Cerevance Announces Promising Data Updates on Innovative Approaches to Treating Parkinson Disease

Nicola Brice, PhD

In recent news, using Cerevance's proprietary Nuclear Enriched Transcript Sort sequencing (NETSseq) platform, nicotinic acetylcholine receptor subunit alpha-6 (nAChR⍺6) expression was shown to selectively enrich relevant dopaminergic neurons in patients with Parkinson Disease (PD).¹

Findings showed that CVN417, a novel and selective modulator of the nAChR⍺6 function, demonstrated equipotent efficacy against nAChR⍺6 function in a rodent model of resting tremor, suggesting it may be a potential therapy treatment in PD. This data set, along with several others, were presented as a poster presentation at the 2023 International Conference on Alzheimer's and Parkinson's Diseases and related neurological disorders (AD/PD), held March 28-April 1, in Gothenburg, Sweden.²

Lead author and presenter, Nicola Brice, PhD, senior director of neuroscience at Cerevance, and colleagues used IHC specimens of human and rat SNoc probed with anti-nAChR⍺6 (GeneTex, G51236, 10 ug/m). The CVN417 activity and selectivity was tested in a Ca2+ flux assay, with HEK293 lines stability expressed as ⍺6 or ⍺4 along with ß subunits. The firing frequency in locus coeruleus was 200 um slices from 3-4-week-old Sprague Dawlev (SD) rats. For voltammetry, investigators used 6-8-week-old C57/BL6/J mice, prepared with 300 um striatal slices. Also, tacrine-induced tremor in male SD rats (170-230 g) were used. The animals were allowed to acclimatize in their environment for at least 5 days prior to the examination.

READ MORE: Preclinical Data Demonstrates Potential of Small-Molecule Inhibitors of α-Synuclein Toxic Oligomers for Parkinson Disease

In the background of the presentation, Brice et al noted, “Cerevance's NETSseq platform is able to identify transcriptomic-based disease targets for a broad range of neurodegenerative disorders using human post-mortem brain tissue. Highly selectively expressed, novel target proteins that are either specific to certain brain circuits or are over- or under-expressed in diseased brains can be identified using NETSseq. Because NETSseq identifies targets that are differently regulated in these diseases, assets targeting new mechanisms that are expected to have greater specificity and significantly fewer off-target side effects can be developed. This enables more informed drug development strategies for a variety of neurodegenerative disorders.²

Cerevance also presented 2 oral symposium presentations at the conference, the first of which, was given by Xiao Xu, PhD, senior research fellow at Ceverance. The presentation detailed the potential of the NETSseq platform to highly generate reproducible molecular profiles from specific neuronal and glial cell types in the human brain. The researchers noted that the data is being harnessed for the identification and selection of novel targets for drug developments such as for KCNK13, a protein coding gene.³

The last symposium oral presentation was presented by Karl Kieburtz, MD, MPH, the Robert J. Joynt Professor in Neurology, senior associate dean for clinical research, and director of the Clinical & Translational Science Institute at the University of Rochester Medical Center. The data presented was from the phase 2 clinical trial (NCT04191577) of CVN424 in patients with PD and motor complications.⁴

In March 2022, findings from the phase 2 trial showed that CVN424, a novel, non-dopaminergic, GPR6 inverse agonist, significantly improved OFF time by 1.3 hours compared with placebo in the high-dose group at 4 weeks (P = .042).⁵ In addition, results demonstrated that CVN424 was safe and well tolerated with low rates of mostly mild and moderate adverse events. In addition to improvements in motor symptoms, patients treated with CVN424 had a statistically significant improvement in daytime alertness, measured with the Epworth Sleepiness Scale (ESS). Also, patients reported better experiences of motor aspects of daily living as measured with the UPDRS Part II. Thus, researchers noted that the data provides evidence for the potential of CVN424 in improving both motor and nonmotor symptoms of PD and potentially to represent a nondopaminergic therapy for PD.

REFERENCES
1. Cerevance Announces Presentations at AD/PD™ 2023 International Conference. News Release. Cerevance. Published March 20, 2023. Accessed April 10, 2023. https://www.cerevance.com/post/cerevance-announces-presentations-at-ad-pd-tm-2023-international-conference
2. Brice, N. Characterisation of CVN417: A Novel and Selective Nicotinic Alpha6 Receptor Antagonist for the Modulation of Motor Dysfunction in Parkinson’s Disease. Presented at the 2023 International Conference on Alzheimer's and Parkinson's Diseases and related neurological disorders (AD/PD), held March 28-April 1, in Gothenburg, Sweden. Abstract 0724.
3. Xu, X. NETSSEQ Reveals Deep Molecular Insights Into Alzheimer’s Disease Progression and Facilitates Identification of Novel Therapeutic Targets. Presented at the 2023 International Conference on Alzheimer's and Parkinson's Diseases and related neurological disorders (AD/PD), held March 28-April 1, in Gothenburg, Sweden. Exploring New Targets in AD, FTD, PD, and LBD session.
4. Kieburtz, K. CVN424, A Novel GPR6 Inverse Agonist Demonstrates Efficacy in an Adjunctive Parkinson’s Disease Phase 2 Clinical Trial. Presented at the 2023 International Conference on Alzheimer's and Parkinson's Diseases and related neurological disorders (AD/PD), held March 28-April 1, in Gothenburg, Sweden. Advances in PD and LBD Diagnosis and Drug Development session.
5. Ceverance reports positive phase 2 clinical trial results with CVN424, a Parkinson disease drug working through a new mechanism. News release. Cerevance. March 31, 2022. Accessed April 10, 2023. https://www.globenewswire.com/news-release/2022/03/31/2414037/0/en/Cerevance-Reports-Positive-Phase-2-Clinical-Trial-Results-with-CVN424-a-Parkinson-s-Disease-Drug-Working-Through-a-New-Mechanism.html