The Foundation brought together four pharmaceutical companies for a consortium to provide critical safety data on LRRK2 inhibitors, which enabled continued development of this promising drug class.
The LRRK2 kinase is a promising disease-modification target. Due to its genetic connection to Parkinson's and industry experience in kinase inhibitors, LRRK2 became a priority target for Parkinson's therapeutic development. However, preclinical research funded The Michael J. Fox Foundation (MJFF) to evaluate Genentech's LRRK2 inhibitors showed changes in lung tissue, which threatened continued development of this drug class.
In 2013, MJFF organized the LRRK2 Safety Initiative to conduct additional safety studies on LRRK2 inhibitors from Genentech, Merck, Pfizer, and Denali Therapeutics (Denali acquired Genentech's compounds and developed additional inhibitors). The LRRK2 Safety Initiative showed that tissue changes occurred across compounds but were reversible and not associated with functional impairment.
MJFF also initiated research into loss-of-function mutations to understand the effects of naturally occurring LRRK2 inhibition. This study found that lower levels of LRRK2 activity cause by genetic variants did not result in any associated health issues.
These findings gave companies the confidence to move forward in developing LRRK2 inhibitors as a treatment for Parkinson's disease. Denali Therapeutics moved into clinical testing in late 2017, joined by Biogen in 2019.
In addition to supporting a robust LRRK2 biology and biomarkers portfolio, MJFF continues to explore the safety and assessment of LRRK2 inhibitors as well as liaise with the pharmaceutical industry to encourage clinical development of this promising drug class.
Effect of selective LRRK2 kinase inhibition on nonhuman primate lung
Fuji, R.N., Flagella, M., Baca, M., et al. Effect of selective LRRK2 kinase inhibition on nonhuman primate lung. Sci Trans Med, 7: 273 (2015). Doi: 10.1126/scitranslmed.aav0820
LRRK2 inhibitors induce reversible changes in nonhuman primate lungs without measurable pulmonary deficits
Baptista, M.A., Merchant, K., Barrett, T., et al. LRRK2 inhibitors induce reversible changes in nonhuman primate lungs without measurable pulmonary deficits. Sci Trans Med, 12: 540 (2020). Doi: 10.1126/scitranslmed.aav0820
The effect of LRRK2 loss-of-function variants in humans
Whiffin, N., Armean, I.M., Kleinman, A. et al. The effect of LRRK2 loss-of-function variants in humans. Nat Med (2020). https://doi.org/10.1038/s41591-020-0893-5
The Michael J. Fox Foundation’s Strategies for Accelerating Translation of LRRK2 into Therapies for Parkinson Disease
Padmanabhan, S., Fiske, B.K., Baptista, M.A.S. The Michael J. Fox Foundation’s Strategies for Accelerating Translation of LRRK2 into Therapies for Parkinson Disease. Cells, 9(8), 1878 (2020). https://doi.org/10.3390/cells9081878
The Michael J. Fox Foundation thanks the four pharmaceutical companies who joined the LRRK2 Safety Initiative and the two contract research organizations who conducted the studies.