Investigational Agitation Treatment AXS-05 Named FDA Breakthrough Therapy

The U.S. Food and Drug Administration (FDA) has granted breakthrough therapy designation to Axsome Therapeutics‘ AXS-05, an investigational oral therapy for the treatment of agitation in people with Alzheimer’s disease.

This designation is intended to accelerate the development and review of potential therapies for serious diseases. It is awarded upon clinical evidence of substantial improvement over existing treatment options. The program’s features include more intensive FDA guidance throughout treatment development, and eligibility for priority review, which can speed the approval process.

“This FDA Breakthrough Therapy designation is an important milestone in the development of AXS-05 for Alzheimer’s disease agitation, a serious, prevalent, and debilitating condition for which there is currently no approved therapy,” Herriot Tabuteau, MD, CEO at Axsome, said in a press release.

Thus far, there are no treatments that have been approved to treat agitation — an umbrella term that refers to feelings of restlessness, emotional distress, aggression, irritability, and a loss of social awareness — that can be common in people with Alzheimer’s disease.

AXS-05, an oral candidate therapy to treat this complication, is composed of two main active components: dextromethorphan and bupropion. Dextromethorphan, commonly used as a cough suppressant, works by modulating the activity of neurotransmitters, which are the chemicals used to send signals between nerve cells. These neurotransmitters, including glutamate, serotonin, and norepinephrine, are known to play a role in the cognitive and behavioral changes in people with Alzheimer’s.

Bupropion stabilizes dextromethorphan, boosting its efficacy. It also increases the availability of dopamine and norepinephrine, and acts on another neurotransmitter called acetylcholine, also thought to be involved in agitation.

The FDA’s decision was based on recent top-line results from the Phase 2/3 ADVANCE-1 trial (NCT03226522).  Expected to be completed in June 2020, the trial concluded early due to concerns related to the COVID-19 pandemic.

The study’s main goal was to evaluate the efficacy and safety of AXS-05 as a potential therapy to lessen agitation in people with Alzheimer’s. Agitation severity was measured using the Cohen-Mansfield Agitation Inventory (CMAI), a 29-item scale to assess the frequency with which patients show physically aggressive, physically non-aggressive, and verbally agitated behaviors. The higher the score, the greater the level of agitation.

The multicenter trial included 366 patients, ages 69 to 90, who were diagnosed with probable Alzheimer’s disease and related agitation. The participants were randomly selected to receive either AXS-05 (159 patients), bupropion only (49 patients), or placebo (158 patients) tablets for five weeks. Escalating doses were given of AXS-05, or dextromethorphan/bupropion, at 30 mg/105 mg once daily, rising at week three to 45 mg/105 mg twice daily, or bupropion. The buproprion was given at 105 mg once daily, rising to 105 mg twice daily at week three.

At the start of the study, known as baseline, the participants’ CMAI scores were 60.8 in the AXS-05 group, 66.1 in the bupropion group, and 59.3 in the placebo group.

The top-line results showed that, after five weeks, patients in the AXS-05 group underwent a statistically significant 48% reduction in their CMAI score — corresponding to 15.4 points — compared with baseline. Meanwhile, those in the placebo group had a drop of 38%, corresponding to 11.5 points. Scores in the bupropion group were 10.0 points lower compared with the beginning of the study.

Importantly, 73% of the participants who received AXS-05 achieved a clinical response defined as a 30% or greater improvement in their initial CMAI score. This was statistically significantly higher than the 57% of patients who achieved a clinical response in the placebo group.

AXS-05 also was superior to the placebo in lessening agitation as measured by the Alzheimer’s Disease Cooperative Study — Clinical Global Impression of Change for Agitation — a clinician’s global assessment of agitation.

The therapy was found to be generally well-tolerated and safe. There was no evidence of cognitive decline as assessed by the Mini-Mental State Examination, a measure of general cognitive function. The most common adverse events reported included somnolence or excessive sleepiness, dizziness, and diarrhea.

“We look forward to working with the FDA over the coming months as we advance the development of AXS-05 for the treatment of Alzheimer’s disease agitation,” Tabuteau said.

AXS-05 was granted fast track designation by the FDA in 2017 and has a breakthrough therapy designation for the treatment of major depression.

“This marks the second Breakthrough Therapy designation received by Axsome for AXS-05, the first being for the treatment of major depressive disorder, and highlights the potential of AXS-05 to address unmet medical needs in multiple difficult-to-treat CNS [central nervous system] disorders,” Tabuteau added.