Precision Betamethasone Microspheres for Transtympanic Delivery & SSNHL Treatment

 描述（由申请人提供）：内耳疾病需要新的治疗选择，包括梅尼埃病、感音神经性听力损失、自身免疫性内耳疾病和耳鸣。在没有FDA批准的药物的情况下，医生使用临时的治疗方法，包括使用标签外的类固醇，缺乏安全性和有效性数据。 奥比斯生物科学公司的内耳缓释药物输送平台Unison，有可能通过单次具有成本效益的鼓室内注射后在内耳保持精确和治疗药物水平超过三十（30）天，显着改善对各种耳部疾病的治疗。Unison平台由以下几部分组成：（1）载药微球-使用Orbis的专利精密颗粒制造技术生产-可以精确控制药物释放，和（2）新型快速成膜剂（FFA），既可作为微球注射的稀释剂，又可作为将微球固定在圆窗膜（RWM）上的薄膜，允许微球连续地将其药物有效载荷递送到内耳超过一个月。第一个使用Unison平台的产品是ORB-202，这是一种用于治疗类固醇反应性耳部疾病的缓释betastatin。一旦FDA成功批准，ORB-202将取代目前的临床实践，即在几周内多次鼓室内注射水性混悬液，这种治疗是痛苦的，不方便的，而且通常无效。 在SBIR第一阶段，奥比斯成功开发了Unison和ORB-202的原型。奥比斯使用其专利的精密颗粒制造技术，成功地封装和控制在体外释放的betastatin，一个强大的，糖皮质激素类固醇。同时，Orbis开发了一种能够在RWM中固定微球超过三十（30）天的FFA，并证明这种新型FFA对小鼠无毒。本SBIR II期提案的目的是证明ORB-202在小型和大型动物的临床前模型中的安全性和有效性，并与FDA举行IND前会议，为SBIR项目III期期间的IND申请做准备。Orbis将首先在豚鼠中建立ORB-202的体外-体内相关性 沿着ORB-202组件的货架稳定性试验（目标1）。随后，Orbis将使用急性耳毒性模型（目的2）在豚鼠中表征ORB-202的安全性、药理学和毒理学。最后，Orbis将在大型动物绵羊模型中建立ORB-202的剂量反应曲线（目标3），以表征内耳液体积接近人类大小的动物的剂量需求。 在第二阶段SBIR计划完成后，奥比斯将确定ORB-202的安全性和有效性，以在小耳和大耳中达到至少三十（30）天的稳定类固醇浓度。 动物模型，从而将所得制剂定位于IND使能的临床前试验。

 DESCRIPTION (provided by applicant): New treatment options are needed for inner ear disorders including Meniere's disease, sensorineural hearing loss, autoimmune inner ear disease, and tinnitus. In the absence of FDA-approved drugs, physicians use improvised treatments, including the administration of off-label steroids, which lack safety and efficacy data These ad hoc approaches often fail to achieve the desired outcomes; a result potentially attributable to insufficient and variable drug exposure in the inner ear. Orbis Biosciences's extended-release inner ear drug delivery platform, Unison, has the potential to significantly improve treatment for a wide-range of otic disorders by maintaining precise and therapeutic drug levels in the inner ear for more than thirty (30) days after a single, cost-effective intratympanic injection. The Unison platform is a composite of: (1) drug-loaded microspheres - produced using Orbis' patented Precision Particle Fabrication technology - that allow for precise control of drug release, and (2) a novel Fast Film- forming Agent (FFA) that severs as both a diluent for microsphere injection and a film that holds the microspheres to the Round Window Membrane (RWM), allowing the microspheres to continuously deliver their drug payload to the inner ear for over a month. The first product to use the Unison platform is ORB-202, an extended release betamethasone for the treatment of steroid-responsive otic disorders. Upon successful FDA approval, ORB-202 will replace the current clinical practice of multiple intratympanic injections of aqueous suspensions spaced over the course of several weeks, a treatment that is painful, inconvenient, and often ineffective. Under SBIR Phase I, Orbis successfully developed a prototype of Unison and ORB-202. Orbis used its patented Precision Particle Fabrication technology to successfully encapsulate and control the in vitro release of betamethasone, a potent, glucocorticoid steroid. Concurrently, Orbis developed a FFA capable of affixing microspheres in the RWM for over thirty (30) days and demonstrated that this novel FFA was non-toxic in mice. The objective of this SBIR Phase II proposal is to demonstrate the safety and efficacy of ORB-202 in preclinical models for both small and large animals and to hold a pre-IND meeting with the FDA in preparation for an IND-filing during Phase III of this SBIR program. Orbis will first establish the in vitro-in vivo correlation of ORB-202 in guinea pigs along with shelf stability testing of the ORB-202 components (Aim 1). Subsequently, Orbis will characterize the safety, pharmacology, and toxicology of ORB-202 in guinea pigs using an acute ototoxicity model (Aim 2). Finally, Orbis will establish the dose-response curve of ORB-202 in a large animal, sheep model (Aim 3), to characterize the dose requirements in an animal with inner ear fluid volume near the size of the human. At the completion of this Phase II SBIR program, Orbis will have established the safety and efficacy of ORB-202 to achieve steady concentration of steroid in the inner ear for a minimum of thirty (30) days in both small and large animal models, thereby positioning the resultant formulation for IND-enabling preclinical trials.