THERAPEUTIC FOCUS - The Unmet Need of Agitation in Alzheimer’s Disease

INTRODUCTION

Over 55 million people globally are currently living with Alzheimer’s disease (AD). This number is expected to rise to 78 million in 2030 and 139 million in 2050 as the global population ages. AD is a hot space in the pharmaceutical industry: the newly FDA-approved drug Lecanemab and Phase 3 trial data from Do­nanemab have both demonstrated efficiency in reducing amyloid plaques in early stage Alzheimer’s disease. These new drugs are encouraging for the medical community and patients alike; how­ever, there are 2,000 patients a day who transition from mild to moderate dementia and begin to experience the associated neu­ropsychiatric symptoms for which there are severely limited re­search studies and treatment options.

There is a growing unmet need for the treatment of late-stage Alzheimer’s disease. While preventative treatment early in the disease progression is the medical gold standard, it is simply not always possible (or financially viable). With late-stage disease comes neuropsychiatric symptoms, including agitation, depres­sion, and sleep disorders. Up to 76% of Alzheimer’s patients suf­fer from neuropsychiatric symptoms, including agitation, which is the clinical term for feelings of frustration often accompanied by actions of aggression as our loved ones become more disori­ented during the moderate to late stages of the disease. Agitation is perhaps the most disruptive of the neuropsychiatric symptoms as it is associated with a higher likelihood of the patient being re­moved from the family home and placed in a care facility. Addi­tionally, treatments at this stage of the disease become increasingly more challenging as the patient is disoriented, angry, and may react strongly to negative stimuli such as hospital trips and procedures with needles.

CURRENT STANDARD OF CARE FOR AGITATION IN ALZHEIMER’S

There is currently one approved treatment for agitation re­lated to AD on the market, an antipsychotic that carries potential side effects of restlessness, dizziness, and an increased risk of death in older patients with dementia-related psychosis. Physi­cians may also prescribe antidepressants, anxiolytics, and an­tipsychotics “off label” to treat agitation, which can carry adverse side effects and compound the patient’s disorientation as the medication levels are adjusted/adjusted.

The previously mentioned amyloid-targeting drugs are as­sociated with brain bleeds and require invasive infusions, which simply aren’t possible for aggressive, violent, or upset patients who refuse to travel to the facility, putting a significant burden on the family and caregivers. IGC Pharma (NYSE American: IGC) is developing a non-invasive treatment for agitation to relieve this burden.

IGC-AD1- A DIFFERENT APPROACH

IGC-AD1 has shown promising results in treating agitation in Alzheimer’s patients. It is the first natural Cannabinoid-based investigational drug to be tested in human FDA trials for the treat­ment of AD. IGC-AD1 is an oral liquid solution, which would be an effective, simpler treatment option for patients. Furthermore, IGC-AD1 is a cannabinoid-based medication that has shown no severe reactions in Phase 1 clinical trials (https://www.clinicaltri­als.gov/study/NCT04749563?intr=IGC_AD1&rank=1).

IGC-AD1 is currently undergoing investigation in a Phase 2 clinical trial (https://clinicaltrials.gov/study/NCT05543681). Interim results from the trail were recently announced in an­nounced in March 2024, and demon­strated that patients dosed with IGC-AD1 had a more significant reduction in agita­tion, as measured by the Cohen Mansfield Agitation Inventory (CMAI), compared to placebo patients. Additionally, positive ef­fects were observed as early as week two of the trial. At week 6 of the trial, the effect size of IGC-AD1 was measured at 0.66 compared to the placebo, with a p-value of 0.037 for combined week two and week six results. Overall, the interim data demonstrates a clinical and statistical re­duction in agitation.

Unlike other pharmaceutical compa­nies in the AD arena, IGC Pharma is pio­neering participant diversity in this trial. Up to 12.5% of the aging population of Puerto Rico has Alzheimer’s Disease, which is an increase from 10.7% of the continental US population, and yet there is a historical un­derrepresentation of Hispanic populations in clinical trials. In order to address this disparity, IGC has extended its clinical trial sites to include the University of Puerto Rico to increase participant diversity. There are additional plans to further expand the trial sites to Canada and Europe, while simul­taneously identifying US trial site locations that offer the trials to underrepresented populations including African Americans and Indigenous Americans.

Additionally, the Phase 2 trial data analysis will involve innovative AI algo­rithms. During the trial, lifestyle logs are recorded for each patient. This log in­volves daily recordings of dietary habits, medications, blood pressure, and other factors. It is important for IGC Pharma to expand trial sites to international locations in order to assess any cultural or geo­graphic relationship with lifestyle factors that may interact with IGC-AD1. The com­pany will be using AI algorithms to detect patterns from the masses of data accrued in the daily lifestyle logs and uncover as­sociations with lifestyle, ethnicity, AD bio­markers, neuropsychiatric biomarkers, epigenetic biomarkers and treatment suc­cess. IGC Pharma is pioneering a holistic approach to AD that encourages a deeper understanding of the patient as a person, which may have been lost in other studies of brain tissue and plaques.

MEETING THE SUPPLYING DEMAND FOR PLANT-BASED DRUGS

Supply chain issues have plagued the pharmaceutical industry throughout 2023, with no exception for cannabinoid-based therapies. In addition to the potential fluc­tuations with third-party manufacturing and transportation, the supply of medical-grade cannabis oil can be impacted by in­consistent lighting, refining, distillation, and purification, as well as insufficient quality analysis for potency, contaminants, and heavy metals.

As the first natural cannabinoid-based investigation drug being tested in human FDA trials for the treatment of AD, it is pivotal for IGC Pharma to ensure that the IGC-AD1 supply chain is steadfast. IGC Pharma’s vertically integrated busi­ness model is a key strategic advantage that is designed to drive quality control and efficiency in the business as it achieves key milestones and scale. In addition to the company’s headquarters in Potomac, MD, IGC Pharma has a manufacturing and processing facility in Vancouver, Washington, and a research and develop­ment facility based near Bogota, Colom­bia. These facilities are designed to accommodate necessary testing and com­mercialization activities as IGC-AD1 pro­gresses through FDA trials to Phase 3, and potentially commercialization.

These facilities integrate the key ele­ments of the IGC-AD1 supply chain to help ensure the best quality product for the ongoing trials while simultaneously provid­ing cost efficiencies, particularly as the company grows and requires more power and precision for extraction and distillation processes while adhering to pharmaceuti­cal good manufacturing practices. Prepa­ration for growth is key as demand for IGC-AD1 is likely to increase cumulatively as the population ages and AD diagnoses increase globally.

SUPPORTING DATA ON IGC-AD1

In Phase 1 clinical trials, IGC-AD1 was found to be safe, well-tolerated, and caused no serious adverse events. The studies found a clinically and statistically significant reduction in neuropsychiatric symptoms: the mean NPI Agitation and NPI-D scores decreased by 36% and 55%, respectively. These NPI Agitation and NPI-D scores indicate that IGC-AD1 may be efficacious at reducing agitation due to AD and associated caregiver distress. Apathy as measured by NPI-Apathy reduced sig­nificantly by 44.44%, 53.84%, and 49.88% in cohorts 1, 2, and 3 that re­ceived the medication once a day, twice a day and three times a day respectively. Ad­ditionally, IGC-AD1 did not show a risk of developing suicidal ideation or behavior as assessed by the C-SSRS in the mild to moderate AD population during the each of the 6-week trials. This is an important finding as many of the current antipsy­chotic treatment options list suicidal ideation as a possible side effect.

Additional investigations into patient diversity and metabolization of THC were undertaken, which found that Puerto Rican populations with increased polymorphisms in the CYP2C9 gene are susceptible to the accumulation of THC and its active metabolite and may experience prolonged elimination.

Murine model preclinical data also supports IGC-AD1’s efficacy in treating AD. The studies found that in Alzheimer’s cell lines, the APIs in IGC-AD1 increased Aβ monomers and decreased Aβ aggrega­tion in a dose–dependent manner. Second, the APIs in IGC-AD1 did not reduce Amyloid Precursor Protein (APP) levels in Alzheimer’s cell lines. APP modulates cell growth, motility, and survival, and when levels decrease the small fragments eventually deposit as plaque. Third, in a Morris Water Maze test, mice dosed with the API in IGC-AD1 had significantly improved times and fewer errors than those in the control group demonstrating that memory improved in transgenic (APP/PS1) mice.

SUMMARY

AD is multifaceted and will require multiple treatment path­ways for successful outcomes. As a response to the serious side effects produced by the current standard of care, IGC-AD1 is a testament to the potential of science, perseverance, and the power of nature. IGC-AD1, inspired by nature, is a drug with the potential to alleviate neuropsychiatric symptoms and the burdens of Alzheimer’s disease.

Ram Mukunda is CEO and has played a pivotal role in IGC’s executive leadership. In 2014, under his leadership, the company successfully completed a Phase 1 trial and is currently executing a Phase 2 trial. He responsible for the company’s thrust into the pharmaceutical sector and its focus on Alzheimer’s research, bringing a wealth of strategic expertise and vision to IGC. With a background encompassing BS in Mathematics and BS and MS degrees in Electrical Engineering, he actively shapes the company’s strategy and oversees its international operations. Frequently traveling to various locations, he provides invaluable support to product and brand development initiatives, ensuring IGC remains at the forefront of innovation. His unwavering dedication is integral to achieving the company’s long-term growth strategy objectives.

Evelyn Gutiérrez is a Chemical Engineer who graduated from the National University of Colombia and is pursuing her Master’s degree in Epidemiology. She possesses a diverse educational background with additional training in Good Clinical Practices, Clinical Monitoring, Pharmacovigilance, and GMP. Accumulating approximately 9 years of professional experience, she has been an integral part of scientific and operational teams within multinational organizations. Since 2019, she has been a key member of the IGC Pharma team, where she has undertaken various successful projects. Notable accomplishments include the planning and establishment of a Research and Development laboratory and the acquisition of a license permitting the handling and utilization of controlled substances, specifically THC. She also played a pivotal role in the process of obtaining certification for the sale of cannabis-based oral formulations to patients.

Claudia Grimaldi is a Director and PFO at IGC. She leads an international team overseeing pre-clinical and FDA-registered clinical trials focused on Alzheimer’s disease. Claudia’s cost-effective strategies, involving prestigious international institutions, have reduced IGC’s pharmaceutical R&D costs by over 50%. This enables IGC to fulfill its mission of providing affordable medications and products for conditions like Alzheimer’s agitation, premenstrual syndrome, and dysmenorrhea. Her teams also ensure timely compliance with organizations such as SEC, FINRA, NYSE, IRS, FDA, IRB, and XETRA 2. Claudia holds an MBA from Meredith College, a BA in psychology from Javeriana University, and certifications from top business schools. She is fluent in Spanish and English.