Emergence of IGC-AD1 as Novel Therapy for Alzheimer Disease Agitation

Ram Mukunda

Agitation and aggression are frequently occurring and distressing behavioral and psychological symptoms of dementia. These symptoms are disturbing for patients with Alzheimer disease (AD), commonly confer risk to the patient and others, and present a major management challenge for clinicians. Over the years, there has been an increased interest from industry leaders and pharmaceutical companies to tackle AD agitation, highlighted by the field’s first approved agent, brexpiprazole (Rexulti; Otsuka/Lundbeck) in May 2023.

More recently, IGC Pharma announced positive interim data from a phase 2 trial assessing its investigational agent IGC-AD1, a tetrahydrocannabinol-based candidate, to treat symptoms of AD. The phase 2 trial, which remains ongoing and enrolling, featured 146 patients, with interim results based on a group of 26 participants. All told, between the IGC-AD1 and placebo groups, results at 6 weeks showed a between-group difference of –10.45 (95% CI, –20.20 to –0.72) in Cohen Mansfield Agitation Inventory (CMAI) score, the primary end point, favoring IGC-AD1.

In the announced results, investigators drew comparisons of IGC-AD1 to brexpiprazole and the phase 3 studies it was approved on. In the 2 phase 3 studies that brexpiprazole was approved on (NCT03548584; NCT1862640), the atypical antipsychotic demonstrated LS treatment differences of –5.32 (95% CI, –8.77 to –1.87) and –3.77 (95% CI, –7.38 to –0.17), respectively, in comparison with placebo over a 12-week span.

Following the data, Ram Mukunda, chief executive officer of IGC Pharma, provided commentary on the significance of the findings, and the potential therapeutic benefit of IGC-AD1. He spoke on the mechanism of action of this agent and its next steps in development. Furthermore, he commented on the lingering symptoms of AD agitation and the seriousness of this symptom, which is experienced by more than 70% of those with the disease.

How was IGC-AD1 founded? What about its mechanism of action makes it unique?

IGC-AD1 emerged from a critical need for a natural, non-toxic remedy to address agitation in Alzheimer’s disease without the side effects commonly associated with antipsychotics and SSRIs. Its genesis lies in a profound understanding of the challenges posed by Alzheimer's disease, a condition that has become a pressing concern in our aging population.

IGC-AD1's mechanism of action involves addressing neuroinflammation, neurotransmitter imbalance, and CB1 receptor dysfunctions associated with agitation in Alzheimer's disease. By targeting these underlying pathways, IGC-AD1 aims to provide comprehensive relief from agitation symptoms.

What truly sets IGC-AD1 apart is its commitment to safety. IGC-AD1 targets the underlying causes of agitation in Alzheimer's disease through a multi-faceted approach. We have two active pharmaceutical ingredients that reduce inflammation and target plaques and tangles. Unlike current antipsychotic therapies with black box warnings, IGC-AD1 aims to provide a safe and effective option for patients and caregivers.

Of the data, what stands out the most? Talk about what we learned from this phase 2 trial thus far.

Our interim findings suggest efficacy in as little as two weeks. The rapid onset of action observed in our interim findings is a significant result as many treatments for mental health issues can take up to 6 weeks to build up efficacy in the body. The rapid response of IGC-AD1 could lead to quicker relief for patients experiencing agitation and may positively impact treatment adherence and overall outcomes.

Moreover, our comparison with the Phase 3 results of Brexpiprazole underscores the remarkable promise of IGC-AD1 as a frontrunner in the treatment landscape. The superior outcomes observed with IGC-AD1, including a larger effect size and statistically significant reduction in agitation, highlight its competitive edge and potentially strong market adoption.

What’s next for the therapy?

Following these positive interim results, our next steps involve discussions with the regulators as we advance toward commercialization. We remain committed to bringing IGC-AD1 to market to address the critical need for innovative Alzheimer's disease therapeutics.

Furthermore, the ongoing Phase 2 trial of IGC-AD1 continues to enroll participants in the US, and Canada. We are encouraged by the progress thus far and remain optimistic about the trial's outcome, although it's important to note that these interim results are based on a small number of patients, and further validation is required.

What are some of the greatest unmet needs in terms of Alzheimer agitation? Are there aspects that people are truly not aware of?

The prevalence of Alzheimer's-related agitation often goes underestimated, with many unaware of its staggering impact. An estimated 60 million individuals worldwide are diagnosed with Alzheimer's disease, with up to 80% of these patients experiencing agitation. Defined by physical or verbal aggression of sufficient severity to impede personal relationships, social interactions, and daily activities, agitation exacts a heavy toll on both patients and caregivers alike.

The psychological toll is profound, with agitation linked to increased rates of admission to care facilities, heightened medication usage, prolonged hospitalizations, and elevated mortality rates. Beyond the emotional strain, these challenges also pose significant financial burdens on both patients and their families.

Raising awareness about the pervasive nature and profound implications of Alzheimer's-related agitation is crucial in fostering understanding, support, and innovative solutions to address this pressing unmet need.