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.

到 2020 年，低收入和中等收入国家 (LMIC) 估计有 2000 万感染艾滋病毒的成年人将接受治疗 一线抗逆转录病毒治疗 (ART)，预计到 2024 年将增加到 2360 万。这种增加 一线抗逆转录病毒治疗将对接受替代二线蛋白酶治疗的患者数量产生级联效应 一线 ART 失败后进行基于抑制剂 (PI) 的 ART。对接受基于 PI 的 ART 的患者的研究表明， ART 治疗 12 个月和 24 个月时的病毒学失败率，以及患者维持基于 PI 的治疗方案失败的情况 累积耐药突变（DRM）会阻碍当前和未来的治疗选择。尽管有电话 为了改善 HIVDR 诊断的可及性，对耐药基因分型的持续迫切且未得到满足的需求已经 未得到满足，禁止适当分配昂贵的三线 ART 方案。及早识别 在没有 HIV 耐药性 (HIVDR) 的情况下，二线 ART 患者无法实现病毒学抑制 对于预防疾病进展和遏制艾滋病毒传播至关重要。当病毒学失败是依从性时—— 中介的三线 ART 不太可能改善患者的治疗结果，同时会增加医疗保健系统的成本，并且 过早地限制未来的治疗选择。 Aldatu 的开创性技术 PANDAA 利用适应性 尽管 HIV 基因组变异性较高，但仍可使用 qPCR 进行 DRM 基因分型。在此之前我们的第二阶段奖项 CRP 使用 PANDAA 成功开发了第一个同时针对六种疾病进行集中基因分型的诊断方法 蛋白酶基因以及 K65R 和 M184VI DRM 中赋予抗性的位置。熊猫准确 传统 qPCR 失败时，基因型 DRM 出现 ≥10%，且具有出色的灵敏度：低至 100 DRM 即使对于探针结合位点已知不匹配的等位基因变体，也可重复检测到拷贝。在这个 CRP，我们利用最近在美国的产品商业化经验来创建诊断产品 用于中低收入国家的营销和销售。第一年我们将扩展现有的质量管理体系 (QMS) 符合医疗器械制造的国际标准。这将调整我们的制造 作为体外诊断 (IVD) 获得 CE 标志的流程。与我们的质量管理体系建立同时 我们将扩大我们的内部制造实践，以便到第二年年底我们将拥有 通过 ISO 134585 认证，每周可生产 ≥800 个 CE IVD HIVDR 基因分型测试的 GMP 生产能力 设施。这将与实施我们的上市策略相协调，以便在 3-5 天内推出该产品 列出国家/地区，我们将确定并审查临床研究合作伙伴、分销商和其他区域 合作伙伴支持 Aldatu 与当地合作伙伴进行谈判和签订合同，并促进与当地合作伙伴的接触 卫生部。在我们上市之前，关键领域的合作者将进行早期现场评估 他们将与桑格测序进行并列比较并评估我们的目标市场 软件。最终结果将是 HIVDR 基因分型诊断的制造和监管资格 在不牺牲准确性的情况下，显着降低测试复杂性、时间负担和成本。