Trofinetide

导语2026年5月12日，Unravel Biosciences（以下简称“Unravel”）公司宣布了一项研发里程碑：其用于治疗雷特综合征（Rett Syndrome, RTT）和皮特-霍普金斯综合征（Pitt Hopkins Syndrome, PTHS）的在研新药 RVL-001 已在概念验证临床试验中完成首例参与者给药。 RVL-001治疗雷特综合征的适应症已于2024年5月获得美国FDA授予的孤儿药认定。本文将从该药物“老药新用”的研发机制、资质进展、临床试验设计特点及受试者筛选标准等方面梳理RVL-001的研发进展。一、 研发背景：源自哈佛大学Wyss研究所的学术基因 对于雷特综合征社群而言，Unravel 可能还是一个相对陌生的名字。事实上，这家成立于2021年的临床阶段生物技术公司，拥有着极其深厚的学术背景。 Unravel 脱胎于全球著名的哈佛大学Wyss仿生工程研究所。其联合创始人兼首席执行官 Richard Novak 博士曾在Wyss研究所担任首席工程师长达十余年，在药物发现系统、先进疾病模型及微流控器官芯片等前沿领域积累了丰富的转化经验。 图1 unravel公司logo（源自官网） RVL-001 赖以被发掘的核心基石——BioNAV™ 药物发现引擎，正是基于 Unravel 从哈佛大学和塔夫茨大学（Tufts University）独家获得授权的技术平台进一步开发而来。该技术的最初雏形，源于一项由美国国防高级研究计划局（DARPA）资助的研究项目。依托哈佛的交叉学科底蕴，Unravel 的研发团队首创了将“患者转录组数据分析”与“高通量体内动物模型”相结合的药物筛选模式，旨在打破传统罕见病新药研发中“耗时长、失败率高”的困局。二、 RVL-001：“老药新用”，基于转录组网络预测的潜在疗法 雷特综合征是一种罕见的神经发育障碍性疾病，会导致患者在认知、运动和自主神经功能方面出现严重障碍。目前，尽管已有一款疗法获批，但临床上仍需要具备实质性疗效且安全耐受的新型治疗方案。 RVL-001 是一种伏立诺他（vorinostat）的特有口服配方。伏立诺他作为一种组蛋白去乙酰化酶（HDAC）抑制剂，最初于2006年获得美国FDA批准上市，用于治疗皮肤T细胞淋巴瘤。因此，RVL-001 针对罕见病雷特综合征的研发，是典型的 “老药新用” 策略。 图2 unravel公司研发管线图（源自官网） 该药物在新适应症上的发掘，正是运用了前文提到的 BioNAV™ 平台。系统建立了一个名为“活体分子双胞胎（Living Molecular Twins）”的动态转录组网络图谱，通过计算预测药物能否将雷特综合征的转录组特征恢复成健康状态，从而将伏立诺他识别为高潜力的候选药物。 图3 vorinostat临床前研究论文 在临床前研究阶段，研究人员首先使用 CRISPR 基因编辑技术构建了雷特综合征非洲爪蟾蝌蚪模型进行体内高通量药物筛选，随后在MeCP2 基因敲除小鼠模型中进行了验证。 结果显示，伏立诺他广泛改善了模型动物的中枢神经系统及胃肠道、呼吸系统等非中枢神经系统异常。文献表明，伏立诺他是首个在症状出现后给药，仍能在多个器官系统中展现出临床前疗效的雷特综合征候选药物。基因网络分析进一步提示，这种跨器官的正常化效应，其机制可能是该药物对细胞微管乙酰化代谢和翻译后修饰的调控。二、 监管资质：获FDA孤儿药认定与优先审查支持 在监管资质方面，RVL-001 已取得阶段性支持，为其后续研发降低了部分政策阻力。• FDA 孤儿药资格： 2024年5月，美国食品药品监督管理局（FDA）正式授予 RVL-001（vorinostat）治疗雷特综合征的孤儿药资格认定（ODD）。• 优先审查与快速通道： 本次在哥伦比亚开展的试验，已通过哥伦比亚国家食品药品监督管理局（INVIMA）的孤儿药与高医疗需求疾病试点项目，获得了优先审查和快速通道（Fast track）批准。 图4 vorinostat（RVL-001）获FDA授予的孤儿药资格（源自官网）三、 RETT REVOLUTION 临床试验设计 目前，针对 RVL-001 的临床概念验证研究已在哥伦比亚麦德林市的安蒂奥基亚大学PECET临床试验组（GIC-PECET）启动，预计将于2027年第一季度完成。（临床试验具体信息：https://clinicaltrials.gov/study/NCT07150013） 图5 RETT REVOLUTION临床试验 针对雷特综合征的临床试验名为 RETT REVOLUTION，其设计采用了 “N-of-1”（单患者自身对照）交叉研究方法，在单盲、安慰剂对照的条件下进行。目标招募 15 名典型雷特综合征患者。给药方案设计 在比较安全性和疗效的分析中，每位患者都将作为自身的对照。试验周期总计20周，患者将依次经历以下阶段：1. 4周安慰剂基线期： 生成基线对照数据；2. 8周低剂量期： 每日口服 80mg/m² 的伏立诺他；3. 8周高剂量期： 剂量递增至每日 160mg/m² 的伏立诺他。四、 关键入排标准 为了研究数据的科学性与患者的安全，试验设立了明确的受试者筛选标准。主要入选标准 • 性别与年龄： 筛选时年龄在 6 岁至 21 岁（含）的女性受试者；• 确诊依据： 符合典型雷特综合征（RTT）诊断标准，且具有明确的致病性 MECP2 基因变异；• 疾病阶段： 处于“退化后阶段”，且在筛选前4个月内行走、手部功能、语言或沟通技能未出现退化；• 既往治疗稳定： 基线前至少4周内维持稳定的药物/非药物治疗方案。如正服用trofinetide/Daybue，需在筛选前6个月内保持剂量稳定。主要排除标准 • 患有与 MECP2 突变无关的具有临床意义的内科疾病，或近期有重大手术计划；• 有脑损伤、中风或缺氧缺血性脑病史；• 筛选时存在具有临床意义的心电图异常（如QT间期延长）、实验室化验值异常或肝病（转氨酶 > 正常范围上限1.5倍）；• 基线前12周内接受过生长激素、IGF-1或胰岛素治疗；正在服用抗凝药或其他HDAC抑制剂。五、 临床疗效与安全性评估指标 本项探索性研究将通过多维度结局指标（评估时间框架均为 20 周），收集 RVL-001 在人体中的安全性和潜在应答数据。1. 主要结局指标 • 安全性与耐受性： 评估治疗相关不良事件，以及因不良事件终止治疗的患者人数。• 转录组生物标志物分析： 通过 RNA 测序评估转录组网络特征的变化，探索该指标衡量疾病分子特征向健康状态恢复的程度。2. 次要结局指标 采用临床常用的标准化量表评估相关症状的变化趋势：• 总体印象与严重程度： 雷特综合征临床总体印象-改善量表（CGI-I）与严重程度量表（CGI-S）；护理人员印象量表 (CareGI-I)。• 行为与运动： 雷特综合征行为问卷（RSBQ）、修订版运动行为评估（R-MBA）。• 睡眠与肠胃： 修改版儿童睡眠习惯问卷（CSHQ）、胃肠道症状评定量表（GSRS）子集。• 癫痫控制： 通过癫痫发作日记评估发作频率的降低。结 语 RVL-001（伏立诺他）在雷特综合征中的研发已获得FDA孤儿药资格认定，目前正式进入临床人体验证阶段。通过特有的“N-of-1”研究设计，本次在哥伦比亚启动的临床试验将为该药物在雷特综合征中的安全性与潜在临床获益提供早期的客观数据。 我们将持续关注 RETT REVOLUTION 试验的进展，并及时分享后续的数据读出。 免责声明：「守望雷特 Rett Watchers」微信公众号专注介绍雷特综合征及其相关疾病的研究进展。本文仅作信息交流之目的，非治疗方案推荐，如需获得治疗方案指导，请前往正规医院就诊。「守望雷特 Rett Watchers」微信公众号不对任何主体因使用本文内容而导致的任何损失承担责任。 版权说明：本文由「守望雷特 Rett Watchers」微信公众号根据公开资料整理编辑，如需转载请注明出处。 文章撰写：布克文章排版：布克

- First quarter DAYBUE ® GAAP net sales of $101 million, up 20% year-over-year; successful launch of DAYBUE STIX underway - First quarter NUPLAZID ® GAAP net sales of $167 million, up 6% year-over-year on a non-GAAP adjusted basis - Reaffirms expectation for topline results from the Phase 2 remlifanserin study in Alzheimer’s disease psychosis between August and October 2026 SAN DIEGO--(BUSINESS WIRE)--Acadia Pharmaceuticals Inc. (Nasdaq: ACAD), today announced its financial results for the first quarter ended March 31, 2026. “Acadia delivered a solid first quarter of 2026 with total revenues of $268 million, driven by a strong start from DAYBUE, which generated sales of $101 million,” said Catherine Owen Adams, Chief Executive Officer. “We are very encouraged by the early enthusiasm for DAYBUE STIX, which is now broadly available in the U.S., and by the initial uptake during our focused launch. NUPLAZID generated sales of $167 million, supported by strong new referrals and underlying demand, with performance strengthening as the quarter progressed. As we look ahead, we remain focused on advancing our deep, differentiated pipeline, with remlifanserin representing a key value driver as we approach expected Phase 2 topline data in Alzheimer’s disease psychosis later this year. We are reaffirming our full year guidance and remain confident in our ability to deliver long‑term value for both patients and shareholders.” Company Updates Full launch of DAYBUE STIX (trofinetide) in the U.S. is underway, with ~30% of STIX patients being either treatment-naive or returning after previously discontinuing the liquid formulation. Phase 2 topline results readout from the remlifanserin Alzheimer’s disease psychosis study remains on track for August to October 2026 timeframe. Accelerated enrollment in the trofinetide clinical trial in Japan, with topline results now anticipated in the September to November 2026 timeframe. Delphi expert consensus panel recently recommended DAYBUE as part of the standard of care for eligible patients with Rett syndrome. 1 Financial Results Revenues GAAP total revenues, comprised of net product sales from NUPLAZID and DAYBUE, were $268 million for the first quarter of 2026, up 10% as compared to GAAP total revenues of $244 million in the first quarter of 2025, and up 11% as compared to non-GAAP adjusted total revenues of $242 million in the first quarter of 2025. GAAP net product sales of NUPLAZID were $167 million for the first quarter of 2026, up 5% compared to GAAP net product sales of $160 million for the first quarter of 2025, and up 6% as compared to non-GAAP adjusted net product sales of $157 million for the first quarter of 2025. Net product sales of DAYBUE were $101 million for the first quarter of 2026, an increase of 20% as compared to $85 million for the first quarter of 2025. A reconciliation of NUPLAZID non‑GAAP adjusted net sales and non‑GAAP adjusted total revenues is provided in Table 1. A description of these adjustments is included under ‘Non-GAAP Financial Measures.’ Research and Development Research and development expenses for the first quarter of 2026 were $77 million, compared to $78 million for the same period of 2025. Selling, General and Administrative Selling, general and administrative expenses for the first quarter of 2026 were $171 million, compared to $126 million for the same period of 2025. The increase in selling, general and administrative expenses during the first quarter was primarily driven by increased investments to support continued growth of NUPLAZID and DAYBUE. Net Income For the first quarter of 2026, Acadia reported net income of $4 million, or $0.02 per diluted share, compared to a net income of $19 million, or $0.11 per diluted share, for the same period in 2025. Cash and Investments At March 31, 2026, Acadia’s cash, cash equivalents, and investment securities totaled $851 million, compared to $820 million at December 31, 2025. Full Year 2026 Financial Guidance (GAAP): Acadia is reaffirming its 2026 guidance as first provided on February 25, 2026: Total revenues in the range of $1.22 to $1.28 billion. NUPLAZID net product sales in the range of $760 to $790 million. DAYBUE net product sales in the range of $460 to $490 million. R&D expense in the range of $385 to $410 million. SG&A expense in the range of $660 to $700 million. Conference Call and Webcast Information Acadia will host a conference call to discuss the first quarter 2026 results today, Wednesday, May 6, 2026 at 1:30 p.m. PT/4:30 p.m. ET. The conference call may be accessed by registering for the call here . Once registered, participants will receive an email with the dial-in number and unique PIN number to use for accessing the call. About NUPLAZID ® (pimavanserin) Pimavanserin is a selective serotonin inverse agonist and antagonist preferentially targeting 5-HT2A receptors. These receptors are thought to play an important role in neuropsychiatric disorders. In vitro, pimavanserin demonstrated no appreciable binding affinity for dopamine (including D2), histamine, muscarinic, or adrenergic receptors. Pimavanserin was approved for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis by the U.S. Food and Drug Administration in April 2016 under the trade name NUPLAZID. About DAYBUE ® (trofinetide) Trofinetide is a synthetic version of a naturally occurring molecule known as the tripeptide glycine-proline-glutamate (GPE). The mechanism by which trofinetide exerts therapeutic effects in patients with Rett syndrome is unknown. Trofinetide was approved for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older by the U.S. Food and Drug Administration in March 2023 under the trade name DAYBUE or DAYBUE STIX. About Acadia Pharmaceuticals Acadia is committed to turning scientific promise into meaningful innovation that makes the difference for underserved neurological and rare disease communities around the world. Our commercial portfolio includes the first and only FDA-approved treatments for Parkinson’s disease psychosis and Rett syndrome. We are developing the next wave of therapeutic advancements with a robust and diverse pipeline that includes mid- to late-stage programs in Alzheimer’s disease psychosis and Lewy body dementia psychosis, along with earlier-stage programs that address other underserved patient needs. At Acadia, we’re here to be their difference. For more information, visit us at acadia.com and follow us on LinkedIn and X . Non-GAAP Financial Measures This press release contains the following financial measures that do not comply with U.S. generally accepted accounting principles (GAAP): non-GAAP adjusted net sales for NUPLAZID for the first quarter of 2025 and non-GAAP adjusted total revenues for the first quarter of 2025. In preparing these non-GAAP financial results, the Company includes adjustments made to reflect the impact of a change in estimate related to NUPLAZID IRA rebate accruals. Please refer to our press release dated February 25, 2026, for additional details. These non-GAAP financial measures complement GAAP results and are used by management to analyze financial performance and evaluate period-to-period changes. Management believes these non-GAAP financial measures are useful to investors and other users of the Company’s financial statements to facilitate period-to-period comparability. These non-GAAP financial measures are not meant to be considered as a substitute for comparable GAAP measures; should be read in conjunction with the Company’s consolidated financial statements prepared in accordance with GAAP; have no standardized meaning prescribed by GAAP; and are unlikely to be comparable with non-GAAP disclosures released by other companies. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include all statements other than statements of historical fact and can be identified by terms such as “may,” “will,” “should,” “could,” “would,” “expects,” “plans,” “anticipates,” “believes,” “estimates,” “projects,” “predicts,” “potential,” “guidance,” “continue” and similar expressions (including the negative thereof) intended to identify forward-looking statements. Forward-looking statements contained in this press release, include, but are not limited to, statements about: (i) our business strategy, objectives and opportunities, including support for and innovations in our pipeline assets and business development opportunities, DAYBUE sales growth, interest in DAYBUE STIX, and potential for enhanced shareholder value; (ii) plans for, including timing, development and progress of commercialization or regulatory timelines for our products, including NUPLAZID and DAYBUE, and our product candidates; (iii) benefits to be derived from and efficacy of our products, including the potential advantages of our products; (iv) the timing and conduct of our clinical trials; and (v) our estimates regarding our future financial performance, profitability, capital requirements or expenses, including our full year 2026 financial guidance. Forward-looking statements are subject to known and unknown risks, uncertainties, assumptions and other factors that may cause our actual results, performance or achievements to differ materially and adversely from those anticipated or implied by our forward-looking statements. Such risks, uncertainties and other factors include, but are not limited to: our dependency on the continued successful commercialization of our products and our ability to maintain or increase sales of our products; our plans to continue commercial growth; the costs of our commercialization plans and development programs, and the financial impact or revenues from any commercialization we undertake; our ability to obtain necessary regulatory approvals for our product candidates and, if and when approved, market acceptance of our products; the risks associated with clinical trials and their outcomes, including risks of unsuccessful enrollment and negative or inconsistent results; our dependence on third-party collaborators, clinical research organizations, manufacturers, suppliers and distributors; the impact of competitive products and therapies; our ability to generate or obtain the necessary capital to fund our operations; our ability to grow, equip and train our specialized sales forces; our ability to manage the growth and complexity of our organization; our ability to maintain, protect and enhance our intellectual property; and our ability to continue to stay in compliance with applicable laws and regulations. Given the risks and uncertainties, you should not place undue reliance on these forward-looking statements. For a discussion of these and other risks, uncertainties and other factors that may cause our actual results, performance or achievements to differ, please refer to our annual report on Form 10-K for the year ended December 31, 2025 as well as our subsequent filings with the Securities and Exchange Commission from time to time. The forward-looking statements contained herein are made as of the date hereof, and we undertake no obligation to update them after this date, except as required by law. ACADIA PHARMACEUTICALS INC. CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS (in thousands, except per share amounts) (Unaudited) Three Months Ended March 31, 2026 2025 Revenues Product sales, net $ 268,062 $ 244,317 Total revenues 268,062 244,317 Operating expenses Cost of product sales (1)(2) 24,791 20,392 Research and development (2) 76,868 78,265 Selling, general and administrative (2) 171,019 126,370 Total operating expenses 272,678 225,027 (Loss) income from operations (4,616 ) 19,290 Interest income, net 8,055 7,901 Other income 542 588 Income before income taxes 3,981 27,779 Income tax expense 344 8,792 Net income $ 3,637 $ 18,987 Earnings per share: Basic $ 0.02 $ 0.11 Diluted $ 0.02 $ 0.11 Weighted average common shares outstanding: Basic 170,517 166,808 Diluted 172,706 167,668 (1) Includes license fees and royalties (2) Includes the following stock-based compensation expense Cost of product sales $ 328 $ 334 Research and development $ 4,142 $ 3,433 Selling, general and administrative $ 10,228 $ 7,613 ACADIA PHARMACEUTICALS INC. CONDENSED CONSOLIDATED BALANCE SHEETS (in thousands) (Unaudited) March 31, 2026 December 31, 2025 (unaudited) Assets Cash, cash equivalents and investment securities $ 851,458 $ 819,686 Accounts receivable, net 135,350 121,457 Interest and other receivables 13,034 26,774 Inventory 31,574 34,670 Prepaid expenses 64,600 59,526 Total current assets 1,096,016 1,062,113 Property and equipment, net 14,652 7,511 Operating lease right-of-use assets 46,274 47,354 Intangible assets, net 106,171 108,893 Restricted cash 7,846 7,845 Long-term inventory 80,719 76,704 Deferred tax assets 249,624 249,879 Other assets 3,928 3,896 Total assets $ 1,605,230 $ 1,564,195 Liabilities and stockholders’ equity Accounts payable $ 12,246 $ 10,903 Accrued liabilities 293,278 266,211 Total current liabilities 305,524 277,114 Operating lease liabilities 39,003 40,554 Other long-term liabilities 12,637 19,137 Total liabilities 357,164 336,805 Total stockholders’ equity 1,248,066 1,227,390 Total liabilities and stockholders’ equity $ 1,605,230 $ 1,564,195 Table 1. ACADIA PHARMACEUTICALS INC. NON-GAAP RECONCILIATION (in millions) (Unaudited) 1Q25 1Q26 GAAP NUPLAZID Net Sales $ 159.7 $ 166.9 Allocation of 2025 Amount $ (2.3 ) $ — Non-GAAP Adjusted NUPLAZID Net Sales $ 157.4 $ 166.9 DAYBUE Net Sales $ 84.6 $ 101.2 Non-GAAP Adjusted Total Revenues $ 242.0 $ 268.1 References Prange EO, Beisang A, Pehlivan D, et al. Expert Consensus on Real-World Use of Trofinetide for Rett Syndrome Using a Modified Delphi Method. Ann Child Neurol. 2026; 4:38-51. Contacts Investor Contact: Acadia Pharmaceuticals Inc. Al Kildani (858) 261-2872 ir@acadia-pharm.com Acadia Pharmaceuticals Inc. Jessica Tieszen (858) 261-2950 ir@acadia-pharm.com Media Contact: Acadia Pharmaceuticals Inc. Deb Kazenelson (818) 395-3043 media@acadia-pharm.com