PSEN1

POTOMAC, Md.--( BUSINESS WIRE )--IGC Pharma, Inc. ("IGC Pharma," "IGC," or the "Company") (NYSE American: IGC) today announced additional positive results of preclinical studies investigating the Company's newly announced therapeutic candidate, TGR-63, a potential treatment for Alzheimer's disease. Previously disclosed results demonstrate that TGR-63 may successfully alleviate plaque burden in Alzheimer's cell lines and animal models. Plaques are a key hallmark and therapeutic target of Alzheimer's disease. "While we continue to progress our Phase 2b trial of IGC-AD1 as a treatment for agitation in dementia due to Alzheimer's, we are excited by the preclinical results of TGR-63, in particular the profound impact of the drug on plaques and on reducing anxiety in a transgenic Alzheimer's mouse model. In line with IGC Pharma's artificial intelligence and machine learning ("AI/ML") initiatives, we plan to leverage cutting-edge AI/ML tools for studying TGR-63's toxicology and protein interactions. By harnessing the power of AI/ML, we expect to accelerate the journey of TGR-63 from preclinical to patient care. We continue progressing IGC-AD1 and TGR-63 enthusiastically and anticipate clinical milestone updates throughout 2024 from our strengthened AD pipeline," said CEO Ram Mukunda. TGR-63 is a patent pending molecule designed to disrupt the structure of the amyloid beta ("Aβ") peptide, one of the key hallmarks of Alzheimer's. TGR-63 targets plaques by addressing the misfolding and aggregation of amyloid-β peptides, specifically the toxic Aβ42 aggregation species associated with neuronal toxicity and cognitive decline. Preclinical investigations also indicate a recovery of behavioral functions in an animal model of Alzheimer's, suggesting that TGR-63 could possibly be used as a treatment for anxiety in human Alzheimer's. The preclinical trial was conducted on APP/PS1 (transgenic) mice that are genetically modified to carry mutations of the Amyloid Precursor Protein (APP) gene that lead to the production of a specific form of Aβ peptide, a key component of amyloid plaque in the brains of individuals with Alzheimer's. During the investigation, two groups of APP/PS1 mice undertook an Open-Field ("OF") test, a behavioral assessment designed to measure anxiety-like behavior, stress and coping responses, and emotional state, among others, in rodent models. The mice in the APP/PS1 group that received TGR-63 treatment showed significant improvements in their emotional well-being and anxiety levels compared to the group that didn't receive treatment. A series of tests were used to measure these improvements. First, in the Open-Field (OF) test, the treated mice displayed a 43% reduction in their overall movement within the test area, which was highly statistically significant (p<.0001). They also showed a 59% reduction in movement within the central zone of the test area (p<.01). Additionally, in a more specialized analysis called the Center Zone Exploration (CZE) Analysis, the TGR-63 treated group exhibited a 55% improvement compared to the untreated group (p<.05). The results from these multiple tests indicate that TGR-63 treatment helped normalize emotional and behavioral responses in our Alzheimer's mouse model, reinforcing its potential as a promising treatment. About IGC Pharma Inc. (dba IGC): IGC Pharma is pursuing innovative solutions to fight Alzheimer's disease and related challenges. IGC Pharma's portfolio comprises five assets, all with a singular mission - to transform the landscape of Alzheimer's treatment. IGC-AD1 and LMP target neuroinflammation, Aβ plaques, and neurofibrillary tangles. IGC-AD1 is currently in a Phase 2b clinical trial for agitation in dementia due to Alzheimer's ( clinicaltrials.gov , NCT05543681). TGR-63 targets Aβ plaque to disrupt the progression of Alzheimer's disease. IGC-M3 targets the inhibition of Aβ plaque aggregation with the potential to create a profound impact on early-stage Alzheimer's. IGC-1C targets tau and neurofibrillary tangles in a forward-thinking approach to Alzheimer's therapy. In parallel, IGC Pharma is at the forefront of Generative AI development, with projects including clinical trials, early detection of Alzheimer's, and drug interactions with cannabinoids. Forward-Looking Statements: This press release contains forward-looking statements. These forward-looking statements are based largely on IGC Pharma's expectations and are subject to several risks and uncertainties, certain of which are beyond IGC Pharma's control. Actual results could differ materially from these forward-looking statements as a result of, among other factors, the Company's failure or inability to commercialize one or more of the Company's products or technologies, including the products or formulations described in this release, or failure to obtain regulatory approval for the products or formulations, where required, or government regulations affecting AI or the AI algorithms not working as intended or producing accurate predictions; general economic conditions that are less favorable than expected; the FDA's general position regarding cannabis- and hemp-based products; and other factors, many of which are discussed in IGC Pharma's U.S. Securities and Exchange Commission ("SEC") filings. IGC Pharma incorporates by reference the human trial disclosures and Risk Factors identified in its Annual Report on Form 10-K filed with the SEC on July 7, 2023, as if fully incorporated and restated herein. Considering these risks and uncertainties, there can be no assurance that the forward-looking information contained in this release will occur.

A woman who never developed Alzheimer's despite a strong genetic predisposition may hold the key to stopping the disease in its tracks. Studying the woman's unique complement of genetic mutations, researchers have found clues that could help cut the link between the early, asymptomatic stage and the late stage, when cognitive decline sets in. Alzheimer's disease has plagued one large Colombian family for generations, striking down half of its members in the prime of life. But one member of that family evaded what had seemed would be fate: Despite inheriting the genetic defect that caused her relatives to develop dementia in their 40s, she stayed cognitively healthy into her 70s. Researchers at Washington University School of Medicine in St. Louis now think they know why. A previous study had reported that, unlike her relatives, the woman carried two copies of a rare variant of the APOE gene known as the Christchurch mutation. In this study, researchers used genetically modified mice to show that the Christchurch mutation severs the link between the early phase of Alzheimer's disease, when a protein called amyloid beta builds up in the brain, and the late phase, when another protein called tau accumulates and cognitive decline sets in. So the woman stayed mentally sharp for decades, even as her brain filled with massive amounts of amyloid. The findings, published Dec. 11 in the journal Cell, suggest a new approach to preventing Alzheimer's dementia. "Any protective factor is very interesting, because it gives us new clues to how the disease works," said senior author David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology. "As people get older, many begin to develop some amyloid accumulation in their brains. Initially, they remain cognitively normal. However, after many years the amyloid deposition begins to lead to the accumulation of the tau protein. When this happens, cognitive impairment soon ensues. If we can find a way to mimic the effects of the APOE Christchurch mutation, we may be able to stop people who already are on the path to Alzheimer's dementia from continuing down that path." Alzheimer's develops over the course of about 30 years. The first two decades or so are silent; amyloid slowly accumulates in the brain without causing ill effects. When amyloid levels reach a tipping point, however, they kick off phase two, which involves multiple interrelated destructive processes: A protein called tau forms tangles that spread through the brain; brain metabolism slows down, and the brain begins to shrink; and people start to experience memory and thinking problems. The disease follows the same pattern in people with genetic and nongenetic forms of Alzheimer's. The Colombian families carry a mutation in a gene called presenilin-1 that causes their brains to develop far too much amyloid buildup beginning in their 20s. People who carry the mutation accumulate amyloid so quickly that they reach the tipping point and start showing signs of cognitive decline in middle age. One rare exception is a woman who had more amyloid in her brain in her 70s than her relatives did in their 40s, but only very minimal signs of brain injury and cognitive impairment. "One of the biggest unanswered questions in the Alzheimer's field is why amyloid accumulation leads to tau pathology," Holtzman said. "This woman was very, very unusual in that she had amyloid pathology but not much tau pathology and only very mild cognitive symptoms that came on late. This suggested to us that she might hold clues to this link between amyloid and tau." A 2019 study had revealed that, along with a mutation in presenilin-1, the woman also carried the Christchurch mutation in both copies of her APOE gene, another gene associated with Alzheimer's disease. But with only one person in the world known to have this particular combination of genetic mutations, there were not enough data to prove that the Christchurch mutation was responsible for her remarkable resistance to Alzheimer's and not simply a coincidental finding. To solve this puzzle, Holtzman and first author Yun Chen, a graduate student, turned to genetically modified mice. They took mice genetically predisposed to overproduce amyloid and modified them to carry the human APOE gene with the Christchurch mutation. Then, they injected a tiny bit of human tau into the mouse brains. Normally, introducing tau into brains already brimming with amyloid seeds a pathological process in which tau collects into aggregates at the site of injection, followed by the spread of such aggregates to other parts of the brain. Not so in the mice with the Christchurch mutation. Much like the Colombian woman, the mice developed minor tau pathology despite extensive amyloid plaques. The researchers discovered that the key difference was the activity levels of microglia, the brain's waste-disposal cells. Microglia tend to cluster around amyloid plaques. In mice with the APOE Christchurch mutation, the microglia surrounding amyloid plaques were revved up and hyperefficient at consuming and disposing of tau aggregates. "These microglia are taking up the tau and degrading it before tau pathology can spread effectively to the next cell," Holtzman said. "That blocked much of the downstream process; without tau pathology, you don't get neurodegeneration, atrophy and cognitive problems. If we can mimic the effect that the mutation is having, we may be able to render amyloid accumulation harmless, or at least much less harmful, and protect people from developing cognitive impairments."

Neuroscientists created the first non-human primate model of hereditary Alzheimer's in marmosets to accelerate the pace of drug discovery and rebuild the foundation for future translational studies. To reimagine existing preclinical trials for Alzheimer's disease, University of Pittsburgh School of Medicine neuroscientists created the first non-human primate model of hereditary Alzheimer's in marmoset monkeys, outlining their approach in Alzheimer's & Dementia: Translational Research & Clinical Interventions. Researchers are now working on characterizing and validating genetic, molecular, functional and cognitive features of aging and Alzheimer's disease in marmosets that harbor mutations in the same gene that is linked to early-onset disease in humans. Scientists hope to accelerate the pace of the drug discovery pipeline and rebuild the foundation for future translational studies while overcoming limitations inherent to existing preclinical models. "We are ambitious about finding a cure for Alzheimer's disease," said senior author Afonso Silva, Ph.D., professor of neurobiology at Pitt. "We are establishing a process for rigorous, minimally invasive standardized testing of the marmoset model of Alzheimer's disease and openly sharing data." Marmoset families are better matched to mimic the genetically diverse human population than a colony of inbred rodents. And because marmosets' life spans are shorter than those of other non-human primates, researchers can comprehensively study their aging within a relatively short period of time. If allowed to age naturally, marmosets will spontaneously develop aggregates of toxic amyloid beta and tau indicative of Alzheimer's-like pathology in the brain. To create marmosets with inheritable predisposition to Alzheimer's disease, researchers introduced a series of mutations in the PSEN1 gene using the Crispr/Cas9 gene engineering system. These same mutations cause early onset Alzheimer's disease in humans. Presenilin-1, the protein encoded by PSEN1, plays a key role in generating amyloid tangles, and, just like human patients, marmosets with a mutation in the PSEN1 gene start developing Alzheimer's-like pathologies during adolescence. In establishing the model, the team is applying a bench-to-bedside approach to marmosets as though they were human patients. To characterize and validate the new model, researchers are employing a battery of non-invasive tests, including behavioral studies, longitudinal analysis of blood biomarkers, and regular PET scans to assess brain function and pathological changes in the brain tissue. The tests are designed to map out and compare the aging trajectory between healthy controls and animals genetically predisposed to early-onset Alzheimer's and correlate progressive changes in the levels of amyloid and tau to changes in cognition. Researchers also plan to look into other factors that accompany disease progression, including brain-blood barrier permeability, vascular stiffness and metabolism, as well as analyze changes in gene expression profiles over time by regularly sampling skin cells. "We need new models to understand underlying biological processes behind normal and pathological aging," said lead and corresponding author Stacey Rizzo, Ph.D., associate professor of neurobiology and deputy director for preclinical research at Pitt's Aging Institute. "Tracking the animals from birth in a well-controlled way would allow us to hypothesize on how molecular and genetic changes translate to pathophysiological consequences in the brain and devise ways to stop them from getting to the point of no return." In 2022, Rizzo and Silva received a five-year, $32.5 million grant from the National Institutes of Health to conduct this project.