Azilect - the one-a-day Parkinson's pill

Dr. Paul Knopf, a scientist and professor at Brown University who lives in Warren, Rhode Island lives a full and active life despite his diagnosis five years ago with Parkinson's Disease. But he finds the frequent need for medication to keep his symptoms under control disruptive to his routine. "I often forget and run out. I carry pills with me. And sometimes, I'm experiencing symptoms, I see that I'm shaking, and I realize, gee, I forgot to take my medication," he said. But beginning soon, patients like Knopf and many of the more than a million Americans who suffer from Parkinson's disease will only have to take medication once a day to control their symptoms. ´

The American Food and Drug Administration has approved the use of Israeli-developed Azilect - the first Parkinson's medication with once-daily dosage. Professors Moussa Youdim and John Finberg of the Technion-Israel Institute of Technology in Haifa - which developed the drug along with Israeli pharmaceutical giant Teva - are confident that increased convenience is only the tip of the iceberg in terms of the benefits that Azilect will be able to bring to Knopf and other Parkinson's patients. Parkinson's disease is a chronic, progressive, neurodegenerative disorder which affects more than four million people worldwide, the cause of which remains mysterious.

Nobody knows the exact cause of the disease with causes believed to involve genes, environmental factors and aging. Symptoms include tremors, slowness of movement, stiffness, gait and posture problems. As the disease progresses, symptoms worsen, and the patient will most likely experience motor complications. Ultimately, the disease impairs the patient's ability to function. Azilect - which was developed under the name Rasagiline - is designed to help block the breakdown of dopamine, an important chemical for the cellular signaling that controls muscle movement. The drug, which is taken once daily, serves both as an initial treatment for early Parkinson's disease patients, and as an adjunct therapy to the drug levodopa in moderate-to-advanced stages of the disease. It is already being taken by Parkinson's patients in fourteen countries, after it was approved and launched in the European Union and Israel in 2005.

The Technion research team that developed the drug and is continuing to explore its properties, believe that as more patients take Azilect and the results of further clinical studies emerge, more of the drug's attributes will emerge. The pharmaceutical will be shown not only to protect the brain and slow the worsening of Parkinson's symptoms, but actually repair damage the disease has done to nerve cells - an ability that pharmaceutical companies around the world have been seeking to accomplish, so far, in vain. In addition, Youdim and his team at the Technion has already moved ahead in combining Rasagiline with another compound that he is working to develop into an effective treatment for Alzheimer's disease. He believes that drugs derived from Rasagiline that can attack other neurological diseases, will follow. For example, Youdim is also working with colleagues at Technion on a possible way to develop the compound into a drug that could benefit heart patients as well. "Its fantastic that we have developed this in Israel in a small laboratory - that we have competed with major drug companies, and have beaten them at their own game," Youdim told ISRAEL21c. "In my view, the beauty of Rasagiline is the way that it can work in combination with other drugs. We are already working on a number of compounds and we see it as a building block for future drug development. Both we and our colleagues at Teva believe that it will be a blockbuster." When it hits US pharmacies in a few weeks, Azilect will represent one of the few treatment options available there for all stages of Parkinson's, including use as a stand-alone early-stage therapy, and in combination with levodopa (a standard treatment for Parkinson's disease) in more advanced stages of the disease. Youdim's confidence is based both on the properties the compound has demonstrated in cell cultures, on animal models, and in the continuing series of new clinical studies underway as more patients begin taking the drug.

The story of Azilect/Ragasiline, dates back nearly half a century. Youdim, born in Iran and educated in Great Britain and Canada, developed his interest in pharmacology and neurochemistry as a young scientist for a very personal reason - his father suffered from depression. His sense of mission drove his decision to leave medicine and dedicate himself to the laboratory. While investigating existing drugs against depression, he encountered a drug that was effective, but had a side effect that made it essentially unmarketable - combined with certain foods like cheese or wine, it could be deadly - what became known as the 'cheese effect'. "No one wanted to go near this drug because of it," he recalls. He later explored a similar drug without the 'cheese effect' and found that it was more effective against Parkinson's than depression - but addition side effects were discovered, and it, too, was ruled out as a commercially viable solution. But he didn't give up, and discovered yet another compound from the same family in Australia, which he began to develop into what would become Ragasiline.

That work was interrupted when he was invited to leave England to come to Israel to found the pharmacology department at the Technion. He thought it was a temporary adventure "creating pharmacology department in a country with no real pharmaceutical companies," but then unexpectedly, found that Israel was the place that he chose to call home. It was in 1979 when he first approached Teva with the idea of developing his compound into a treatment for Parkinson's. He was turned down. At the time, the still-young Teva focused solely on the business of creating generic versions of popular drugs and couldn't afford the luxury of indulging in developing new drugs of its own. But in his laboratory, he continued to explore the properties of the drug, which he continued to believe held one of the keys to stopping degeneration in the brain. "I really believed in it, I was like Moses in the desert - everyone had given up on these type of drugs, I kept at it and we did a lot of work on it."

By 1987, times had changed. Teva was larger, more financially stable, and became interested in getting into the complicated and expensive business of creating new drugs. The company contacted Youdim, they came to terms and the Technion-Teva collaboration began rolling forward with the goal of developing Ragasiline. "We were very cynical and didn't believe that Teva was really committed to developing a new drug," Youdim recalls, "but they convinced us they were very serious." And now - nearly 20 years later, the proof is in the fact that the drug will be available in the US. Hopes are high in the company that Azilect could represent a turning point in the treatment of Parkinson's disease. Azilect is the third drug to be developed by Teva, today a multi-million dollar manufacturer of generic pharmaceuticals. Its breakthrough medication Copaxone - which was developed at the Weizmann Institute - is one of the most commonly prescribed drugs for the treatment of multiple sclerosis.

Teva hopes that Azilect will become as essential an element in treating Parkinson's as Copaxone has become regarding MS. According to the company's president and CEO Israel Makov, Azilect "represents a key milestone in our commitment to develop and bring to market novel therapies for neurological diseases." The hard-won FDA approval for Azilect came after the submission of data from three large, multicenter, multinational, double-blind, randomized, placebo-controlled clinical studies. These studies in over 1,600 patients demonstrated that Azilect given once daily was effective, and well-tolerated, given as initial monotherapy in the early stages of Parkinson's disease or when added to levodopa and other therapies in more advanced stages of the disease. The drug is being welcomed by the US medical community. "The approval of Azilect by the FDA represents important news for people with Parkinson's disease," said Dr. Warren Olanow, professor and chairman of the Department of Neurology at Mount Sinai School of Medicine. "Patients can now look forward to an effective new treatment option that improves symptoms and offers the simplicity of once-daily dosing."

More studies are underway, including a major investigation of Azilect's effect on 1500 patients by Teva studying the drug's effect on slowing the progression of Parkinson's disease. Youdim is clearly optimistic when he speaks of the future outcomes of this study and others and the developments he expects will emerge from them... both in terms of what the studies will show, and his drug's potential for future uses in fighting a wide range of diseases. He said that there is "no question" that in animal models, Azilect has both a "neuroprotective and neurorescue activity" and it would be "interesting and fantastic" if an ability to repair nerve cells is proven to be true. He is especially excited by an ongoing study which he says seems to indicate that Azilect's effectiveness actually increases over time, as opposed to how most drugs decrease effectiveness over time.

Other interesting directions are a paper that he says has an anti-depressant effect - important in view of the fact that more than 50 percent of Parkinson's patients suffer from clinical depression - and cognitive enhancing activity, which could be important in harnessing Rasagiline as a tool in the fight against Alzheimer's. Youdim's work takes place at the Eve Topf and National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Teaching, which acts as an independent extension of the Department of Pharmacology at Technion-Rappaport Faculty of Medicine and has a close interaction with Rappaport Family Research Institute.