Optimism from a Realist
As the title suggests, by trait I am a realist, sometimes at the verge of being a pessimist (my husband, children and honest friends will vouch for this, though not happily). But as I sat down to pull my thoughts together to write this blog, I quickly recognized a deep sense of optimism and excitement for the emergence of Parkinson’s disease targeted therapies that could slow down the progression of the disease. I focus on therapeutic aspects because I have spent the last 25 years in the pharmaceutical industry helping to discover and develop drugs for diseases affecting the central nervous system, including Parkinson’s disease. To state that this has been a sobering experience would be an understatement – primarily because only one of the projects I initiated has made it past human proof of concept/Phase 2 studies into large Phase 3 trials that could provide data to eventually get approval for the medicine by regulatory authorities. This, sadly, exemplifies the success rate of pharmaceutical development; ~1.5% of discovery stage projects succeed at delivering a drug to the market.
So, what is the source of my optimism for the so-called disease-modifying therapies for Parkinson’s disease? I will start with the basic science discoveries as a follow-up to recent blogs by Drs. Farrer and West. First, the field has garnered unprecedented insights into the neurobiological basis of Parkinson’s disease on the basis of human genetic studies as well as studies of cellular mechanisms associated with the causative genes. Chief among these are mutations in genes encoding alpha-synuclein, the major component of the Lewy pathology, glucocerebrosidase (GCase), an enzyme that regulates cells’ garbage disposal system called lysosomes and Leucine-Rich Repeat Kinase 2 (LRRK2), a kinase that appears to have multiple cellular functions. Studies of these genes have already spurred drug discovery efforts that have resulted in a therapeutic pipeline (more on this follows). Importantly, insights into cellular mechanisms are emerging where mutations in several disease-causing genes appear to converge on to cellular trafficking and quality control processes that ultimately cause the Lewy pathology and cell death. More importantly, the same cellular processes also appear to be affected in non-familial or idiopathic Parkinson’s disease. These discoveries provide exciting therapeutic opportunities to put a brake on the pathophysiologic results of disease-causing insults. It is, therefore, of no surprise that a number of pharmaceutical companies have now invested in therapeutic programs for Parkinson’s disease in order to take advantage of the progress in the basic science discoveries.
The second major source of my optimism is founded on rapidly emerging, multimodal data on studies of natural history of Parkinson’s disease. One particularly unique study to highlight here is an observational study called Parkinson’s Progression Markers Initiative (PPMI), which was kicked off in 2010 by the Michael J Fox Foundation as a public-private partnership. As the largest study of its kind for Parkinson’s disease, its goal is facilitate therapy development through a better understanding of how disease manifestations, from clinical symptoms to investigational biomarkers, change over time in individual patients as compared to age-matched healthy subjects. Although the study is still underway and in fact, has been expanded from the original cohort of idiopathic Parkinson’s patients to include those with known mutations in genes encoding alpha-synuclein, GCase and LRRK2, it has already provided key data on rates of progression for clinical and biomarker end-points. These data are being used to design clinical trials of novel therapeutics. The study also has begun to shed light on sub-populations of patients that differ in their clinical symptoms and progression rate. Such insights are, again, useful in the design of clinical trials of novel therapies. Finally, although the investigational biochemical biomarker data (for example on levels of total alpha-synuclein in the cerebrospinal fluid) have not provided the coveted marker of progression of the disease, they have shown definitively the need for a marker of pathogenic species of alpha-synuclein. The thousands of biospecimens that are being collected as part of the PPMI study now offer a priceless resource to identify novel markers of disease progression. This study is a testament to the generosity and dedication of Parkinson’s patients to contribute to scientific discoveries through their participation in an observational study.
The third area upon which my optimism is based, and one that has seen transformational advances in recent years, is related to devices that objectively measure activity and physiological parameters (e.g., sleep) in individual patients. Since motor symptoms are a defining feature of Parkinson’s disease, the wearable devices that allow “real-time” monitoring of movement of patients have the potential to aid not only in diagnosis but also importantly in monitoring therapeutic responses through continuous data collection. A number of device companies and pharmaceutical companies are engaged in assessment of the wearable devices and generation of data that could ultimately lead to regulatory approval of drugs on the basis of objective but deeper data.
In closing, 2017 represents 200th anniversary of James Parkinson’s first description of the disease through “An Essay on the Shaking Palsy”. It is at once humbling and exciting to consider the progress made since then, the majority in the last decade, at understanding Parkinson’s disease at a systemic, cellular and molecular level. The result is the emergence of a robust therapeutic pipeline aiming to slow the progression of this disease. Thus human clinical trials have begun on 5 novel therapies targeting alpha-synuclein as well as a therapy targeting the GCase pathway. There also are several other molecules targeting GCase or LRRK2 at the threshold of starting human clinical studies. History from other neurodegenerative diseases indicates that many challenges still remain but the battle to slow down Parkinson’s disease is now poised to be fought with a diverse set of deep data, drugs and devices that are informed by patient-centric studies.
Kalpana M. Merchant, Ph.D. spoke at the 4th World Parkinson Congress in Portland, Oregon. She serves as Chief Executive Officer of Chaperone Therapeutics, Inc. and has been its President since March 23, 2017. She is also President and CSO at TransThera Consulting Co. and serves as Adjunct Professor of Neurology at Northwestern University Feinberg School of Medicine and Adjunct Professor of Biology at Indiana University Purdue University at Indianapolis.
Ideas and opinions expressed in this post reflect that of the authors solely. They do not reflect the opinions or positions of the World Parkinson Coalition®