The Search for the Holy Grail of Parkinson Therapies
The best available medication for treating the symptoms of Parkinson disease (PD) has, in essence, remained unchanged for decades. But recent developments and promising clinical research point toward potential therapies that would not only broaden the repertoire for symptomatic treatment but also push the field closer to the holy grail of Parkinson therapy: disease-modifying treatments that slow or even reverse its progress.
“As much as, on the one hand, all of us as investigators really should be put to the task of delivering today, especially over the last 5 years there has been an exponential increase in the number of molecules going into clinical trials, the number of industry companies entering the field, the number of approaches to potential therapeutics in PD,” said Tanya Simuni, MD, the Arthur C. Nielsen, Jr, Research Professor of Parkinson’s Disease and Movement Disorders at Northwestern University’s Feinberg School of Medicine in Chicago, Illinois, and chief of movement disorders in the school’s Department of Neurology.
Such developments would have widespread benefits: PD affects an estimated 1 million patients in the United States and 10 million worldwide, according to the American Parkinson Disease Association. It’s now well known that in addition to causing motor disability, PD affects just about every domain of a patient’s functionality, including cognitive dysfunction, mood dysfunction, sleep disorders, blood pressure control, and bowel control. “It truly is a multisystem disease,” Simuni said.
The go-to treatment of PD symptoms has been levodopa since its discovery in the 1960s. The therapy was a major scientific breakthrough and a crucial step in the therapeutic development of treating and managing the symptoms of PD. Nearly 60 years after its discovery, doctors still acknowledge that levodopa remains the most efficacious therapy available for suppressing the 4 cardinal clinical features of PD: bradykinesia, tremor, rigidity, and postural instability.
“The bottom line is that standard, generic levodopa is still the gold standard. It’s the most symptomatically effective,” said Andrew Feigin, MD, the co-executive director of the Fresco Institute for Parkinson’s and Movement Disorders at New York University’s Langone Health in New York City.
But levodopa has well-documented limitations. If a patient takes levodopa in intermittent doses, there is a cyclical overshoot of the concentration of the medicine in the body that causes dyskinesia, which can be socially and physically limiting for the patient. And the therapeutic window gets narrower as the disease progresses and a patient’s sensitivity to these “on-off” fluctuations becomes greater.
“We always used to dose 2 or 3 times a day, but if you really look at the pharmacokinetics of these drugs and how they work in the blood and the system, that’s not very efficient,” said Fernando Pagan, MD, director of the Georgetown University Medical Center’s Movement Disorders Program and medical director of the Medstar Georgetown University Hospital, a National Parkinson Foundation Center of Excellence, in Washington, DC. “The patients are basically on a rollercoaster ride throughout the day.”
To combat this, recent and ongoing research efforts have focused on expanding the repertoire of treatment options and finding smoother delivery systems to improve quality of life. One such option is Rytary, a long-acting, slower-release preparation of levodopa approved by the FDA in 2015.
“When the longer-acting formulations are no longer beneficial, we can even deliver the medicines continuously through pumps or infusion cords,” Pagan said. For instance, Duopa is levodopa in the form of an intestinal gel that is administered through a surgically placed tube. Systems that could provide the levodopa in an ongoing, reliable manner that bypasses the gastrointestinal tract are of great interest as well.
“Skin delivery systems, for instance, are a very attractive area of research,” said Chad Christine, MD, professor of neurology at the University of California, San Francisco, and a movement disorder specialist. “It might be some sort of patch, or a subcutaneous system that is able to reliably deliver levodopa to a person’s body in a near-continuous way, that doesn’t involve a tube into the stomach.”
Smoother delivery mechanisms are accompanied by a broadening array of adjunctive drugs for adverse effects of symptomatic treatment, such as psychosis.
“Patients need these drugs to help their movements, so we can’t just take them off because they’re having visual hallucinations,” Feigin said. Nuplazid, to treat psychosis, was FDA approved in 2016; Northera was approved in 2014 for PD patients who have developed orthostatic hypertension.
Apomorphine is a rescue medication for sudden, unexpected “off” periods when symptoms unpredictably come back. Right now, apomorphine is typically injected, but “as you can imagine, not everyone wants to take an injection. Or, if you’re out in public, it might be a little bit harder,” said movement specialist Rachel Dolhun, MD, vice president for medical communications at The Michael J. Fox Foundation for Parkinson’s Research in New York City.
Two medications in the late stages of clinical testing could offer other options, according to Dolhun: an inhaled, quick-onset form of levodopa, similar to an asthma inhaler; and a reformulation of apomorphine in an under-the-tongue, Listerine-like strip.
Although it will not be in widespread clinical practice for some time, gene therapy is another investigative avenue for more efficient levodopa delivery, according to Patrik Brundin, MD, PhD, professor and director of the Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan.
Instead of simply administering more levodopa and increasing dopamine throughout the brain and body, where adverse effects may occur, gene therapy seeks to increase the ability to make dopamine in a more focused way in the brain’s motor circuit.
“It's like any operation in medicine: You need the right dose, and having it in the right place is key,” said Bernard Ravina, MD, MS, chief medical officer of Voyager Therapeutics in Cambridge, Massachusetts, a biotech firm that focuses on severe neurological diseases.
In October 2017, at the Michael J. Fox Foundation’s Parkinson’s Disease Therapeutics Conference in New York, Ravina presented research findings demonstrating that the AADC gene, which codes for the AADC enzyme that in turn converts levodopa into dopamine, could be encased in a viral shell and infused directly into the brain’s putamen. The therapeutic gene then made its way into the neurons of the putamen and triggered the production of the enzyme, thus creating dopamine.
While the process was conceptually straightforward, Ravina said, the challenge had been that the ability to achieve its completion surgically hadn’t existed before. The breakthrough came with the use of magnetic resonance imaging scans to guide the surgeon. A dye is added to the therapeutic gene, making it identifiable in scans of the patient taken during surgery; the surgeons are then able to adjust and direct it.
“It’s like laparoscopic surgery. You wouldn’t take out someone's gall bladder if you couldn’t see it,” noted Ravina. “And you shouldn’t put in a gene therapy if you don’t know where it’s going.”
For patients with advanced PD who have run out of medication options, an important therapeutic approach is deep brain stimulation (DBS), which became FDA approved 15 years ago and has been continuously refined since.
Researchers have recently used computer models to predict optimal stimulation and adjust such parameters as the frequency, amplitude, and pulse of the stimulation. “There are hundreds of different settings, so we’re trying to figure out which kind of settings will [optimize patients’] benefits, and how we can find them” as quickly as possible, said neurologist Irene Malaty, MD, medical director of the National Parkinson Foundation Center of Excellence at the University of Florida College of Medicine in Gainesville, Florida, where she also holds the Dein Professorship in Parkinson’s.
Improvements in DBS’s pulse generators have been accompanied by increases in the number of contacts in the electrode used for DBS. Multiple contacts can enhance the directional ability of DBS, thereby limiting adverse effects and improving therapeutic benefit.
Already in the testing phase, “newer [contacts] will allow much greater control in targeting the parts of the brain that are most receptive to DBS,” Christine said. In the future, DBS may even be able to self-regulate through the ability to record results from different positioning of electrodes, known as “adaptive DBS.”
Although DBS advances are exciting, and although DBS was a clinical revolution when first created, it nevertheless is not capable of actually changing the course of PD. At this point in time, just 1 modality that is readily available has shown much potential for slowing or stopping the progress of the disease in preclinical models. It is decidedly low-tech: exercise. Research results demonstrate persistent benefits in people who have exercised at high enough levels, said Burton Scott, MD, PhD, a movement disorders neurologist at Duke University School of Medicine in Durham, North Carolina.
“And we can extrapolate that finding to pretty much any exercise that’s safe,” Scott said, from tai chi to gardening, cycling to yoga. In fact, he noted, “I have a number of patients who are almost evangelical about boxing.”
Beyond exercise, the most promising therapy in its potential for disease modification is the diabetes medication exenatide, a synthetic form of a protein found in the saliva of the Gila monster, a denizen of the Arizona desert.
A recent clinical trial found that in the course of a 48-week period, patients with PD who received exenatide retained more motor function than patients who received placebo. It was led by neurologist Thomas Foltynie, MD, PhD, senior lecturer in the Unit of Functional Neurosurgery at University College of London, England.
“Many things have helped slow disease progression in vitro or in animal models, but nothing has translated into people,” Foltynie said. “[The trial] was statistically significant and [because of] that, it was a first. It’s an encouraging and exciting finding, but it does have to replicated.”
If the results are replicated in a phase 3, multi-center trial with more patients over a longer period, the drug could be “gamechanging,” Brundin said. “Every patient will go onto exenatide.”
What’s more, exenatide is a relatively well-tolerated drug, and the recent trial could be the first step toward something that patients with PD could use independently, according to Foltynie. Exenatide is a diabetes drug that targets metabolism, but its mechanism of action in the trial patients is unclear. There may be some overlap between the causes of PD and diabetes, according to Foltynie.
“It’s sort of rebranding neurodegeneration as a metabolic process. Diabetes is all about peripheral insulin resistance, and PD seems to be about central insulin resistance,” Foltynie said. “A lot of parallels are emerging, and we don’t know all the details, but it’s tantalizing that it’s something we can learn more about in the future.”
While investigators still do not know what causes PD, much has been learned about its associated biological and molecular changes. One breakthrough was the discovery that a characteristic of PD is a pathological accumulation of misfolded proteins in the brain, primarily alpha-synuclein, that become insoluble and block the normally effective “clearance system,” according to Simuni. Thus, “synuclein has been recognized as a prioritized target in therapy to try to modify the disease,” Brundin said.
The molecules at the forefront of normalizing alphasynuclein levels in the brain are antibody therapies, according to Simuni, using either manufactured antibodies and injecting them or elsewise vaccinating patients against the synuclein altogether. In addition to antibody therapies, “there are a range of other therapies where small molecules stop the aggregation of synuclein, [and] there are [other substances] that perhaps enhance the degradation of synuclein. It’s a major, major thrust” of research, Brundin said.
Repurposing chemotherapy drugs is another area of alphasynuclein research. Low doses of leukemia-modulating agents that cross the blood-brain barrier induce a cell’s ability to self-regulate, a process called autophagy.
“When you turn on that autophagy in the neurons, that’s like turning on a garbage disposal system,” said Pagan. “So, the cell can get rid of those sticky cytotoxic proteins like alphasynuclein that build up.”
A drug called nilotinib that may have that autophagy effect is currently in a phase 2 clinical trial, according to Pagan; at least 5 alpha-synuclein–targeting programs are currently in either phase 1 or 2 clinical trials, according to an article in Experimental Neurology. In recent years, researchers have begun to accept that perhaps PD is not a single disease.
Most likely, different molecular mechanisms all result in a clinical picture that is somewhat similar, but patients indisputably differ from one another: Some progress rapidly, some develop dementia after 5 years, and yet others are fine, cognitively, after 20 years with PD. “When you’ve met 1 person with PD, you’ve met 1 person with PD,” Dolhun said pointedly. “Everybody’s symptoms and course are so unique.”
To this end, another pathway is to subcategorize versions of PD rather than approaching it as 1 disease.
“Similar to what is being done in oncology now, routinely, is tailoring the therapy to the underlying specific risk profile of the individual,” Simuni said. By the time motor symptoms become obvious, an individual may have lost 80% of the neurons that are most affected by the disease. “So, the disease has made a very substantial progression in terms of the biology of the changes in their brain before it has even waved the flags of symptoms that makes us alerted to the fact that it’s there,” Malaty said.
Currently, no objective way exists to diagnose or accurately track the progression of PD. Huge research efforts in the diagnosis realm, according to Brundin, include the search for a reliable biomarker, such as a blood test, a spinal fluid test, or a brain image to detect the first signs that synuclein has misfolded. In a “dream scenario,” Brundin said, such tests could be used early to screen individuals who are at known high risk of PD. Then, doctors could administer a therapy that could prevent progression or even stop a patient from developing PD at all. Dolhun said, “we’ve got a lot of shots on goal.”