Developing and commercialising a non-invasive test of adrenal insufficiency for children on steroids.

开发并商业化针对使用类固醇的儿童肾上腺功能不全的非侵入性测试。

• 批准号: MR/W002795/1
• 负责人: Charlotte Elder
• 金额: $ 19.87万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW002795%2F1
• 关键词: Developing; commercialising; non; invasive; test

The adrenal glands sit above the kidneys and are part of the body's endocrine system and produce the vital stress hormone cortisol. Adrenal insufficiency (AI) is the inability of the body to produce adequate cortisol levels and, untreated, leads to circulatory collapse and death through adrenal crisis. Diagnosis of AI is frequently missed due to non-specific symptoms. Causes of AI in UK include Addison's disease (adrenalitis), brain tumours and adrenal suppression from steroid medication for inflammatory conditions (e.g. arthritis, asthma, cancers). Globally major causes are TB and AIDS. AI is usually permanent but in patients taking steroid medication, it may be temporary necessitating repeated testing. Concern about AI related to steroid use is rising, with widespread prescription of potent steroids in all medical specialties and recognition that all steroids can cause AI. In August 2020 the NHS National Patient Safety Agency released an alert for UK healthcare organisations to issue Steroid Emergency Cards to all patients at risk of AI, including those on inhaled steroids. Nearly half a million UK children are prescribed inhaled steroids (preventers) for asthma, many on doses exceeding recommendations. The Short Synacthen Test (SST) is the most popular diagnostic test for AI worldwide. Synacthen stimulates the adrenal glands to produce cortisol. Blood tests are taken before Synacthen is given and 30-60 minutes after in order to measure the rise in cortisol. The SST is invasive, requiring intravenous cannulation and blood sampling, and resource-intensive due to the need for skilled personnel and a hospital day-care admission. This leads to raised thresholds for investigation and delayed diagnosis, especially in children, putting patients at risk of adrenal crisis. The practical challenge is identifying, diagnosing and treating patients suffering from steroid excess and AI. Dr Elder has undertaken fundamental work developing a new non-invasive test for AI, "The Nasacthin Test", with the drug, tetracosactide (Synacthen), given via a nasal spray and the resultant cortisol response measured on saliva samples. This will enable the investigation of children at home or in clinic, without requirement for hospital attendance and blood sampling. The new drug is a combination of tetracosactide with chitosan, a nasal drug enhancer, which aids absorption from the nose into the bloodstream. To date the team have completed five pilot clinical trials testing different doses and formulations (mixtures) and found the new drug, Nasacthin, to be reliably absorbed and well tolerated in children. The non-invasive Nasacthin test will allow early diagnosis, prevent adrenal crisis and help paediatricians understand the burden of disease created by steroids. The challenge is creating a clinical development plan and commercialising Nasacthin. Before approval to use the Nasacthin test in clinical practice further clinical studies are required. Data are required on the response to Nasacthin in healthy children of different ages and sex to enable doctors to define what cortisol threshold constitutes a 'pass' or a 'fail' on the new test. Currently the diagnostic thresholds for the SST are derived from adult data and this project will establish the first normal ranges in children. This is important for doctors to have confidence in the new test and will facilitate adoption into clinical practice. Diurnal is ideally placed to help Dr Elder as a leading international endocrinology company focused on developing therapies for AI with experienced clinical, regulatory and commercial teams. Dr Elder's secondment to Diurnal will allow progression of her career, boosting her skills in drug development. It will bring a new product to market, to benefit the UK economy, and make a major contribution to the reduction in disease burden and risk of death of children using inhaled and other steroids.

肾上腺位于肾脏上方，是人体内分泌系统的一部分，产生重要的应激激素皮质醇。肾上腺功能不全（AI）是身体无法产生足够的皮质醇水平，如果不治疗，会导致循环衰竭和肾上腺危象死亡。由于非特异性症状，AI的诊断经常被错过。在英国，AI的原因包括Addison病（肾上腺素），脑肿瘤和类固醇药物治疗炎症（如关节炎，哮喘，癌症）引起的肾上腺抑制。全球的主要原因是结核病和艾滋病。AI通常是永久性的，但在服用类固醇药物的患者中，它可能是暂时的，需要重复测试。对与类固醇使用有关的AI的担忧正在上升，在所有医学专业中广泛使用强效类固醇处方，并认识到所有类固醇都可能导致AI。2020年8月，NHS国家患者安全局发布了一项警报，要求英国医疗机构向所有有AI风险的患者（包括吸入类固醇的患者）发放类固醇紧急卡。近50万英国儿童接受吸入性类固醇（预防剂）治疗哮喘，其中许多人的剂量超过了建议。Short Synacthen Test（SST）是全球最流行的AI诊断测试。Synacthen刺激肾上腺产生皮质醇。在给予Synacthen之前和之后30 - 60分钟进行血液测试，以测量皮质醇的上升。SST是侵入性的，需要静脉插管和血液采样，并且由于需要熟练的人员和医院日托入院而需要资源密集型。这导致调查和延迟诊断的阈值提高，特别是在儿童中，使患者面临肾上腺危象的风险。实际的挑战是识别，诊断和治疗患有类固醇过量和AI的患者。埃尔德博士已经开展了基础性工作，开发了一种新的非侵入性AI测试，“Nasacthin测试”，通过鼻腔喷雾剂给予药物，tetracosactide（Synacthen），并在唾液样本上测量由此产生的皮质醇反应。这将使在家中或诊所对儿童进行调查成为可能，而不需要到医院就诊和采血。这种新药是一种由四乳糖和壳聚糖组成的组合物，壳聚糖是一种鼻腔药物增强剂，有助于从鼻子吸收到血液中。到目前为止，该团队已经完成了五项试验性临床试验，测试了不同的剂量和配方（混合物），并发现新药Nasacthin在儿童中可靠地吸收和耐受性良好。非侵入性Nasacthin测试将允许早期诊断，预防肾上腺危象，并帮助儿科医生了解类固醇造成的疾病负担。挑战在于制定临床开发计划并将Nasacthin商业化。在批准在临床实践中使用Nasacthin测试之前，需要进行进一步的临床研究。需要不同年龄和性别的健康儿童对Nasacthin反应的数据，以使医生能够定义皮质醇阈值在新测试中构成“通过”或“失败”。目前SST的诊断阈值来自成人数据，本项目将建立儿童的第一个正常范围。这对于医生对新测试的信心非常重要，并将促进临床实践的采用。作为一家领先的国际内分泌公司，Diurnal非常适合帮助Elder博士，专注于与经验丰富的临床，监管和商业团队开发AI疗法。埃尔德博士借调到《每日》杂志将使她的职业生涯取得进展，提高她在药物开发方面的技能。它将为市场带来一种新产品，使英国经济受益，并为减少使用吸入和其他类固醇的儿童的疾病负担和死亡风险做出重大贡献。

项目成果

Home Waking Salivary Cortisone to Screen for Adrenal Insufficiency

首页 唤醒唾液可的松来筛查肾上腺功能不全

• DOI: 10.1056/evidoa2200182
• 发表时间: 2023
• 期刊: NEJM Evidence
• 作者: Debono M

Salivary Steroid Collection in Children Under Conditions Replicating Home Sampling.

在复制家庭采样的条件下收集儿童唾液类固醇。

• DOI: 10.1210/clinem/dgac419
• 发表时间: 2022
• 期刊: The Journal of clinical endocrinology and metabolism
• 作者: Tonge JJ

Real world evidence supports waking salivary cortisone as a screening test for adrenal insufficiency.

现实世界的证据支持唤醒唾液可的松作为肾上腺功能不全的筛查测试。

• DOI: 10.1111/cen.14975
• 发表时间: 2023
• 期刊: Clinical endocrinology
• 影响因子: 3.2
• 作者: Debono M