Novel PET Imaging Tracer Shows Promise for Parkinson Disease Diagnosis

Andrea Pfeifer, PhD

Data were presented on the promise of ACI-12589, a novel alpha-synuclein (a-syn) positron emission tomography (PET) tracer with potential as a biomarker for Parkinson disease (PD), at the 2021 Alzheimer Association International Conference (AAIC) held July 26-30. AC Immune, which plans to further examine the imaging tracer in a first-in-human (FiH) clinical trial, also recently acquired a vaccine targeting a-syn, Affiris PD01, which will be put into clinical development and evaluated via a biomarker-based phase 2 study for patients with PD.

Findings regarding ACI-12589 were presented by Francesca Capotosti, PhD, research scientist, AC Immune SA, who concluded that the compound was safe in the IND-enabling toxicology study, leading to the development of the FiH clinical study to further investigate the potential for differential diagnosis in PD. ACI-12589 demonstrated both low nanomolar affinity and significant target occupancy in saturation binding experiments when using PD brain homogenates. 

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 non-diseased 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.¹ 

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“Through the development of companion diagnostics such as ACI-12589 in PD, we are working to better enable the advancement of the neurodegenerative disease treatment paradigm towards earlier treatment and prevention,” Andrea Pfeifer, PhD, CEO, AC Immune SA, said in a statement.² “We expect the continued development of this program, alongside the advancement of our recently acquired industry-leading anti-a-syn vaccine, to solidify our position at the forefront of PD drug development. We are pleased to have the opportunity to discuss ACI-12589 with the scientific community at AAIC ahead of the anticipated readout from its first-in-human study later this quarter.”

Following an initial screening of AC Immune’s confirmation-specific, small weight molecule library (Morphomer library), human brain derived a-syn aggregates from diseased donors were studied in a medicinal chemistry optimization program and used to develop a proprietary binding assay. Target occupancy and signal specificity data were identified via autoradiography and radio binding experiments on synucleinopathy tissue samples. Autoradiography techniques were also used to assess selectivity to Alzheimer disease (AD) and frontotemporal lobar degeneration, following which, selected samples were 18F radiolabeled, with pharmacokinetics and then evaluated in non-human primates. 

As with the ACI-12589 compound, AC Immune is spearheading efforts for the Affiris PDO1 vaccine following publication of results from a phase 1 study in Lancet Neurology, which showed PD01 successfully generated antibody responses against pathological forms of a-syn. Investigators from the phase 1 study also found that the vaccine was safe and well-tolerated when administered over longer periods of time.³ According to investigators, additional studies are necessitated to further evaluate safety and efficacy. 

“We believe very strongly that active vaccination will play an important role in the long-term management and possible prevention of neurodegenerative diseases,” Pfeifer said in separate statement. “By acquiring a clinically validated vaccine program against a-syn, we are advancing AC Immune to the forefront of Parkinson’s disease drug development, with a wholly-owned a-syn portfolio that now covers a full spectrum of treatment modalities addressing this well-characterized target.”⁴

For more coverage of AAIC 2021, click here.

REFERENCES

1. 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.
2. AC Immune presents full phase 1b results on anti-abeta vaccine and discussed its first-in-class diagnostic for Parkinson’s disease at AAIC 2021. News release. AC Immune SA. July 29, 2021. https://finance.yahoo.com/news/ac-immune-presents-full-phase-113000722.html
3. Volc D, Poewe W, Kutzelnigg A, et al. Safety and immunogenicity of the a-synuclein active immunotherapeutic PD01A in patients with Parkinson’s disease: a randomised, single-blinded, phase 1 trial. Lancet Neurol. Published online July 1, 2020. doi:10.1016/S1474-4422(20)30136-8
4. AC Immune announces strategic acquisition of industry-leading Parkinson’s Disease vaccine candidate and equity investment led by Athos Service GmbH. News release. AC Immune SA. July 27, 2021. https://www.globenewswire.com/news-release/2021/07/27/2269302/0/en/AC-Immune-Announces-Strategic-Acquisition-of-Industry-leading-Parkinson-s-Disease-Vaccine-Candidate-and-Equity-Investment-Led-by-Athos-Service-GmbH.html