AC Immune Receives 2 Grants to Study Parkinson Disease Small Molecules From Michael J. Fox Foundation

Marco Baptista, PhD

According to a recent announcement, the Michael J. Fox Foundation for Parkinson’s Research (MJFF) awarded 2 grants, totaling $1.5 million, to AC Immune SA to develop first-in-class brain penetrant small molecules for patients with Parkinson disease (PD). The research, which will focus on targeting alpha-synuclein (α-syn) and the NOD-like receptor protein 3 (NLRP3) inflammasome pathway, add to the existing collaborative efforts by the companies that date back to 2015.¹

AC Immune will use the first grant towards an existing early-stage program that develops small molecules designed to prevent the intracellular aggregation and spreading of α-syn, which historically has been shown to slow disease progression for PD and other related disorders such as multiple system atrophy and dementia with Lewy bodies.

"Our foundation continues to invest in state-of-the-art research to improve our understanding of α-syn pathology and neuroinflammation in PD, with the objective to translate these discoveries into therapeutic strategies for PD," Marco Baptista, PhD, vice president, Research Programs, MJFF, said in a statement.¹ "We are pleased to award these 2 grants to AC Immune to drive the development of therapies that may slow or stop disease progression."

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The second grant will be used to research the therapeutic potential of a mechanistically novel, brain penetrant, small molecule inhibitors of the NLRP3 inflammasome activation for the treatment of PD. This is a pathway that regulates the production of potentially toxic inflammatory cytokines and has been shown to decrease neuroinflammation and increase neuronal survival across neurodegenerative disease systems once inhibited.

"We are extremely proud to receive these new grants and grateful to the MJFF for their continued support of our efforts to develop novel candidates in PD. A-syn and NLRP3 inflammasome both play a major role in several neurodegenerative diseases representing untapped promising targets for research and development," Andrea Pfeifer, chief executive officer, AC Immuna SA, said in a statement.¹ "Our Morphomer technology platform once again demonstrates its potential to deliver brain penetrant small molecule protein aggregation inhibitors and builds on AC Immune’s extensive experience in medicinal chemistry, protein biochemistry, and cell biology related to targeting misfolded and aggregation-prone proteins."

AC Immune’s portfolio in PD includes an anti-α-syn vaccine ACI-7104, which is currently ready for phase 2, a preclinical stage anti-α-syn antibody, and ACI-12589, a next–generation PET imaging tracer.

Earlier this year, findings from an IND-enabling toxicology study showed that ACI-12589 is safe and has potential as a biomarker for PD. Presented at the 2021 Alzheimer’s Association International Conference, July 26-30, the PET tracer demonstrated both low nanomolar affinity and significant target occupancy in saturation binding experiments when using PD brain homogenates.²

Additionally, ACI-12589 showed target engagement via high-resolution autoradiography across multiple alpha synucleinopathies, namely PD, multiple system atrophy, and dementia with Lewy bodies. When comparing diseased to nondiseased samples using classical autoradiography, ACI-12589 showed high specific signal in the former. The compound also displayed no binding to Tau or TDP-43 aggregates and has at least 30-fold selectivity when compared to amyloid-β. These findings helped lead the company’s first-in-human clinical trial for ACI-12589, which is currently ongoing.

REFERENCES

1. AC Immune awarded 2 Michael J. Fox Foundation grants to advance small molecule Parkinson disease programs. AC Immune SA. News release. December 15, 2021. Accessed December 17, 2021. https://www.globenewswire.com/news-release/2021/12/15/2352556/0/en/AC-Immune-Awarded-Two-Michael-J-Fox-Foundation-Grants-to-Advance-Small-Molecule-Parkinson-s-Disease-Programs.html

2. Capotosti F, Vokali E, Molette J, et al. The development of [18F]ACI-12589, a high affinity and selective alpha-synuclein radiotracer as a biomarker for Parkinson’s disease and other synucleinopathies. Presented at: AAIC 2021; Denver, Colorado; July 26-30, 2021. Poster 53943.