Long-term non-fluctuating dopamine agonist delivery for Parkinson's disease

描述（由申请人提供）：帕金森病（PD）是一种进行性神经退行性疾病，与多巴胺能黑质纹状体神经元的丧失有关。美国有超过150万PD患者，每年约有5万名新患者。帕金森病对症治疗的基石是多巴胺替代疗法，多巴胺激动剂（DA）被用作单药治疗，以改善疾病早期的症状，或在对LD反应恶化的患者中作为左旋多巴（LD）的辅助治疗。越来越多的证据表明，PD患者的运动波动和运动障碍可能是由多巴胺受体的脉动性刺激引起的，例如口服当前的DA治疗后。连续给药，而不是脉冲给药，可以预防这些运动功能障碍，一个安全、长期、持续释放的给药系统，提供稳定的药物水平，将更好地满足越来越多的PD患者的需求。Titan Pharmaceuticals, Inc.开发了一种皮下（SQ）植入式药物输送系统，该系统可以在单次治疗后连续提供6个月或更长时间的血浆药物水平。该技术最近已在一种名为Probuphine的产品的多个三期临床试验中得到验证，该产品可释放药物丁丙诺啡，用于治疗阿片类药物成瘾。基于在帕金森猴子身上使用阿帕吗啡释放植入物的初步研究，治疗性血浆DA水平的持续、无波动释放可以达到6个月；控制帕金森病的症状和消除运动障碍的发作，常见的每日搏动给药。尽管动物实验取得了成功，但由于阿波啡固有的皮肤刺激性和炎症性，阿波啡SQ植入物的潜在临床应用可能不切实际。然而，在抑制运动运动障碍长达6个月的显著结果，同时提供症状缓解PD症状，使我们相信，新型植入物，与其他批准用于治疗PD的DA配制，具有减少或没有皮肤刺激性/炎症特性，将有可能为美国和全球越来越多的PD患者提供新的更好的治疗范例。本提案的目的是评估新型DA种植体的非临床安全性和有效性，为潜在的临床研究选择候选种植体配方。具体目的1是研究SQ植入物释放DA的安全性、耐受性和药代动力学特征。具体目的2评估这些DA植入物在缓解帕金森病症状和预防帕金森猴运动障碍发作方面的安全性和有效性。特异性目的3评估这些DA植入物逆转和/或减少帕金森灵长类动物先前建立的运动障碍的能力。这些研究的结果可能适用于早期和晚期PD患者长期DA植入治疗的临床开发，减轻当前多巴胺替代治疗模式相关的“开/关”波动和治疗相关的运动障碍。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with a loss of dopaminergic nigrostriatal neurons. There are over 1.5 million PD patients in the US, with about 50,000 new patients each year. The cornerstone of symptomatic treatment for PD is dopamine replacement therapy, and dopamine agonists (DA) are used as monotherapy to improve symptoms in early disease or as adjuncts to levodopa (LD) in patients whose response to LD is deteriorating, and those who are experiencing fluctuations in their response to LD. There is increasing evidence that motor fluctuations and dyskinesias in PD may be caused by pulsatile stimulation of dopamine receptors such as occurs after oral administration of current DA therapies. Continuous, as opposed to pulsatile delivery of DA therapies may prevent these motor dysfunctions, and a safe, long-term, sustained release delivery system that provides stable drug levels would better meet the needs of a growing population of PD patients. Titan Pharmaceuticals, Inc. has developed a subcutaneous (SQ) implantable drug delivery system that provides continuous plasma drug levels for 6 months or longer following a single treatment. The technology has been recently validated in multiple Phase 3 clinical trials for a product, Probuphine", which releases the drug buprenorphine for the treatment of opiate addiction. Based on pilot studies with apomorphine-releasing implants in Parkinsonian monkeys, continuous, non-fluctuating release of therapeutic plasma levels of DA is attainable for 6 months; controlling Parkinson's symptoms and eliminating the onset of dyskinesias commonly seen with daily, pulsatile DA delivery. Despite the success of the pilot animal study, the potential clinical application of apomorphine SQ implants may be impractical due to apomorphine's inherent skin-irritant and inflammatory properties. However, the striking results in suppressing motor dyskinesias for up to 6 months while providing symptomatic relief to PD symptoms lead us to believe that novel implants, formulated with other DA approved for the treatment of PD, with reduced or no skin irritant/inflammatory properties, will potentially provide a new and better treatment paradigm for the growing number of PD patients in the U.S., and globally. The objective of this proposal is to assess the nonclinical safety and efficacy of novel DA implants to select a candidate implant formulation for potential clinical studies. Specific aim 1 is the safety, tolerability and pharmacokinetic profiling of DA release from SQ implants in dogs. Specific aim 2 assesses the safety and efficacy of these DA implants in relieving PD symptoms and preventing the onset of motor dyskinesias in Parkinsonian monkeys. Specific aim 3 evaluates the ability of these DA implants to reverse and/or reduce previously established motor dyskinesias in Parkinsonian primates. Results from these studies will potentially be applicable to the clinical development of a long-term DA implant treatment of early- and late-stage PD patients, that alleviates the 'ON/OFF' fluctuations and treatment-related dyskinesias associated with current dopamine-replacement treatment modalities. PUBLIC HEALTH RELEVANCE: The proposed research aims to develop a better therapy for Parkinson disease (PD) for which there are over 1.5 million PD patients in the US, with approximately 50,000 new patients each year. Current dopamine- replacement treatments for this progressive disease result in motor complications and dyskinesias that are believed to be the result of pulsatile stimulation of dopamine receptors. We propose to develop a subcutaneous implantable product that can provide, non-fluctuating delivery of a dopamine agonist for 6 months to 1 year following a single treatment, which we believe will be safe and more effective than current drug treatment modalities for this chronic, neurodegenerative disease.