Innovative 3D Printed Intravaginal Ring AnelleO-PRO, the first Single Administration of Progesterone for Infertility

摘要-- 不孕症影响美国约13 - 15%的育龄夫妇。体外受精（IVF）的成功， 大多数使用辅助生殖技术（ART），依赖于持续的外源性孕酮 补充，以建立和维持怀孕。这种补充剂必须在8至10天内服用 妊娠数周，直到胎盘孕酮的产生足以维持妊娠。但目前的 诸如阴道凝胶、插入物或IM注射的治疗选择具有若干缺点和副作用， 患者依从性低。为了满足对持续孕酮的改进产品的迫切需求， AnelleO正在开发AnelleO-PRO，一种阴道环（IVR）， 28天，覆盖整个ART治疗期（8 - 10周），只有2 - 3个环。孕酮补充 IVR提供了一个患者友好的选择，控制，持续释放孕酮， 剂量。AnelleO的下一代IVR技术基于一种新颖的方法， 3D打印技术（数字光合成，通过连续液体界面生产实现，CLIP ™）， 实现快速、具有成本效益的IVR制造，用于ART和其他应用的连续药物释放。AnelleO 正在应用历史教训和以前关于IVR的研究，以解决关键差距和需求， 产品.该IIB期项目以迭代的方式促进第I期和正在进行的第II期取得的进展， 为IND提交铺平道路的透彻、合理的设计流程。该项目的具体目标是：1） 体内GLP绵羊安全性和药代动力学（PK）研究。Anelleo将设计GLP 3D CLIP IVR， 根据I期和II期的体外和体内安全性数据选择设计，并进行体外质量控制 问题研究该目的还包括GLP PRO IVR在绵羊中的体内GLP安全性和PK，以模拟临床研究 人体设计和选定IVR设计的体内PK。2)IND使能研究（10993 ISO试验） 选择IVR设计。基于IND前会议的FDA指南并与监管团队合作， CDMO/CRO，AnelleO将设计IVR的GLP批次并进行IND启用测试。3)准备和 提交AnelleO-PRO的IND申请。与监管团队和医学/CMC/临床前团队合作 专家，AnelleO将准备并提交AnelleO-PRO的IND申请。这项工作对于推进 AnelleO-PRO是一种安全且与当前用于孕酮的产品等同或上级的技术 关键的绵羊GLP和ISO10993研究将确定以下药物的安全性和有效性： 我们的产品用于ART，并为临床试验和商业化铺平道路。AnelleO-PRO的开发 用于持续递送孕酮以覆盖整个ART治疗期，仅用2 - 3个环施用 这将是开创性的，因为目前还没有FDA批准的3D打印IVR用于交付ART或任何自然PRO 其他迹象。AnelleO的IVR平台技术将提供可定制的，持续的和受控的药物 通过阴道途径提供药物，因此也可以满足广泛的妇女健康 应用.

Abstract - Infertility affects ~13-15% of reproductive-aged couples in the US. The success of in vitro fertilization (IVF), the most used Assisted Reproductive Technology (ART), depends on sustained exogenous progesterone supplementation to establish and maintain pregnancy. This supplementation must be administered over 8 to10 weeks of gestation until placental progesterone production is adequate to maintain pregnancy. However, current treatment options such as vaginal gel, inserts, or IM injection, have several drawbacks and side effects that lead to low patient compliance. In response to the critical need for improved products for sustained progesterone supplementation, AnelleO is developing AnelleO-PRO, an intravaginal ring (IVR) delivering progesterone over 28 days to cover the entire ART treatment period (8-10 weeks) with only 2-3 rings. Progesterone supplementation with an IVR provides a patient friendly option for controlled, sustained release of progesterone with less frequent dosing. AnelleO’s next-generation IVR technology is based on a novel approach that applies a state-of-the-art 3D printing technology (Digital Light Synthesis, enabled by continuous liquid interface production, CLIP™) to achieve rapid, cost-effective IVR fabrication for continuous drug release for ART and other applications. AnelleO is applying historical lessons and previous studies on IVRs to address key gaps and needs to yield better products. This Phase IIB project fosters progress made in Phase I and in the ongoing Phase II in an iterative, incisive, rational design process to pave the way to an IND submission. The Specific Aims for this project are: 1) In vivo GLP sheep safety and pharmacokinetic (PK) study. Anelleo will engineer GLP 3D CLIP IVRs with final design selected based on in vitro and in vivo safety data from Phases I and II, and conduct in vitro quality control studies. This Aim also includes in vivo GLP safety and PK in sheep for GLP PRO IVR to mimic clinical study design in human, and in vivo PK for a selected IVR design. 2) IND-enabling studies (10993 ISO testing) for the selected IVR design. Building on FDA guidance from a pre-IND meeting and working with a regulatory team and CDMOs/CROs, AnelleO will engineer a GLP batch of the IVR and conduct IND-enabling testing. 3) Prepare and submit an IND application for AnelleO-PRO. Working with a regulatory team and medical/CMC/preclinical experts, AnelleO will prepare and submit an IND application for AnelleO-PRO. This work is critical for advancing AnelleO-PRO as a safe and equivalent or superior technology to current products used for progesterone supplementation in ART. The pivotal sheep GLP and ISO10993 studies will establish the safety and efficacy of our product for ART and pave the way to clinical trials and commercialization. The development of AnelleO-PRO for sustained delivery of progesterone to cover the entire ART treatment period with only 2-3 ring administrations will be groundbreaking, as there is no FDA approved 3D printed IVR for delivery of natural PRO for ART or any other indication. AnelleO’s IVR platform technology will offer customizable, sustained, and controlled drug delivery of pharmaceuticals via the vaginal route, and thus can also meet a broad range of women’s health applications.