses and other current assets 14,548 12,012 Total current assets 178,180 233,288 Property and equipment, net 5,068 5,585 Operating lease right-of-use assets 11,823 12,586 Intangible assets, net 3,273 3,682 Deferred tax assets 193,019 212,324 Other assets 4,257 3,608 Total assets $ 395,620 $ 471,073 Liabilities and stockholders’ equity Accounts payable $ 3,227 $ 7,830 Accrued research and development costs 6,720 21,331 Accrued expenses and other current liabilities 32,406 44,254 Current portion of operating lease liabilities 3,157 3,126 Current portion on convertible senior notes - 199,560 Total current liabilities 45,510 276,101 Operating lease liabilities, net of current portion 13,452 14,543 Convertible senior notes, net of current portion 198,647 198,309 Revolving credit facility 425,000 300,000 Other liabilities 34,738 28,415 Total stockholders’ deficit (321,727) (346,295) Total liabilities and stockholders’ deficit $ 395,620 $ 471,073 Condensed Consolidated Statements of Income (Loss) (In thousands, except per share amounts) (unaudited) Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 Total revenues 1 $ 94,396 $ 107,382 $ 169,273 $ 211,443 Collaborative arrangements revenue 1 94,396 107,382 169,273 211,443 Costs and expenses: Research and development 30,388 34,577 56,203 47,424 Selling, general and administrative 36,964 52,484 74,569 83,601 Restructuring 2,067 13,011 2,504 13,011 Acquired in-process research and development - 1,090,449 - 1,090,449 Total costs and expenses 2 69,419 1,190,521 133,276 1,234,485 Income (loss) from operations 24,977 (1,083,139) 35,997 (1,023,042) Other income (expense): Interest expense and other financing costs (7,470) (1,840) (14,701) (3,367) Interest and investment income 1,369 8,757 2,538 16,029 Gain on derivatives - - - 19 Other income (expense), net (6,101) 6,917 (12,163) 12,681 Income (loss) before income taxes 18,876 (1,076,222) 23,834 (1,010,361) Income tax expense (19,736) (13,256) (28,856) (33,403) GAAP net loss 1,2 (860) (1,089,478) (5,022) (1,043,764) Less: GAAP net loss attributable to noncontrolling interests - (27,291) - (27,291) GAAP net loss attributable to Ironwood Pharmaceuticals, Inc. $ (860) $ (1,062,187) $ (5,022) $ (1,016,473) GAAP net loss per share—basic $ (0.01) $ (6.84) $ (0.03) $ (6.56) GAAP net loss per share—diluted $ (0.01) $ (6.84) $ (0.03) $ (6.56) _________________ 1 Figures presented for the three and six months ended June 30, 2024 include a $17.0 million increase and $13.0 million reduction to collaborative arrangement revenues, respectively, as a result of an adjustment recorded for Ironwood’s estimate of LINZESS gross-to-net reserves as of June 30, 2024. 2 Figures presented for the three and six months ended June 30, 2023 include a one-time charge of approximately $1.1 billion related to acquired IPR&D from the acquisition of VectivBio in the second quarter of 2023. Reconciliation of GAAP Results to Non-GAAP Financial Measures (In thousands, except per share amounts) (unaudited) A reconciliation between net income (loss) on a GAAP basis and on a non-GAAP basis is as follows: Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 GAAP net loss 1,2 $ (860) $ (1,089,478) $ (5,022) $ (1,043,764) Adjustments: Mark-to-market adjustments on the derivatives related to convertible notes, net - - - (19) Amortization of acquired intangible assets 204 4 409 4 Restructuring expenses 2,067 13,011 2,504 13,011 Acquisition-related costs 359 35,681 1,146 35,681 Tax effect of adjustments (262) (543) (461) (543) Non-GAAP net income (loss) 1,2 $ 1,508 $ (1,041,325) $ (1,424) $ (995,630) A reconciliation between basic and diluted net income (loss) per share on a GAAP basis and on a non-GAAP basis is as follows: Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 GAAP net loss attributable to Ironwood Pharmaceuticals, Inc. per share – basic and diluted $ (0.01) $ (6.84) $ (0.03) $ (6.56) Plus: Net income (loss) per share attributable to noncontrolling interests - (0.18) - (0.18) Adjustments to GAAP net income (loss) per share (as detailed above) 0.01 0.31 0.02 0.31 Non-GAAP net income (loss) per share– basic and diluted $ 0.00 $ (6.71) $ (0.01) $ (6.43) Weighted average number of common shares used to calculate net loss per share — basic and diluted 159,014 155,367 158,357 154,912 _________________ 1 Figures presented for the three and six months ended June 30, 2024 include a $17.0 million increase and $13.0 million reduction to collaborative arrangement revenues, respectively, as a result of an adjustment recorded for Ironwood’s estimate of LINZESS gross-to-net reserves as of June 30, 2024. 2 Figures presented for the three and six months ended June 30, 2023, include a one-time charge of approximately $1.1 billion related to acquired IPR&D from the acquisition of VectivBio in the second quarter of 2023. Reconciliation of GAAP Net Loss to Adjusted EBITDA (In thousands) (unaudited) A reconciliation of GAAP net loss to adjusted EBITDA: Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 GAAP net loss 1,2 $ (860) $ (1,089,478) $ (5,022) $ (1,043,764) Adjustments: Mark-to-market adjustments on the derivatives related to convertible notes, net - - - (19) Restructuring expenses 2,067 13,011 2,504 13,011 Interest expense 7,470 1,840 14,701 3,367 Interest and investment income (1,369) (8,757) (2,538) (16,029) Income tax expense 19,736 13,256 28,856 33,403 Depreciation and amortization 506 265 1,019 551 Acquisition-related costs 359 35,681 1,146 35,681 Adjusted EBITDA 1,2 $ 27,909 $ (1,034,182) $ 40,666 $ (973,799) _________________ 1 Figures presented for the three and six months ended June 30, 2024 include a $17.0 million increase and $13.0 million reduction to collaborative arrangement revenues, respectively, as a result of an adjustment recorded for Ironwood’s estimate of LINZESS gross-to-net reserves as of June 30, 2024. 2 Figures presented for the three and six months ended June 30, 2023, include a one-time charge of approximately $1.1 billion related to acquired IPR&D from the acquisition of VectivBio in the second quarter of 2023. U.S. LINZESS Commercial Collaboration 1 Revenue/Expense Calculation (In thousands) (unaudited) Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 LINZESS U.S. net sales as reported by AbbVie 2 $ 211,183 $ 269,686 $ 467,783 $ 519,900 AbbVie & Ironwood commercial costs, expenses and other discounts 3 80,950 78,998 154,312 145,406 Commercial profit on sales of LINZESS $ 130,233 $ 190,688 $ 313,471 $ 374,494 Commercial Margin 4 62% 71% 67% 72% Ironwood’s share of net profit 65,117 95,344 156,736 187,247 Reimbursement for Ironwood’s commercial expenses 9,298 9,407 19,394 19,135 Adjustment for Ironwood’s estimate of LINZESS gross-to-net reserves 17,000 - (13,000) - Ironwood’s U.S. collaborative arrangements revenue 5 $ 91,415 $ 104,751 $ 163,130 $ 206,382 _________________ 1 Ironwood collaborates with AbbVie on the development and commercialization of linaclotide in North America. Under the terms of the collaboration agreement, Ironwood receives 50% of the net profits and bears 50% of the net losses from the commercial sale of LINZESS in the U.S. The purpose of this table is to present calculations of Ironwood’s share of net profit (loss) generated from the sales of LINZESS in the U.S. and Ironwood’s collaboration revenue/expense; however, the table does not present the research and development expenses related to LINZESS in the U.S. that are shared equally between the parties under the collaboration agreement. Please refer to the table at the end of this press release for net profit for the U.S. LINZESS brand collaboration with AbbVie. 2 LINZESS net sales are recognized using AbbVie’s revenue recognition accounting policies and reporting conventions. As a result, certain rebates and discounts are classified as LINZESS U.S. commercial costs, expenses and other discounts within Ironwood’s calculation of collaborative arrangements revenue. 3 Includes certain discounts recognized and cost of goods sold incurred by AbbVie; also includes commercial costs incurred by AbbVie and Ironwood that are attributable to the cost-sharing arrangement between the parties. 4 Commercial margin is defined as commercial profit on sales of LINZESS as a percent of total LINZESS U.S. net sales. 5 Figures presented for the three and six months ended June 30, 2024 include a $17.0 million increase and $13.0 million reduction to collaborative arrangement revenues, respectively, as a result of an adjustment recorded for Ironwood’s estimate of LINZESS gross-to-net reserves as of June 30, 2024. US LINZESS Full Brand Collaboration 1 Revenue/Expense Calculation (In thousands) (unaudited) Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 LINZESS U.S. net sales as reported by AbbVie 2 $ 211,183 $ 269,686 $ 467,783 $ 519,900 AbbVie & Ironwood commercial costs, expenses and other discounts 3 80,950 78,998 154,312 145,406 AbbVie & Ironwood R&D Expenses 4 9,736 10,356 17,372 19,006 Total net profit on sales of LINZESS $ 120,497 $ 180,332 $ 296,099 $ 355,488 _________________ 1 Ironwood collaborates with AbbVie on the development and commercialization of linaclotide in North America. Under the terms of the collaboration agreement, Ironwood receives 50% of the net profits and bears 50% of the net losses from the commercial sale of LINZESS in the U.S. The purpose of this table is to present calculations of the total net profit (loss) generated from the sales of LINZESS in the U.S., including the commercial costs and expenses and the research and development expenses related to LINZESS in the U.S. that are shared equally between the parties under the collaboration agreement. 2 LINZESS net sales are recognized using AbbVie’s revenue recognition accounting policies and reporting conventions. As a result, certain rebates and discounts are classified as LINZESS U.S. commercial costs, expenses and other discounts within Ironwood’s calculation of collaborative arrangements revenue. 3 Includes certain discounts recognized and cost of goods sold incurred by AbbVie; also includes commercial costs incurred by AbbVie and Ironwood that are attributable to the cost-sharing arrangement between the parties. 4 Expenses related to LINZESS in the U.S. are shared equally between Ironwood and AbbVie under the collaboration agreement.

Reported positive topline results from global Phase III STARS trial of once-weekly apraglutide in adults with short bowel syndrome with intestinal failure (SBS-IF) Reported positive results from Phase II exploratory STARGAZE trial of apraglutide in patients with steroid-refractory gastrointestinal acute Graft-versus-Host Disease (SR GI aGVHD) LINZESS® (linaclotide) EUTRx prescription demand growth of 10% year-over-year Revises FY 2024 financial guidance due to a LINZESS gross-to-net change in estimate BOSTON--(BUSINESS WIRE)-- Ironwood Pharmaceuticals, Inc. (Nasdaq: IRWD), a GI-focused healthcare company, today reported its first quarter 2024 results and recent business performance. “In the first quarter of 2024, we made significant advancements across our portfolio,” said Tom McCourt, chief executive officer of Ironwood. “LINZESS maintained its strong demand momentum, experiencing a rise in prescription volume by a robust 10% year-over-year, while continuing to generate meaningful cash flow. Particularly noteworthy during the quarter was the positive Phase III clinical data for apraglutide, which validates its potential as the first and only once-weekly GLP-2 analog for adult patients with short bowel syndrome who are dependent on parenteral support. The positive results from the STARS trial, coupled with our proven track record of effective commercial execution, uniquely position Ironwood in the market and reinforce our belief in the long-term value potential of apraglutide for patients and shareholders. We are working swiftly and plan to NDA as soon as possible for apraglutide for adult SBS patients dependent on parenteral support. In addition, we remain focused on executing across our strategic priorities by advancing our other GI pipeline assets, driving robust LINZESS demand growth, and delivering sustained profits and cash flow.” First Quarter 2024 Financial Highlights1 (in thousands, except for per share amounts) Q1 2024 Q1 2023 Total revenue2 $74,877 $104,061 Total operating expenses 63,857 43,964 GAAP net income (loss)2 (4,162) 45,714 GAAP net income (loss) – per share basic2 (0.03) 0.30 GAAP net income (loss) – per share diluted2 (0.03) 0.25 Adjusted EBITDA2 12,757 60,383 Non-GAAP net income (loss) 2 (2,933) 45,695 Non-GAAP net income (loss) per share – basic (0.02) 0.30 Non-GAAP net income (loss) per share – diluted (0.02) 0.25 1 Refer to the Reconciliation of GAAP Results to Non-GAAP Financial Measures table and to the Reconciliation of GAAP Net Income (Loss) to Adjusted EBITDA table at the end of this press release. Refer to Non-GAAP Financial Measures for additional information. 2 Figures presented in Q1 2024 include a $30.0 million reduction to collaborative arrangements revenue due to a LINZESS gross-to-net change in estimate related to the year ended December 31, 2023. First Quarter 2024 Corporate Highlights U.S. LINZESS Prescription Demand: Total LINZESS prescription demand in the first quarter of 2024 was 50 million LINZESS capsules, a 10% increase compared to the first quarter of 2023, per IQVIA. U.S. Brand Collaboration: LINZESS U.S. net sales are provided to Ironwood by its U.S. partner, AbbVie Inc. (“AbbVie”). LINZESS U.S. net sales were $256.6 million in the first quarter of 2024, a 3% increase compared to $250.2 million in the first quarter of 2023. Ironwood and AbbVie share equally in U.S. brand collaboration profits. Based on information subsequently provided by AbbVie, Ironwood recorded a $30 million reduction to collaborative arrangements revenue in its first quarter 2024 financial statements as a result of a LINZESS gross-to-net change in estimate related to the year ended December 31, 2023. See the LINZESS U.S. Commercial Collaboration table at the end of the press release. LINZESS commercial margin, excluding the gross-to-net change in estimate, was 71% in the first quarter of 2024, compared to 73% in the first quarter of 2023. See the U.S. LINZESS Full Brand Collaboration table at the end of this press release. Net profit for the LINZESS U.S. brand collaboration, net of commercial and research and development (“R&D”) expenses and excluding the gross-to-net change in estimate, was $175.6 million in the first quarter of 2024, compared to $175.2 million in the first quarter of 2023. See the U.S. LINZESS Full Brand Collaboration table at the end of this press release. Collaboration Revenue to Ironwood: Ironwood recorded $71.7 million in collaboration revenue in the first quarter of 2024 related to sales of LINZESS in the U.S., a decrease compared to $101.6 million for the first quarter of 2023, due to a $30.0 million reduction to collaborative arrangements revenue from a LINZESS gross-to-net change in estimate as noted above. See the U.S. LINZESS Commercial Collaboration table at the end of the press release. In January 2024, Ironwood announced a publication in The Lancet Gastroenterology & Hepatology of new linaclotide Phase III data in children and adolescents aged 6-17 years with functional constipation. The data highlighted additional efficacy endpoints from the company’s pivotal Phase III trial, which formed the basis of the June 2023 U.S. Food and Drug Administration (“FDA”) approval of linaclotide for the treatment of functional constipation in this population. Additional details can be found here. Pipeline Updates Apraglutide Ironwood is advancing apraglutide, a next-generation, synthetic glucagon-like peptide-2 (“GLP-2”) analog for short bowel syndrome patients dependent on parenteral support (“PS”), a severe chronic malabsorptive condition. Ironwood believes apraglutide has the potential to improve the standard of care for adult patients with SBS who are dependent on PS as the first and only GLP-2 with once-weekly administration, if approved. In February 2024, Ironwood announced positive topline results from its pivotal Phase III clinical trial, STARS, which evaluated the efficacy and safety of once-weekly subcutaneous apraglutide in reducing PS dependency in adult patients with short bowel syndrome with intestinal failure (“SBS-IF”). Based on the results from the STARS clinical trial, Ironwood plans to submit a new drug application and other regulatory filings for apraglutide for use in adult patients with SBS who are dependent on PS. Additional details on the topline results can be found here. Data from the Phase III STARS study was accepted as a late-breaker oral presentation and will be presented on May 21, 2024 at Digestive Disease Week® (DDW) 2024 in Washington D.C. In March 2024, Ironwood announced positive, primary results up to Day 91 for its Phase II exploratory trial, STARGAZE, to evaluate apraglutide in patients with steroid-refractory gastrointestinal acute Graft-versus-Host Disease (“SR GI aGvHD”), which evaluated the safety and tolerability of once-weekly apraglutide in SR GI aGvHD patients treated with standard of care, including systemic corticosteroids and ruxolitinib. The STARGAZE study will continue through its two-year endpoint, where apraglutide will be re-evaluated for safety and efficacy. Additional details can be found here. CNP-104 Ironwood has a collaboration and license option agreement with COUR Pharmaceuticals Development Company, Inc. (“COUR”). This agreement grants Ironwood an option to acquire an exclusive license to research, develop, manufacture and commercialize, in the U.S., products containing CNP-104 (“CNP-104”), a tolerizing immune modifying nanoparticle, for the treatment of primary biliary cholangitis (“PBC”), a rare autoimmune disease targeting the liver. If successful, CNP-104 has the potential to be the first approved disease modifying therapy for PBC. COUR is currently conducting a clinical study with CNP-104 evaluating the safety, tolerability, pharmacodynamic effects and efficacy of CNP-104 in PBC patients. Enrollment is complete and topline data is expected in the third quarter of 2024. IW-3300 Ironwood is currently advancing IW-3300, a guanylate cyclase-C agonist being developed for the potential treatment of visceral pain conditions, such as interstitial cystitis / bladder pain syndrome (“IC/BPS”) and endometriosis. Ironwood is continuing the Phase II proof of concept study in IC/BPS. First Quarter 2024 Financial Results Total Revenue. Total revenue in the first quarter of 2024 was $74.9 million, compared to $104.1 million in the first quarter of 2023. As noted above, revenue was lower year-over-year primarily due to the $30.0 million LINZESS gross-to-net change in estimate recorded to collaborative arrangements revenue. Total revenue in the first quarter of 2024 consisted of $71.7 million associated with Ironwood’s share of the net profits from the sales of LINZESS in the U.S., including the $30.0 million reduction, and $3.2 million in royalties and other revenue. Total revenue in the first quarter of 2023 consisted of $101.6 million associated with Ironwood’s share of the net profits from the sales of LINZESS in the U.S. and $2.5 million in royalties and other revenue. Operating Expenses. Operating expenses in the first quarter of 2024 were $63.9 million, compared to $44.0 million in the first quarter of 2023. Operating expenses in the first quarter of 2024 consisted of $37.6 million in selling, general and administrative (“SG&A”) expenses, $25.8 million in R&D expenses and $0.4 million in restructuring expenses. Operating expenses in the first quarter of 2023 consisted of $31.1 million in SG&A expenses and $12.9 million in R&D expenses. Interest Expense. Interest expense was $7.2 million in the first quarter of 2024, primarily in connection with Ironwood’s convertible senior notes and revolving credit facility. Interest expense was $1.5 million in the first quarter of 2023, in connection with Ironwood’s convertible senior notes. Interest and Investment Income. Interest and investment income was $1.2 million in the first quarter of 2024. Interest and investment income was $7.3 million in the first quarter of 2023. Gain on Derivatives. Ironwood recorded a gain on derivatives of an insignificant amount in the first quarter of 2023, as a result of the change in fair value of its note hedge warrants. Ironwood’s note hedge warrants terminated unexercised upon expiration in April 2023. Income Tax Expense. Ironwood recorded $9.1 million of income tax expense in the first quarter of 2024, the majority of which was non-cash, as Ironwood continues to utilize net operating losses to offset taxable income for federal purposes and in many states. Ironwood recorded $20.1 million of income tax expense in the first quarter of 2023, the majority of which was non-cash, as Ironwood continued to utilize net operating losses to offset taxable income for federal purposes and in many states. GAAP Net Income (Loss). GAAP net loss was $4.2 million, or ($0.03) per share (basic and diluted), in the first quarter of 2024, which includes a $30.0 million reduction to collaborative arrangements revenue due to a LINZESS gross-to-net change in estimate, compared to GAAP net income of $45.7 million, or $0.30 per share (basic) and $0.25 per share (diluted), in the first quarter of 2023. Non-GAAP Net Income (Loss). Non-GAAP net loss was $2.9 million, or ($0.02) per share (basic and diluted), in the first quarter of 2024, which includes a $30.0 million reduction to collaborative arrangements revenue due to a LINZESS gross-to-net change in estimate, compared to non-GAAP net income of $45.7 million, or $0.30 per share (basic) and $0.25 per share (diluted), in the first quarter of 2023. Non-GAAP net income excludes the impact of mark-to-market adjustments on the derivatives related to Ironwood’s 2022 Convertible Notes, amortization of acquired intangible assets, restructuring expenses and acquisition-related costs, all net of tax effect. See Non-GAAP Financial Measures below. Adjusted EBITDA. Adjusted EBITDA was $12.8 million in the first quarter of 2024, which includes a $30.0 million reduction to collaborative arrangements revenue due to a LINZESS gross-to-net change in estimate, compared to $60.4 million in the first quarter of 2023. Adjusted EBITDA is calculated by subtracting mark-to-market adjustments on derivatives related to Ironwood’s 2022 Convertible Notes, restructuring expenses, net interest expense, income taxes, depreciation and amortization, and acquisition-related costs, from GAAP net income. See Non-GAAP Financial Measures below. Cash Flow Highlights. Ironwood ended the first quarter of 2024 with $121.5 million of cash and cash equivalents, compared to $92.2 million of cash and cash equivalents at the end of 2023. In the first quarter of 2024, Ironwood repaid $25.0 million of the outstanding principal balance on its revolving credit facility used to partially finance the VectivBio acquisition. The outstanding principal balance on the revolving credit facility was $275.0 million as of March 31, 2024. Ironwood generated $45.0 million in cash from operations in the first quarter of 2024, compared to $80.2 million in cash from operations in the first quarter of 2023. Ironwood 2024 Financial Guidance. Ironwood has revised its FY 2024 financial guidance due to a LINZESS gross-to-net change in estimate related to the year ended December 31, 2023. Ironwood now expects: Prior 2024 Guidance (February 15, 2024) Revised 2024 Guidance2 (May 9, 2024) U.S. LINZESS Net Sales3 Low-single digits % growth Mid-single digits % decline Total Revenue $435 to $455 million $405 to $425 million Adjusted EBITDA1 >$150 million Excludes potential CNP-104 option exercise >$120 million Excludes potential CNP-104 option exercise 1 Adjusted EBITDA is calculated by subtracting restructuring expenses, net interest expense, income taxes, depreciation and amortization, and acquisition-related costs from GAAP net income. For purposes of the 2024 guidance, Ironwood has assumed it will not incur material expenses related to business development activities in 2024 and excludes any costs associated with potential CNP-104 option exercise. Ironwood does not provide guidance on GAAP net income or a reconciliation of expected adjusted EBITDA to expected GAAP net income because, without unreasonable efforts, it is unable to predict with reasonable certainty the non-GAAP adjustments used to calculate adjusted EBITDA. These adjustments are uncertain, depend on various factors and could have a material impact on GAAP net income for the guidance period. Management believes this non-GAAP information is useful for investors, taken in conjunction with Ironwood’s GAAP financial statements, because it provides greater transparency and period-over-period comparability with respect to Ironwood’s operating performance. These measures are also used by management to assess the performance of the business. Investors should consider these non-GAAP measures only as a supplement to, not as a substitute for or as superior to, measures of financial performance prepared in accordance with GAAP. In addition, these non-GAAP financial measures are unlikely to be comparable with non-GAAP information provided by other companies. 2 Based on information provided by AbbVie, Ironwood estimates a $60.0 million LINZESS gross-to-net change related to the year ended December 31, 2023, and has recorded a $30.0 million reduction to collaborative arrangements revenue in its first quarter 2024 financial statements to reflect this change in estimate. 3 2024 U.S. LINZESS Net Sales guidance presented as year-over-year change relative to 2023 U.S. LINZESS Net Sales as reported by AbbVie of $1,073.2 million. Non-GAAP Financial Measures Ironwood presents non-GAAP net income and non-GAAP net income per share to exclude the impact, net of tax effects, of net gains and losses on derivatives related to Ironwood’s 2022 Convertible Notes that are required to be marked-to-market, amortization of acquired intangible assets, restructuring expenses, and acquisition-related costs. Non-GAAP adjustments are further detailed below: The gains and losses on the derivatives related to Ironwood’s 2022 Convertible Notes were highly variable, difficult to predict and of a size that could have a substantial impact on the company’s reported results of operations in any given period. Amortization of acquired intangible assets are non-cash expenses arising in connection with the acquisition of VectivBio and are considered to be non-recurring. Restructuring expenses are considered to be a non-recurring event as they are associated with distinct operational decisions. Included in restructuring expenses are costs associated with exit and disposal activities. Acquisition-related costs in connection with the acquisition of VectivBio are considered to be non-recurring and include direct and incremental costs associated with the acquisition and integration of VectivBio to the extent such costs were not classified as capitalizable transaction costs attributed to the cost of net assets acquired through acquisition accounting. Ironwood also presents adjusted EBITDA, a non-GAAP measure, as well as guidance on adjusted EBITDA. Adjusted EBITDA is calculated by subtracting mark-to-market adjustments on derivatives related to Ironwood’s 2022 Convertible Notes, restructuring expenses, net interest expense, income taxes, depreciation and amortization, and acquisition-related costs from GAAP net income. The adjustments are made on a similar basis as described above related to non-GAAP net income, as applicable. Management believes this non-GAAP information is useful for investors, taken in conjunction with Ironwood’s GAAP financial statements, because it provides greater transparency and period-over-period comparability with respect to Ironwood’s operating performance. These measures are also used by management to assess the performance of the business. Investors should consider these non-GAAP measures only as a supplement to, not as a substitute for or as superior to, measures of financial performance prepared in accordance with GAAP. In addition, these non-GAAP financial measures are unlikely to be comparable with non-GAAP information provided by other companies. For a reconciliation of non-GAAP net income and non-GAAP net income per share to GAAP net income and GAAP net income per share, respectively, and for a reconciliation of adjusted EBITDA to GAAP net income, please refer to the tables at the end of this press release. Ironwood does not provide guidance on GAAP net income or a reconciliation of expected adjusted EBITDA to expected GAAP net income because, without unreasonable efforts, it is unable to predict with reasonable certainty the non-GAAP adjustments used to calculate adjusted EBITDA. These adjustments are uncertain, depend on various factors and could have a material impact on GAAP net income for the guidance period. Conference Call Information Ironwood will host a conference call and webcast at 8:30 a.m. Eastern Time on Thursday, May 9, 2024 to discuss its first quarter 2024 results and recent business activities. Individuals interested in participating in the call should dial (888) 596-4144 (U.S. and Canada) or (646) 968-2525 (international) using conference ID number and event passcode 3416473. To access the webcast, please visit the Investors section of Ironwood’s website at at least 15 minutes prior to the start of the call to ensure adequate time for any software downloads that may be required. The call will be available for replay via telephone starting at approximately 11:30 a.m. Eastern Time on May 9, 2024, running through 11:59 p.m. Eastern Time on May 23, 2024. To listen to the replay, dial (800) 770-2030 (U.S. and Canada) or (609) 800-9909 (international) using conference ID number 3416473. The archived webcast will be available on Ironwood’s website for 1 year beginning approximately one hour after the call has completed. About Ironwood Pharmaceuticals Ironwood Pharmaceuticals (Nasdaq: IRWD), an S&P SmallCap 600® company, is a leading gastrointestinal (GI) healthcare company on a mission to advance the treatment of GI diseases and redefine the standard of care for GI patients. We are pioneers in the development of LINZESS® (linaclotide), the U.S. branded prescription market leader for adults with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC). LINZESS is also approved for the treatment of functional constipation in pediatric patients ages 6-17 years-old. Ironwood is also advancing apraglutide, a next-generation, long-acting synthetic GLP-2 analog being developed for rare gastrointestinal diseases, including short bowel syndrome with intestinal failure (SBS-IF) as well as several earlier stage assets. Building upon our history of GI innovation, we keep patients at the heart of our R&D and commercialization efforts to reduce the burden of GI diseases and address significant unmet needs. Founded in 1998, Ironwood Pharmaceuticals is headquartered in Boston, Massachusetts, with a site in Basel, Switzerland. We routinely post information that may be important to investors on our website at . In addition, follow us on X and on LinkedIn. About LINZESS (Linaclotide) LINZESS® is the #1 prescribed brand in the U.S. for the treatment of adult patients with irritable bowel syndrome with constipation (“IBS-C”) or chronic idiopathic constipation (“CIC”), based on IQVIA data. LINZESS is a once-daily capsule that helps relieve the abdominal pain, constipation, and overall abdominal symptoms of bloating, discomfort and pain associated with IBS-C, as well as the constipation, infrequent stools, hard stools, straining, and incomplete evacuation associated with CIC. LINZESS relieves constipation in children and adolescents aged 6 to 17 years with functional constipation. The recommended dose is 290 mcg for IBS-C patients and 145 mcg for CIC patients, with a 72 mcg dose approved for use in CIC depending on individual patient presentation or tolerability. In children with functional constipation aged 6 to 17 years, the recommended dose is 72 mcg. LINZESS is not a laxative; it is the first medicine approved by the FDA in a class called GC-C agonists. LINZESS contains a peptide called linaclotide that activates the GC-C receptor in the intestine. Activation of GC-C is thought to result in increased intestinal fluid secretion and accelerated transit and a decrease in the activity of pain-sensing nerves in the intestine. The clinical relevance of the effect on pain fibers, which is based on nonclinical studies, has not been established. In the United States, Ironwood and AbbVie co-develop and co-commercialize LINZESS for the treatment of adults with IBS-C or CIC. In Europe, AbbVie markets linaclotide under the brand name CONSTELLA® for the treatment of adults with moderate to severe IBS-C. In Japan, Ironwood's partner, Astellas, markets linaclotide under the brand name LINZESS for the treatment of adults with IBS-C or CIC. Ironwood also has partnered with AstraZeneca for development and commercialization of LINZESS in China, and with AbbVie for development and commercialization of linaclotide in all other territories worldwide. LINZESS Important Safety Information INDICATIONS AND USAGE LINZESS® (linaclotide) is indicated for the treatment of both irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) in adults and functional constipation (FC) in children and adolescents 6 to 17 years of age. It is not known if LINZESS is safe and effective in children with FC less than 6 years of age or in children with IBS-C less than 18 years of age. IMPORTANT SAFETY INFORMATION WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS LESS THAN 2 YEARS OF AGE LINZESS is contraindicated in patients less than 2 years of age. In nonclinical studies in neonatal mice, administration of a single, clinically relevant adult oral dose of linaclotide caused deaths due to dehydration. Contraindications LINZESS is contraindicated in patients less than 2 years of age due to the risk of serious dehydration. LINZESS is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. Warnings and Precautions LINZESS is contraindicated in patients less than 2 years of age. In neonatal mice, linaclotide increased fluid secretion as a consequence of age-dependent elevated guanylate cyclase (GC-C) agonism, which was associated with increased mortality within the first 24 hours due to dehydration. There was no age dependent trend in GC-C intestinal expression in a clinical study of children 2 to less than 18 years of age; however, there are insufficient data available on GC-C intestinal expression in children less than 2 years of age to assess the risk of developing diarrhea and its potentially serious consequences in these patients. Diarrhea In adults, diarrhea was the most common adverse reaction in LINZESS-treated patients in the pooled IBS-C and CIC double-blind placebo-controlled trials. The incidence of diarrhea was similar in the IBS-C and CIC populations. Severe diarrhea was reported in 2% of 145 mcg and 290 mcg LINZESS-treated patients and in <1% of 72 mcg LINZESS-treated CIC patients. In children and adolescents 6 to 17 years of age, diarrhea was the most common adverse reaction in 72 mcg LINZESS-treated patients in the FC double-blind placebo-controlled trial. Severe diarrhea was reported in <1% of 72 mcg LINZESS treated patients. If severe diarrhea occurs, dosing should be suspended and the patient rehydrated. Common Adverse Reactions (incidence ≥2% and greater than placebo) In IBS-C or CIC adult patients: diarrhea, abdominal pain, flatulence, and abdominal distension. In FC pediatric patients: diarrhea. Please see full Prescribing Information including Boxed Warning: LINZESS® and CONSTELLA® are registered trademarks of Ironwood Pharmaceuticals, Inc. Any other trademarks referred to in this press release are the property of their respective owners. All rights reserved. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Investors are cautioned not to place undue reliance on these forward-looking statements, including statements about Ironwood’s ability to execute on its mission; Ironwood’s strategy, business, financial position and operations; Ironwood’s ability to drive growth and profitability; the commercial potential of LINZESS; our financial performance and results, and guidance and expectations related thereto; LINZESS prescription demand growth, LINZESS U.S. net sales growth, total revenue and adjusted EBITDA in 2024; our plan to NDA for apraglutide as soon as possible and apraglutide's potential, if approved, to be the first and only once-weekly GLP-2 analog for adult SBS patients who are dependent on PS; our belief that the positive results from the STARS Phase III trial, coupled with our proven track record of effective commercial execution, position Ironwood uniquely in the market and reinforce our belief in the long-term value potential of apraglutide for patients and shareholders; our plan to NDA for apraglutide for adult SBS patients dependent on PS as soon as possible; and the timing of topline data for CNP-104 and that, if successful, CNP-104 has the potential to be the first approved disease modifying therapy for PBC. These forward-looking statements speak only as of the date of this press release, and Ironwood undertakes no obligation to update these forward-looking statements. Each forward-looking statement is subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statement. Applicable risks and uncertainties include those related to the effectiveness of development and commercialization efforts by us and our partners; preclinical and clinical development, manufacturing and formulation development of linaclotide, apraglutide, CNP-104, IW-3300, and our other product candidates; the risk of uncertainty relating to pricing and reimbursement policies in the U.S., which, if not favorable for our products, could hinder or prevent our products’ commercial success; the risk that clinical programs and studies, including for linaclotide pediatric programs, apraglutide, CNP-104 and IW-3300, may not progress or develop as anticipated, including that studies are delayed or discontinued for any reason, such as safety, tolerability, enrollment, manufacturing, economic or other reasons; the risk that findings from our completed nonclinical studies and clinical trials may not be replicated in later trials and earlier-stage clinical trials may not be predictive of the results we may obtain in later-stage clinical trials or of the likelihood of regulatory approval; the risk of competition or that new products may emerge that provide different or better alternatives for treatment of the conditions that our products are approved to treat; the risk that we are unable to execute on our strategy to in-license externally developed products or product candidates; the risk that we are unable to successfully partner with other companies to develop and commercialize products or product candidates; the risk that healthcare reform and other governmental and private payor initiatives may have an adverse effect upon or prevent our products’ or product candidates’ commercial success; the efficacy, safety and tolerability of linaclotide and our product candidates; the risk that the commercial and therapeutic opportunities for LINZESS, apraglutide or our other product candidates are not as we expect; decisions by regulatory and judicial authorities; the risk we may never get additional patent protection for linaclotide, apraglutide and other product candidates, that patents for linaclotide, apraglutide or other products may not provide adequate protection from competition, or that we are not able to successfully protect such patents; the risk that we are unable to manage our expenses or cash use, or are unable to commercialize our products as expected; the risk that the development of any of our linaclotide pediatric programs, apraglutide, CNP-104 and/or IW-3300 is not successful or that any of our product candidates does not receive regulatory approval or is not successfully commercialized; outcomes in legal proceedings to protect or enforce the patents relating to our products and product candidates, including abbreviated new drug application litigation; the risk that financial and operating results may differ from our projections; developments in the intellectual property landscape; challenges from and rights of competitors or potential competitors; the risk that our planned investments do not have the anticipated effect on our company revenues; developments in accounting guidance or practice; Ironwood’s or AbbVie’s accounting practices, including reporting and settlement practices as between Ironwood and AbbVie; the risk that our indebtedness could adversely affect our financial condition or restrict our future operations; and the risks listed under the heading “Risk Factors” and elsewhere in our Annual Report on Form 10-K for the year ended December 31, 2023, and in our subsequent Securities and Exchange Commission filings. Condensed Consolidated Balance Sheets (In thousands) (unaudited) March 31, 2024 December 31, 2023 Assets Cash and cash equivalents $ 121,540 $ 92,154 Accounts receivable, net 72,015 129,122 Prepaid expenses and other current assets 14,619 12,012 Total current assets 208,174 233,288 Property and equipment, net 5,288 5,585 Operating lease right-of-use assets 12,208 12,586 Intangible assets, net 3,478 3,682 Deferred tax assets 206,273 212,324 Other assets 3,398 3,608 Total assets $ 438,819 $ 471,073 Liabilities and stockholders’ equity Accounts payable $ 6,222 $ 7,830 Accrued research and development costs 11,880 21,331 Accrued expenses and other current liabilities 31,398 44,254 Current portion of operating lease liabilities 3,142 3,126 Current portion on convertible senior notes 199,800 199,560 Total current liabilities 252,442 276,101 Operating lease liabilities, net of current portion 14,004 14,543 Convertible senior notes, net of current portion 198,477 198,309 Revolving credit facility 275,000 300,000 Other liabilities 29,414 28,415 Total stockholders’ deficit (330,518) (346,295) Total liabilities and stockholders’ deficit $ 438,819 $ 471,073 Condensed Consolidated Statements of Income (Loss) (In thousands, except per share amounts) (unaudited) Three Months Ended March 31, 2024 2023 Total revenue1 74,877 104,061 Collaborative arrangements revenue1 71,700 101,600 Operating expenses: Research and development 25,815 12,847 Selling, general and administrative 37,605 31,117 Restructuring expenses 437 - Total operating expenses 63,857 43,964 Income from operations 11,020 60,097 Other income (expense): Interest expense and other financing costs (7,231) (1,527) Interest and investment income 1,169 7,272 Gain on derivatives - 19 Other income (expense), net (6,062) 5,764 Income before income taxes 4,958 65,861 Income tax expense (9,120) (20,147) GAAP net income (loss)1 $ (4,162) $ 45,714 GAAP net income (loss) per share—basic1 ($0.03) $0.30 GAAP net income (loss) per share—diluted1 ($0.03) $0.25 ______________________________ 1 Figures presented in Q1 2024 reflect a $30.0 million reduction to collaborative arrangements revenue due to a LINZESS gross-to-net change in estimate related to the year ended December 31, 2023. Reconciliation of GAAP Results to Non-GAAP Financial Measures (In thousands, except per share amounts) (unaudited) A reconciliation between net income (loss) on a GAAP basis and on a non-GAAP basis is as follows: Three Months Ended March 31, 2024 2023 GAAP net income (loss)1,2 $ (4,162) $ 45,714 Adjustments: Mark-to-market adjustments on the derivatives related to convertible notes, net - (19) Amortization of acquired intangible assets 204 - Restructuring expenses 437 - Acquisition-related costs 787 - Tax effect of adjustments (199) - Non-GAAP net income (loss)1,2 $ (2,933) $ 45,695 ______________________________ 1 Q1 2024 GAAP and non-GAAP net loss reflect costs associated with the acquisition of VectivBio in the second quarter of 2023. 2 Q1 2024 GAAP and non-GAAP net loss reflect a $30.0 million reduction to collaborative arrangements revenue due to a LINZESS gross-to-net change in estimate related to the year ended December 31, 2023. A reconciliation between basic net income (loss) per share on a GAAP basis and on a non-GAAP basis is as follows: Three Months Ended March 31, 2024 2023 GAAP net income (loss) – basic $ (0.03) $ 0.30 Adjustments to GAAP net income (loss) per share (as detailed above) 0.01 (0.00) Non-GAAP net income (loss) per share – basic $ (0.02) $ 0.30 Weighted average number of common shares used to calculate net income (loss) per share — basic 157,700 154,452 A reconciliation between diluted net income (loss) per share on a GAAP basis and on a non-GAAP basis is as follows: Three Months Ended March 31, 2024 2023 GAAP net income (loss) per share – diluted $ (0.03) $ 0.25 Adjustments to GAAP net income (loss) per share (as detailed above) 0.01 (0.00) Non-GAAP net income (loss) per share – diluted $ (0.02) $ 0.25 Weighted average number of common shares used to calculate net income (loss) per share — diluted 157,700 186,680 Reconciliation of GAAP Net Income (Loss) to Adjusted EBITDA (In thousands) (unaudited) A reconciliation of GAAP net income (loss) to adjusted EBITDA: Three Months Ended March 31, 2024 2023 GAAP net income (loss)1,2 $ (4,162) $ 45,714 Adjustments: Mark-to-market adjustments on the derivatives related to convertible notes, net - (19) Restructuring expenses 437 - Interest expense 7,231 1,527 Interest and investment income (1,169) (7,272) Income tax expense 9,120 20,147 Depreciation and amortization 513 286 Acquisition-related costs 787 - Adjusted EBITDA1,2 $ 12,757 $ 60,383 ______________________________ 1 Q1 2024 GAAP net loss and adjusted EBITDA reflect costs associated with the acquisition of VectivBio in the second quarter of 2023. 2 Q1 2024 GAAP net loss and adjusted EBITDA reflect a $30.0 million reduction to collaborative arrangements revenue due to a LINZESS gross-to-net change in estimate related to the year ended December 31, 2023. U.S. LINZESS Commercial Collaboration1 Revenue/Expense Calculation (In thousands) (unaudited) Three Months Ended March 31, 2024 2023 LINZESS U.S. net sales as reported by AbbVie2 $ 256,600 $ 250,214 AbbVie & Ironwood commercial costs, expenses and other discounts3 73,362 66,408 Commercial profit on sales of LINZESS $ 183,238 $ 183,806 Commercial Margin4 71% 73% Ironwood’s share of net profit 91,619 91,903 Reimbursement for Ironwood’s commercial expenses 10,096 9,728 Ironwood’s portion of gross-to-net change in estimate5 (30,000) - Ironwood’s collaborative arrangements revenue $ 71,715 $ 101,631 ______________________________ 1 Ironwood collaborates with AbbVie on the development and commercialization of linaclotide in North America. Under the terms of the collaboration agreement, Ironwood receives 50% of the net profits and bears 50% of the net losses from the commercial sale of LINZESS in the U.S. The purpose of this table is to present calculations of Ironwood’s share of net profit (loss) generated from the sales of LINZESS in the U.S. and Ironwood’s collaboration revenue/expense; however, the table does not present the research and development expenses related to LINZESS in the U.S. that are shared equally between the parties under the collaboration agreement. Please refer to the table at the end of this press release for net profit for the U.S. LINZESS brand collaboration with AbbVie. 2 LINZESS net sales are recognized using AbbVie’s revenue recognition accounting policies and reporting conventions. As a result, certain rebates and discounts are classified as LINZESS U.S. commercial costs, expenses and other discounts within Ironwood’s calculation of collaborative arrangements revenue. 3 Includes certain discounts recognized and cost of goods sold incurred by AbbVie; also includes commercial costs incurred by AbbVie and Ironwood that are attributable to the cost-sharing arrangement between the parties. 4 Commercial margin is defined as commercial profit on sales of LINZESS as a percent of total LINZESS U.S. net sales. 5 Based on information provided by AbbVie, Ironwood estimates a $60.0 million LINZESS gross-to-net change related to the year ended December 31, 2023, and has recorded a $30.0 million reduction to collaborative arrangements revenue in its first quarter 2024 financial statements to reflect this change in estimate. US LINZESS Full Brand Collaboration1 Revenue/Expense Calculation (In thousands) (unaudited) Three Months Ended March 31, 2024 2023 LINZESS U.S. net sales as reported by AbbVie2 $ 256,600 $ 250,214 AbbVie & Ironwood commercial costs, expenses and other discounts3 73,362 66,408 AbbVie & Ironwood R&D Expenses4 7,636 8,650 Total net profit on sales of LINZESS5 $ 175,602 $ 175,156 ______________________________ 1 Ironwood collaborates with AbbVie on the development and commercialization of linaclotide in North America. Under the terms of the collaboration agreement, Ironwood receives 50% of the net profits and bears 50% of the net losses from the commercial sale of LINZESS in the U.S. The purpose of this table is to present calculations of the total net profit (loss) generated from the sales of LINZESS in the U.S., including the commercial costs and expenses and the research and development expenses related to LINZESS in the U.S. that are shared equally between the parties under the collaboration agreement. 2 LINZESS net sales are recognized using AbbVie’s revenue recognition accounting policies and reporting conventions. As a result, certain rebates and discounts are classified as LINZESS U.S. commercial costs, expenses and other discounts within Ironwood’s calculation of collaborative arrangements revenue. 3 Includes certain discounts recognized and cost of goods sold incurred by AbbVie; also includes commercial costs incurred by AbbVie and Ironwood that are attributable to the cost-sharing arrangement between the parties. 4 R&D expenses related to LINZESS in the U.S. are shared equally between Ironwood and AbbVie under the collaboration agreement. 5 Total net profit on sales of LINZESS does not reflect the estimated gross-to-net change related to the year ended December 31, 2023. View source version on businesswire.com: Contacts Investors: Greg Martini, 617-374-5230 gmartini@ironwoodpharma.com Matt Roache, 617-621-8395 mroache@ironwoodpharma.com Media: Beth Calitri, 978-417-2031 bcalitri@ironwoodpharma.com Source: Ironwood Pharmaceuticals, Inc. View this news release online at: