Drugs in the Pipeline

Experimental medications that show promise in enabling people with Parkinson’s to attain a reasonable quality of life and manage their condition more effectively have never been more numerous. Our recent survey of the “drugs in the pipeline” has identified no fewer than 14 compounds that are in the process of being tested by the worldwide pharmaceutical industry. Here, we report on some of the more interesting and promising agents that are currently in clinical trials.

Long-time PDF News & Review readers will be familiar with series of phases that a pharmaceutical agent must go through from its initial discovery (patent application) to its release for general use (FDA approval). For newly-diagnosed patients, an explanation of the four main categories or phases (Phase I, Phase II and Phase III and Phase IV) can be found in the News section of our website.

With Sinemet (levodopa/carbidopa) as the “gold standard,” or “the drug others have to beat,” scientists are pursuing tests of prodrugs (compounds that are not yet drugs until the body causes them to change into active agents). One of these etilevodopa (levodopa ethyl ester), now in Phase III trials. This dissolvable form of levodopa, currently being studied in Israel by Dr. Eldad Melamed (where the drug is manufactured) in a new dispersible form, is likely to be particularly useful to patients whose responses to other forms of the drug are either delayed or erratic. Dr. Eldad Melamed and Dr. Werner Poewe (Austria) told a recent gathering of the Movement Disorders Congress that when etilevodopa is combined with carbidopa to prevent nausea, the agent works faster than Sinemet and this, it is hoped, will result in fewer dose-failure episodes that are commonly seen in advanced patients.

Another busy area of clinical trials is that of the dopamine agonists. One of these, now in Phase III trials, is SPM-962 (rotigotine), an agonist that is delivered through a transdermal patch. Dr. Olivier Rascol (France) has reported that delivering the drug through the skin means that it is less likely to be broken down than it is when delivered through other organs – and may therefore be effectively used in lower doses.

Another, new agonist, also in Phase III trials, is sumanirole. From six posters at the Movement Disorders Congress last November, we learned of its promise both in relieving symptoms and in promoting quality of life even in the later stages of the disease.

At the same conference, we also learned some new insights into Mirapex, a widely-used agonist that was released several years ago. Dr. Joseph Jankovic (Houston) reported that the drug increases the activity of the Nurr 1 gene that is essential for the development and survival of midbrain dopaminergic neurons. This suggests a novel mechanism by which Mirapex exerts neuroprotective and, possibly, disease-modifying effects.

Also in the category of dopamine agonists is apomorphine hydrochloride, used in Europe for years and now awaiting final FDA approval in its status as an “orphan drug” (which provides financial incentives to manufactures to encourage them to develop drugs for limited populations). It is taken in the form of sublingual (under the tongue) tablets or as an injectable to “rescue” patients from severe “off” states. While it must be taken with carbidopa or domperidone to prevent nausea, it is also useful in small dosages according to Dr. Ubaldo Bonuccelli, a scientist from Pisa, Italy, for improving drug-induced dyskinesias.

Laboratory scientists consider the brain’s JNK-signaling pathway to be neurodegenerative, that is, leading to programmed cell death. By blocking this pathway, a new compound known as CEP-1347 - now in Phase II/III trials – may promote neuronal survival. While it doesn’t affect PD symptoms nor interact with antiparkinson drugs, scientists have found it to be helpful in regenerating sick or damaged neurons in animals and hope that it can also be found to slow neuronal loss in people who suffer with Parkinson’s.

At the most recent annual meeting of the American Neurological Association, Dr. Andrew Siderowf (U/Penn) told us about rasagiline mesylate, also in Phase III trials. In addition to improving the quality of life in patients during early studies, this MAO-B inhibitor - similar to the well-known selegiline (Eldepryl), but stronger showed some symptomatic benefits, as measured by scores on the UPDRS, the commonly-used rating scale. The drug has yet another plus: it doesn’t metabolize to methamphetamine and thus shouldn’t cause sleep problems.

Spheramine - a tiny capsule containing human retinal cells, has moved into Phase II/III trials, according to its surgical chief, Dr. Roy A.E. Bakay (Chicago). When implanted into PD patients’ putamens, they have been found to produce the dopamine that is needed for normal movement.

Adenosine A2a receptors are abundant in the output neurons of the striatum, the brain’s control center for movement, balance and walking. Blocking these neurons seems to help express the benefit of levodopa while easing the drug-induced dyskinesias that are so often a side effect of the drug. Three blocking compounds are now moving into Phase II studies, having shown advantages in both animal and early human studies. The first, of these non-dopaminergic therapies is NIL-A, a neuroimmunophilin ligand that has shown symptomatic reverses in animal models of parkinsonism. Two others - LY40187 (found to be neuroprotective and neurotrophic in rodents) and SLV318 (found to ease depression and anxiety without affecting antiparkinson effects of dopaminergic drugs) – are headed for clinical trials.

Finally, there are the NSAIDs (non-steroidal anti-inflammatory drugs) that have shown neuroprotective effects in parkinsonism-induced animals by decreasing excitotoxicity (the overexcitement of neurons causing them to die). These phenomenon were the subject of a talk by Dr. Melvin D. Yahr (New York). Could it be that, years after finding that aspirin protects against cardiac problems, ibuprofen may be found to be therapeutic in PD?

N.B. Readers should please remember that these notes were written in early January, 2003 and reflects the status of each drug as of the end of 2002. For regular updates, readers can visit the Parkinson’s Pipeline Project at www.pdpipeline.org. This project, spear-headed by Perry Cohen, PhD, a patient representative for Parkinson’s at the FDA and a consultant to the PDF, is a three part approach helping publicize and advance the evaluation and approval of new treatments for PD. Part of the project includes the development of a web-based database to track the scientific and regulatory developments in treatments for PD. Volunteers are needed to support the research project; please see the website for more information.