— Small molecule DPX-101 has the potential to be the first disease-modifying therapy to reverse cognitive deficits such as memory loss in Alzheimer’s disease —
— Company plans to initiate Phase 1 clinical trial in first half of 2025 —
TORONTO, February 4, 2025— Damona Pharmaceuticals, a clinical-stage biopharmaceutical company focused on discovering and developing small molecules for the treatment and prevention of cognitive deficits associated with brain disorders, announced today the publication of data demonstrating that DPX-101 reverses cognitive deficits induced by amyloid deposition in a widely used preclinical model of Alzheimer’s disease. The publication, “Procognitive and Neurotrophic Benefits of α5-GABA-A Receptor Positive Allosteric Modulation in a β-Amyloid Deposition Mouse Model of Alzheimer’s Disease Pathology,” will be published in the March 2025 issue of Neurobiology of Aging and can be viewed online.
“Current approved drugs for Alzheimer’s disease slow decline, but none of them reverse lost cognitive functions,” said John Reilly, CEO of Damona. “These preclinical results highlight the potential of DPX-101 to improve cognitive deficits while also providing disease-modifying effects in Alzheimer’s disease. The data provide an important proof of concept for our novel approach to restore cognitive functions associated with brain disorders by precisely targeting the α5 subunit of the GABA-A receptor to augment its function and restore contacts between neurons. We look forward to advancing our best-in-class DPX-101 program into clinical development toward our goal of restoring optimal brain function for patients suffering from early-stage Alzheimer’s disease as well as the treatment of cognitive impairment in depression and schizophrenia.”
Reduced levels of somatostatin (SST) and reduced numbers of SST-expressing GABAergic neurons (critical inhibitory neurons in the central nervous system) have been linked to cognitive deficits—impairments in the ability to understand, remember, and think clearly—in Alzheimer’s disease and other brain disorders. SST cells inhibit pyramidal cell dendrites mainly through α5-GABA-A receptors (α5-GABAA-R). Positive allosteric modulation of these receptors has shown cognitive and neurotrophic benefits in disease models of stress and aging. DPX-101 is a receptor-positive allosteric modulator (PAM) designed to target the α5 subunit of the GABA-A receptor selectively to augment its function and restore contacts between neurons. This study evaluated the ability of DPX-101 to prevent cognitive deficits and neuronal spine loss in the early stages of β-amyloid deposition and to reverse them in late stages in a widely used preclinical model of Alzheimer’s disease.
Summary and key findings:
Damona’s preclinical small molecule DPX-101 improved working memory deficits and prevented neuronal shrinkage and spine loss in early and late stages of β-amyloid deposition in the 5xFAD mouse model of Alzheimer’s disease-related β-amyloid pathology. Specifically:
· Acute administration of DPX-101 prevented spatial working memory deficits at 2 months of age
· Chronic administration of DPX-101 reversed spatial working memory deficits at 5 months of age
· Chronic administration of DPX-101 prevented pyramidal cell atrophy
· Chronic administration of DPX-101 preserved pyramidal cell spine density, spine count, and dendritic length at early and late time points, despite ongoing β-amyloid accumulation
· The cognitive and neurotropic effects of DPX-101 occurred independent of β-amyloid buildup
About DPX-101
DPX-101 is an investigational positive allosteric modulator (PAM) that selectively targets the α5 subunit of the GABA-A receptor (α5-GABAA-R) to enhance its function. The α5-GABAA-R subtype is a promising target for reversing cognitive impairment due to its location in the hippocampus and frontal cortex regions of the brain and its unique role in somatostatin-containing GABAergic interneuron tonic inhibition within microcircuits that are critical for healthy cognition. In preclinical studies, DPX-101 demonstrated highly selective activation of the α5-GABAA-R and a broad therapeutic window with no side effects. In preclinical models of stress, depression, aging, and Alzheimer’s disease, DPX-101 reversed memory deficits and restored connections between brain cells. In a preclinical model of schizophrenia, DPX-101 reversed hyperactivity of dopamine neurons, a hallmark of schizophrenia. DPX-101 is orally available, passes the blood-brain barrier, and achieves appropriate plasma and brain levels.
About Damona Pharmaceuticals
Damona Pharmaceuticals is a clinical-stage biopharmaceutical company dedicated to discovering and developing transformational precision medicines for patients suffering from cognitive deficits associated with brain disorders. Damona’s approach combines deep expertise in brain microcircuits with precision chemistry and targeted neuropharmacology to develop small-molecule therapeutics that restore optimal brain function. The company’s scientific founder—Etienne Sibille, PhD, Scientific Director of the Neurobiology of Depression and Aging Program at the Centre for Addiction and Mental Health (CAMH) in Toronto—and collaborators have made pioneering discoveries regarding the unique role of the α5-GABA-A receptor subtype in cognition and demonstrated its potential for reversing cognitive deficits in models of multiple brain disorders. Damona’s lead clinical program, DPX-101, is designed to reverse cognitive impairment and restore connections between brain cells. Learn more at www.damonapharma.com.
Contact:
Mary Moynihan
M2Friend Biocommunications
+1 (802) 951-9600
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