In December 2013, we entered into a worldwide collaboration with Roche to develop and commercialize certain antibodies that target α-synuclein, including PRX002. Together, we and Roche aim to develop PRX002 as a disease-modifying treatment for Parkinson’s disease and potentially other related synucleinopathies.
Prothena has expertise in developing unique therapies to treat neurological diseases. The research we have been conducting for over a decade has provided us a deep understanding of the biology involved in Parkinson’s disease (PD), which is the second most common neurodegenerative disorder after Alzheimer’s disease.
In the United States alone, at least one million people suffer from PD, and about 60,000 new cases are reported annually. Early in the course of the disease, the most obvious symptoms are movement-related and include shaking, rigidity, slowness of movement and difficulty with walking. Later, cognitive and behavioral problems may arise. Dementia can occur in the advanced stages of the disease. Throughout the course of the disease, patients with PD may experience sensory, sleep and emotional problems.
Parkinson’s disease is a degenerative disorder of the central nervous system. The motor symptoms classically associated with PD result from the loss of dopamine-generating cells in the substantia nigra, a region located in the area of the brain called the midbrain. Current treatments for PD are effective at managing the early motor symptoms of the disease, mainly through the use of dopamine replacement therapy (e.g., peripheral decarboxylase inhibitors combined with levodopa) and dopamine agonists, but eventually lead to dose-limiting side effects. As the disease progresses and dopamine neurons continue to be lost, these drugs become less effective at controlling the symptoms.
Our goal is to slow or halt the progressive course of the disease, which is a current unmet need. To achieve this, we are focusing on a protein called α-synuclein.
Synucleins are a family of proteins, of which there are three known members: α-synuclein, β-synuclein, and ɣ-synuclein. The α- and β-synuclein proteins are found primarily in brain tissue. The ɣ-synuclein protein is found primarily in the peripheral nervous system and retina, as well as several tumor types. While the role synuclein proteins play in normal cellular functioning has not been definitively determined, there are data to suggest that synucleins assist with the stability of cellular membranes and/or their turnover.
Mutations in α-synuclein have been associated with multiple neurodegenerative illnesses, as this protein is a prominent component of Lewy bodies and Lewy neurites (abnormal protein clusters inside neurons). Lewy bodies and neurites are pathological hallmarks of several neurological disorders; collectively these are known as synucleinopathies. Synucleinopathies include PD; dementia with Lewy bodies; multiple system atrophy; and certain other neurological disorders. In synucleinopathies, the synuclein protein can misfold and aggregate to form insoluble fibrils (threadlike structures) that are thought to contribute to the pathology of the disease.
There is genetic evidence that α-synuclein plays a fundamental role in PD. In rare cases of familial forms of PD, there are mutations in the α-synuclein gene. Duplicate or triplicate copies of the relevant gene cause an increased level of the α-synuclein protein and the formation of fibrils that contribute to the disease. These genetic findings that implicate α-synuclein’s contributions to PD are substantiated further by an increasing body of evidence demonstrating that pathogenic forms of α-synuclein can be propagated and transmitted from neuron to neuron. Recent studies in cellular and animal models suggest targeting pathogenic α-synuclein may improve the health of neurons and disrupt the spread of α-synuclein-associated neurodegeneration.
Prothena’s scientists have generated monoclonal antibodies targeting α-synuclein. We have designed these antibodies to slow or reduce the neurodegeneration associated with α-synuclein misfolding and/or its transmission. We have identified a lead clinical candidate, PRX002, that is progressing towards clinical studies. In December 2013, Prothena and Roche entered into a worldwide collaboration to develop PRX002 for treatment of Parkinson’s disease and potentially other related synucleinopathies.
An Investigational New Drug application, or IND, for PRX002 was filed and accepted by the FDA in March 2014. Together with Roche, we initiated a Phase 1 clinical trial for PRX002 for the treatment of Parkinson’s disease in April 2014. This initial Phase 1 clinical trial of PRX002 was a randomized, double-blind, placebo-controlled, single ascending dose study in healthy subjects. It was designed to assess PRX002 for safety, tolerability, pharmacokinetics and immunogenicity. In March 2015, we announced top line results from that trial, which showed that PRX002 was safe and well-tolerated, meeting the primary objective of the study. Further, results from this study showed that administration of PRX002 leads to mean reduction of free serum alpha-synuclein levels of up to 96%. These overall results were highly statistically significant (p<0.00001). Reduction of free serum alpha-synuclein, a protein potentially involved in the onset and progression of Parkinson’s disease and the target of PRX002, was shown to be robust, rapid and dose-dependent after just a single dose. Based upon initial safety and tolerability observed in the single ascending dose study in healthy volunteers, in July 2014, together with Roche, we initiated a multiple ascending dose Phase 1 clinical trial of PRX002 in patients with Parkinson’s disease. This second Phase 1 clinical trial of PRX002 is a randomized, double-blind, placebo-controlled, multiple ascending dose study. It is designed to assess PRX002 for safety, tolerability, pharmacokinetics and immunogenicity, and will also evaluate exploratory biomarkers. Our scientists have published a number of scientific papers describing effects of these antibodies in multiple preclinical models that share common features with PD. Some of this work has been conducted with academic centers of excellence under a collaborative agreement. These include:
- Reducing C-Terminal-Truncated Alpha-Synuclein by Immunotherapy Attenuates Neurodegeneration and Propagation in Parkinson’s Disease-Like Models
D. Games, E. Valera, B. Spencer, E. Rockenstein, M. Mante, A. Adame, C. Patrick, K. Ubhi, S. Nuber, P. Sacayon, W. Zago, P. Seubert, R. Barbour, D. Schenk, E. Masliah
Journal of Neuroscience 34(28): 9441–9454 (2014)
- Axonopathy in an α-Synuclein Transgenic Model of Lewy Body Disease Is Associated with Extensive Accumulation of C-Terminal-Truncated α-Synuclein
D. Games, P. Seubert, E. Rockenstein, C. Patrick, M.Trejo, K. Ubhi, B. Ettle, M. Ghassemiam, R. Barbour, D. Schenk, S. Nuber, E. Masliah
Journal of American Pathology 182 (3), 940-953 (2013)
- Passive Immunization Reduces Behavioral and Neuropathological Deficits in an Alpha-Synuclein Transgenic Model of Lewy Body Disease
E. Masliah, E. Rockenstein, M. Mante, L. Crews, B. Spencer, A. Adame, C. Patrick, M. Trejo, K. Ubhi, T. Rohn, S. Mueller-Steiner, P. Seubert, R. Barbour, L. McConlogue, M. Buttini, D. Games, D. Schenk
PLoS ONE 6 (4), 1-17 (2011)