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

长期非波动多巴胺激动剂治疗帕金森病

• 批准号: 8113878
• 负责人: Rajesh A Patel
• 金额: $ 19.5万
• 依托单位: TITAN PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113878
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Apomorphine; Buprenorphine; Canis familiaris; Chronic; Clinic; Clinical; Clinical Research; Data; Development; Disease; Dopamine; Dopamine Agonists; Dopamine Receptor; Dose; Drug Formulations; Drug Kinetics; Dyskinetic syndrome; Early treatment; Employee Strikes; Ethylenes; Functional disorder; Implant; Implantable Infusion Pumps; Individual; Inflammation; Inflammatory; Involuntary Movements; Lead; Lesion; Levodopa; Lisuride; Modality; Monitor; Monkeys; Motor; Nature; Neurodegenerative Disorders; Neurons; Nodule; Opiate Addiction; Oral; Oral Administration; Parkinson Disease; Parkinsonian Disorders; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase III Clinical Trials; Pilot Projects; Plasma; Population; Primates; Progressive Disease; Property; Relative (related person); Replacement Therapy; Reporting; Research; Safety; Sampling; Site; Skin; Staging; Symptoms; System; Technology; Therapeutic; Titan; Treatment Protocols; base; clinical application; experience; implantation; improved; meetings; novel; practical application; pramipexol; prevent; public health relevance; response; skin irritant; skin irritation; subcutaneous; success; vinyl acetate

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.

描述（由申请人提供）：帕金森病（PD）是一种与多巴胺能黑质纹状体神经元丧失相关的进行性神经退行性疾病。美国有超过 150 万 PD 患者，每年新增约 50,000 名患者。 PD 对症治疗的基石是多巴胺替代疗法，多巴胺激动剂 (DA) 用作单一疗法，以改善疾病早期的症状，或作为左旋多巴 (LD) 的辅助疗法，用于对 LD 反应恶化的患者以及正在经历 LD 治疗的患者。他们对 LD 反应的波动。越来越多的证据表明，PD 中的运动波动和运动障碍可能是由多巴胺受体的脉冲刺激引起的，例如口服当前 DA 疗法后发生的情况。与脉冲式 DA 疗法相反，连续给药可以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不断增长的 PD 患者群体的需求。 Titan Pharmaceuticals, Inc. 开发了一种皮下 (SQ) 植入式药物输送系统，可在单次治疗后提供 6 个月或更长时间的连续血浆药物水平。该技术最近已在产品 Probuphine 的多个 3 期临床试验中得到验证，该产品释放药物丁丙诺啡用于治疗阿片成瘾。基于在帕金森猴中释放阿扑吗啡植入物的初步研究，连续、非波动的释放治疗性血浆 DA 水平可在 6 个月内控制帕金森病症状并消除日常脉冲 DA 常见的运动障碍发作；尽管试点动物研究取得了成功，但由于阿扑吗啡固有的皮肤刺激性和炎症特性，阿扑吗啡 SQ 植入物的潜在临床应用可能不切实际，但其在抑制运动障碍长达 6 个月的同时提供症状的效果却令人瞩目。帕金森病症状的缓解使我们相信，由其他批准用于帕金森病治疗的 DA 配制而成的新型植入物，具有减少或无皮肤刺激/炎症特性，将有可能提供一种新的、更好的治疗方法对于美国和全球不断增长的 PD 患者来说，这是一个范例。该提案的目的是评估新型 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 是狗 SQ 植入物释放 DA 的安全性、耐受性和药代动力学分析。具体目标 2 评估这些 DA 植入物在缓解帕金森猴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灵长类动物中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，缓解与当前多巴胺替代相关的“开/关”波动和治疗相关的运动障碍治疗方式。 公共健康相关性：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。目前针对这种进行性疾病的多巴胺替代治疗会导致运动并发症和运动障碍，这被认为是多巴胺受体脉冲刺激的结果。我们建议开发一种皮下植入式产品，可在单次治疗后 6 个月至 1 年内提供多巴胺激动剂的非波动性输送，我们相信对于这种慢性神经退行性疾病，这将比目前的药物治疗方式更安全、更有效疾病。