Phase 2 trials initiated with aplindore in Parkinson’s disease and RLS

Dopamine agonists currently available for the treatment of Parkinson’s disease and Restless Legs Syndrome (RLS) are full agonists at dopamine-2 (D2) receptors and require a long titration period--up to seven weeks in Parkinson’s disease and four weeks in RLS. Titration is the process of establishing the appropriate dose of a drug for a particular patient by increasing doses incrementally over a period of time. Currently available dopamine agonist treatments for Parkinson’s disease produce side effects in many patients that include daytime somnolence or drowsiness, dyskinesias (sudden episodes of abnormal involuntary movements), and hallucinations. While dopamine agonists have proved effective in the treatment of RLS, many patients still suffer side effects of augmentation (a worsening of symptoms), nausea, constipation, and hypotension. 

Neurogen believes that many of the side effects of existing drugs to treat Parkinson’s disease and RLS are associated with overstimulation of the unaffected parts of the brain due to the full dopamine agonist nature of these drugs. We believe that aplindore’s D2 partial agonist profile may restore sufficient dopaminergic activity to areas of the brain that are deficient without over-stimulating the unaffected parts of the brain and thereby offer an improved side-effect profile and shorter titration period.

Development Status

Parkinson’s disease

In February 2008, we announced the initiation of a Phase 2 dose-ranging, randomized, double blind, placebo-controlled, multi-center, parallel design exploratory study of the safety, tolerability, efficacy and pharmacokinetics of aplindore in patients with early stage Parkinson’s disease. Up to five cohorts of eight patients each will receive two weeks of treatment, with doses of aplindore administered twice per day. Cohorts will be treated sequentially and depending on results, once per day dosing may be employed.

Restless Legs Syndrome (RLS)

Also in February 2008, we announced today the commencement of a Phase 2 study of aplindore in RLS.  This trial is a single-blind, placebo-controlled, multi-center, crossover study designed to determine the efficacy and safety of three doses of aplindore, administered once per day for at least three nights compared to placebo. The primary endpoint will be the number of periodic limb movements (PLM) per hour of sleep for patients receiving aplindore versus those receiving placebo. Neurogen intends to explore additional subjective outcomes and sleep measures in several secondary endpoints.  Up to 24 adult patients with RLS are expected to participate in the study. Each patient will be assigned to a treatment sequence of study drug and placebo.  Polysomnography will be used to objectively measure various sleep parameters.

About Parkinson’s Disease

Parkinson’s disease is a brain disorder that occurs when certain nerve cells (neurons) in a part of the brain called the substantia nigra die or become impaired. Normally, these cells produce a vital chemical, dopamine, which allows smooth, coordinated function of the body's muscles and movement.  When approximately 80% of the dopamine-producing cells are damaged, the symptoms of Parkinson’s disease appear. The loss of dopamine production in the brain causes the primary symptoms of Parkinson’s disease. The key signs of Parkinson disease are: tremor, slowness of movement, rigidity, and difficulty with balance.

Parkinson’s disease affects both men and women in almost equal numbers.  It shows no social, ethnic, economic or geographic boundaries.  In the United States, it is estimated that 60,000 new cases are diagnosed each year, joining the 1.5 million Americans who currently have Parkinson disease.  While the condition usually develops after the age of 65, 15% of those diagnosed are under 50. (source: National Parkinson Foundation)

About Restless Legs Syndrome

Restless legs syndrome (RLS) is a sensorimotor disorder characterized by a distressing urge to move the legs and sometimes also other parts of the body, usually accompanied by a marked sense of discomfort or pain in the leg or other affected body part. RLS is triggered by rest or inactivity, and its symptoms are temporarily relieved by movement. It follows a circadian pattern, with symptoms most intense in the evening and nighttime hours.

According to the National Sleep Foundation’s 1998 Sleep in America poll, 25% of adults report experiencing unpleasant feelings in their legs a few nights a month or more, 15% a few nights a week or more, and 8% every night or almost every night. Of those who reported such RLS symptoms, 50% said that the leg pain kept them from getting a good night’s sleep. (source: Restless Legs Syndrome Foundation)

Background on aplindore

We announced in 2006 that Neurogen had acquired from Wyeth Pharmaceuticals, a division of Wyeth (NYSE: WYE), worldwide development and commercialization rights to aplindore, a small molecule partial agonist for the D2 dopamine receptor. Neurogen acquired worldwide rights to aplindore for an initial license fee payment of $3 million and will also pay Wyeth milestones upon the successful achievement of clinical development and regulatory events, as well as royalties on worldwide sales.

Aplindore was initially developed by Wyeth for schizophrenia and has been studied in six Phase I and Phase II clinical trials involving over 100 healthy volunteers and over 100 schizophrenic patients. The drug demonstrated excellent brain receptor occupancy and pharmacologic activity at low doses, but proved inappropriate for the treatment of this disease at the dose range tested. We believe that at doses significantly lower than those used in previous trials, aplindore may prove to be an attractive treatment for Parkinson’s disease and RLS.