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. Thesaurus Terms:
"(--)-2amino-3-)3,4-Dihydroxyphenyl)Propanoic Acid; (--)-3-(3,4-Dihydroxyphenyl)-L-Alanine; 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine; 2,6-Benzothiazolediamine, 4,5,6,7-Tetrahydro-N6-Propyl-, (S)-; 2-Amino-4,5,6,7-Tetrahydro-6-Propylaminobenzothiazole; 2-Amino-6-Propylaminotetrahydrobenzothiazole; 3,4-Dihydroxyphenethylamine; 3-Hydroxy-L-Tyrosine; 4-(2-Aminoethyl)-1,2-Benzenediol; 4h-Dibenzo(De,G)Quinoline-10,11-Diol, 5,6,6a,7-Tetrahydro-6-Methyl-, (R)-; 6,14-Ethenomorphinan-7-Methanol, 17-(Cyclopropylmethyl)-Alpha-(1,1-Dimethylethyl)-4,5-Epoxy-18,19-Dihydro-3-Hydroxy-6-Methoxy-Alpha-Methyl-, (5alpha,7alpha(S))-; Abnormal Movements; Addiction, Opiate; Administration, Oral; Animals; Apomorphine; Blood Plasma; Buprenorphine; Canine Species; Canis Familiaris; Chronic; Clinic; Clinical; Clinical Research; Clinical Study; Clinical Trials, Phase Iii; Data; Degenerative Diseases, Nervous System; Degenerative Neurologic Disorders; Dependence, Opiate; Development; Disease; Disorder; Dogs; Dopamine; Dopamine Agonists; Dopamine Receptor; Dopamine Receptor Agonists; Dopaminergic Agonists; Dose; Drug Administration, Oral; Drug Delivery Systems, Implantable; Drug Formulations; Drug Kinetics; Drugs; Dysfunction; Dyskinesias; Dyskinetic Syndrome; Early Treatment; Employee Strikes; Ethylenes; Formulation; Formulations, Drug; Functional Disorder; Hydroxytyramine; Inflm; Idiopathic Parkinson Disease; Implant; Implantable Infusion Pumps; Individual; Inflammation; Inflammatory; Infusion Pumps, Implantable; Involuntary Movements; L-3,4-Dihydroxyphenylalanine; L-Dopa; Lead; Lesion; Levodopa; Lewy Body Parkinson Disease; Lisuride; Lysurid; Mptp; Mammals, Dogs; Mammals, Primates; Medication; Methylergol Carbamide; Modality; Monitor; Monkeys; Motor; N-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine; Ndul; Nature; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; Neurodegenerative Diseases; Neurodegenerative Disorders; Neurologic Degenerative Conditions; Neurologic Diseases, Degenerative; Neurons; Nodule; Opiate Addiction; Oral; Oral Administration; Paralysis Agitans; Parkinson; Parkinson Disease; Parkinson's; Parkinson's Disease; Parkinsonian; Parkinsonian Condition; Parkinsonian Diseases; Parkinsonian Disorders; Parkinsonian Syndrome; Parkinsonism; Parkinsons Disease; Patients; Pb Element; Perfusion Pumps, Implantable; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmacokinetics; Pharmacologic Substance; Pharmacological Substance; Phase 3 Clinical Trials; Phase Iii Clinical Trials; Physiopathology; Pilot Projects; Plasma; Population; Primary Parkinsonism; Primates; Progressive Disease; Property; Property, Loinc Axis 2; Protocols, Treatment; Pyridine, 1,2,3,6-Tetrahydro-1-Methyl-4-Phenyl-; Rgm; Regimen; Relative; Relative (Related Person); Replacement Therapy; Reporting; Research; Reticuloendothelial System, Serum, Plasma; Safety; Sampling; Serum, Plasma; Site; Skin; Staging; Strikes; Strikes, Employee; Symptoms; System; System, Loinc Axis 4; Technology; Therapeutic; Titan; Treatment Protocols; Treatment Regimen; Treatment Schedule; Urea, N'-((8alpha)-9,10-Didehydro-6-Methylergolin-8-Yl)-N,N-Diethyl-; Acetic Acid Ethenyl Ester; Application In Practice; Base; Beta-(3,4-Dihydroxyphenyl)-L-Alanine; Canine; Clinical Applicability; Clinical Application; Disease/Disorder; Domestic Dog; Drug/Agent; Experience; Heavy Metal Pb; Heavy Metal Lead; Implantation; Improved; Intraoral Drug Delivery; Meetings; Methylphenyltetrahydropyridine; Neurodegenerative Illness; Neuronal; Novel; Opioid Addiction; Opioid Dependence; Pathophysiology; Phase 3 Study; Phase 3 Trial; Phase Iii Trial; Pilot Study; Practical Application; Pramipexol; Pramipexole; Prevent; Preventing; Protocol, Phase Iii; Public Health Relevance; Response; Skin Irritant; Skin Irritation; Study, Phase Iii; Subcutaneous; Success; Vinyl Acetate"