Breakthrough Clinical Results
Cerevance announced upcoming presentations at the Alzheimer's Association International Conference (AAIC) 2025. Key presentations include Phase 1 data on CVN293, an investigational KCNK13 inhibitor targeting neuroinflammation in neurodegenerative diseases, showing good CNS exposure and tolerability. Another presentation will detail findings from their NETSseq platform, highlighting astrocyte function in Alzheimer's disease. CVN293 is a highly selective oral inhibitor aiming to reduce neuroinflammation by inhibiting KCNK13, a potential regulator of NLRP3 inflammasome activation. Cerevance's NETSseq platform analyzes brain tissue to identify subtle molecular changes driving disease progression.
Key Highlights
- Phase 1 data on CVN293, a KCNK13 inhibitor, shows good CNS exposure and tolerability.
- NETSseq platform reveals deep molecular insights into astrocyte function in Alzheimer's disease.
- CVN293 aims to reduce neuroinflammation and slow disease progression in neurodegenerative disorders.
- CVN293's mechanism of action involves inhibiting KCNK13, a potential regulator of NLRP3 inflammasome activation.
Incidence and Prevalence
Global Epidemiology of Neurodegenerative Diseases
Prevalence and Incidence Patterns
Alzheimer's disease and Parkinson's disease are the two most common neurodegenerative diseases in the world, and their incidence rates are increasing as our society ages. Neurodegenerative diseases (NDs) are a major cause of disability and mortality worldwide. The increasing incidence rates of neurodegenerative diseases create a significant social and economic burden.
Parkinson's Disease Epidemiology
Age-standardized Parkinson's disease prevalence (per 100,000) was 2,168.18 (+/-95.64) in White men, but 1,036.41 (+/-86.01) in Blacks, and 1,138.56 (+/-46.47) in Asians. The incidence ratio in Blacks as compared to Whites (0.74; 95% CI = 0.732-0.748) was higher than the prevalence ratio (0.58; 95% CI = 0.575-0.581). The incidence ratio for Asians (0.69; 95% CI = 0.657-0.723) was similar to the prevalence ratio (0.62; 95% CI = 0.617-0.631).
Bayesian mapping of Parkinson's disease revealed a concentration in the Midwest and Northeast regions of the US. Mean county incidence by quartile ranged from 279 to 3,111, and prevalence from 1,175 to 13,800 (per 100,000). Prevalence and incidence in urban counties were greater than in rural ones (p < 0.01). Cluster analysis supported a nonrandom distribution of both incident and prevalent Parkinson's disease cases (p < 0.001). Parkinson's disease is substantially more common in Whites, and is nonrandomly distributed in the Midwest and Northeastern US.
Internationally, prevalence of Parkinson's disease has increased over and above demographic changes.
Motor Neuron Diseases
The burden of motor neuron diseases is increasing and currently more relevant in high-income countries but increasing at the highest rate in low and middle-income countries. Epidemiological studies have shown a variation of incidence, mortality and prevalence of ALS between geographical areas and different populations.
In a study of motor neuron disease, a retrospective case-control study was carried out on 15 negroid African and 45 white patients with the disease seen over 8 years. The chance of presenting with the "flail arm" variant of motor neuron disease was four times as high in the African group than the white group (odds ratio 4.33, p=0.05, 95% confidence interval 0.99-18.92). Race may influence the phenotype and progression of motor neuron disease.
Multiple Sclerosis Racial Differences
Grey matter (-0.9%/year versus -0.5%: P =0.02), white matter (-0.7%/year versus -0.3%: P =0.04) and nuclear thalamic (-1.5%/year versus -0.7%/year: P =0.02) atrophy rates were approximately twice as fast in African Americans with multiple sclerosis compared to Caucasian Americans. African Americans also exhibited higher proportions of microcystoid macular pathology (12.1% versus 0.9%, P =0.001). Retinal nerve fibre layer (-1.1% versus -0.8%: P =0.02) and ganglion cell+ inner plexiform layer (-0.7%/year versus -0.4%/year: P =0.01) atrophy rates were faster in African versus Caucasian Americans.
Disease Burden and Treatment Status
Currently, there are no cures or treatments to halt the progression of neurodegenerative diseases. In a systematic review of bruxism in neurodegenerative diseases, Parkinson's disease showed the highest prevalence rates, followed by multiple sclerosis, Alzheimer's disease, chorea-acanthocytosis and frontotemporal dementia.
Emerging Mechanism of Action
Emerging Mechanisms of Action for Neurodegenerative Disease Treatment
Targeting Neuroinflammation
Neuroinflammation has emerged as a critical target for neurodegenerative disorders. Recent research highlights the importance of microglial polarization in Alzheimer's disease (AD) therapy, with strategies focusing on shifting from pro-inflammatory M1 to anti-inflammatory M2 phenotypes.
Baicalein, a flavonoid with anti-inflammatory properties, has shown significant promise by: - Shifting BV-2 microglia from pro-inflammatory M1 to anti-inflammatory M2 phenotype - Inhibiting microglial apoptosis and pro-inflammatory factors (TNF-α, IL-1β, IL-6) - Promoting microglial Aβ uptake and anti-inflammatory factors (IL-4, IL-10) - Decreasing Aβ plaque deposition in APP/PS1 mice brain - Attenuating NLRP3 inflammasome activation and neuronal apoptosis - Modulating microglial polarization through the HMOX1/PDE4D axis - Improving learning and memory ability in 3×Tg-AD mice through the CX3CR1/NF-κB signaling pathway
Bacopa monnieri (BM) ameliorates Aβ-induced cognitive impairment by: - Reducing oxidative stress biomarkers and proinflammatory cytokines - Decreasing cholinesterase activity in AD rats - Restoring Bax/Bcl-2 imbalance and increasing neurotrophic factors expression - Eliminating amyloid plaques and normalizing Aβ-induced increase in phospho-tau - Interacting with glycogen synthase kinase (GSK-3β) and restoring Wnt/β-catenin signaling
Melatonin (MT) demonstrates protective effects against sleep deprivation-induced cognitive impairment by reducing neuroinflammation and inhibiting the TLR4/MyD88/NF-κB signaling pathway.
Targeting Metabolic Pathways
PPAR-α agonists like GW7647 show therapeutic potential by: - Reducing Aβ burden and improving cognitive defects in APP/PS1 mice - Inhibiting neuronal cell death and iron deposit - Decreasing lipid peroxidation and inflammation - Directly binding with GPx4 intron3 to promote GPx4 transcription - Reducing iron transport capability in APPsw cells
Nicotinamide adenine dinucleotide (NAD+) demonstrates neuroprotective effects by: - Mitigating chronic sleep restriction-induced cognitive decline - Decreasing oxidative stress and mitochondrial impairments in microglia - Inhibiting ROS production and promoting M1 to M2 phenotype conversion - Regulating the cGAS-STING/NF-κB pathways to alleviate neuroinflammation
Novel Molecular Targets
Calmodulin (CaM) acetylation is reduced in plasma of AD patients and mice: - HDAC9 was identified as the main deacetylase for CaM - HDAC9 inhibition increased CaM acetylation and CaMKIIα activity - Improved hippocampus-dependent memory in AD mice
Histone deacetylase 3 (HDAC3) inhibition shows promise for mitigating behavioral and neuroimmune deficits in various brain diseases, including neurodegenerative conditions.
Imidazoline I receptors (I-IRs) are emerging as relevant targets in AD: - Novel I-IR ligands with imidazole-linked heterocycle structures show promise - Oral administration of 2-(benzo[b]thiophen-2-yl)-1H-imidazole ameliorates cognitive impairment and reduces neuroinflammation markers
GLP-1 and GLP-1 receptor agonists (dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, and tirzepatide): - Improve cognitive and motor function in neurodegenerative diseases - Modulate neuroinflammation, oxidative stress, and proliferative pathways
Dihydroartemisinin (DHA) alleviates hippocampal deficits and improves spatial learning in hTau transgenic mice by: - Upregulating Tau O-GlcNAcylation and attenuating Tau hyperphosphorylation - Binding to O-GlcNAc transferase (OGT) and promoting OGT nuclear export
Group III metabotropic glutamatergic receptors (mGluRs) ligands show neuroprotective potential in preclinical models of AD, with compounds activating mGlu4 or mGlu7 receptors exhibiting protective effects.
Innovative Approaches
Antisense oligonucleotide (ASO) therapy has emerged as a promising approach: - Tofersen became the first ASO drug approved by the FDA in 2023 for ALS - Specifically binds to SOD1 mRNA, inhibiting the production of toxic SOD1 protein
For amyotrophic lateral sclerosis (ALS), therapeutic strategies targeting TDP-43 pathology include: - Direct and indirect interventions - Modulating aberrant TDP-43 liquid-liquid phase separation (LLPS) - Future research focusing on targeting TDP-43 structural polymorphisms
Innovative delivery systems like Neutrophil membrane-coated MOF nanozyme (Neu-MOF/Fla) represent a biomimetic approach that: - Recognizes pathological inflammatory signals of AD - Delivers photo-triggered anti-inflammatory CO and MOF-based hydrolytic nanozymes to brain lesions - Suppresses neuroinflammation and mitigates Aβ burden
Multifunctional delivery systems like RVG-DDQ/PDP@siBACE1 combined with protein kinase B (AKT) agonist (SC79) show promise for targeting and penetrating the blood-brain barrier (BBB), with synergistic functions including scavenging reactive oxygen species, decreasing Aβ production, and alleviating neuroinflammation.
Immunotherapy approaches targeting disease-specific proteins show promise, including monoclonal antibodies and vaccine-based approaches for Huntington's disease and prion diseases.
Drug used in other indications
CVN293 Clinical Trials Information
Based on the available information, there is no data regarding CVN293 clinical trials for neurodegenerative disease or any other indications. The specific intervention models, administration protocols, or treatment regimens for this compound cannot be determined from the provided context.
Without documented clinical trial information, it is not possible to identify which therapeutic areas beyond neurodegenerative disorders CVN293 might be targeting, nor can the specific intervention methodologies being utilized in any potential clinical trial designs be described.