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）：帕金森氏病（PD）是一种进行性神经退行性疾病，与多巴胺能性黑质神经元丧失有关。美国有超过150万PD患者，每年约有50,000名新患者。 PD有症状治疗的基石是多巴胺替代疗法，多巴胺激动剂（DA）被用作单一治疗，以改善早期疾病的症状或左旋多巴辅助（LD）的症状，其对LD的反应正在恶化，以及那些对LD响应而发生波动的患者。有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于多巴胺受体的搏动刺激（例如口服当前DA疗法后发生的）引起的。与DA疗法的脉动递送相反，连续的可能会阻止这些运动功能障碍，并且提供稳定的药物水平的安全，长期，持续的释放递送系统将更好地满足不断增长的PD患者的需求。 Titan Pharmaceuticals，Inc。开发了一种皮下（SQ）植入药物递送系统，该系统在一次治疗后提供6个月或更长时间的连续等离子体药物水平。该技术最近在多个第3阶段临床试验中已被验证，用于释放药物丁丙诺啡用于治疗阿片类药物成瘾的药物。基于对帕金森尼猴子中磷灰碱释放植入物的试验研究，持续的，持续的，不可释放的da和6个月的Parace spackins and；尽管动物研究成功，但通常会出现脉冲DA的疾病，但由于阿泊氨酸的临床应用可能是不切实际的DA批准用于治疗PD，具有降低或没有皮肤刺激性/炎症特性的DA可能会为美国日益增长的PD患者以及全球的PD患者提供新的更好的治疗范例。该提案的目的是评估新型DA植入物的非临床安全性和功效，以选择候选植入物制剂进行潜在的临床研究。具体目标1是DA释放在狗中释放的DA释放的安全性，耐受性和药代动力学分析。具体目标2评估了这些DA植入物在缓解PD症状并防止帕金森尼猴子运动障碍发作的安全性和功效。特定目标3评估了这些DA植入物在帕金森氏症灵长类动物中逆转和/或减少先前确定的运动运动障碍的能力。这些研究的结果可能适用于早期和晚期PD患者长期DA植入物治疗的临床发展，可减轻与当前多巴胺替代治疗方式相关的“开/关”波动和与治疗相关的运动障碍。 公共卫生相关性：拟议的研究旨在为帕金森氏病（PD）开发更好的治疗疗法，在美国有超过150万PD患者，每年约有50,000名新患者。当前对这种进行性疾病的多巴胺替代治疗导致运动并发症和动力障碍，这被认为是多巴胺受体脉动刺激的结果。我们建议开发一种皮下植入产品，该产品可以在一次治疗后6个月至1年提供非裂开的多巴胺激动剂，我们认为这将比目前的这种慢性神经退行性疾病更安全，更有效。