ACP-103 to Treat Parkinson's Disease

Introduction: In Parkinson's disease (PD), levodopa-induced dyskinesias and motor fluctuations are frequent, disabling complications. Therefore, it is imperative to find nondopaminergic approaches to the palliation of parkinsonian signs. Previously, we demonstrated that drugs that block 5HT2A receptors benefit motor dysfunction in parkinsonian animals.

Objective: To test our hypothesis that blockade of serotonin 2A/2C receptors (5HT2A/C) will lessen the severity of parkinsonian signs and levodopa-associated motor response complications in PD patients.

Methods: In a placebo-controlled, proof-of-principle study, the effect of the 5HT2A/C receptor inverse agonist ACP-103 on levodopa induced motor complications and parkinsonian signs will be assessed in up to 20 patients with moderately advanced Parkinson's disease. Efficacy will be assessed through the use of validated motor function scales. Safety will be monitored by means of frequent clinical evaluations and laboratory tests.

Risks and benefits: Risks involved in this study are a minor increase over minimal risks and are deemed reasonable in relation to potential benefits. This investigation should lead to a better understanding of the pathophysiology and treatment of levodopa-induced motor complications in PD.

• INCLUSION CRITERIA:

Patients who meet all of the following inclusion criteria will be eligible to participate in the study:

• Patient is between the ages of 30 and 80 (inclusive);
• Patient has been diagnosed with idiopathic Parkinson's disease based on the presence of a characteristic clinical history and neurological findings;
• Patient has relatively advanced disease with levodopa-associated motor response complications, including peak-dose dyskinesias and wearing-off fluctuations;
• Patient is willing to adhere to protocol requirements as evidenced by written, informed consent.

Exclusion criteria

Patients meeting any of the following exclusion criteria will not be enrolled or will be immediately excluded from the study, as appropriate:

• Patient has a history of any medical condition that can reasonably be expected to subject the patient to unwarranted risk, including bronchospasm or lung disease, renal and hepatic disease, clinically significant cardiac arrhythmias and/or myocardial ischemia;
• Patients with clinically significant orthostatic hypotension;
• Patient has clinically significant laboratory abnormalities including renal and hepatic functions elevation greater than twice the upper limit of normal;
• Patient is unable to be treated with levodopa/carbidopa alone or with a single, relatively short-acting dopamine agonist, such as pramipexole or ropinirole;
• Patient is taking a prohibited concomitant medication as listed below:

The following medications are forbidden for at least one month prior to randomization and during the course of the study:

• Anticoagulants: etomidate, erythromycin, oral azole antifungals, cyclosporine, cisapride, astemizole;
• NMDA antagonists: e.g. amantadine, budipine, memantine, remacemide, dextromethorphan;
• Any other investigational drug;
• Drugs which are not used primarily to treat Parkinson's disease but which may modify parkinsonian symptoms: neuroleptics, metoclopramide, compazine, beta blockers;
• Drugs with significant muscarinic receptor antagonist activity: Cogentin, Akineton, Artane, Ditropan, Detrol, Elavil, Anafranil, Norpramine, Sinequan, Tofranil, and Pamelor;
• Drugs known to improve dyskinesias: amantadine, dextromethorphan, beta-blockers, fluoxitene, clozapine, quetiapine, olanzapine, buspirone, other anxiolytics, antipsychotics, cannabinoid receptor antagonists, adenosine A2a antagonist;
• Drugs known to exacerbate dyskinesias: sodium valproate, CNS stimulants;
• Drugs known to have 5HT receptor affinity: ritanserin, sumatriptan
• Drugs known to interact with serotonergic mechanisms excluding 5HT3 receptor based antiemetics;
• Dopamine agonists known to have a relatively long half-life: cabergoline and pergolide.
• Patient who has not been using or unwilling to continue using an adequate contraceptive method (such as oral contraception, surgical sterilization, IUD, diaphragm in conjunction with spermicidal foam and condom on the male partner, or systemic contraception) for the last 30 days, or is not at least one year post-menopausal (if female);
• Patient is pregnant or breastfeeding;
• Patient has prior bilateral pallidotomy or other ablative surgeries for treatment of PD;
• Patient has cognitive impairment (MMSE less than 24);
• Patient has participated in a clinical study with an investigational drug within the last 30 days;
• Patient has a condition (such as active drug or alcohol abuse) that, in the opinion of the investigators, would interfere with compliance or safety;
• Patient is unwilling to sign an informed consent or to comply with protocol requirements.
• Any previous exposure to ACP-103