Immediate Impact

The ACCORD-2 trial evaluated the use of AXS-05 (Auvelity), a medication developed by Axsome Therapeutics, in managing Alzheimer’s disease (AD) agitation. The study included 167 patients aged 65 to 90 years with probable AD per the National Institute on Aging and Alzheimer’s Association and a diagnosis of agitation according to the International Psychogeriatric Association's provisional definition of agitation. ​

Patients had a Mini-Mental State Examination (MMSE) between 10 and 24 and a Neuropsychiatric Inventory for Agitation/Aggression score ≥4. All were rollover after completion of the ADVANCE-2 double trial. The trial excluded predominantly non-AD dementia, agitation symptoms not secondary to AD, and concurrent medical conditions that may interfere with study conduct.

The ACCORD-2 Phase 3 trial achieved the primary endpoint, with AXS-05 statistically significantly delaying the time to relapse of AD agitation compared to placebo (HR = 0.276, relapse risk 3.7 X higher with placebo). ACCORD-2 also met the key secondary endpoint (prevention of relapse of AD agitation) and reduced worsening for AD agitation compared to placebo, as assessed by the Clinical Global Impression-Severity (CGI-S) for AD agitation. AXS-05 was well tolerated, with no new safety signals. These results support the use of AXS-05 as a safe and effective treatment for AD agitation, building on data from previous positive Phase 2/3 studies. If approved, AXS-05 would be a new treatment with a nonantipsychotic mechanism of action for the treatment of AD agitation.

Dr Jain –

Importance to Science: 8
Importance to the Molecule: 8
Importance to the Medication Class: 9

I have scored very highly on all 3 because this is impressive data, and a disease state that is very underserved. The fact that this is not an atypical antipsychotic and won't be seen as a "chemical restraint" but as a true treatment of this condition will be seen very favorably by all the stakeholders. That includes payers, patients, and clinicians. This is a significant advancement. It is also a significant commercial opportunity. This is, all the way around, a significant positive step in the right direction for everyone involved.

This update makes me appreciate the broad nature of both this molecule and its mechanism of action. It’s more than an antidepressant! This is a huge shift in this therapeutic area. We used to think atypicals/antipsychotics were the only class to consider. This study, in one quick move, is changing the paradigm. If approved, it completely upends the treatment paradigm. The next medications will need to demonstrate a balance of efficacy and safety to match up to this medication if they are to have commercial viability.

This medication could replace the current standard of care, which is the use of atypicals. This has the potential, if studies are replicated and safety is further proven, to radically change our approach to the treatment of such patients.

Dr McIntyre –

Importance to Science: 8
Importance to the Molecule: 9
Importance to the Medication Class: 9 

Agitation is a common therapeutic target. Only one antipsychotic is approved to treat agitation in elderly patients with cognitive disorders, and it has many unacceptable side effects and safety concerns. There is a pressing need for therapeutics for agitation and certainly non-antipsychotic treatments. 

The market will react positively to this news; it is critical for decision-making by payers, and it’s a more attractive option to prescribers than an antipsychotic. It is also a treatment that has legacy data in major depressive disorder. These data replicate and extend other evidence that glutamate-based therapeutics have clinically meaningful benefits in the treatment of agitation, so it is reasonable to intuit that other glutamatergic therapies in various phases of development may consider agitation as an additional therapeutic target in development. 

These data will provide motivation to build out a sales force, the agitation area where Brex-pip has struggled due to an inadequate sales force with frontline prescribers in agitation. This can be approved. There has been hesitancy to build this space by many sponsors. This data will add to the rationale for building an adequate sales force and treatment support infrastructure, which is a critical component of an agitation therapeutics as the level of care often involves nursing homes, care homes, etc, rather than the conventional primary care clinic. The confidence to begin thoughtful, comprehensive implementation is supported by this area, which will only help them further.

The key issue at this point is that all sponsors with glutamate agents being developed for other psychiatric disorders should contemplate potential development in agitation. A lot of evidence supports anti-agitation effects of glutamate agents, and these data provide further proof of the concept. The other part is that there has been a prevailing view of safety concerns with this class of agents; they were also shown to be safe with this vulnerable population. 

These data provide reason to believe that the algorithmic selecting and sequencing of treatment for agitation should include consideration of an antidepressant glutamate agent first rather than an antipsychotic, which has a high risk of tardive dyskinesia and other drug-induced movement disorders that, in many cases, are irreversible. In addition, antipsychotics have significant sedation and cognitive-interfering effects, unlike this agent.

Dr Grossberg – 

Importance to Science: 7 
Importance to the Molecule: 7  
Importance to the Medication Class: 8 

AXS-05 (dextromethorphan-bupropion) is the first drug to show safety and/or efficacy in 4 placebo-controlled trials for treating Agitation in Alzheimer's Disease (AAD), which is not an antipsychotic. Currently, only brexpiprazole (an antipsychotic) is approved by the US Food and Drug Administration (FDA) for treating AAD.

Agitation affects more than 50% of AD patients and is one of the most impactful neuropsychiatric symptoms of AD, a cause of distress for both patients and care partners. Unlike antipsychotics, which carry a boxed warning relative to increased mortality in patients with dementia, this compound would not have the same warning. AXS-05 is mechanistically unique in that it is a N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist. AXS-05 is already FDA-approved for major depression. We now know that the molecule also has anti-agitant effects in AD.

Potential FDA approval of AXS-05 may shift our thinking away from strictly using antipsychotics on or off-label for AAD. This will be another option without the usual antipsychotic liabilities such as metabolic, extrapyramidal, sedating, or autonomic side-effects. This unique molecule also combines bupropion, a CYP450-2D6 inhibitor, with dextromethorphan (DMT) to increase the half-life and increase the levels of DMT. AXS-05 may alter practice levels by offering another treatment option for AAD.

NOTE: The manufacturer plans to file a Supplemental New Drug Application (sNDA) for FDA approval later this year.

Dr Kunovac – 

Importance to Science: 7
Importance to the Molecule: 8
Importance to the Medication Class: 7

The data, as presented, is unequivocal. Auvelity is effective in delaying agitation recurrence in people with AD. Randomized withdrawal studies are quite robustly designed and very informative for clinical practice. They address the question, "Is there a benefit for patients who respond to the therapeutic in maintaining the treatment for a longer duration?" 

While antipsychotics and benzodiazepines are effective in the management of people with agitation secondary to AD, they are also associated with many adverse effects. These data are encouraging as they offer patients and carers an alternative therapeutic. A safety review should be completed to confirm the benefit/risk profile of this therapeutic. Taken in isolation, this update is encouraging. However, a comprehensive safety review is necessary to support an overall recommendation.

Taken in isolation, these data support the use of Auvelity as a therapeutic solution for a significant unmet medical need. As stated previously, a comprehensive safety and efficacy review, if favorable, will have a significant impact on practice. The key word is "non-antipsychotic."

Dr Mattingly – 
Importance to Science: 8
Importance to the Molecule: 9
Importance to the Medication Class: 9

With a 3.7-fold delay in the time to relapse for agitation in Alzheimer's, the phase 3 ACCORD 2 trial represents an important finding for individuals living with Alzheimer’s. The hazard ratio for agitation relapse was 0.276 for the patients who were continued on AXS-05 (Auvelity) vs those who were randomized to placebo. AXS-05 significantly prevented relapse of AD agitation compared to placebo (8.4% vs 28.6%; P = 0.001). 

This trial demonstrated a favorable safety profile in a vulnerable population, which on average was 74 years of age and had an average MMSE of 21. In general, AXS-05 was well tolerated, with no new safety signals. Falls were reported in 2 participants (2.4%) in the AXS-05 group; only one was deemed related to study medication. Dizziness was reported in 1 participant in the AXS-05 group. AXS-05 was not associated with sedation or cognitive decline as measured by MMSE. No deaths were reported in either treatment group. 

As a non-antipsychotic agent, this represents a significant development for individuals with Alzheimer’s agitation and their families.