Julie’s

In the Pipeline…

With Dr. Eric Siemers<= /o:p>

Medical Ad= visor

Eli Lilly = and Company

Clinical Associate Professor of

Neurology,= IU School of Medicine

A swing and a miss: TCH346 for slowing the progression= of Parkinson’s disease

While the symptomatic treatment of most motor symptoms of= PD continues to improve, finding a method to slow the underlying progression of the disease continues to be elusive. In November 2006, the journal Lancet Neurology published an important study of an investigational drug for PD developed by Novartis. The study did provide clear and interpretable results, but unfortunately those results were negative.

TCH346 is chemically related to other medications for PD, namely selegiline and rasagiline. Those medications function by inhibiting a particular enzyme known as MAO B. Beginning with the well known DATATOP study, tantalizing suggestive evidence has accrued suggesting that selegiline and rasagiline might slow underlying disease progression, in addition to providing symptomatic relief.&= nbsp; TCH346 does not inhibit the enzyme MAO B, but rather was developed to mimic other functional aspects of selegiline and rasagiline. It is not thought to have any dire= ct immediate effect on PD symptoms.

The possible disease-slowing properties of selegiline and rasagiline were first attributed to their effects on MAO B, but with additi= onal laboratory work, a different action of these drugs was suggested. Brain cells containing dopamine and other chemical messengers die prematurely for unknown reasons in patients w= ith PD. Cell death can occur in different ways in the body, and the brain in particular has developed a specialized form of programmed cell death known as apoptosis. During the first years of life, hu= mans lose vast numbers of neurons in a way Mother Nature has developed to “= ;use it or lose it”. A= s we develop during infancy and childhood, the cells that are active continue to survive, but cells that are not stimulated must be removed. Apoptosis is a way for those cells= to die and be removed from the brain in a way that does not disturb the surrounding cells. Many studi= es have suggested, but not proven, that unwanted apoptotic cell death may be important in the pathology of PD. TCH346 was developed to slow or stop apoptosis, with the hope that t= his drug would slow the rate of cell death in PD.

In this clinical trial of TCH346, 301 patients were randomized to 0.5 mg, 2.5 mg, or 10 mg of TCH346 or to placebo. The patients in this study were ne= wly diagnosed and could not be taking any medications for PD. Patients were treated for 12= -18 months with TCH346 or placebo. The primary measure (“primary outcome variable”) for the study was = the time needed until the patient did require standard medications such as levo= dopa (Sinemet) to control their symptoms. For a drug that slowed disease progression, on average patients taki= ng the drug would not need standard PD medications as soon as patients who took placebo. Many other measures = of PD symptoms were also collected in trial.&nbs= p; These included a well known measure of PD severity known as the Unif= ied Parkinson’s Disease Rating Scale and a quality of life scale specific= ally developed for PD known as the PDQ-39.

TCH346 was well tolerated in the study, and in fact the s= ide effects reported with TCH346 were very similar to those reported with place= bo. Unfortunately, there were no differences in any of the efficacy outcome measures including the time until a standard PD drug was required.

In the paper published in Lancet Neurology and in an accompanying editorial, the authors and an outside expert discuss how and w= hy this study could have been so convincingly negative. As for most drugs developed for PD= and other diseases, before clinical trials are started, animal models are used = to assess whether the drug has the appropriate effects. For PD, animal models have been developed that use toxins to artificially kill dopamine cells in the brain. These toxins, MPTP and 6-OHDA, have been used for many years in PD drug development, but were developed originally to test drugs that treated the symptoms associated wit= h PD – they were not developed with the idea that the toxins cause cell de= ath in the same way as human PD. = The results of this trial and of other recent negative trials would suggest tha= t, for drugs intended to slow PD progression, success using these animal models does not predict success in patients. There are other challenges in clinical trials of patients with neurological diseases, such as the difficulty in knowing whether enough a d= rug enters the brains of patients to have the desired effect.

As noted in the paper and editorial, this negative study follows other large negative studies involving PD progression. Other drugs with negative trials h= ave included vitamin E, a drug used for ALS (Lou Gerhig’s disease) known = as riluzole, and more recently a drug developed by Cephalon (CEP-1347) and GDNF. In the case of each of = these drugs, the caveats regarding the lack of predictability of the animal models would apply. In the Lancet Ne= urology paper, the trial authors noted, “The failure of TCH346 to provide neuroprotection in Parkinson’s disease in this trial has important implications for future studies of putative neuroprotective treatments. The cost of undertaking these stud= ies is substantial (around US$30 million) and the inability to identify clinical benefits with TCH346 despite strongly positive laboratory results could discourage future investment in view of the limitations of current animal models, including their failure to mirror the non-dopaminergic features of = the disease, difficulty in selecting the correct dose, problems in defining a v= alid endpoint, and the uncertainty of obtaining regulatory approval and labeling= of a disease modifying drug even if the results of a clinical trial are positive.”

While this somewhat gloomy view is no doubt in part a reflection of the disappointment of the authors, the point that these negat= ive studies can discourage future investment should be considered carefully by = the PD community. While these res= ults are discouraging, there is reason to hope that the underlying problems in PD drug development can be addressed. Progress in the development of new animal models has been extremely rapid, although these models are not yet available. These new models make use of recent human genetic data and therefore may be more predictive of a positive resul= t in humans. Difficulties in establishing the correct dose in patients can be circumvented by the use of biomarkers that could establish relatively quickly whether a drug is having= its desired effect in the brain. Promising but preliminary clinical results with the drug CoQ have already been established; more definitive studies could show an effect on d= isease progression. In a time when negative results such as those from TCH346 and other drugs are disseminated= , it becomes even more important for the PD advocacy community to come forward to articulate the hope of the future. It is only with continued resolve and increasing efforts that the solution to slowing the progression of PD can be found. <= /p>