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.

在2020年，低收入和中等收入国家（LMIC）的2000万成人估计正在接受 一线抗逆转录病毒疗法（ART）预计到2024年将增加到2360万。 一线艺术将对开处方的替代二线蛋白酶的患者数量产生级联影响。 一线艺术失败后，基于抑制剂（PI）的艺术。对基于PI的艺术的患者的研究表明很高 ART 12和24个月的病毒衰竭率，患者维持基于PI的治疗方案 积累抗药性突变（DRM），妨碍当前和将来的治疗选择。尽管电话 为了改善HIVDR诊断的访问，持续的紧急和未满足的抗药性需求具有 没有得到满足，禁止适当分配昂贵的三线艺术选择。早期识别 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HIV传播至关重要。当病毒性衰竭是依从性时 - 中介三线艺术不太可能改善患者的预后，同时增加医疗保健系统成本，并且 过早限制未来的治疗选择。 Aldatu的开创性技术Pandaa使用适应 使QPCR用于DRM​​基因分型目的地，HIV的高基因组变异性。我们在此之前的第二阶段奖 CRP使用熊猫成功开发了第一个诊断，以简单聚焦的基因分型为六个 蛋白酶基因中的抗性限制位置，以及K65R和M184VI DRM。熊达准确 基因型DRM≥10％，而常规QPCR失败，具有出色的敏感性：只有100 drm 即使在探针结合位点具有已知不匹配的Allic变体也可重复检测到的副本。在这个 CRP，我们基于我们最近在美国的产品商业化经验来创建诊断产品 用于LMIC的营销和销售。在第一年，我们将扩大我们现有的质量管理系统（QMS） 符合国际医疗设备制造标准。这将使我们的制造业保持一致 将CE标记为体外诊断（IVD）的过程。与我们的QMS建立同时发生 我们将扩大内部制造实践，以便到第二年底，我们将拥有 在ISO 134585认证中，GMP产生≥800的能力，每周CE IVD HIVDR基因分型测试 设施。这将通过实施我们的上市策略来协调，以在3-5的短短中引入该产品 清单国家，我们将确定和审查的临床研究伙伴，分销商和其他地区 合作伙伴支持Aldatu进行谈判和与当地合作伙伴签约，并支持与 健康部。我们的首选推出将在Key中的合作者进行早期网站评估之前 目标市场将与Sanger测序进行并排比较并评估我们 软件。最终结果将是HIVDR基因分型诊断的制造和监管资格 这大大降低了测试复杂性，时间燃烧和成本，而无需牺牲准确性。