While people are living longer, it also means they are also susceptible to aging diseases. Parkinson’s disease is a progressive degenerative disorder of the central nervous system (CNS) that affects one in 100 people over age 60. With an estimated seven to 10 million patients living with Parkinson’s worldwide, it is the second most common neurodegenerative disorder after Alzheimer’s disease.

Parkinson’s is characterized by the neuronal accumulation of aggregated alpha-synuclein in the CNS and peripheral nervous system that results in a wide spectrum of worsening progressive motor and non-motor symptoms. Current treatments for Parkinson’s disease are symptomatic and only address a subset of symptoms such as motor impairment, dementia, or psychosis. Symptomatic therapies do not target the underlying cause of the disease and lose effectiveness, often leading to debilitating side effects as the disease progresses.

Prothena is a clinical-stage biotechnology company focused on the discovery and development of novel therapies with the potential to fundamentally change the course of progressive, life-threatening diseases in the neuroscience category such as Parkinson’s. As CEO, Gene Kinney, Ph.D., leads Prothena’s efforts in this mission. Dr. Kinney is a member of Prothena’s founding leadership team and previously served as the company’s chief scientific officer and chief operating officer. Before joining Prothena Kinney held positions with Elan Pharmaceuticals Inc., Janssen, Merck, Bristol-Myers Squibb, and was an assistant professor at the Emory University School of Medicine.

As part of a new industry series, WuXi AppTec Communications asked Kinney his thoughts on Prothena’s research, its potential, and what new developments are on the horizon for this ravaging disease.

WuXi: How would you describe the progress being made today towards our ability to develop new drugs to treat neurological disorders, including Parkinson’s disease?

Gene Kinney: Neurodegenerative diseases such as Parkinson’s and Alzheimer’s remain areas of some of the highest unmet need in medicine. Currently available medicines for patients suffering from these diseases are somewhat effective in treating the symptoms resulting from the underlying loss of brain cells, but become less useful as the underlying disease progresses.  Unfortunately, there are no treatments yet that have demonstrated the ability to favorably alter the progressive course of these diseases.

Scientists at Prothena have been studying the potential to intervene in progressive neurogenerative processes for decades and we believe that advances in neuroscience are accelerating thanks to the lessons learned from pioneering studies in these areas combined with the development of new scientific tools and techniques such as better biomarkers and imaging capabilities, and also activities like the BRAIN Initiative. The brain is the most complex organ in the body, and today’s advancements will build on our knowledge to help pave the way to new therapeutic approaches for a whole range of diseases.

WuXi: Can you give us some more examples of these advances?

Gene Kinney: As one example of such advances, imaging technologies that visualize the amyloid in the brain of a patient with Alzheimer’s disease have only been available for use in clinical studies for a little more than a decade, which is a relatively short amount time in terms of neuroscience drug development. Despite this limited time frame, such tools are now routinely deployed to help select appropriate patient populations for clinical studies and to monitor for reduction in amyloid in the brains of patients following intervention.  Based in part on the utility and success of these imaging agents in the Alzheimer’s field, efforts are underway to develop similar imaging tools for Parkinson’s disease clinical research.  Significant progress has already been achieved in this regard and I expect additional substantive breakthroughs in this area soon.

Another example of even more recent advances can be found in the area of Parkinson’s disease and how we measure the effect of therapies on the symptoms of the disease. The Unified Parkinson’s Disease Rating Scale (UPDRS) has for decades been a common clinical outcome measure to monitor disease symptoms in studies, but in recent years new smartphone technology is being piloted to assess motor symptoms of Parkinson’s such as balance, gait and tremor. The smartphone measures relationship to UPDRS and may ultimately provide additional sensitivity to assess therapeutic efficacy in patients.

WuXi: Has better understanding of neurodegenerative diseases helped advanced research?

Gene Kinney: Progress around understanding the basic biology of neurodegenerative diseases has allowed for a better understanding of tolerability findings that have substantial impact on decisions of dose selection and dose frequency.  For example, the initial observations of Amyloid Related Imaging Abnormalities (ARIA-E) following treatment with anti-Ab agents was appropriately met with concern and caution leading to dose selection strategies that, in retrospect, may have limited the effectiveness of these agents.  More recent evidence suggests that ARIA may be caused by the on-target removal of Ab from cerebral vasculature.  This evolving understanding of the basic biology has led to new thinking about how this clinical event should be managed in the context of clinical trials. Moreover, the understanding that in Parkinson’s disease there is a paucity of a-synuclein deposition on cerebrovascular led to predictions that ARIA was not likely to be a common side effect following treatment with anti-a-synuclein agents. This knowledge translated into actionable decisions related to dose level and dosing frequency in current clinical studies of anti- a-synuclein agents.

Taken together, many important advances are resulting in new approaches in our efforts to alter the disease course of neurodegenerative conditions. These advances have already impacted clinical trial conduct in the areas of patient selection, dose selection, dosing frequency and the determination of safety and efficacy endpoints.

In light of these advances and given the incredible unmet medical need, we are now seeing pharmaceutical companies, many of whom had stepping back for a number of years from investing in neuroscience drug development, reinvesting through collaborations and their own R&D efforts, so this is a particularly exciting time to be active in this space.

WuXi: What are researchers learning about the causes of Parkinson’s disease?

Gene Kinney: Parkinson’s is the second most common degenerative neurological disorder after Alzheimer’s disease, affecting seven to 10 million people worldwide. Fortunately, it is the focus of many research efforts around the world and a better understanding the diseases’ biologic underpinnings can and has informed new therapeutic approaches.

An aspect of the disease that has gained broader understanding in recent years is that in addition to the motor symptoms classically associated with Parkinson’s disease, we now know that non-motor symptoms such as loss of sense of smell, sleep disturbances, changes in skin innervation, and/or gastrointestinal motility issues, may present many years earlier. Said another way, Parkinson’s is no longer believed to be a disease affecting only areas of the brain that mediate movement, but instead is a whole-body disease that affects movement as well as a number of other functions.  These understandings may ultimately help with earlier and more accurate diagnoses of the disease and/or in the identification of individuals that have a higher likelihood of ultimately progressing to Parkinson’s disease – something that we expect will be important for new treatments that aim to slow disease progression.

We are also learning more about the factors that cause the dopamine-producing cells in the brain to die, including a protein known as alpha-synuclein (or α-synuclein). In patients with Parkinson’s, aggregated α-synuclein form “clumps” called Lewy bodies that are a hallmark of the disease. We see that α-synuclein also plays a role in other neurodegenerative diseases collectively known as synucleinopathies, including dementia with Lewy bodies and multiple system atrophy.

Several years ago, it was demonstrated in cellular and mouse models that soluble aggregated α-synuclein protein can spread from cell to cell, and that this is one mechanism related to disease progression. This finding suggests that an anti-α-synuclein immunotherapy approach may have the potential to prevent cell-to-cell transmission of α-synuclein and reduce neuronal toxicity.

WuXi: Is Parkinson’s disease caused by genetic abnormalities, environmental factors or a combination of the two?

Gene Kinney: Since the cause of Parkinson’s disease is currently unknown, the exact factors involved remain to be definitively determined.  In a small number of cases, a single genetic mutation for example, Leucine-Rich Repeat Kinase (LRRK2) is associated with the development of Parkinson’s disease.  In a similar manner, there are extreme environmental toxins that have been known to result in Parkinsonian symptoms for example; MPTP is a neurotoxicant inducer of Parkinson’s.  Despite these rare cases, most cases of Parkinson’s disease occur in people with no genetic risk or apparent family history.  A common assumption is that Parkinson’s disease, in the majority of patients, occurs due to a complex interaction of genetic and environmental factors.

WuXi: What scientific breakthroughs are needed to better understand the causes and progression of Parkinson’s?

Gene Kinney: The greatest medical benefit in considering treatments with the ability to favorably alter the course of Parkinson’s disease would be to treat patients at the earliest stage while symptoms remain mild and manageable and/or to prevent the disease entirely before symptoms appear. Within the context of that lens, the single most important breakthrough would be the ability to identify patients at risk and/or in the earliest stages of their disease when changes in the brain are occurring, but before there are clinical symptoms.  The development of biomarkers that track the progression of Parkinson’s disease in ways that can be used in the context of clinical trial outcome measures would represent valuable tools. At Prothena, we have collaboration with the Michael J Fox Foundation for Parkinson’s Research that aims to accelerate the discovery of novel biomarkers and develop assays to measure Parkinson’s disease progression. New and better brain imaging techniques that can tell us about the spread of α-synuclein pathology and/or neurodegeneration throughout the brain would also be incredibly helpful in understanding the progression of the disease and help in the design of clinical studies for new therapies.

WuXi: What is Prothena’s approach to Parkinson’s and how are you applying it?

Gene Kinney: Prothena developed PRX002/RG7935, an antibody that targets α-synuclein, a protein believed to misfold and aggregate to form the protein structures, called Lewy bodies, that are highly implicated in Parkinson’s disease pathology. PRX002/RG7935 is a potential therapeutic approach that is designed to preferentially target aggregated α-synuclein to clear it, prevent new aggregates from forming, prevent transmission from one neuron to the next and slow or reduce neurodegeneration.

We are developing this investigational drug through a worldwide collaboration with Roche and patients with early Parkinson’s disease may be eligible to enroll in the ongoing Phase 2 PASADENA clinical study of PRX002/RG7935, which Roche is currently conducting. (You can learn more about the clinical trial here)

Beyond our work with PRX002/RG7935, we remain interested in the rapid pace of scientific advancement within the field and are evaluating novel approaches for the treatment of Parkinson’s disease and related neurodegenerative disorders on an ongoing basis.

WuXi: How does this approach differ from others?

Gene Kinney: Motor symptoms classically associated with Parkinson’s result from the loss of dopamine-generating neurons in the midbrain which leads to issues with movement, including tremors, difficulty walking and other motor symptoms. Current treatments are somewhat effective at managing these motor symptoms, mainly through a medication known as levodopa or through dopamine agonists, which are drugs that act like dopamine to stimulate brain cells. However, as Parkinson’s progresses and dopamine-producing neurons continue to be lost, these drugs eventually become less effective at treating the motor symptoms.

Our drug candidate, PRX002/RG7935, takes a different approach by directly targeting the disease-causing α-synuclein protein. In patients with Parkinson’s, α-synuclein aggregates and forms the protein structures that are thought to contribute to the disease. The approach we are taking with PRX002/RG7935 aims to impact the underlying disease process by preferentially targeting the pathogenic forms of α-synuclein and blocking its ability to be taken up by healthy neurons, while also promoting its clearance.

WuXi: Are there learnings from Parkinson’s research that can be applied to other progressive neurological disorders?

Gene Kinney: There is growing consensus that the sequential cell-to-cell transmission of disease-causing proteins might be relevant to disease progression in several other neurodegenerative diseases. For example, the transmission of pathology between brain regions has also been proposed in Alzheimer’s disease with the Ab and tau proteins. More recently, this has also been proposed in frontotemporal dementia where, particularly for patients with a behavioral component of the disease, there are strong indications of a cell-to-cell spreading of TDP-43 pathology.

The approach we are taking in Parkinson’s disease is similar to the approach we take to design antibodies that aim to optimally target pathogenic proteins implicated other neurodegenerative diseases. The knowledge about common mechanisms of disease propagation at the molecular level and our increasing understanding of how to effectively intervene in this process, enables us to develop highly targeted antibodies that aim to intercept the transmission process and prevent further neurodegeneration.

WuXi: How will treatments for Parkinson’s, Alzheimer’s and other neurodegenerative diseases evolve? Are cures possible?

Gene Kinney: This is an exciting time for neuroscience research, and I am extremely optimistic about the prospect of new and better treatments emerging in the near future. Armed with better understanding of disease pathophysiology, new tools for imaging the brain, decoding DNA, and evaluating and monitoring symptoms, I believe we will see tremendous improvements in quality of life for patients with Parkinson’s and other neurodegenerative diseases. As our understanding continues to evolve, I fully anticipate that one day, the scientific and medical communities will be able to effectively identify and stop these types of diseases even before symptoms emerge.