Azilact - rasagiline mesylate: scientific information about the drug for Parkinson's disease

By: Dr. Oren Cohen and Dr. Sharon Hassin, Parkinson's and Movement Disorders Clinic, Department of Neurology and the Center for Neuroscience, Haim Sheba Medical Center, Tel Hashomer. 
introduction: 

In February 2005, the drug Azilect (rasagiline mesylate 1 mg once a day) was approved for use in European countries and Israel, the fruit of an original Israeli development in Parkinson's patients as monotherapy (single treatment) in patients with early disease or in combination with other drugs in Parkinson's patients in intermediate and advanced stages The request for approval in Europe and the United States was accompanied by a publicity campaign, which emphasized that this drug, unlike the other drugs in use today, not only has an effect on the symptoms of the disease, but also a protective effect on nerve cells that can slow down or stop the course of the disease.

It was recently reported that the Food and Drug Administration informed "Teva" that Agilect (the name it will be given in America) given once a day deserves approval. The drug under the trade name Azilect was recently approved for use in Israel and is marketed in pharmacies, but has not yet been included in the health basket and therefore is not prescribed at this stage by the health insurance funds. Azilect is currently marketed in Israel and England, Germany, Austria and Scandinavian countries. It will soon be marketed in other European countries as well. The purpose of this review is to present the drug and summarize the medical knowledge published in the medical literature so far.

Parkinson's disease 

Parkinson's disease is caused by the death of dopamine-producing cells in the substantia nigra of the brainstem. The lack of dopamine is the cause of the clinical manifestations of the disease, which include tremors, muscle stiffness, slowness and postural problems.

Many factors are considered to contribute to the development of the disease and include hereditary and external factors. In recent years, several genes have been identified in which mutations cause those rare cases of familial Parkinson's, as well as other genes associated with the tendency to develop the disease. The external factors include a variety of environmental toxins, which people with a certain genetic profile will be exposed to during their lifetime, will tend to develop the disease. Possible mechanisms involved in the death processes of dopaminergic cells include oxidative stress, neurotoxicity of glutamate, disruption of the function of cellular organelles related to energy production (mitochondria), disruption in maintaining the intracellular balance of calcium or iron, or the inhibition of programmed cell death processes (apoptosis).

Most of the drugs used today to treat Parkinson's disease increase the dopaminergic activity in the brain and thus improve the movement clinical manifestations of the disease. They include a variety of levodopa preparations, dopaminergic agonists, anticholinergic preparations, antiglutamatergic preparations, inhibitors of the enzyme catechol-O-methyltransferase (COMT) and inhibitors of the enzyme monoamine oxidase type B (MAO-B.

It is worth noting that so far we do not have a treatment that has been unequivocally proven to be able to slow down the process that leads to the death of the dopaminergic cells and thus change the course of the disease. There are preparations with antioxidant properties (vitamins E and C), mitochondria strengtheners (coenzyme Q10), glutamate antagonists (amantadine) and more, which theoretically may protect nerve cells (this feature is called neuroprotection), but their ability to affect or Slowing down the deterioration of the disease has not yet been proven in highly reliable clinical trials in humans.

Rasagiline

The substance rasagiline (N-propargyl-1-(R) aminoindan), is a substance developed by a team of researchers from the Technion led by Professor Moussa Zaim. Rasagiline is similar in its chemical structure to the compound selegiline (an old and accepted drug for use in Parkinson's disease and also known as Yomax). Like selegiline, rasagiline is also a unique and irreversible inhibitor of the MAO-B enzyme that breaks down dopamine in the basal ganglia (the region of the dopaminergic cells). According to laboratory tests, the inhibition efficiency of rasagiline is 5-10 times higher than that of selegiline, and it has another advantage - it does not break down like selegiline into amphetamine which is a stimulant and methamphetamine. The MAO-B is found in high concentration in the dopaminergic cells there It plays an important role in dopamine metabolism: it is responsible for one of the dopamine release pathways.

Picture number 1: Chemical structure of Rasagiline (N-propargyl-1-(R) aminoind)
Rasagiline as a treatment for Parkinson's disease

In the early stages of development and before it was tried in humans, the effect of rasagiline on the survival of nerve cells in tissue cultures was tested. It was found that the addition of rasagiline to cell cultures from human and rat fetal brains improves the viability of dopamine-producing cells. In another experiment, they showed that the administration of rasagiline to mice and monkeys that were exposed to a neurotoxin that creates Parkinson's syndrome (the dangerous MPTP toxin that caused a serious illness in drug addicts in the 80s and has since been used to create a model for Parkinson's disease in animals) resulted in a significant decrease in the tissue, biochemical and behavioral changes of the animals.

Human experiments

Safety check: 

The first stage of the human trials was to test the safety of the use of the drug. After testing in healthy subjects, the safety of the drug was tested in a large number of patients with Parkinson's disease in medical centers in Israel, Europe and the United States. In all cases, it was proven that the treatment was well tolerated, the side effects were few and similar to the placebo group (a group of patients who participate in the study and receive a demi-inbo pill that does not contain a drug) and no serious side effects were observed.

Efficacy test in patients with early disease: 

The next step was to test the effectiveness of the drug and its effect on the motor symptoms of Parkinson's disease. A large experiment to test the effectiveness and safety of the drug was an experiment called the TEMPO study. This trial was a multicenter, randomized, double-blind, placebo-controlled trial in which 404 early-stage Parkinson's patients were recruited. The patients were randomly divided into groups treated for 26 weeks with rasagiline or placebo. A marked improvement in motor function and quality of life was observed in the groups of patients treated with the drug.

Two large studies of rasagiline in patients with more advanced disease and motor fluctuations were completed about a year ago and their results were published in prestigious scientific journals. In the two studies, LARGO, which included 687 patients, and PRESTO, in which 472 patients participated, a significant dose-dependent reduction in the daily OFF time was found in patients treated with rasagiline compared to patients treated with placebo. In one of the studies, an improvement was also observed in other indices such as motor function and an index for performing daily activities. The drug was well tolerated without special side effects.

From the results of the studies described above, it can be learned that rasagiline has a beneficial effect on the symptoms of the disease. However, the question arises as to whether this effect is a result of increasing dopaminergic activity, as in other drugs, or whether at least part of the clinical improvement results from the slowing down of the basic disease process of dopaminergic cell death. In order to answer this question, a study was carried out, the results of which were recently published in the prestigious journal Archives of Neurology. This study, which was a direct continuation of the TEMPO study, was designed using the delayed start method. in rasagiline for another six months. The assumption was that if rasagiline only has a symptomatic effect, then the patients who were previously treated with placebo and now with rasagiline will improve to the same level as the patients who were treated with rasagiline in the first place. If, on the other hand, rasagiline has an effect on the course of the disease The movement of improvement in these patients parallels that of the patients treated with rasagiline from the beginning, but will not infect it. The results of the experiment showed that the motor deterioration was significantly slower in the patients who were treated with rasagiline from the beginning, which could indicate that rasagiline has an effect in slowing down the course of the disease.

Estimated mechanism of action: 

The studies described above raise the possibility that the drug may have an effect on slowing down the course of Parkinson's disease. It seems that such an effect, if indeed it exists, does not depend on the drug's ability to inhibit the MAO-B enzyme, and several mechanisms have been proposed to explain it, including the action of proteins that protect the cell from harmful oxidation products, reducing the stimulating activity of glutamate. Improving the survival of nerve cells by encouraging the creation of substances that help the proliferation and growth of cells or improving communication between cells.

Looking ahead:

The tests carried out so far show that rasagiline has a mild symptomatic effect in Parkinson's patients and in this respect it is probably not superior to the drugs currently available for the treatment of the disease. However, although this has not been proven unequivocally, the results of the studies raise the possibility that treatment with the drug could protect the nerve cells and slow down the progression of the disease. Also, it is still too early to determine whether the drug is safe enough since there are not enough trials carried out so far to detect rare but serious side effects. This will require postmarketing follow-up in a large number of patients and over time.

Summary: 

Rasagiline, a strong, selective and irreversible inhibitor of MAO-B, has shown efficacy and short-term safety in the treatment of early Parkinson's patients, and results from experiments indicate the possibility that the drug will be effective not only as a symptomatic treatment, but can also influence the course of the disease. However, this possible effect has not yet been unequivocally proven, as well as the safety of the drug in long-term treatment. Experiments in the treatment of a large number of patients and over time will be able to provide answers to these questions and determine the place of the drug in the future treatment strategy for patients with Parkinson's disease.