The Promise of Axsome Therapeutics’ AXS-05 in Addressing Alzheimer’s Agitation: A Safer Alternative to Off-Label Antipsychotics

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is characterized by cognitive decline and a range of neuropsychiatric symptoms, including agitation. Agitation in AD is marked by excessive motor activity, verbal aggression, physical aggression, and emotional distress, significantly impacting the quality of life of patients and their caregivers. Current treatment strategies for AD agitation often involve the off-label use of antipsychotic medications and sedatives. While these drugs may provide some symptomatic relief, they carry substantial risks, especially for elderly patients, including increased mortality, cardiovascular events, and cognitive impairment. This has created an urgent need for safer and more effective therapeutic options. Axsome Therapeutics' AXS-05, a novel, orally administered, rapidly acting, and potentially long-lasting investigational medicine, shows promising potential in addressing AD agitation, offering a safer alternative to traditional off-label treatments. This essay will explore the challenges of managing AD agitation, the risks associated with current off-label treatments, and the potential benefits of AXS-05 as a more targeted and safer therapeutic approach.

Agitation is a common and distressing symptom in AD, affecting a substantial proportion of patients at some point during the disease course. It is a complex behavioral syndrome influenced by various factors, including neurobiological changes, environmental stressors, and individual characteristics. The management of AD agitation is challenging due to its fluctuating nature, the heterogeneity of symptoms, and the limited availability of approved treatments. Non-pharmacological interventions, such as environmental modifications, behavioral strategies, and caregiver support, are often the first line of approach. However, these interventions may not be sufficient for moderate to severe agitation, necessitating the use of pharmacological agents.

The pharmacological management of AD agitation has traditionally relied on the off-label use of antipsychotic medications, including both typical (first-generation) and atypical (second-generation) antipsychotics. These drugs are primarily designed to treat psychotic disorders, such as schizophrenia, but their sedating and behavioral effects have led to their widespread use in managing agitation in other conditions, including AD. Sedatives, such as benzodiazepines, are also commonly used to manage acute episodes of agitation. While these medications may provide some short-term relief, their use in elderly patients with AD is associated with significant risks.

Antipsychotic medications carry a "black box" warning from the U.S. Food and Drug Administration (FDA) regarding an increased risk of mortality in elderly patients with dementia-related psychosis. This increased risk is attributed to cardiovascular events, such as stroke and sudden cardiac death, as well as infections, such as pneumonia. Antipsychotics can also cause a range of other adverse effects, including extrapyramidal symptoms (movement disorders), metabolic disturbances (weight gain, diabetes), and cognitive impairment. These side effects can significantly impair the functional abilities and quality of life of patients with AD, who are already vulnerable due to their underlying cognitive decline. Similarly, sedatives, such as benzodiazepines, can cause sedation, confusion, and an increased risk of falls in elderly patients, further exacerbating their frailty and vulnerability.

The limitations and risks associated with current off-label treatments for AD agitation highlight the urgent need for safer and more effective therapeutic options. Axsome Therapeutics' AXS-05 is an investigational medicine that offers a novel approach to addressing AD agitation. AXS-05 is an oral, rapidly acting, and potentially long-lasting agent that combines dextromethorphan (DM), an N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist, with bupropion, a norepinephrine-dopamine reuptake inhibitor. The combination of DM and bupropion is designed to enhance the bioavailability and efficacy of DM by inhibiting its metabolism. This unique mechanism of action allows AXS-05 to target multiple neurotransmitter systems implicated in the pathophysiology of AD agitation, including glutamatergic, dopaminergic, and noradrenergic pathways.

The efficacy and safety of AXS-05 in treating AD agitation have been evaluated in several clinical trials, including the pivotal Phase 2/3 ADVANCE-1 trial. This randomized, double-blind, placebo-controlled trial enrolled patients with AD agitation and assessed the effects of AXS-05 on agitation symptoms using the Cohen-Mansfield Agitation Inventory (CMAI) total score. The results of the ADVANCE-1 trial showed that AXS-05 significantly reduced agitation symptoms compared to placebo, with a rapid onset of effect and sustained improvement over the treatment period. The trial also demonstrated a favorable safety profile for AXS-05, with generally mild to moderate adverse events and no significant increase in serious adverse events or mortality compared to placebo. These findings suggest that AXS-05 may offer a safer and more effective alternative to traditional off-label treatments for AD agitation.

The potential benefits of AXS-05 in addressing AD agitation extend beyond its efficacy and safety profile. The unique mechanism of action of AXS-05, targeting multiple neurotransmitter systems, may provide a more comprehensive and targeted approach to managing the complex neurobiological underpinnings of agitation. The rapid onset of effect of AXS-05 is particularly advantageous in managing acute episodes of agitation, providing timely relief to patients and caregivers. The potential for long-lasting effects of AXS-05 may also contribute to sustained improvement in agitation symptoms, reducing the burden of frequent symptom exacerbations and the need for frequent medication adjustments.

Furthermore, the oral administration of AXS-05 offers a convenient and non-invasive route of delivery, which is particularly important for elderly patients who may have difficulty with other routes of administration. The favorable safety profile of AXS-05, with a lower risk of serious adverse events compared to antipsychotics, may also improve treatment adherence and reduce the risk of complications associated with polypharmacy. The potential of AXS-05 to improve agitation symptoms may also have broader benefits for patients with AD and their caregivers, including improved quality of life, reduced caregiver burden, and decreased risk of institutionalization.

However, it is important to acknowledge that AXS-05 is still an investigational medicine, and further research is needed to fully characterize its long-term efficacy and safety profile. Ongoing and future clinical trials will provide additional data on the effects of AXS-05 on various aspects of AD agitation, including specific behavioral symptoms, functional outcomes, and caregiver burden. These trials will also help to identify potential predictors of treatment response and optimize dosing strategies for individual patients. Additionally, post-marketing surveillance will be essential to monitor the long-term safety of AXS-05 in real-world clinical practice.

In conclusion, AD agitation is a challenging and distressing symptom that significantly impacts the lives of patients and caregivers. Current treatment strategies often involve the off-label use of antipsychotic medications and sedatives, which carry substantial risks, especially for elderly patients. Axsome Therapeutics' AXS-05 offers a promising alternative to these traditional treatments, with a novel mechanism of action, rapid onset of effect, and favorable safety profile. The results of clinical trials, including the pivotal ADVANCE-1 trial, suggest that AXS-05 may significantly reduce agitation symptoms in patients with AD, offering a safer and more targeted therapeutic approach. While further research is needed to fully characterize the long-term efficacy and safety of AXS-05, its potential to address the unmet need for safer and more effective treatments for AD agitation is substantial. As the prevalence of AD continues to rise with the aging population, the development of innovative and safer therapeutic options, such as AXS-05, is crucial to improving the lives of individuals affected by this devastating disease.