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

摘要- 在美国，大约13%-15%的育龄夫妇会受到不孕症的影响。体外受精(IVF)的成功， 最常用的辅助生殖技术(ART)，依赖于持续的外源性孕酮 补充以确定和维持妊娠。这种补充剂必须在8到10天内服用 妊娠数周，直到胎盘孕酮的产生足以维持妊娠。但是，当前 治疗方案，如阴道凝胶、嵌入物或IM注射，有几个缺点和副作用，导致 患者依从性低。回应对持续黄体酮改进产品的迫切需求 补充，AnelleO正在开发AnelleO-Pro，一种提供黄体酮的阴道内环(IVR) 28天，覆盖整个ART治疗期(8-10周)，只有2-3个环。补充黄体酮 IVR为孕酮的可控、持续释放提供了一种患者友好的选择，且频率较低 给药。AnelleO的下一代IVR技术基于一种新的方法，该方法应用了最先进的 3D打印技术(数字光合成，通过连续液体界面生产实现，Clip™)以 实现快速、经济高效的IVR制造，用于ART和其他应用的持续药物释放。AnelleO 正在应用历史经验教训和以前关于静脉注射受体的研究，以解决关键差距和需要更好地产生 产品。这一IIB阶段项目促进了在第一阶段和正在进行的第二阶段迭代中取得的进展， 精辟、合理的设计流程，为IND提交铺平道路。本项目的具体目标是：1) GLP绵羊体内安全性及药代动力学(PK)研究Anelleo将使用Final设计GLP 3D Clip IVR 根据I期和II期的体内外安全性数据选择的设计，并进行体外质量控制 学习。这一目的还包括体内GLP安全性和绵羊PK，用于GLP PRO IVR模拟临床研究 在人体内设计，并在体内PK选定的IVR设计。2)支持IND的研究(10993国际标准化组织测试) 精选IVR设计。以FDA在IND前会议上的指导为基础，并与监管团队和 CDMO/CRO，AnelleO将设计一批GLP IVR，并进行IND使能测试。3)准备和 提交AnelleO-PRO的IND申请。与监管团队和医疗/CMC/临床前合作 专家表示，AnelleO将为AnelleO-PRO准备并提交IND申请。这项工作对推动 AnelleO-Pro是一种安全的、等同于或优于目前用于黄体酮的产品的技术 艺术方面的补充。关键的绵羊GLP和ISO10993研究将确定 我们的产品为ART和临床试验和商业化铺平了道路。AnelleO-PRO的发展 黄体酮的持续释放覆盖整个ART治疗期，只需2-3次环状给药 将是开创性的，因为没有FDA批准的3D打印IVR来交付用于ART或任何 其他迹象。AnelleO的IVR平台技术将提供可定制、持续和受控的药物 通过阴道途径给药，因此也可以满足广泛的妇女健康 申请。

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.