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Making Precision Medicine in Parkinson Disease a Reality: A Look at Challenges, Opportunities


How are researchers leveraging what is currently known about the pathogenesis and progression of Parkinson disease into the development of potential novel therapies, and what role should neurologists and patients play in addressing this neurodegenerative condition?

As the second-most common neurodegenerative condition worldwide, the prevalence of Parkinson disease (PD) is increasing at a faster rate than any other neurodegenerative disease, with cases expected to reach between 8.7 million and 9.3 million by 2030.

The current gold standard of treatment for PD, levodopa, works to replace the loss of dopaminergic cells, although it causes several potentially debilitating adverse effects, particularly dyskinesia. Moreover, levodopa is known to lose efficacy over time, leading to the recurrence of motor and nonmotor symptoms, known as “OFF” periods, that contribute to significant cost burden and impedes work productivity and employment.

With prevalence of PD rising amid a growing aging population, clinical trials investigating novel therapies for treatment of the disease have begun to take a more targeted approach to address the wide array of symptoms that vary from patient to patient, but routine practice has yet to leverage genetic testing, which is relatively new for neurodegenerative diseases, and lack of education among physicians has been challenge.

Addressing the heterogenous nature of the condition, Shalini Padmanabhan, PhD, director of Research Programs at the Michael J. Fox Foundation for Parkinson’s Research (MJFF), said that current mechanisms such as motor scales and genetic status can help to identify certain symptoms, such as cognitive deficits, as well as determine how present symptoms may progress.

“For example, patients with GBA mutations present with greater cognitive dysfunction whereas those with LRRK2 mutations present with milder cognitive deficits…This type of classification or subtyping of patients based on their clinical manifestation is important as it helps select patients for interventional trials,” said Padmanabhan in an email exchange with The American Journal of Managed Care® (AJMC®).

However, there remain several challenges and unknowns in PD, ranging from a proper scale for diagnosis to better comprehension of its clinical heterogeneity, as well as encouraging patients and clinicians to take part in the latest research.

In a recent webinar by MJFF, “The Promise of Precision Medicine for Parkinson Disease,” panelists discussed what is known in PD, what is not known, and how current knowledge of the disease is being leveraged in clinical trials for emerging therapies.

Carole Ho, MD, chief medical officer and head of development for Denali Therapeutics, said that today’s PD therapeutics pipeline is robust, with a broad array of new mechanisms to address the progression of the disease. This includes therapies that target alpha synuclein, a protein suggested to have a central role in the pathogenesis of PD, as well as the beta-glucocerebrosidase enzyme and LRRK2.

LRRK2 is the focus of a current late-stage clinical trial by Denali Therapeutics and Biogen, who are examining their drug candidate, DNL151, among patients with the mutation and those with sporadic disease. Working as a brain-penetrant inhibitor of LRRK2, the 2 companies intend to commence patient enrollment for the trial this year.

“There’s a clear unmet medical need to move beyond effective but temporary approaches to symptomatic treatment with dopamine replacement,” said Ho, who moderated the discussion.

Not only do temporary approaches such as levodopa or deep brain stimulation lose efficacy over time, they also may not provide sufficient therapeutic benefit for some patients; panelist Roy Alcalay, MD, MS, associate professor of Neurology at Columbia University Medical Center, said that, “if you speak to 10 people with PD and collect their symptoms, what bothers them, and response to medications, you’ll often get 10 different answers.”

In exploring the heterogeneity of PD, Alcalay said that by understanding the differences in reported symptoms and genetics linked with the pathogenesis and progression of the disease, it will allow for more clinical trials to divide patients into subgroups by genes. This can not only delineate who may best benefit from a particular therapy, but also help drive the development of targeted therapies.

In fact, the Restock International PD Study, or ROPAD, has worked to screen patients for known PD genes and mutations, such as LRRK2. While promising, genetic testing is not yet recommended for patients with PD. There are no approved therapies available to treat patients any differently from their current care, noted panelist Christine Klein, MD, professor of neurology and neurogenetics at University of Lubeck.

Moreover, she said that although there is good information on about 1000 mutation carriers, there is still a substantial amount of missing data that require more clinical work.

With genetics and clinical phenotypes still being better understood in PD, Ho mentioned the potential of creating a framework, called molecular-driven PD subtyping, that would look at biomarkers, pathology, and genetics to identify specific molecular PD subtypes that may respond to particular therapies.

Discussing known PD phenotypes, panelist Mark Cookson, PhD, senior investigator for the Laboratory of Neurogenetics at the National Institute on Aging, highlighted alpha synuclein, which works as a neuronal protein, and LRRK2, which mediates its effects largely through nonneuronal cells. “Genetics become useful and have some real utility by telling us a little bit about the underlying biology,” added Cookson.

However, genetic mutations and alterations do not always inevitably lead to illness, noted Cookson, and those who do develop PD will do so in an age-dependent manner. “The genetics is really incredibly important for our understanding of risk, but it doesn't act alone, it acts in this framework of an aging brain,” said Cookson.

As researchers continue to unravel the mechanisms influencing the pathogenesis and progression of PD, clinical trials are trying to leverage the limited knowledge available, said Pablo Sarri, PhD, global head of the Rare and Neurological Diseases Research Therapeutic Area for Sanofi Genzyme. Speaking about his involvement in these clinical trials, Sarri said that the current field for therapeutic development is trying to use genetics to select the patient population and match each participant with the right treatment.

Recently, Sanofi Genzyme sought to examine the efficacy of venglustat, a treatment showing promise in Gaucher disease, among patients with GBA mutations, the common genetic form of PD, although its MOVES-PD phase 2 trial was discontinued as it did not meet its efficacy goals. 

Sarri said that beyond genetics, to match patients with the right drug, he wants the PD community to take it one step further by starting to understand more of the biology and trying to use a biochemical endpoint in distinguishing potential benefits.

“Alpha synuclein, lysosomal biology are going to drive us in that direction—those are sort of the main two from my bias,” said Sarri.

Padmanabhan agreed—genetics and fluid biomarkers only explain a part of the clinical heterogeneity, but not all of it.

“In the future, developing and applying more quantitative assessments of the disease manifestation and progression and incorporating better biochemical endpoints that inform us of progression will be critical for patients and trialists,” said Padmanabhan.

However, these innovative ideas would prove fruitless without addressing a notable challenge, which is patient involvement in clinical trials. In an email exchange with AJMC®, Susanne Schneider, MD, PhD, of the Department of Neurology at Ludwig-Maximilians-University of München in Munich, Germany, said that the PD community needs to “improve ways to recruit (and thereby to achieve homogeneity of the cohorts studied) and to monitor (with better biomarkers) the patients in future clinical trials.”

“These aspects may be part of the reason why we have not yet been able to demonstrate clear disease modifying effects for PD drugs,” said Schneider, who also served as coauthor of an article discussing emerging treatments for genetic PD. “It is possible that some of the drugs tested in the past may have disease modifying effects, but we failed to pick them up.”

Although a routine approach in oncology, she said that precision medicine and the use of genetic testing are relatively new to the field of neurodegenerative diseases and, as such, warrant greater investigation and acceptance in routine practice.

“In my experience, many doctors and patients do not see an incentive to take part in genetic testing studies if there is no direct implication for them.…I believe that better education for general neurologists and patients would be helpful to achieve higher rates of acceptance of the concept and thereby higher numbers of participants,” said Schneider.

Right now, Schneider says it is timely for current drug trials to collect information about the genetic background, similar to that of the ROPAD trial in recruiting patients based on the genetic subtype.

“Other trials (directed at idiopathic PD) should, in my view, also collect and store DNA to allow retrospective subanalysis in the future if more information about genetics become available,” said Schneider.

Ultimately, the limited understanding of the complex nature of PD remains an obstacle, but by beginning to leverage genetics and biomarkers more frequently in clinical trials and routine practice, integration of precision medicine may become a reality in the field of PD.

“Since the approaches of diagnosing and tracking a patient’s clinical symptoms have traditionally been qualitative, efforts are underway to understand patient reported outcomes through online studies like Fox Insight and to leverage large amounts of data generated through the use of digital sensors within studies like the Foundation’s landmark study, Parkinson’s Progression Markers Initiative, to better quantify the disease severity and progression,” said Padmanabhan in the email exchange.

“With molecular phenotyping efforts, precision medicine approaches could evolve to treat a broader population of PD in the future.”

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