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

描述(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丢失有关。美国有超过150万帕金森氏症患者，每年约有5万名新患者。帕金森病对症治疗的基础是多巴胺替代疗法，而多巴胺激动剂(DA)被用作单一疗法来改善早期疾病的症状，或者作为左旋多巴(LD)的辅助药物，用于对LD的反应恶化，以及那些对LD的反应波动的患者。越来越多的证据表明，帕金森病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，比如口服现有的DA疗法后就会发生这种情况。与脉冲给药相反，连续给药可能会预防这些运动功能障碍，而提供稳定药物水平的安全、长期、缓释给药系统将更好地满足日益增长的帕金森病患者的需求。泰坦制药公司开发了一种皮下(SQ)植入式给药系统，可在单一治疗后提供持续6个月或更长时间的血浆药物水平。这项技术最近在一种名为普罗布芬的产品的多个第三阶段临床试验中得到验证，该产品可以释放治疗阿片成瘾的药物丁丙诺啡。根据对帕金森病猴子的阿朴吗啡释放植入物的试点研究，连续、无波动地释放治疗性血浆DA水平可持续6个月；控制帕金森症状并消除日常脉冲式DA释放中常见的运动障碍。尽管动物试验取得了成功，但由于阿朴吗啡固有的皮肤刺激性和炎症特性，阿朴吗啡SQ植入物的潜在临床应用可能不切实际。然而，在长达6个月的时间里抑制运动障碍，同时缓解PD症状的显著结果使我们相信，与其他被批准用于治疗PD的DA一起配制的新型植入物，具有减少或没有皮肤刺激/炎症特性，将潜在地为美国和全球越来越多的PD患者提供一种新的更好的治疗范例。该建议的目的是评估新型DA植入物的非临床安全性和有效性，以选择用于潜在临床研究的候选植入物配方。具体目标1是SQ植入剂中DA释放的安全性、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猴子帕金森病症状和预防运动障碍发作方面的安全性和有效性。具体目标3评估这些DA植入物逆转和/或减少先前在帕金森病灵长类动物中建立的运动障碍的能力。这些研究的结果将有可能应用于早期和晚期帕金森病患者的长期DA植入治疗的临床开发，该治疗方法可以缓解与当前多巴胺替代治疗方式相关的“开/关”波动和治疗相关的运动障碍。 公共卫生相关性：这项拟议的研究旨在开发一种更好的帕金森病(PD)治疗方法，美国有超过150万帕金森病患者，每年约有50,000名新患者。目前对这种进展性疾病的多巴胺替代治疗会导致运动并发症和运动障碍，据信是由于多巴胺受体的搏动性刺激造成的。我们建议开发一种皮下植入产品，能够在单一治疗后提供6个月至1年的无波动递送多巴胺激动剂，我们相信这将比目前治疗这种慢性神经退行性疾病的药物治疗方式更安全和有效。

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.