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

到2020年，估计低收入和中等收入国家（LMIC）有2000万成年艾滋病毒感染者将接受 一线抗逆转录病毒治疗（ART），预计到2024年将增加到2360万。这种增加的机会 一线抗逆转录病毒治疗将对处方替代二线蛋白酶的患者数量产生级联效应- 抑制剂（PI）为基础的艺术后，一线艺术失败。对基于PI的ART患者的研究显示， ART治疗12个月和24个月时的病毒学失败率，以及维持失败的PI方案的患者 积累耐药突变（DRM），阻碍当前和未来的治疗选择。尽管有人呼吁 为了更好地获得艾滋病诊断，对耐药基因分型的持续迫切和未满足的需求， 这就阻碍了对昂贵的三线抗逆转录病毒治疗方案的适当分配。及早识别 二线抗逆转录病毒治疗患者在不存在艾滋病毒耐药性的情况下无法实现病毒学抑制（HIVDR） 对预防疾病进展和遏制艾滋病毒传播至关重要。如果病毒学失败是因为坚持- 中等的三线ART不太可能改善患者结局，同时增加医疗保健系统成本， 过早地限制了未来的治疗选择。Aldatu的开创性技术PANDAA利用适应性， 尽管HIV的基因组变异性很高，但qPCR仍能用于DRM基因分型。在此之前，我们的第二阶段奖励 CRP使用PANDAA成功地开发了第一个同时针对六种基因分型的诊断方法。 蛋白酶基因中的抗性赋予位置，以及K65 R和M184 VI DRM。PANDAA准确地 当常规qPCR失败时，基因型DRM存在≥10%，具有优异的灵敏度：低至100 DRM 即使在探针结合位点具有已知错配的等位基因变体的情况下，也可重复检测拷贝。在这 CRP，我们建立在我们最近在美国的产品商业化经验，创造一个诊断产品 用于在中低收入国家的营销和销售。在第一年，我们将扩大我们现有的质量管理体系（QMS） 符合医疗器械生产的国际标准。这将使我们的制造业 作为体外诊断（IVD）获得CE认证的过程。在建立质量管理体系的同时， 我们将扩大我们的内部制造实践，以便在第二年年底之前， 在ISO 134585认证的GMP生产中，每周可进行≥800次CE IVD HIVDR基因分型检测 设施。这将与实施我们的进入市场战略相协调，以便在3-5年内推出产品 列出国家，我们将确定并审查临床研究合作伙伴、经销商和其他区域 支持Aldatu与当地合作伙伴进行谈判和签订合同， 卫生部。我们的上市之前将由合作者进行早期现场评估， 目标市场，他们将与桑格测序进行并行比较，并评估我们的 软件最终结果将是HIV DR基因分型诊断试剂的生产和监管资格 这显著降低了测试复杂性、时间负担和成本，而不牺牲准确性。

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.