Commercialization of PANDAA qDx for rapid drug resistance genotyping of protease inhibitor ART failures in resource-limited settings.

PANDAA qDx 的商业化，用于在资源有限的环境中对蛋白酶抑制剂 ART 失败的快速耐药基因分型。

• 批准号: 10686963
• 负责人: Iain James MacLeod
• 金额: $ 98.18万
• 依托单位: ALDATU BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-17 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686963
• 关键词: Acceleration; Adherence; Adoption; Adult; Affect; African; Award; Binding Sites; Biological Assay; Botswana; COVID-19 diagnostic; COVID-19 test; COVID-19 testing; Certification; Childhood; Clinical; Clinical Research; Computer software; Contracts; Country; Data Analyses; Dedications; Development; Diagnostic; Diagnostic tests; Dideoxy Chain Termination DNA Sequencing; Disease Progression; Documentation; Drug resistance; Early identification; Ensure; Evaluation; Failure; Feedback; Funding; Future; Genomics; Genotype; HIV; HIV drug resistance; Health; Healthcare Systems; Hospitals; Improve Access; Institution; International; Ivory Coast; Logistics; Management Information Systems; Marketing; Mediating; Mediation; Medical Device; New England; Nigeria; Notification; Outcome; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Phase; Positioning Attribute; Preparation; Process; Production; Protease Inhibitor; Qualifying; Quality Control; Regimen; Reporting; Reproducibility; Research; Resistance; Resource-limited setting; Resources; Sales; Sampling; Senegal; Side; Site; Small Business Innovation Research Grant; South Africa; System; Technology; Testing; Time; Training; Translating; Treatment Failure; Uganda; Validation; Work; antiretroviral therapy; clinical decision-making; commercialization; commercialization readiness; cost; data management; data quality; design; experience; genetic variant; genomic variation; implementation study; improved; in-vitro diagnostics; innovation; low and middle-income countries; manufacture; manufacturing process; meetings; pathogen; platform-independent; premature; prevent; programs; prospective; resistance mutation; software development; transmission process

In 2020, 20M adults living with HIV in low- and middle-income countries (LMICs) are estimated to be receiving first-line antiretroviral therapy (ART) and this is expected to increase to 23.6M by 2024. This increase in access to first-line ART will have a cascade effect on the number of patients prescribed alternative, second-line protease- inhibitor (PI)-based ART following first-line ART failure. Studies of patients on PI-based ART have shown high rates of virologic failure at 12 and 24 months on ART, and patients maintained on failing PI-based regimens accumulate drug resistance mutations (DRMs) that hamper current and future treatment options. Despite calls for improved access to HIVDR diagnostics, the persistent urgent and unmet need for resistance genotyping has not been met, prohibiting the appropriate allocation of expensive third-line ART options. Early identification of second-line ART patients unable to achieve virologic suppression in the absence of HIV drug resistance (HIVDR) is crucial to prevent disease progression and curb HIV transmission. When virologic failure is adherence- mediate, third-line ART is unlikely to improve patient outcomes, while increasing healthcare system costs, and prematurely restricting future treatment options. Aldatu’s pioneering technology, PANDAA, uses adaptation to enable qPCR for DRM genotyping despite the high genomic variability of HIV. Our Phase II award preceding this CRP used PANDAA to successfully develop the first diagnostic for simultaneous focused genotyping of six resistance-conferring positions in the protease gene, and the K65R and M184VI DRMs. PANDAA accurately genotypes DRMs present ≥10% where conventional qPCR fails, with excellent sensitivity: as few as 100 DRM copies detected reproducibly even with allelic variants with known mismatches in the probe-binding sites. In this CRP, we build upon our recent product commercialization experience in the USA to create a diagnostic product for marketing and sale in LMICs. In the first year we will expand our existing quality management system (QMS) to be compliant with international standard for medical device manufacturing. This will align our manufacturing processes to achieve CE marking as an in vitro diagnostic (IVD). Concurrent with the establishment of our QMS we will expand our in-house manufacturing practices such that by the end of the second year we will have the capacity for the GMP production of ≥800, CE IVD HIVDR genotyping tests per a week in an ISO 134585-certified facility. This will be coordinated with implementing our go-to-market strategy to introduce the product in 3-5 short list countries, and we will have identified and vetted clinical study partners, distributors, and other regional partners to support Aldatu in negotiations and contracting with local partners and facilitating engagement with Ministries of Health. Our go-to-market launch will be preceded by early site evaluations by collaborators in key target markets where they will perform side-by-side comparisons with Sanger sequencing and evaluate our software. The net result will be the manufacturing and regulatory qualification of an HIVDR genotyping diagnostic that significantly reduces test complexity, time burden and costs, without sacrificing accuracy.

据估计，2020年，中低收入国家将有2000万艾滋病毒携带者 一线抗逆转录病毒疗法(ART)，预计到2024年这一数字将增加到2360万。访问权限的增加 一线抗逆转录病毒治疗将对开出替代、二线蛋白酶的患者数量产生级联效应- 在一线抗逆转录病毒治疗失败后，基于抑制剂(PI)的抗逆转录病毒治疗。对基于PI的抗逆转录病毒治疗患者的研究表明 接受抗逆转录病毒治疗12个月和24个月的病毒学失败率，以及接受失败的PI方案的患者 积累抗药性突变(DRM)，阻碍当前和未来的治疗选择。尽管有电话 为了更好地获得HIVDR诊断方法，对耐药性基因分型的持续迫切和未得到满足的需求 没有得到满足，禁止适当分配昂贵的三线抗逆转录病毒治疗方案。及早识别 在没有艾滋病毒耐药性的情况下无法实现病毒学抑制的二线抗逆转录病毒治疗患者(HIVDR) 对防止疾病进展和遏制艾滋病毒传播至关重要。当病毒学上的失败是坚持- 中介的三线抗逆转录病毒治疗不太可能改善患者的结果，同时增加医疗系统成本，以及 过早地限制未来的治疗选择。Aldatu的开创性技术PANDAA使用自适应 尽管艾滋病毒具有很高的基因组变异性，但启用qPCR进行DRM基因分型。我们在此之前的第二阶段奖 CRP使用PANDAA成功地开发出第一种用于同时聚焦的6种基因分型的诊断方法 K65R和M184VIDRM。PANDAA准确 在常规定量聚合酶链式反应失败的情况下，基因型DRM呈现10%的≥，具有极好的灵敏度：低至100DRM 即使在探针结合位点存在已知错配的等位变异情况下，也可重复检测到拷贝。在这 基于我们最近在美国的产品商业化经验，我们创造了一种诊断产品 用于在LMIC中进行营销和销售。在第一年，我们将扩展我们现有的质量管理体系(QMS) 符合医疗器械制造的国际标准。这将使我们的制造 实现CE标记为体外诊断(IVD)的过程。在建立我们的质量管理体系的同时 我们将扩大我们的内部制造业务，以便在第二年年底之前，我们将拥有 每周在≥134585认证的ISO800，CE IVD HIVDR基因分型测试中生产GMP的能力 设施。这将与实施我们的进入市场战略相协调，在3-5个月内推出产品 列出国家/地区，我们将确定和审查临床研究合作伙伴、分销商和其他地区 合作伙伴在与当地合作伙伴的谈判和合同中支持Aldatu，并促进与 卫生部。在我们投放市场之前，将由KEY的合作者进行早期站点评估 目标市场，他们将在那里与桑格排序进行并排比较，并评估我们的 软件。最终结果将是HIVDR基因分型诊断的制造和监管资格 这大大降低了测试的复杂性、时间负担和成本，而不会牺牲准确性。