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Contact stomatitis can occur as a result of cinnamon exposure. The condition can easily be managed by withdrawal of the antigen. A short course of systemic corticosteroid can produce dramatic improvement if symptoms are severe.

White Tongue Lesions: Candida, Contact Stomatitis, Oral Lichen Planus?

New data from the phase 3 ACCORD trial (NCT04797715) assessing AXS-05 (Axsome Therapeutics), a novel, investigational n-methyl-D-aspartate (NMDA) receptor antagonist, showed that study met its primary end point, statistically significantly delaying the time to relapse of agitation symptoms in adults with Alzheimer disease agitation (ADA) as compared with placebo. Investigators reported AXS-05 was well tolerated during the trial's open label treatment period, as well, suggesting that the therapy can significantly and safely reduce the risk of relapse and supporting the continued development of AXS-05 for agitation in patients with AD.

In the open-label treatment period with AXS-05, investigators observed statistically significant improvement on the Cohen Mansfield Agitation Inventory (CMAI) at all time points starting at week 1 (

<.001) with mean reductions from baseline of 6.7 points at week 1 and 20.6 points at week 5 (

<.001), according to the results. AXS-05 delayed the time to relapse of agitation symptoms, representing a 3.6-fold lower risk of relapse compared with placebo (HR, 0.275; 

=.014). AXS-05 also met the key secondary end point of relapse prevention with a 7.5% relapse incidence rate for AXS-05-treated patients and 25.9% for those treated with placebo (

“I think it's important for all of us to keep in mind that AD is not just a cognitive disorder. Many patients—in fact, the majority of patients—during the course of the disease will exhibit some type of behavioral or neuropsychiatric disturbance. This can happen more likely toward the moderate and more advanced stages, but it can occur throughout the disease,” coauthor George Grossberg, MD, professor and director of the division of geriatric psychiatry at the Saint Louis University School of Medicine said in a 

. “Of these neuropsychiatric or behavioral disturbances, agitation is one of the most common. In fact, it's estimated that maybe 50% or more of patients with AD will have clinically significant agitated behaviors throughout the mild, moderate, or more advanced stages of the disease.”

The ACCORD trial, for which the findings were presented at the 2023 Clinical Trials on Alzheimer Disease (CTAD) conference, held October 24-27, in Boston, Massachusetts, enrolled 178 individuals with a diagnosis of probable AD and clinically meaningful agitation in the open-label period and treated with AXS-05 (mean CMAI total score at baseline, 70.9) for 9 weeks. In the randomized discontinuation phase of the trial, 108 participants were randomized to continue AXS-05 (n = 53) or switched to placebo (n = 55). The participants who achieved a sustained clinical response during the open-label period were randomly assigned 1:1 to continue treatment with AXS-05 or placebo in a double-blind fashion for up to 26 weeks. The primary end point in the study was time from randomization to relapse of agitation and the secondary end point was the percentage of participants who relapsed.

In the double-blind period of this trial, investigators observed that 28.3% of patients AXS-05-treated experienced adverse events and 22.2% reported them in the placebo group. In the AXS-05-treated group, none of the patients discontinued the treatment because of adverse events but 1.9% in the placebo group did discontinue. The authors noted that there was no evidence of cognitive decline in those treated with AXS-05 and that the treatment was not associated with sedation.

“Agitation, which is seen in up to 70% of people with AD, is among the most complex, challenging and costly aspects of care and is associated with multiple negative outcomes such as increased caregiver burden, morbidity, mortality, earlier nursing home placement, and overall functional impairment,” Cecilia Brain, MD, PhD, vice president of medical affairs at Axsome, said in a statement.

 “The detailed efficacy and safety results of the ACCORD trial support the potential of AXS-05 in this area of significant unmet medical need.”

REFERENCES
1. Axsome Therapeutics Presents Results of the ACCORD trial of AXS-05 in Alzheimer’s Disease Agitation at the Clinical Trials on Alzheimer’s Disease (CTAD) 2023 Conference. News Release. Axsome Therapeutics. Published October 24, 2023. Accessed October 25, 2023. https://axsometherapeuticsinc.gcs-web.com/news-releases/news-release-details/axsome-therapeutics-presents-results-accord-trial-axs-05
2. Cummings J, Grossberg G, Andersson C, et al. Efficacy and Safety Of AXS-05 in Agitation Associated With Alzheimer’s Disease: Results From ACCORD, a Phase 3, Double-Blind, Placebo-Controlled, Relapse Prevention Trial. Presented at: CTAD Conference 2023; October 24-27; Boston, MA. LP093.

Findings from phase 3 ACCORD clinical trial demonstrated rapid and sustained clinical response in patients with Alzheimer disease agitation with no new safety signals reported. 

Clinical Topics

Axsome's AXS-05 Significantly Reduced Risk of Relapse in Alzheimer Agitation in Phase 3 ACCORD Trial 

Arcutis Biotherapeutics announced this week approval by the US FDA of the company’s supplemental new drug application (sNDA) for roflumilast cream 0.15% (Zoryve) for the treatment of mild-to-moderate atopic dermatitis (AD) in adults and children as young as age 6 years. The steroid-free topical is applied once daily and has been developed specifically for long-term disease control, according to an Arcutis news release. Arcutis expects the product to be available by the end of July.

“People suffering from AD experience intense itch, rash, and sensitive skin, which warrant effective, safe, and well-tolerated treatments,” Jonathan Silverberg, MD, PhD, MPH, professor of dermatology, and the director of clinical research and director of contact dermatitis at The George Washington University School of Medicine and Health Sciences in Washington, DC,” said in the Arcutis statement. “ZORYVE was developed with the AD patient in mind, to deliver the drug in a moisturizing vehicle that is formulated without common sensitizers or irritants and does not further disrupt the abnormal skin barrier. It’s also important to note that in clinical trials ZORYVE monotherapy provided safe and effective long-term disease control to AD patients.”

AD is a chronic condition and the instability of the disease can make individuals feel as though they “are constantly chasing their AD flares,” Lawrence F Eichenfield, MD, professor of dermatology and pediatrics and vice chair of the department of dermatology at UC San Diego School of Medicine, said in the release. Eichenfield, an investigator for the INTEGUMENT clinical trial program of roflumilast cream 0.15% in AD, emphasized the rapid improvement in itch observed with the cream, stating that pruritis is the most bothersome reported disease symptom. “In clinical trials, 9 in 10 patients saw some improvement at 4 weeks, with 69% of patients demonstrating a clinically meaningful improvement" of at least 50% in eczema area and severity index (EASI) score.

Roflumilast is a “next-generation” topical phosphodiesterase 4 (PDE4) inhibitor. PDE4 inhibitors can have a direct effect on itch-signaling nerves of the skin, as well as on the inflammatory pathways.

The FDA based its approval of the Arcutis sNDA on positive results from the 3 phase 3 INTEGUMENT registration trials, a phase 2 dose-ranging study, and two phase 1 pharmacokinetic studies. INTEGUMENT-1 

) were identical, parallel-group, double-blind, vehicle-controlled, trials that evaluated the safety and efficacy of roflumilast cream 0.15% or vehicle applied once-daily to affected skin for 4 weeks. The studies enrolled 1337 adults and children aged 6 years and older with mild to moderate AD. 

Both studies met the shared primary endpoint, a Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of clear (0) or almost clear (1) and a 2-grade improvement from baseline at week 4 (INTEGUMENT-1: 32.0% roflumilast cream vs 15.2% vehicle) and INTEGUMENT-2: 28.9% roflumilast cream vs 12.0% vehicle) 

 <.001 for both). In both studies, 40% of all participants treated with roflumilast cream achieved a vIGA-AD score of 0 or 1 at week 4, with significant improvement seen as early as week 1 (

Within 24 hours of the first application, participants treated with roflumilast reported significant improvement in pruritis as measured by change from baseline in scores on the Worst-Itch-Numeric Rating Scale (WI-NRS) compared with vehicle-treated participants. Moreover, nearly one-third (more than 30%) of treated participants in both phase 3 trials achieved WI-NRS “success” after 4 weeks, defined a at least a 4-point reduction on the 0 to 10 scale (

The incidence of treatment emergent adverse events was low in both active treatment groups and vehicle arms, most reported as mild to moderate in severity.

Roflumilast cream 0.15% was also evaluated in the INTEGUMENT open label extension (OLE) study, which enrolled 658 participants rolled over from either of the phase 3 trials. At any time after 4 weeks of once-daily application a participant reached a vIGA-AD score of clear (0), they were switched to twice-weekly application (130 participants; 19.8% of study population). All other participants continued once-daily application. Overall, 61.5% and 66.2% of patients who rolled over from the roflumilast cream arm in INTEGUMENT-1 or INTEGUMENT -2 demonstrated EASI 75 after 28 weeks and 56 weeks, respectively.

“Topical steroids have been the foundation of treatment for AD for the past 50 years. Having a new and effective steroid-free option, without some of the risks associated with topical and systemic steroids, is a welcome advancement for dermatologists, patients, and caregivers,” investigator Eichenfield said.

Roflumilast cream for AD is currently being evaluated at a lower dose of 0.05% for children aged 2 to 5 years, according to Arcutis. The company also has completed its clinical development program for roflumilast foam 0.3% for the treatment of scalp and body psoriasis and intends to submit an sNDA in the third quarter of 2024.

Source: FDA approves Arcutis’ ZORYVE (roflumilast) cream 0.15% for the treatment of atopic dermatitis in adults and children down to 6 years of age. News release. Arcutis Biotherapeutics. July 9, 2024. Accessed July 9, 2024. https://investors.arcutis.com/news-releases/news-release-details/fda-approves-arcutis-zoryver-roflumilast-cream-015-treatmen

The steroid-free cream was developed for long-term use and has been proven safe in an open-label extension study following successful phase 3 trials.  

Roflumilast Cream 0.15% Approved for Treatment of Atopic Dermatitis in People Aged 6 Years and Older  

Tochi Iroku-Malize, MD, discusses the recent ACIP voting on updated vaccine recommendations for COVID-19, influenza, and RSV

Respiratory Virus Vaccine Update: AAFP Board Chair Details ACIP 2024-25 Recommendations

Tochi Iroku-Malize, MD, discusses the ACIP's updated recommendations for immunization against COVID-19, influenza, and RSV. 

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