Slowing down or modifying disease progression
Current drugs for Parkinson’s treat the symptoms but do not stop the progression. One of the biggest investments in Parkinson’s research is in trying to find a drug that will slow down or modify the disease progression.
The drug rasagiline (Azilect®) was studied recently to determine if it could slow down the rate of progression in Parkinson’s. Researchers conducted a double-blind, delayed-start trial in which 1176 people who were not on Parkinson medications were randomly assigned to either receive rasagiline (at a dose of 1 mg per day or 2 mg per day) for 72 weeks or placebo for 36 weeks, followed by rasagiline (at a dose of 1 mg per day or 2 mg per day) for 36 weeks (the delayed-start group).
The study results were mixed: people who had an early start with rasagiline at a dose of 1 mg per day had a smaller increase in worsening of their Parkinson’s symptoms than the placebo group; however, early treatment with rasagiline at a dose of 2 mg per day did not show similar results.
The study concluded: “Early treatment with rasagiline at a dose of 1 mg per day provided benefits that were consistent with a possible disease-modifying effect, but early treatment with rasagiline at a dose of 2 mg per day did not. Because the two doses were associated with different outcomes, the study results must be interpreted with caution.”
The study’s authors noted that it will be important to determine whether these results can be confirmed and whether the benefits seen at 18 months will endure and translate into reduced cumulative disability in clinically meaningful areas such as impairment of gait and balance and cognitive function.
Continuous dopaminergic stimulation
The standard oral medication for handling motor fluctuations in Parkinson’s is levodopa which is a short-acting drug. However, for some people, levodopa’s beneficial effects wear off before the next dose of medication is due. Infusion therapies for Parkinson’s aim to provide a more continuous stimulation of the brain receptors for dopamine, when oral medications are no longer effective. This type of treatment is known as continuous dopaminergic stimulation.
Infusion therapies / DUODOPATM
Infusion therapies have been examined in Europe and the UK, in the form of pumps that infuse the drugs apomorphine or lisuride into the tissue under the skin where the medication is then absorbed into the bloodstream.
“What’s new is there is now an alternative infusion technology that uses the best available drug for oral use, levodopa, but infuses it through the duodenum, so it goes into the bowel, on a continuous basis,” says Dr. Anthony Lang, director of the Morton and Gloria Shulman Movement Disorder Centre at Toronto Western Hospital.
In this technology, Duodopa, a form of levodopa/carbidopa that is concentrated into a gel, is pumped through a small tube that is placed through the stomach and into the duodenum.
One advantage of this style of medication delivery is that “you can formulate the exact dose, at certain times of the day, in a much more precise way than when using oral preparations; so you can adjust the dose by 1 mg rather than in 50 mg steps,” says Dr. Mark Guttman, director of the Centre for Movement Disorders in Markham, Ontario.
However, Duodopa therapy also has some drawbacks: it requires a surgical procedure, which could lead to complications; the equipment, such as the pump and tubing, could be subject to technical problems; managing and maintaining the equipment and medication requires careful monitoring and nursing support; some people might find it burdensome having to carry a pump at all times.
“It’s a complicated way of giving a medication, so the average person with Parkinson’s would not be a candidate because they would do well with taking oral medications three to five times a day,” says Lang. “It’s better suited to people who are taking levodopa many times a day and have bad and often unpredictable motor fluctuations.”
Guttman notes, “It could be seen as an option for people who are considering deep brain stimulation (DBS) surgery but either don’t qualify for DBS or don’t want to take the risks. This may be a reasonable strategy for small numbers of people.”
Duodopa has been approved by Health Canada under the Notice of Compliance with Conditions policy.
It is not yet available in Canada and is not funded by provincial governments. The biggest stumbling block for all the infusion technologies is likely the expense. Duodopa, for instance, is expected to cost $60,000 – $70,000 a year.
There are two sides to the issue.
Lang says, “The challenge is that the studies that have been done on this form of treatment are rather small and, because of the complex nature of the treatment and the way it’s provided, it’s very difficult to do the standard randomized, double-blind controlled studies that are done with the usual medication therapy.”
“When these drugs– apomorphine, lisuride and Duodopa – are provided in very controlled, careful, experienced environments, as is the case in Europe and elsewhere, patients have shown very striking improvements; so I think that these treatments are quite valuable and should be available to patients in Canada and the United States. Importantly, I am not advocating widespread, uncontrolled use of these treatments but rather limited availability for carefully selected patients through a small number of experienced movement disorders centres.”
Guttman is among the voices calling for a more measured approach to the introduction of Duodopa in Canada. He sees a need for “more formal studies, especially in Canada, so researchers and clinicians can get some experience with it.” He acknowledges, “We’ve never had anything in Parkinson’s that costs $60,000 a year for the rest of a person’s life; so the provincial health authorities want to make sure that there is good utility for it and that there is an economic model that can show that this will be money well spent.”
Enhancing the effect of dopamine
A new monoamine-oxidase B inhibitor
Monoamine-oxidase-B inhibitors (MAO-B compounds) enhance the effect of dopamine by preventing its breakdown. International phase III clinical trials are underway for a new investigative drug to determine its effectiveness and safety as an add-on dose to either levodopa or dopamine agonist medications.
Dr. Jonathan Brotchie, senior scientist at the Toronto Western Research Institute, University Health Network, highlights three promising drugs that are currently being studied and that could change Parkinson’s treatment:
Fipamezole is a drug which, when taken with dopamine medication, appears to do two things: reduce the problem of dyskinesia and increase the time the dopamine medication works. “I think this could change the way we treat Parkinson’s in a relatively short time,” says Brotchie.
The experimental drug BIIB014 is one of the first non-dopamine approaches to treating Parkinson’s. “It reverses a different chemical imbalance in the brain than our current therapies,” says Brotchie. “Because it is non-dopaminergic, we anticipate that it won’t have the same side-effects as current dopamine therapy.”
Preliminary studies have shown that BIIB014 can successfully do two things: One, alleviate Parkinson’s symptoms, when given on its own. “That’s probably the first time we’ve had a drug which isn’t replacing dopamine that can do that,” says Brotchie. Two, it appears that, when added to existing therapies, BIIB014 can improve the action of those therapies, decreasing the “off” time between the action of each pill. “This means that you either have to take fewer tablets every day or each tablet works longer.”
PYM50028 / Cogane
PYM50028, also known as Cogane. “Cogane has potential to restore the dopamine system in the brain, not just provide symptomatic benefit,” says Brotchie. “It could be disease-modifying, meaning it has the potential to change the course of the disease and maybe even reverse the disease progression.”
For the past decade, scientists have been exploring ways to increase the levels of glial cell-derived neurotrophic factor (GDNF) in the brain in Parkinson’s to help brain cells survive or even grow back. GDNF is a protein that is made in the brain and helps brain cells grow when the brain is developing or recovering from injury. Previous approaches have involved injecting GDNF into the brain through surgery or gene therapy. However, Cogane offers the possibility of delivering GDNF to the brain via a pill. The idea is that after you swallow the pill, the drug gets into the brain and then switches on the brain’s ability to make GDNF.
Noting that the animal data and early human data on safety and dosage look promising, Brotchie says, “I think Cogane offers the best hope today for a drug that could actually reverse the disease. And if you could reverse the disease early enough, you could change its impact on your life. Parkinson’s would then be something that you could be diagnosed with but, if you received the drug early enough and if the drug lives up to its promise, you could imagine that it might start to reverse symptoms and even reverse the disease process.”