At the end of 2017, MEDI1341, our high affinity ɑ-synuclein monoclonal antibody, entered the first clinical trials to explore its potential as a disease modifying drug for Parkinson’s disease, an age-related neurodegenerative disorder that affects approximately 10 million people worldwide. Despite significant progress in understanding disease mechanisms and substantial drug discovery-related efforts over recent years, no medicines are currently available that can prevent or slow Parkinson’s disease progression. Thus, the development of disease-modifying treatments for Parkinson’s is an important unmet clinical need.
ɑ-synuclein is a protein, found in large amounts in the brain, that has a tendency to form clumps (aggregates) and has been implicated as a cause of Parkinson’s disease. For example, ɑ-synuclein aggregates are the major constituent of Lewy bodies and Lewy neurites, which are pathological, insoluble inclusions found inside the brain cells of people with Parkinson’s disease. In addition, missense mutations and multiplications in the ɑ-synuclein gene cause familial genetic forms of Parkinson’s disease.
Post-mortem histopathological studies indicate that the progressive neurodegeneration observed in Parkinson’s may result from the spread or propagation of ɑ-synuclein ‘Lewy’ pathology between neuroanatomically connected regions of the brain. In support of this theory, recently published experimental studies have demonstrated that pathologically relevant ɑ-synuclein aggregates can propagate between cells in culture via an extracellular phase, and pathological ɑ-synuclein aggregates can spread throughout the brain in mouse models of Parkinson’s disease. In these experimental models, it has been shown that administration of antibodies directed against ɑ-synuclein can block its uptake into cells and prevent its spread, as well as clearing ɑ-synuclein aggregates. These findings have helped to validate the development of antibody-based drug approaches that target extracellular ɑ-synuclein as a potential treatment of Parkinson’s disease.
MEDI1341 is a high affinity ɑ-synuclein-specific, fully human IgG1 monoclonal antibody that specifically binds to the C‑terminal region of human ɑ-synuclein. It is engineered for reduced effector function by virtue of a triple mutation introduced into the fragment crystallisable (Fc) region of the antibody in order to markedly reduce any risk of bystander neuroinflammatory responses in the brain. MEDI1341 recognises both monomeric and pathological aggregated forms of ɑ-synuclein.
In a series of well-designed pre-clinical experimental studies, we have shown that MEDI1341 blocks the cell-to-cell propagation of ɑ-synuclein aggregates in vitro and that passive systemic immunisation of mice with MEDI1341 weekly for three months strongly and robustly reduces the spread of ɑ-synuclein aggregates along axons from one side of the brain to the other. In further pre-clinical studies, we have shown that peripheral administration of MEDI1341 dose-dependently and robustly suppresses free ɑ-synuclein levels in brain interstitial fluid and cerebrospinal fluid, demonstrating that MEDI1341 can enter the brain and sequester extracellular ɑ-synuclein. Finally, pre-clinical safety toxicology studies have been completed with MEDI1341 and no safety findings were observed in animals.
We believe that MEDI1341 is an exciting highly differentiated novel candidate drug with the potential to sequester extracellular ɑ-synuclein and modify the underlying disease process of Parkinson’s disease; planned Phase I clinical studies will provide critical insight into the pharmacodynamics effects of MEDI1341.
In 2017, we took a strategic decision to enter a collaborative agreement with Takeda Pharmaceuticals to jointly evaluate MEDI1341, a compound we hope has the potential to be a world class asset, while at the same time sharing the known risks and costs of developing neuroscience drug programmes. In this collaboration, we will oversee all of the Phase I clinical studies, after which Takeda will take the lead on further development activities.