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: 8001701
• 负责人: Rajesh A Patel
• 金额: $ 30万
• 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 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8001701
• 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丢失相关的进行性神经退行性疾病。美国有超过150万PD患者，每年约有50，000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）可作为单药治疗来改善早期疾病的症状，或在对左旋多巴（LD）的反应恶化的患者和对LD的反应出现波动的患者中作为左旋多巴（LD）的替代药物。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，例如在口服当前DA治疗后发生的。与DA治疗的脉冲递送相反，连续递送可预防这些运动功能障碍，并且提供稳定药物水平的安全、长期、持续释放递送系统将更好地满足不断增长的PD患者群体的需求。Titan Pharmaceuticals，Inc.已经开发了皮下（SQ）植入式药物递送系统，其在单次治疗后提供持续6个月或更长时间的血浆药物水平。该技术最近已在多个3期临床试验中验证了一种产品，Probuphine”，它释放药物丁丙诺啡用于治疗阿片类药物成瘾。基于在帕金森病猴中使用阿扑吗啡释放植入物的初步研究，可实现治疗性DA血浆水平的连续、非波动释放持续6个月;控制帕金森病症状并消除日常脉动DA递送常见的运动障碍发作。尽管试点动物研究的成功，阿扑吗啡SQ植入剂的潜在临床应用可能是不切实际的，由于阿扑吗啡的固有皮肤刺激性和炎症特性。然而，在抑制运动障碍长达6个月同时提供PD症状的症状缓解方面的惊人结果使我们相信，与批准用于治疗PD的其他DA一起配制的具有减少的或没有皮肤刺激/炎症特性的新型植入物将潜在地为美国越来越多的PD患者提供新的和更好的治疗范例，和全球范围内。本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制剂。具体目标1是SQ植入物在犬中DA释放的安全性、耐受性和药代动力学特征。具体目标2评估了这些DA植入物在帕金森病猴中缓解PD症状和预防运动障碍发作的安全性和有效性。具体目标3评价了这些DA植入物逆转和/或减少帕金森病灵长类动物先前建立的运动障碍的能力。这些研究的结果将可能适用于早期和晚期PD患者的长期DA植入治疗的临床开发，该治疗可消除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。 公共卫生关系：该研究旨在为帕金森病（PD）开发更好的治疗方法，美国有超过150万PD患者，每年约有5万名新患者。目前用于这种进行性疾病的多巴胺替代治疗导致运动并发症和运动障碍，其被认为是多巴胺受体的脉动刺激的结果。我们建议开发一种皮下植入式产品，可以在单次治疗后提供6个月至1年的多巴胺受体激动剂的非波动输送，我们认为这将是安全的，比目前这种慢性神经退行性疾病的药物治疗方式更有效。