IND-enabling preclinical development of a system for the multipurpose prevention of HIV and unintended pregnancy

摘要(带下划线的更改) 这项研究计划的广泛、长期目标是开发一种阴道内多用途预防 提供艾滋病毒暴露前预防(PrEP)和避孕的技术(MPT)产品 发展中世界。MPT是美国国立卫生研究院、世卫组织和主要非政府组织的高度优先事项。我们的战略是基于 使用我们的专利和新颖的“阴道内珠子”提供同类最好的HIV PrEP候选对象 与FDA批准的避孕IVR相结合。 Truvada®(TDF-FTC组合)是FDA批准的唯一用于HIV PrEP的药物产品。然而，最近 研究表明NRTI与阴道线粒体毒性有关，包括在我们的第一阶段发现的数据 SBIR的努力。在我们最初的第二阶段SBIR(1月18日)的提交中，我们介绍了TDF的临床前结果- FTC微珠配方，以及使微珠技术适应卡替格列韦(CBT)-利培韦林(RPV)的建议 组合。当时，FDA刚刚批准了Juluca®，到目前为止，Juluca®仍然是唯一的两种药物 (多洛替格列韦[DTG]+利培韦林)治疗艾滋病毒的药物。在过去的12个月里，有几个职位- Juluca®的市场研究已经发表，表明其安全性和有效性都有所提高。此外， DTG-RPV组合也可以作为PrEP试剂，水平很低，半衰期长，但 已知的潜在线粒体毒性比NRTIs。另一方面，CBT和RPV的组合，尽管 在后期临床试验中，尚未得到监管机构的批准。因此，考虑到重要的 DTG-RPV药物组合相对于CBT-RPV的监管和科学优势，我们改变了我们的产品 发展重心向前者倾斜。 我们最初提交的材料的主要问题之一是缺乏初步数据。作为回应，我们 为建议的药物选择重新提交此申请和临床前结果。简而言之，1个月 在绵羊模型上进行了药代动力学(PK)研究，以评价DTG-RPV微球的可行性 与避孕药IVR(NuvaRing®)配合使用时。这些珠子显示出了平均 体内释放2.4 mg/d DTG和0.6 mg/d RPV。由此产生的平均宫颈阴道液(CVF)水平为 537 ng/mlDTG和807 ng/mlRPV表明持续给药的浓度高于其 各自的EC50水平。这些珠子的载药量使我们可以将它们的公式定为3个月 珠子使其可以与每月一次的Nuvering®(在这种情况下，一颗珠子将 在3个月内连续三个月使用IVR)或一年一次的Annovera®(这里是四颗珠子 将需要在12个月内进行一次IVR)，具体取决于用户的选择。 第二阶段SBIR重新提交提出了以下修订计划：在第一年，我们将生产预制 临床批次的DTG和RPV珠子；并在绵羊和猕猴身上进行使能IND的安全性/PK研究。 在第二年，我们将在猕猴模型中测试该配方的有效性。最后，我们将执行IND启用 铅配方提交IND的化学、制造和控制(CMC)活动。 我们已经获得了13项IND批准，也是有史以来唯一的缓释抗病毒药物输送装置 由FDA批准的(Vitrasert®)是由该提案的首席调查员开发的。成功 这项建议中描述的工作的完成将允许对这种新型阴道内MPT进行人体测试。

SUMMARY (changes are underlined) The broad, long-term goal of this research program is to develop an intravaginal multipurpose prevention technology (MPT) product to provide HIV pre-exposure prophylaxis (PrEP) and contraception to women in the developing world. MPT is a high priority for the NIH, the WHO and for leading NGOs. Our strategy is based on delivering the best-in-class HIV PrEP candidates using our proprietary and novel “intravaginal beads” in conjunction with FDA-approved contraceptive IVRs. Truvada® (TDF-FTC combination) is the only FDA-approved drug product for HIV PrEP. However, recent studies have shown NRTI-associated vaginal mitochondrial toxicity, including the data found in our Phase I SBIR efforts. In our original Phase II SBIR (Jan ’18) submission, we presented pre-clinical results for a TDF- FTC bead formulation, and a proposal to adapt the bead technology to the cabotegravir (CBT)-rilpivirine (RPV) combination. At that time, the FDA had just approved Juluca®, which till date remains to be the only two-drug (dolutegravir [DTG] + rilpivirine) medication for HIV treatment. In the past twelve months, several post- marketing studies of Juluca® have been published showing enhanced safety and efficacy. Additionally, the DTG-RPV combination can also act as PrEP agents at very low levels and has a long half-life with lesser known potential for mitochondrial toxicity than NRTIs. On the other hand, the CBT-RPV combination, although in late-stage clinical trials, is not yet approved by the regulatory agencies. Hence, given the significant regulatory and scientific advantages of DTG-RPV drug combination over CBT-RPV, we shifted our product development focus towards the former. One of the main concerns with our original submission was the lack of preliminary data. In response, we resubmit this application with pre-clinical results for the proposed drug selection. Briefly, a 1-month pharmacokinetics (PK) study was performed in a sheep model to evaluate feasibility of the DTG-RPV beads when delivered in combination with a contraceptive IVR (NuvaRing®). The beads demonstrated an average in vivo release of 2.4 mg/d DTG and 0.6 mg/d RPV. The resulting average cervicovaginal fluid (CVF) levels were 537 ng/ml DTG and 807 ng/ml RPV suggesting sustained delivery at concentrations greater than their respective EC50 levels. The drug loading capacity of these beads allows us to formulate them as 3-month beads making it feasible for use in combination with either a monthly Nuvaring® (in this scenario, one bead will be used for three consecutive monthly IVRs over a 3-month period) or a yearly Annovera® (here, four beads will be required for one IVR over a 12-month period), depending on the user’s choice. This Phase II SBIR resubmission proposes the following revised plan: In Year 1, we will manufacture pre- clinical batches of DTG and RPV beads; and conduct IND-enabling safety/PK studies in sheep and macaques. In Year 2, we will test the formulation for efficacy in a macaque model. Finally, we will perform IND-enabling chemistry, manufacturing and controls (CMC) activities for the lead formulation to submit an IND. We have been granted 13 IND approvals, and the only sustained release antiviral drug delivery device ever approved by the FDA (the Vitrasert®) was developed by the Principal Investigator of this proposal. Successful completion of the work described in this proposal will allow human testing of this novel intravaginal MPT.