Atazanavir Sulfate

FLORHAM PARK, N.J., Oct. 27, 2024 (GLOBE NEWSWIRE) -- Phathom Pharmaceuticals, Inc. (Nasdaq: PHAT), a biopharmaceutical company focused on developing and commercializing novel treatments for gastrointestinal (GI) diseases, today announced that the company will present data from multiple investigational studies for its first-in-class treatment VOQUEZNA® (vonoprazan) tablets at the American College of Gastroenterology (ACG) 2024 Annual Scientific Meeting, being held October 25-30 in Philadelphia, PA. VOQUEZNA is approved for the relief of heartburn associated with Non-Erosive Gastroesophageal Reflux Disease (Non-Erosive GERD), for the treatment of all severities of Erosive Esophagitis, commonly referred to as Erosive GERD, and relief of related heartburn, and in combination with antibiotics for the eradication of Helicobacter pylori (H. pylori) infection.1 VOQUEZNA is the first and only U.S. Food and Drug Administration (FDA)-approved potassium-competitive acid blocker (PCAB).2 Evaluating On-Demand VOQUEZNA Treatment from the PHALCON-NERD-201 Trial3In an oral presentation being presented Monday, October 28 at ACG, Ronnie Fass, M.D., director of the Division of Gastroenterology and Hepatology and medical director of the Digestive Health Center at MetroHealth in Cleveland, Ohio, and lead investigator of the PHALCON-NERD-201 trial, will provide results from a post-hoc analysis of the Phase 2 study. This research, recognized with the ACG Outstanding Research Award in the ‘Esophagus’ category, evaluated the efficacy of As Needed (On-Demand) dosing of VOQUEZNA, compared to placebo, for relief of episodic heartburn in participants with Non-Erosive GERD following a 4-week VOQUEZNA daily dosing “run-in” period. As previously reported, the primary analysis of the study demonstrated that all three VOQUEZNA doses tested (10 mg, 20 mg and 40 mg) had higher percentages of heartburn completely relieved within three hours of dosing and sustained for 24 hours, with significant differences reported as early as one hour. Use of As Needed dosing in this population is investigational as VOQUEZNA has been neither evaluated nor approved by the FDA as an As Needed treatment for Non-Erosive GERD. To understand the practical application of As Needed dosing for VOQUEZNA, the new analysis examined daily heartburn symptom burden at baseline, during daily VOQUEZNA treatment, and upon switching to As Needed treatment after achieving symptom control during the run-in period. It also further evaluated the rate of symptom improvement upon treating new onset heartburn episodes during the As Needed dosing period.3 “As a healthcare provider, the concept of a novel As Needed dosing option for Non-Erosive GERD is highly compelling. I am pleased that ACG has recognized this data as a recipient of the ACG Outstanding Research Award, further reinforcing its importance to the GI community,” said Ronnie Fass, M.D. “The low frequency of heartburn after discontinuing daily VOQUEZNA treatment, coupled with the rapid onset of improvement following As Needed dosing, suggests that transitioning from daily dosing to As Needed treatment is a viable option for patients who previously respond well to daily therapy of VOQUEZNA. These promising results warrant further investigation in a larger and extended As Needed study period.” The double-blind, placebo-controlled PHALCON-NERD Phase 2 study randomized 207 patients who were eligible for On-Demand (“As Needed”) treatment following a 4-week daily dosing run-in period in which patients received VOQUEZNA 20 mg once-daily. Patients without heartburn in the last seven days of the run-in period were evenly randomized to receive 10 mg, 20 mg or 40 mg of VOQUEZNA, or placebo, for six weeks. Results of the study were published in Alimentary Pharmacology & Therapeutics in September 2023.4 Results:3 Patients eligible for the On-Demand period (n=207) were highly symptomatic with a reported mean of 16.1% [95% CI: (13.5%, 18.7%)] heartburn-free days during screening. Heartburn-free days increased during the run-in period to a mean of 82.9% [95% CI: (80.4%, 85.4%)] and remained well above pre-treatment levels (means 71% to 75%) throughout the six-week On-Demand period.The difference in the improvement of treated heartburn episodes between the active and placebo groups became evident within the first hour of dosing (10 mg [75.5%, p<0.0001], 20 mg [69.1%, p = 0.0010], 40 mg [75.5%, p<0.0001], placebo [57.0%]).Over 90% of heartburn episodes treated with VOQUEZNA improved within two hours. Non-Erosive GERD is the largest category of GERD and is characterized by reflux-related symptoms in the absence of esophageal mucosal erosions. An estimated 45 million U.S. adults are living with Non-Erosive GERD, and approximately 15 million are treated with a prescription medicine annually. Despite longstanding treatment options, many patients continue to suffer from heartburn symptoms. As Needed dosing is a unique and differentiated dosing regimen for which proton pump inhibitors (PPIs), a mainstay of GERD treatment, are not approved in the U.S.5 In July 2024, VOQUEZNA was approved by the FDA as a daily dosing treatment for the relief of heartburn associated with Non-Erosive GERD in adults.1 Nocturnal GERD Symptoms in Non-Erosive GERD6 In a poster presentation on Monday, October 28 at ACG, which has received ACG’s Presidential Poster Award, Dr. Catiele Antunes, M.D., Yale New Haven Hospital, will present data looking at the common, yet infrequently evaluated, nocturnal symptoms among patients with Non-Erosive GERD. The study included an exploratory analysis of a validated patient-reported outcomes scale, the Nocturnal Gastro-esophageal reflux disease Symptom Severity and Impact Questionnaire (N-GSSIQ), to determine the severity, morning impact, and concern about nocturnal GERD. “We are very pleased to continue to add to the body of clinical research evaluating the potential benefits of VOQUEZNA for GERD patients,” said Eckhard Leifke, M.D., Chief Medical Officer at Phathom. “In our study, patients who experienced nocturnal GERD symptoms prior to VOQUEZNA treatment found effective and meaningful relief with daily dosing, reinforcing its potent and durable acid suppression profile in helping to address both daytime and nighttime heartburn. While these findings are exploratory, they show promise for the many individuals suffering from nocturnal GERD symptoms.” Results:6 Among 772 subjects, the mean percentage of heartburn-free nights during the screening period was 29.6%, 25.8% and 31.1%, for patients randomized to placebo, VOQUEZNA 10 mg and 20 mg, respectively.After 4 weeks, the least-square (LS) mean percentage of heartburn-free nights was significantly better with 59.9% for VOQUEZNA 10 mg (LS mean difference=16.5%, p<0.0001 vs. placebo), and 56.4% for VOQUEZNA 20 mg (LS mean difference=13.1%, p<0.0001 vs. placebo), compared to 43.3% for placebo. The median percentage of heartburn-free nights was 70.4% for VOQUEZNA 10 mg and 71.0% for VOQUEZNA 20 mg, compared to 45.5% for placebo.N-GSSIQ scores showed significant improvement with VOQUEZNA compared to placebo in total score (LS mean difference vs. placebo of -2.9 and -1.8 for VOQUEZNA 10 mg and 20 mg, respectively; p<0.005 for both comparisons), nocturnal symptom severity (LS mean difference vs. placebo of -5.4 and -3.5 for VOQUEZNA 10 mg and 20 mg; p<0.001 for both comparisons), and concern about nocturnal GERD (LS mean difference vs. placebo of -2.0 for both VOQUEZNA 10 mg and 20 mg; p<0.0001). In addition to these data presentations, Phathom will sponsor a product theater highlighting VOQUEZNA as an approved treatment for GERD and will also have a presence on the exhibit floor at booth #757 throughout the conference. Following the conclusion of ACG 2024, the abstracts will be posted to the publications and scientific section of the Phathom company website. VOQUEZNA is marketed exclusively by Phathom Pharmaceuticals, Inc. and is currently available via prescription. Please visit voqueznapro.com to learn more about VOQUEZNA. About Non-Erosive Gastroesophageal Reflux DiseaseNon-Erosive GERD is the largest category of GERD and is characterized by reflux-related symptoms in the absence of esophageal mucosal erosions. There are over 65 million U.S. patients living with GERD, and it is estimated that approximately 70% of this population have Non-Erosive GERD. Symptoms of Non-Erosive GERD may impact overall quality of life and can include episodic heartburn, especially at night, regurgitation, problems swallowing, and chest pain.7,8 About VOQUEZNA®VOQUEZNA® (vonoprazan) tablets contain vonoprazan, an oral small molecule potassium-competitive acid blocker (PCAB). PCABs are a novel class of medicines that block acid secretion in the stomach. VOQUEZNA is approved in the U.S. for the treatment of adults with Erosive Esophagitis, also known as Erosive GERD, the relief of heartburn associated with Erosive GERD, the relief of heartburn associated with Non-Erosive GERD, and for the treatment of H. pylori infection in combination with either amoxicillin or amoxicillin and clarithromycin. Phathom in-licensed the U.S. rights to vonoprazan from Takeda, which markets the product in Japan and numerous other countries in Asia and Latin America. About Phathom Pharmaceuticals, Inc.Phathom Pharmaceuticals is a biopharmaceutical company focused on the development and commercialization of novel treatments for gastrointestinal diseases. Phathom has in-licensed the exclusive rights to vonoprazan, a first-in-class potassium-competitive acid blocker (PCAB) that is currently marketed in the United States as VOQUEZNA® (vonoprazan) tablets for the treatment of heartburn associated with Non-Erosive GERD in adults, the healing and maintenance of healing of Erosive GERD in adults and associated heartburn, in addition to VOQUEZNA® TRIPLE PAK® (vonoprazan tablets, amoxicillin capsules, clarithromycin tablets) and VOQUEZNA® DUAL PAK® (vonoprazan tablets, amoxicillin capsules) for the treatment of H. pylori infection in adults. For more information about Phathom, visit the company’s website at www.phathompharma.com and follow on LinkedIn and X. INDICATIONS AND USAGE VOQUEZNA® (vonoprazan) is a potassium-competitive acid blocker (PCAB) indicated in adults: for the healing of all grades of Erosive Esophagitis (Erosive Gastroesophageal Reflux Disease or Erosive GERD) and relief of heartburn associated with Erosive GERD.to maintain healing of all grades of Erosive GERD and relief of heartburn associated with Erosive GERD.for the relief of heartburn associated with Non-Erosive GERD.in combination with amoxicillin and clarithromycin for the treatment of Helicobacter pylori (H. pylori) infection.in combination with amoxicillin for the treatment of H. pylori infection. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS VOQUEZNA is contraindicated in patients with a known hypersensitivity to vonoprazan or any component of VOQUEZNA, or in patients receiving rilpivirine-containing products. For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with VOQUEZNA, refer to the Contraindications section of the corresponding prescribing information. WARNINGS AND PRECAUTIONS Presence of Gastric Malignancy: In adults, symptomatic response to therapy with VOQUEZNA does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in patients who have a suboptimal response or an early symptomatic relapse after completing treatment with VOQUEZNA. In older patients, also consider endoscopy. Acute Tubulointerstitial Nephritis: Acute tubulointerstitial nephritis (TIN) has been reported with VOQUEZNA. If suspected, discontinue VOQUEZNA and evaluate patients with suspected acute TIN. Clostridioides difficile-Associated Diarrhea: Published observational studies suggest that proton pump inhibitors (PPIs) may be associated with an increased risk of Clostridioides difficile-associated diarrhea (CDAD), especially in hospitalized patients. VOQUEZNA may also increase the risk of CDAD. Consider CDAD in patients with diarrhea that does not improve. Use the shortest duration of VOQUEZNA appropriate to the condition being treated. CDAD has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with VOQUEZNA, refer to Warnings and Precautions section of the corresponding prescribing information. Bone Fracture: Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine, especially in patients receiving high dose (multiple daily doses) and long-term therapy (a year or longer). Bone fracture, including osteoporosis-related fracture, has also been reported with vonoprazan. Use the shortest duration of VOQUEZNA appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to the established treatment guidelines. Severe Cutaneous Adverse Reactions (SCAR): Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with VOQUEZNA. Discontinue VOQUEZNA at the first signs or symptoms of SCAR or other signs of hypersensitivity and consider further evaluation. Vitamin B12 (Cobalamin) Deficiency: Long-term use of acid-suppressing drugs can lead to malabsorption of Vitamin B12 caused by hypo- or achlorhydria. Vitamin B12 deficiency has been reported postmarketing with vonoprazan. If clinical symptoms consistent with vitamin B12 deficiency are observed in patients treated with VOQUEZNA, consider further workup. Hypomagnesemia and Mineral Metabolism: Hypomagnesemia has been reported postmarketing with vonoprazan. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. Consider monitoring magnesium levels prior to initiation of VOQUEZNA and periodically in patients expected to be on prolonged treatment, in patients taking drugs that may have increased toxicity in the presence of hypomagnesemia or drugs that may cause hypomagnesemia. Treatment of hypomagnesemia may require magnesium replacement and discontinuation of VOQUEZNA. Consider monitoring magnesium and calcium levels prior to initiation of VOQUEZNA and periodically while on treatment in patients with a preexisting risk of hypocalcemia. Supplement with magnesium and/or calcium, as necessary. If hypocalcemia is refractory to treatment, consider discontinuing VOQUEZNA. Interactions with Diagnostic Investigations for Neuroendocrine Tumors: Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Temporarily discontinue VOQUEZNA treatment at least 4 weeks before assessing CgA levels and consider repeating the test if initial CgA levels are high. Fundic Gland Polyps: Use of VOQUEZNA is associated with a risk of fundic gland polyps that increases with long-term use, especially beyond one year. Fundic gland polyps have been reported with vonoprazan in clinical trials and during postmarketing use with PPIs. Most patients who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of VOQUEZNA appropriate to the condition being treated. ADVERSE REACTIONS: Healing of Erosive GERD: The most common adverse reactions (≥2% of patients in the VOQUEZNA arm) include gastritis (3%), diarrhea (2%), abdominal distention (2%), abdominal pain (2%), and nausea (2%). Maintenance of Healed Erosive GERD: The most common adverse reactions (≥3% of patients in the VOQUEZNA arm) include gastritis (6%), abdominal pain (4%), dyspepsia (4%), hypertension (3%), and urinary tract infection (3%). Relief of Heartburn Associated with Non-Erosive GERD: The most common adverse reactions (≥2% of patients in the VOQUEZNA arm) include abdominal pain (2%), constipation (2%), diarrhea (2%), nausea (2%), and urinary tract infection (2%). Treatment of H. Pylori Infection (VOQUEZNA and Amoxicillin): The most common adverse reactions (≥2% in any treatment arm) include diarrhea (5%), abdominal pain (3%), vulvovaginal candidiasis (2%), nasopharyngitis (2%), dysgeusia (1%), headache (1%), and hypertension (1%). Treatment of H. Pylori Infection (VOQUEZNA, Amoxicillin and Clarithromycin): The most common adverse reactions (≥2% in any treatment arm) include dysgeusia (5%), diarrhea (4%), vulvovaginal candidiasis (3%), headache (3%), abdominal pain (2%), hypertension (2%), and nasopharyngitis (<1%). For more information on adverse reactions and laboratory changes with amoxicillin or clarithromycin, refer to Adverse Reactions section of the corresponding prescribing information. DRUG INTERACTIONS VOQUEZNA has the potential for clinically important drug interactions, including interactions with drugs dependent on gastric pH for absorption, drugs that are substrates for certain CYP enzymes, and some diagnostic tests. Avoid concomitant use of VOQUEZNA with atazanavir or nelfinavir. See full Prescribing Information for more details about important drug interactions. Consult the labeling of concomitantly used drugs to obtain further information about interactions with vonoprazan. For information about drug interactions, contraindications, and warnings and precautions of antibacterial agents (amoxicillin or clarithromycin) indicated in combination with VOQUEZNA, refer to their corresponding prescribing information. USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding is not recommended during treatment. Because of the potential risk of adverse liver effects shown in animal studies with vonoprazan, advise patients not to breastfeed during treatment with VOQUEZNA. Renal Impairment: For the healing of Erosive GERD, dosage reduction is recommended in patients with severe renal impairment (eGFR < 30 mL/min). Use of VOQUEZNA is not recommended for the treatment of H. pylori infection in patients with severe renal impairment. Hepatic Impairment: For the healing of Erosive GERD, dosage reduction is recommended in patients with moderate to severe hepatic impairment (Child-Pugh Class B and C). Use of VOQUEZNA is not recommended for the treatment of H. pylori infection in patients with moderate to severe hepatic impairment. You are encouraged to report suspected adverse reactions by contacting Phathom Pharmaceuticals at 1-888-775-PHAT (7428) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Please see full Prescribing Information for VOQUEZNA. Forward-Looking StatementsThis press release contains forward-looking statements. Words such as “may,” “will,” “should,” “expect,” “plan,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplates,” “believes,” “estimates,” “predicts,” “potential” or continue” and similar expressions, are intended to identify forward-looking statements. Investors are cautioned not to place undue reliance on these forward-looking statements, including statements about the ability of vonoprazan to relieve symptoms of GERD following As Needed dosing and to suppress nocturnal symptoms among patients with Non-Erosive GERD. The inclusion of forward-looking statements should not be regarded as a representation by Phathom that any of its plans will be achieved. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in Phathom’s business, including, without limitation: additional data related to vonoprazan to relieve symptoms of GERD following As Needed dosing may be inconsistent with the data produced as of the date hereof, and further analysis of existing data and analysis of new data may lead to conclusions different from those established as of the date hereof; the inherent risks of clinical development of vonoprazan; Phathom’s dependence on third parties in connection with product manufacturing, research and preclinical and clinical testing; regulatory developments in the United States and foreign countries; unexpected adverse side effects or inadequate efficacy of vonoprazan that may limit its development, regulatory approval and/or commercialization, or may result in recalls or product liability claims; Phathom’s ability to obtain and maintain intellectual property protection and non-patent regulatory exclusivity for vonoprazan; Phathom’s estimates regarding patient population and commercial coverage could prove to be inaccurate; and other risks described in the Company’s prior press releases and the Company’s filings with the Securities and Exchange Commission (SEC), including under the heading “Risk Factors” in the Company’s most recent Annual Report on Form 10-K and any subsequent filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and Phathom undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. References VOQUEZNA. Prescribing Information. Phathom Pharmaceuticals; 2024.Data on file. Phathom Pharmaceuticals, Inc. Florham Park, NJFass R, et al. Heartburn Frequency and Symptom Improvement Rates of Treated Episodes when Switching From Daily to On-Demand Vonoprazan Treatment for Non-Erosive Reflux Disease; American College of Gastroenterology (ACG) 2024 abstract; October 25-30, Philadelphia, PA.Fass R, Vaezi M, Sharma P, et al. Randomised clinical trial: Efficacy and safety of on-demand vonoprazan versus placebo for non-erosive reflux disease. Accessed September 17, 2024. Available at: https://doi-org.libproxy1.nus.edu.sg/10.1111/apt.17728Antunes C, Aleem A, Curtis SA. Gastroesophageal reflux disease. NCBI Bookshelf. Accessed January 21, 2024. Available at: https://www-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/books/NBK441938/?report=printableAntunes C, et al. Vonoprazan Improves Nocturnal Gastroesophageal Reflux Symptoms in Non-Erosive Reflux Disease; American College of Gastroenterology (ACG) 2024 abstract; October 25-30, Philadelphia, PA.Machiacado JD, Greer JB, Yadav D. (2021) Epidemiology of Gastrointestinal Diseases. In: Pitchumoni CS, Dharmarajan T, (eds). Geriatric Gastroenterology. Springer, Cham. https://doi-org.libproxy1.nus.edu.sg/10.1007/978-3-030-30192-7_7Antunes C, Aleem A, Curtis SA. Gastroesophageal reflux disease. NCBI Bookshelf. Accessed January 21, 2024. Available at: https://www-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/books/NBK441938/?report=printable MEDIA CONTACTNick Benedetto1-877-742-8466media@phathompharma.com INVESTOR CONTACTEric Sciorilli1-877-742-8466ir@phathompharma.com © 2024 Phathom Pharmaceuticals. All rights reserved.VOQUEZNA, VOQUEZNA DUAL PAK, VOQUEZNA TRIPLE PAK, Phathom Pharmaceuticals, and their respective logos are registered trademarks of Phathom Pharmaceuticals, Inc. 10/24US-VPZ-24-0557

摘要：在过去十年中，人工智能（AI）和机器学习（ML）已成为最被期待对药物研究与开发（R&D）产生变革性影响的突破性技术。这在一定程度上是由计算技术的革命性进步和之前对大量数据收集/处理的限制的并行消散所驱动的。与此同时，将新药推向市场并提供给患者的费用已变得令人望而却步。认识到这些逆风，AI/ML技术因其自动化特性、预测能力以及随之而来的预期效率提升而受到制药行业的欢迎。在过去的15-20年中，ML方法已被用于药物发现，其复杂性不断增加。AI/ML在药物开发中开始产生积极干扰的最新方面是在临床试验的设计、执行和分析中。COVID-19大流行可能会进一步加速临床试验中AI/ML的利用，因为临床试验执行中对数字技术的依赖增加了。随着我们走向一个日益将AI/ML整合到R&D的世界，重要的是要超越相关的流行词和噪音。认识到科学方法在对数据进行推断时并未过时同样重要。这样做将有助于区分希望与炒作，并导致对AI/ML在药物开发中最佳使用的明智决策。本文旨在阐明关键概念，呈现用例，并最终提供洞察力和对AI/ML方法在R&D中最佳使用的平衡观点。 1.引言 人工智能（AI）和机器学习（ML）在过去十年中蓬勃发展，得益于计算技术的革命性进步。这使得在收集和处理大量数据方面的能力有了变革性的提高。与此同时，将新药推向市场并提供给患者的成本已变得令人望而却步。在本文的其余部分，我们使用“R&D”一词来一般性地描述与药物开发相关的研究、科学和流程，从药物发现到临床开发和执行，最后是生命周期管理阶段。开发新药是一个漫长而昂贵的过程，成功率很低，如下估计所示：平均每种药物的研发投资为13亿美元；每种药物的中位开发时间为非肿瘤药物5.9至7.2年，肿瘤药物为13.1年；所有药物开发项目最终获得批准的比例为13.8%。认识到这些逆风，AI/ML技术因其自动化特性、预测能力以及随之而来的预期效率提升而受到药物开发行业的欢迎。显然，从患者和商业的角度来看，需要使药物开发更加高效，从而降低成本，缩短开发时间，并增加成功率（POS）。在过去的15-20年中，ML方法已被用于药物发现，其复杂性不断增加。AI/ML在药物开发中开始产生积极干扰的最新方面是在临床试验的设计、运营和分析中。COVID-19大流行可能会进一步加速临床试验中AI/ML的使用，因为患者数据收集中对数字技术的依赖增加了。通过本文，我们尝试对AI/ML在药物开发中的当前状态进行一般性回顾，并展示可能产生重大影响的新领域。我们希望本文能提供一个平衡的观点，有助于区分希望与炒作，并最终通知和促进AI/ML的最佳使用。我们首先概述与AI/ML相关的基本概念和术语。然后，我们尝试提供关于何时、何地以及如何最佳使用AI/ML技术的见解，强调临床试验数据分析，我们将与传统的基于推断的统计方法进行比较。这之后是AI/ML在R&D中的当前状态总结，包括正在进行的临床试验运营中的用例说明。最后，我们提出未来的视角和挑战。 2.AI和ML：关键概念和术语 在这一部分，我们提供了与AI和ML及其相互依赖性相关的主要概念和术语的概述（见图1和表I）。AI是一种用于创建具有类似人类行为的系统的技术。ML是AI的应用，其中AI是通过使用数据训练的算法实现的。深度学习（DL）是一种ML类型，其灵感模糊地来自人脑的结构，称为人工神经网络。 图1 人工智能与机器学习的年表 人类智能与大脑观察、理解和对不断变化的外部环境做出反应的能力有关。AI领域不仅试图了解人脑的工作原理，还试图构建能够以安全有效的方式对不断变化的外部环境做出反应的智能系统（见图2，AI的简要概述）。研究人员通过专注于人类行为的忠实度或理性（做正确的事情）在思想和行动上，追求了不同版本的AI。AI的子领域可以是一般的，专注于感知、学习、推理，或者是特定的，如下棋。包括哲学、数学和神经科学在内的众多学科为AI技术的发展做出了贡献。作为AI应用的ML，使用统计方法在数据中寻找模式，数据可以是文本、图像或任何数字存储的东西。ML方法通常被分类为监督学习、无监督学习和强化学习。（见图3，监督学习和无监督学习的简要概述。） 图2 人工智能简介 图3 监督学习和无监督学习的简要概述 3.当前状态 AI/ML技术有潜力通过在R&D的多个领域带来显著改进，增加药物开发的成功可能性：新目标识别、理解目标-疾病关联、药物候选选择、蛋白质结构预测、分子化合物设计和优化、了解疾病机制、开发新的预后和预测生物标志物、生物测量数据从可穿戴设备、成像、精准医疗，以及最近的临床试验设计、执行和分析。COVID-19大流行对临床试验执行的影响可能会加速AI和ML在临床试验执行中的使用，因为对数字技术用于数据收集和现场监测的依赖增加了。在临床前领域，自然语言处理（NLP）被用来帮助从生物医学文献、非结构化电子病历（EMR）和保险索赔中提取科学见解，最终帮助识别新目标；预测建模被用来预测蛋白质结构，并促进分子化合物设计和优化，以实现选择具有更高成功概率的药物候选。来自基因组学、成像和使用数字可穿戴设备的高维数据的增加量，导致了ML方法在处理“大p，小n”问题上的快速进步，其中变量数量（“p”）大于样本数量（“n”）。这种方法还为使用来自真实世界数据源的“大数据”进行研究提供了好处，以（i）丰富对药物受益风险概况的理解；（ii）更好地理解治疗序列模式；以及（iii）识别可能从一种治疗中受益更多的患者亚组（精准医疗）。 虽然AI/ML在过去二十年中在药物发现、转化研究和临床前阶段的使用日益复杂，但它们在临床试验运营和数据分析方面的应用却较为缓慢。我们使用“临床试验运营”来指代执行和开展临床试验所涉及的流程，包括选址选择、患者招募、试验监测和数据收集。临床试验数据分析指的是对从试验中收集的参与者临床数据进行数据管理、统计编程和统计分析。在试验运营方面，患者招募一直是一个特别的挑战，估计有80%的试验未能达到入组时间线，大约30%的3期试验因入组挑战而提前终止。试验现场监测（涉及亲自前往现场）是一个重要且昂贵的质量控制步骤，由监管机构强制执行。此外，随着多中心全球试验的开展，临床试验监测已变得劳动密集、耗时且成本高昂。此外，从“最后一个受试者最后访问”的试验里程碑到最后一阶段3试验分析结果提交给监管机构批准的数据包的持续时间，在过去的二十年中基本没有变化，这为AI/ML的积极干扰提供了巨大的机会。缩短这段时间将对我们更快地将药物提供给患者同时降低成本产生巨大影响。中间的步骤包括清洗和锁定试验数据库、生成最后阶段3试验分析结果（通常涉及数百个汇总表、数据列表和图表）、编写临床研究报告、完成疗效和安全性的综合摘要，以及最终创建数据提交包。COVID-19的影响可能会进一步加速将AI/ML整合到临床试验运营中，由于对100%或部分虚拟（或“分散的”）试验的推动增加，以及增加使用数字技术收集患者数据。AI/ML方法可以用来增强患者招募和项目入组，并且还允许实时自动化和“智能”监测临床数据质量和试验现场性能监测。我们相信AI/ML在临床试验运营和临床试验数据分析方面具有潜在的变革性影响，特别是在试验数据分析、临床研究报告的创建和监管提交数据包方面。 4.案例研究 下面，我们提供一些用例来说明AI/ML方法如何被使用或正在改进R&D中的现有方法。 4.1.案例研究1（药物发现）—用于蛋白质结构预测和药物再利用的深度学习 蛋白质的生物学机制由其三维（3D）结构决定，该结构编码在其一维（1D）氨基酸序列中。对蛋白质结构的了解被应用于理解它们的生物学机制，并帮助发现可以抑制或激活蛋白质以治疗目标疾病新疗法。蛋白质错误折叠已被知道在许多疾病中很重要，包括2型糖尿病以及阿尔茨海默病、帕金森病、亨廷顿病和肌萎缩侧索硬化症等神经退行性疾病。鉴于蛋白质1D氨基酸序列与其3D结构之间的知识差距，开发能够准确预测3D蛋白质结构以协助新药发现和理解蛋白质折叠疾病的方法具有重大价值。DeepMind（谷歌）开发的AlphaFold是一种AI网络，用于根据其氨基酸序列确定蛋白质的3D形状。它应用了深度学习方法来预测蛋白质的结构。AlphaFold的核心是一个卷积神经网络，该网络在蛋白质数据银行结构上进行了训练，以预测蛋白质序列中每一对残基之间的距离，给出64×64区域的距离图的概率估计。然后将这些区域拼接在一起，以产生整个蛋白质的距离预测，生成符合距离预测的蛋白质结构。2020年，AlphaFold发布了五个研究不足的SARS-CoV-2靶标的结构预测，包括SARS-CoV-2膜蛋白、Nsp2、Nsp4、Nsp6和木瓜样蛋白酶（C末端域），这将有助于加深对研究不足的生物系统的理解。Beck等人开发了一种基于深度学习的药靶相互作用预测模型，称为分子变换器-药物靶标相互作用（MT-DTI），以基于化学序列和目标蛋白的氨基酸序列预测结合亲和力，而无需它们的结构信息，这可以用来识别可能抑制SARS-CoV-2核心蛋白功能的强效FDA批准药物。Beck等人计算鉴定了几种已知抗病毒药物，如阿扎那韦、瑞德西韦、依法韦、利托那韦和多鲁特格拉韦，预计它们对SARS-CoV-2 3C样蛋白酶表现出抑制效力，并可能作为SARS-CoV-2感染临床试验的候选治疗药物。 4.2.案例研究2（转化研究/精准医疗）—用于开发预测生物标志物的机器学习 现在已经发表了几个成功的案例研究，表明由ML预测模型衍生的生物标志物被用于临床开发中的患者分层。开发了预测模型，以测试从细胞系筛选数据中衍生的模型是否可以用来预测患者对厄洛替尼（非小细胞肺癌和胰腺癌治疗）和索拉非尼（肾癌、肝癌和甲状腺癌治疗）的反应。预测模型以IC50值作为因变量，未处理细胞的基因表达数据作为自变量。整个细胞系面板被用作训练数据集，使用相同药物治疗的患者肿瘤样本生成的基因表达数据被用作测试数据集。测试数据集中的任何信息都没有用于训练药物敏感性预测模型。BATTLE临床试验数据被用作独立测试数据集，以评估通过细胞系数据训练的药物敏感性预测模型的性能。选择并使用了最佳模型来预测IC50值，定义模型预测的药物敏感和耐药组。Li等人将预测模型应用于BATTLE试验中厄洛替尼组的患者分层。模型预测的厄洛替尼敏感患者组的中位无进展生存期（PFS）为3.84个月，而模型预测的厄洛替尼耐药患者的PFS为1.84个月，这表明模型预测的厄洛替尼敏感患者的PFS益处是厄洛替尼耐药患者的两倍以上。同样，模型预测的索拉非尼敏感组的中位PFS益处为2.66个月，超过索拉非尼耐药组，p值为0.006，风险比为0.32（95%CI，0.15至0.72）。模型预测的索拉非尼敏感和模型预测的索拉非尼耐药组的中位PFS分别为4.53和1.87个月。 4.3.案例研究3—非参数贝叶斯学习用于临床试验设计和分析 许多现有的ML方法专注于使用适当的训练数据学习模型类别中的一组参数，这通常被称为模型选择。然而，在实践中遇到的一个重要问题是潜在的模型过拟合或欠拟合，以及发现潜在的数据结构和相关原因。例子包括但不限于：选择聚类问题中的聚类数量、隐马尔可夫模型中的隐藏状态数量、潜在变量模型中的潜在变量数量，或非线性回归中使用的复杂特征。因此，适当地训练ML方法以在真实世界条件下可靠地执行并提供值得信赖的预测是很重要的。交叉验证通常被用作一种有效的方法，以评估ML方法在调整参数选择方面的表现如何。 非参数贝叶斯学习已成为现代机器学习框架中的强大工具，因其灵活性而受到青睐，为模型选择提供了一个非参数的贝叶斯框架。更具体地说，贝叶斯非参数模型允许我们使用无限维参数空间，并仅涉及给定样本集上可用参数的有限子集。其中，狄利克雷过程是目前常用的贝叶斯非参数模型，特别是在狄利克雷过程混合模型（也称为无限混合模型）中。狄利克雷过程混合提供了一种非参数方法来建模密度并在观察到的变量中识别潜在的簇，而无需预先指定混合模型中的组件数量。随着马尔可夫链蒙特卡洛（MCMC）技术的进步，可以从无限混合中直接采样或使用有限截断。 在临床试验设计中有许多此类贝叶斯非参数模型的应用。例如，在肿瘤剂量寻找临床试验中，非参数贝叶斯学习可以提供高效有效的剂量选择。在首次人体肿瘤试验中，通常会招募患有多种癌症类型的患者，这会导致异质性。在免疫肿瘤学和细胞疗法中，这种问题可能更加突出。忽视不同肿瘤类型在安全性或有效性方面的异质性的设计可能导致剂量选择不精确和未来目标人群的识别效率低下。Li等人提出了基于非参数贝叶斯学习的自适应剂量寻找设计，这些设计基于贝叶斯逻辑回归模型（BLRM），允许跨多个人群的数据驱动信息借用，同时考虑到异质性，从而提高剂量搜索的效率和最佳剂量水平估计的准确性。Liu等人将另一种常用的剂量寻找设计，改进的毒性概率区间（mTPI）设计，扩展到BNP-mTPI和fBNP-mTPI，通过在不同适应症中使用贝叶斯非参数学习。这些设计使用狄利克雷过程，这在先验近似中更加灵活，并且可以根据新兴数据的学习自动将患者分组到相似的簇中。 非参数贝叶斯学习也可以应用于主协议，包括篮子、伞形和平台试验，这些试验允许在单一试验中调查多种疗法、多种疾病或两者兼有。使用非参数贝叶斯学习，这些试验有增强的潜力，通过自适应决策加速生成有效性和安全性数据。这可以影响在重大未满足的医疗需求领域减少药物开发时间线。例如，在评估潜在的COVID-19疗法时，自适应平台试验迅速出现为一个关键工具，例如，在自适应COVID-19治疗试验（ACTT）和RECOVERY试验中，使用这种方法证明了瑞德西韦和地塞米松的临床效益。 主协议中的一个关键问题是是否适合跨不同治疗或适应症借用。例如，在理想情况下，篮子试验中的每种肿瘤亚型应该分别进行测试；然而，由于罕见的遗传突变，这通常是不可行的。由于小样本量和变异性，以及如果对亚组信息进行天真的汇总，可能会有潜在的偏差和I型错误膨胀。不同的贝叶斯层次模型（BHMs）已经被开发出来，以克服使用独立测试或天真汇总方法的限制，例如贝叶斯层次混合模型（BHMM）和可交换性-非可交换性（EXNEX）模型。然而，所有这些模型都高度依赖于预先指定的混合参数。当对不同疾病亚型之间的异质性有限的先验信息时，参数的误指定可能是一个问题。为了克服现有参数借用方法的潜在限制，贝叶斯非参数学习正在成为一种强大的工具，允许灵活的收缩建模，用于个体亚组之间的异质性，并自动捕获额外的聚类。Bunn等人表明，这些模型比其他更常用的方法需要的假设更少，并允许在篮子试验中进行更可靠的数据驱动决策。Hupf等人进一步将这些灵活的贝叶斯借用策略扩展到纳入历史或现实世界数据。 4.4.案例研究4—机器学习在精准医疗中的应用 根据最近的估计，在具有新颖疗法的3期试验中，有54%在临床开发中失败，其中57%的失败是由于疗效不足，一个主要因素是未能识别适当的目标患者人群和正确的剂量方案，包括正确的剂量水平和联合伙伴。因此，精准医疗已成为制药行业药物开发的优先事项。一种可能的方法是系统地应用ML模型（a）构建一个预测成功概率的概率模型；（b）识别具有更高治疗益处概率的患者亚组。这将实现患者与正确治疗的最佳匹配，并最大化资源和患者受益。训练数据集可以包括所有正在进行的早期阶段数据、已发布数据和现实世界证据，但限于同一类药物。 建立概率模型的一个主要挑战是定义可以最好地衡量治疗效果的终点。早期临床试验（特别是在肿瘤学中）经常采用与关键性试验不同的主要疗效终点，因为相对更短的随访时间和需要更快的决策。例如，常见的肿瘤学终点是I/II期的总响应率或完全响应率，以及关键性III期试验中的无进展生存期（PFS）和/或总生存期（两者都衡量长期效益）。在肿瘤学中，I/II期试验通常使用单臂设置来建立概念验证并产生治疗益处的假设，而在关键性试验中，特别是在具有对照臂的随机III期试验中，目的是展示优于现有疗法的治疗益处。从早期阶段到晚期阶段的目标终点的变化使得使用早期阶段数据预测关键性试验中的POS非常具有挑战性。使用具有相似机制和/或适应症的药物的先前试验的训练数据集可以帮助建立短期终点和长期终点之间的关系，这最终决定了药物开发的成功。 此外，可以使用无监督学习对患者进行聚类。例如，使用狄利克雷过程的非参数贝叶斯层次模型可以对患者进行分组（无需预先指定的簇数量），具有关键的预测或预后因素，以代表不同水平的治疗益处。这种深度学习方法将为精准医疗临床开发带来效率。 4.5.案例研究5—AI/ML辅助工具用于临床试验监督 由赞助商对试验进行监督是一项关键的质量控制措施，由监管机构强制执行，以确保试验的科学完整性和受试者的安全。随着数据收集的复杂性增加（体积、种类和速度的增加），以及合同研究组织（CRO）/供应商的使用，赞助商对试验现场表现和临床数据的监督变得具有挑战性、耗时且极其昂贵。在所有研究阶段（不包括估计的现场间接成本和赞助商监督研究的成本），试验现场监督是临床试验支出的前三个成本驱动因素之一（占总成本的9-14%）。 对于试验现场表现的监督，基于风险的监督（RBM）最近作为一种潜在的成本节约和有效的替代传统监督的方法出现（赞助商派遣研究监督员按预先指定的时间表访问现场，进行100%源数据验证（SDV））。虽然RBM改进了传统监督，但CRO使用的不一致的RBM方法以及当前操作/临床试验数据审查的前瞻性质—意味着赞助商检测现场表现关键问题的能力可能被延迟或损害（特别是在精益组织中，由于资源有限，CRO的监督具有挑战性）。 对于临床数据质量的监督，目前常用的方法主要依赖于基于已知风险因素的审查传统受试者和/或汇总数据列表和汇总统计数据。缺乏实时数据和广泛可用的自动化工具限制了赞助商前瞻性风险缓解的能力。这种延迟审查可能对试验结果产生重大影响，例如，在急性环境中，主要终点使用电子患者报告结果（ePRO）数据—月度传输可能为时已晚，无法防止不完整或不正确的数据输入。更大的影响是研究团队监督的系统性差距，可能导致关键数据质量问题。 一个潜在的解决方案是使用AI/ML辅助工具来监督试验现场表现和临床数据质量。这样的工具可以提供一个总体框架，覆盖在CRO系统之上，用于监督临床数据质量和现场。在AI/ML的协助下，研究团队可能能够使用高级形式的RBM（风险和信号检测阈值的改进预测）和实时临床数据监督，以提高效率/质量，并在资源有限的环境中降低成本。这种工具可以应用ML和预测分析到当前的RBM和数据质量监督—有效地将当前的研究监督转移到下一代RBM。利用正在进行的试验的累积数据和类似试验的可用数据，不断改进数据质量和现场表现检查，可能对赞助商保护患者安全、缩短试验持续时间和试验成本的能力产生变革性影响。 在数据质量审查方面，研究团队将通过研究团队确定影响试验结果的关键终点的数据字段和组成部分。对于临床数据监督，AI/ML辅助工具可以利用预测分析和R Shiny可视化跨数据库检查和实时“智能监督”进行临床数据质量监督。通过“智能监督”，我们指的是使用AI/ML技术，这些技术不断从累积的试验数据中学习，并改进数据质量检查，包括编辑检查。同样，对于试验现场表现监督，AI/ML工具可以从Transcelerate（一个非营利的跨制药联盟）的关键风险指标（KRIs）库和团队指定的阈值开始，以识别基于运营数据的问题现场。此外，AI/ML工具的“智能”特性可以使用累积数据不断改进构成RBM的目标现场监督的精度。本文的作者目前正在与麻省理工学院的研究团队合作，推进贝叶斯概率编程方法的研究，这可能有助于开发具有上述特征的AI/ML工具，用于监督临床试验数据质量和试验现场表现。 5.总结 AI/ML作为研究与开发（R&D）领域的一个分支，拥有巨大的增长潜力。与大多数技术进步一样，这既带来了挑战，也带来了希望。由于数字技术的使用，现代数据收集的数据量和维度将持续显著增加。这将增加AI/ML技术深化对生物系统的理解、为新适应症重新利用药物以及在药物开发中指导临床试验的研究设计和分析的机会。 尽管最近ML/AI方法的发展代表了重大的技术进步，但如果我们不能区分混杂因素、使用可靠的算法、查看正确的数据，并且完全理解终点和数据收集背后的临床问题，得出的结论可能是误导性的。正确训练ML算法以在实践中使用各种数据场景是至关重要的。此外，并非每个研究问题都可以利用AI/ML来解答，特别是当存在高变异性、数据有限、数据收集质量差、患者人群代表性不足或试验设计有缺陷时。患者人群代表性不足的问题特别令人关注，因为它可能导致系统性偏差。此外，与其他AI/ML被使用的空间一样，需要谨慎行事，解决患者隐私和生物伦理问题。 了解在R&D中DL/AI与ML与传统基于推断的统计方法最有效的时候也很重要。在下面的图4中，我们尝试根据数据集的维度提供建议。在图5中，我们尝试提供类似的建议，这次是基于药物开发的不同方面。尽管许多ML算法能够处理具有“大p，小n”问题的高维数据，但变量/预测因子的数量增加，特别是那些与响应无关的，仍然是一个挑战。随着不相关变量/预测因子的数量增加，噪声的体积变得更大，导致大多数ML算法的预测性能降低。 图4. 根据数据维度的ML/AI应用 图5. 基于药物开发的不同方面的ML/AI应用 总之，适当理解R&D和高级ML/AI技术的结合可以为药物开发和患者提供巨大的好处。AI/ML工具的实施和可视化可以提供用户友好的平台，以最大化效率并促进在R&D中使用突破性技术。然而，对因果关系和相关性之间差异的清晰理解至关重要，同样重要的是认识到，复杂的预测能力的发展并没有使科学方法过时。可信的推断仍然需要健全的统计判断，这在药物开发中尤其关键，因为直接关系到患者的健康和安全。这进一步强调了对ML/AI技术以及R&D中适当的特定领域知识的全面理解对于其在药物开发中的最佳使用至关重要。 为促进抗体行业的交流与创新，2024年10月16-17日第七届金秋十月抗体产业发展大会如约而至。会议旨在为研究人员提供一个互动交流的平台，有助于推动抗体产业的进一步发展。 会议内容 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