Parkinson’s Disease Clinical Trials: How Close Are We to Disease-Modifying Therapies?


  • Since the development of SINEMET in 1975, there has been little change in the standard of care for Parkinson’s disease given the high clinical failure rate of potential treatments partially driven by the inability of these compounds to pass the blood brain barrier
  • Learning from the past failures, the scientific community has studied novel approaches to address the blood brain barrier issue and investigated the pathology of Parkinson’s disease, while regulators have released new clinical trial guidelines in another neurogenerative disease with relevant insights for PD therapies on alternative clinical trial designs to demonstrate a lasting effect on the disease course
  • As the scientific and regulatory barriers in Parkinson’s disease are beginning to be addressed, biotechnology firms are developing innovative therapies based on academic studies showing potential therapeutic targets and pathways, which have been generated with increasing quantity over the past few years using genetic and pre-clinical studies


This blog post is PART III of CBPartners’ 3-part series: 2019 Key Considerations for CNS Investment read PART I: Central Nervous System (CNS) Drug Development Strategy: What is the Role of External Investment in this High-Risk Disease Space? and PART II: Alzheimer’s Disease Clinical Trials: Where do we go now?

Current Parkinson’s disease treatment dynamics

Parkinson’s disease (PD) is a neurodegenerative disorder that predominately affects dopamine-producing neurons in a specific area of the brain called the substantia nigra. The disease is characterized by the slow progression of symptoms and declining dopamine levels in the brain. In order to treat PD and many other neurogenerative diseases, a drug has to penetrate the blood brain barrier that acts as a defense system for the central nervous system by preventing most molecules from accessing the brain. While important for brain homeostasis, the blood brain barrier poses a significant challenge in administering drugs to the brain. This situation, alongside administration issues and other hurdles, has contributed to a high failure rate for therapies in clinical development for PD and other neurodegenerative diseases. As a result, PD has experienced little change in the treatment standard of care (SoC) since 1975 when SINEMET (Carbidopa-levodopa, $RXL) was released. This oral dopamine replacement therapy is used for the treatment of motor symptoms associated Parkinson’s disease. While symptom-relieving PD drugs have come to market (e.g., apomorphine, MAO-B inhibitors, and COMT inhibitors) over the years, curative or disease-modifying therapies (DMTs) is still out of reach.

Key learnings from PD drug development barriers

The high pivotal trial failure rate facing DMTs for PD and other neurodegenerative diseases is likely driven by several key development barriers. First of all, the inability to cross the blood-brain barrier. Most small molecules are unable to pass the highly selective endothelial cell border surrounding the brain, and a more targeted route of administration or mechanism of action is necessary. Secondly, the limited understanding of PD pathology. To date, the cause of PD is still unknown; however, the clinical community can agree that the reversal of PD will require more than just treating a dopamine deficiency. Genetic and environmental factors are now known to be key drivers of the disease progression and etiology, adding additional complexity to treatment discovery. Researchers have recently identified genes that may contribute to disease causation, notably LRRK2 and glucocerebrosidase (GBA) and hope that these targets will be the key to developing DMTs for PD in the near future. Several small biotechnology companies founded by academics are currently working on PD DMT development (e.g., DENALI and MEDGENESIS). Given the limited exposure of large pharmaceutical companies to PD drug development, it is likely that PD DMT will be mainly handled by the biotech firms.

Finally, there is still a lack of consensus on the appropriate trial design to test DMTs. Unlike symptom relieving therapies, DMTs have to prove their ability to permanently alter the course of disease progression by targeting the underlying pathophysiology with the effect persisting even in the absence of continued exposure to the therapy. In the absence of a gold standard for clinical trial design to test DMTs in CNS, there is a lack of guidance on how a therapeutic candidate should demonstrate its clinical effectiveness. This situation leaves manufacturers at the risk of regulatory denial if the clinical trial design is not considered to be appropriate by the Food and Drug Administration (FDA), European Medicines Agency (EMA), or other regulatory bodies. FDA has recently published some guidance on clinical trial design requirements for Alzheimer’s disease (AD) and the insights could provide manufacturers with some rules of thumb on future PD clinical trial methodology. Within the guidance, a delayed start or treatment switch methodology is proposed to demonstrate a persistent effect on disease course in order to address challenges associated with the limited study duration or the early stage disease. This means a portion of the subjects enrolled would be randomized to the investigational agent or placebo and those on placebo will be crossed over to the active treatment arm. If the switched patients fail to catch up with those who receive the drug throughout the trial, then a DMT could be shown to demonstrate a persistent therapeutic effect. With the scientific and regulatory changes, it is possible that we are getting closer to a neuroprotective therapy in PD.

CBP Takeaways

1) With the increasing number of scientific discoveries regarding potential PD root causes, we can expect a gradual increase in the pipeline PD products. Genetic studies have elucidated an increasing number of possible therapeutic targets and relevant pathways in the recent years, which can result in PD moving into a phenotype-driven disease space. This trend has been accompanied by various innovations to efficiently transport small molecules and biologics across the blood brain barrier. However, there are several caveats to note. Despite LRRK2 being known as the greatest genetic contributor to PD, only a small amount of PD cases is associated with genetic variants and this trend appears to vary across ethnic backgrounds. Furthermore, it is still unclear if targeting LRRK2 can result in PD disease modification. This suggests the importance of studying multiple genetic variants simultaneously (instead of focusing on just one mechanism of action), conducting stepwise proof of concept studies to de-risk assets early in the development, utilizing combination strategies, and segmenting the patient population based on specific biomarkers.

2) The recent publication of FDA draft guidance for AD drug development can be used to provide relevant insights regarding how to design PD clinical studies, specifically in measuring clinically relevant treatment effects with DMTs. Given the difficulty in obtaining such insights with limited study duration or early stage disease, the randomized start or withdrawal is noted as a credible approach in assessing disease modification. While it is encouraging to see the regulatory bodies being open to innovative trial design, a successful clinical trial strategy will require careful considerations on therapeutic target selection, patient segmentation, and study protocol preparation. As the manufacturers have to navigate these high-risk situations (e.g., uncertain PD pathology, novel therapeutic targets, and innovative trial designs), there is a need to consider how to communicate with the regulatory bodies throughout the process and collaborate with external parties for spreading the risks, maintaining rights, validating the approaches as early as possible, and supporting the promising assets from R&D to commercial launch.