Alzheimer Disease Symptoms: More Than Memory Loss and Confusion

As scientists continue to unravel the complex brain changes involved in the onset and progression of Alzheimer disease, many questions remain, despite significant advances in our understanding of the pathophysiology and clinical presentation of the disease. Although disease modification is an important goal, symptom-controlling medications are needed.

Alzheimer disease and other related dementias are best known for their decreases in cognitive abilities, but a host of other symptoms—agitation, anxiety, depression, psychosis, insomnia—often reduce patients’ quality of life, create additional challenges for caregivers, and lead to institutionalization. Neuropsychiatric symptoms are now recognized as hallmarks of dementia and are important targets for the development of effective treatments.

These core symptoms of mild and major neurocognitive disorders tend to be some of the more distressing and challenging effects of the disease. Despite this, the FDA has yet to approve any pharmacological treatments for these symptoms, leaving off-label treatments for alleviating noncognitive behavioral symptoms as first-line options. Since these are repurposed drugs, they provide only modest benefits and harmful adverse events (AEs) and are often associated with increased apathy, stroke, and mortality.

There is a great need for safe and effective treatments of neuropsychiatric symptoms of patients in the symptomatic phases of Alzheimer disease in order to improve their memory and behavior. As such, several therapies are being assessed to meet this need, with the majority of them having progressed to phase 3 trials (see TABLE).

Unmet Clinical Need in Psychosis

The risk of developing psychotic symptoms associated with Alzheimer disease and related neurodegenerative disorders is high: Approximately 20% to 40% of patients will have these symptoms. Their presence, often the first manifestation of the condition, is concomitant with greater adverse outcomes, such as mortality, rapid disease progression, functional deterioration, and increased behavioral symptoms.

“At the moment, there’s a huge unmet need in treating psychosis in people with Alzheimer disease,” Clive Ballard, MD, told NeurologyLive. “It’s a common symptom in people with Alzheimer disease, depending on the stage of the illness, and over the course of the illness, the majority [of patients have it]. The symptoms are distressing for the persons themselves or for caregivers, they accelerate in placement in nursing homes and other types of institutions, and they’re associated with more rapid decline.

“They’re not just distressing. They actually have a major impact on disease outcome for individuals,” he added. The professor of age-related diseases and dean of the University of Exeter Medical School said that, unlike other neuropsychiatric symptoms in those with Alzheimer disease that respond well to nonpharmacological interventions, suych as agitation, there is a lack of evidence that patients with psychosis respond antipsychotic medications.

One such treatment being studied for Alzheimer disease psychosis is pimavanserin (Nuplazid), an oral 5-HT2A inverse agonist that targets serotonin. It is currently licensed in the United States as a treatment for psychosis in those with Parkinson disease.

After a 6-week period in a phase 2 trial (NCT02035553) of 179 participants, a daily dose of 34 mg of pimavanserin showed significant benefit in the reduction of psychosis in study participants with severe psychosis related to Alzheimer disease.¹ In the trial, researchers randomized nursing home patients likely to have psychosis related to Alzheimer disease in a 1:1 ratio to either 17-mg, twice-daily tablets of pimavanserin or placebo. Symptoms were measured utilizing the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH) psychosis score at 2, 4, 6, 9, and 12 weeks of dosing.

With regard to the primary end point, the pimavanserin-treated group had a 3.76-point improvement in psychosis compared with a 1.93-point improvement in the placebo group (delta, —1.84; Cohen’s d, —0.32; P = .0451), as measured by the NPI-NH psychosis score at week 6. Following the 6-week efficacy evaluation, investigators continued pimavanserin therapy for another 6 weeks to test its safety. There was no significant advantage reported between pimavanserin and placebo at week 12.

Investigators found that pimavanserin was well tolerated. Common AEs in both groups included falls, urinary tract infection, and agitation. No negative effect on cognition or motor function measured by the Mini-Mental State Examination (MMSE) was reported.

A prespecified subgroup analysis demonstrated that pimavanserin-treated participants with more severe psychosis—those with a total score above 12 on the 2 main NPI-NH psychosis items&mdash;had a substantively larger and significant reduction in psychosis.² Pimavanserin demonstrated a statistically significant reduction in psychosis versus placebo on the NPI-NH psychosis score at week 6 (delta, —4.43; Cohen’s d, —0.73; P = .0114;). The amount of those achieving ≥30% improvement was 88.9% versus 43.3% (P <.001) and ≥50% improvement, 77.8% versus 43.3% (P = .008) for pimavanserin and placebo, respectively. The results show that this patient population saw a greater benefit than the overall trial population.

“What’s really encouraging about the results is that these are the patients we really feel we need to treat with pharmacological therapies,” Ballard said. “These are the patients that we want to really improve and respond, so it was a really good signal that those were the patients who were doing really well with the pimavanserin treatment.”

Pimavanserin has been granted breakthrough therapy designation status by the FDA for dementia-related psychosis. Researchers are currently conducting the phase 3 HARMONY study (NCT03325556), which began September 2017, to evaluate the ability of pimavanserin to prevent relapse of psychotic symptoms associated with dementia-related psychosis and will include patients with Alzheimer disease, dementia with Lewy bodies, Parkinson disease dementia, frontotemporal dementia, and vascular dementia.

HARMONY consists of a 12-week open-label stabilization period where all participants receive 34 mg of pimavanserin once daily, however, a dose reduction to 20 mg daily will be allowed if clinically justified. Following the 12-week stabilization period, participants that meet pre-specified criteria for treatment response will be randomized either to continue receiving 34 mg, switch to a 20-mg dose, or be given placebo. The primary outcome measure is the time from randomization to relapse in the double-blind period, and the secondary measure is the time from randomization to discontinuation in the double-blind period, for any reason. The study is expected to be completed March 2020.

“We’ve been in a very difficult position where [antipsychotics] have been the only available pharmacological treatments, but even then, they’re off-label and they’re associated with a lot of harms. So actually, if pimavanserin does turn out to be a more effective and safer alternative, that would be a great step forward in treating these distressing symptoms,” Ballard noted.

When asked about what’s garnering his excitement in the Alzheimer space, Ballard responded by citing the increasing number of treatments for psychiatric and neuropsychiatric symptoms, like psychosis and agitation, beginning to progress through clinical trials. “That’s been a huge unmet need. We’ve been in the same sort of void for 20 years, so it’s great to see more stuff coming into that space,” he said.

Mediti Pharma’s MP-101 is another agent currently under evaluation in a phase 2 trial (NCT03044249) as a possible treatment option for dementia-related psychosis and agitation and aggression. The 10-week, proof-of-concept trial, set to be completed January 2021, is studying an escalating dose of MP-101 administered orally once daily, from 20 mg up to 60 mg. The primary outcome includes the change from baseline in the NPI-NH score.

Lack of Medications for Distressing Behavioral Symptoms

Behavioral symptoms such as agitation and aggression affect almost 4.3 million of the 5.4 million persons with Alzheimer disease. Agitation is common and persistent and is often a major cause of distress. Although intervention may have a positive clinical impact, the current approaches lack efficacy, safety, and/or acceptability. Sedatives, anxiety drugs, and other medications are often given to these patients, as there are no available dedicated treatments.

Nabilone, a synthetic cannabinoid currently approved in the United States for treating nausea caused by chemotherapy, is one agent under investigation for treatment of agitation and aggression among patients with Alzheimer disease. Krista Lanctôt, PhD, a psychiatry and pharmacology professor at the University of Toronto, presented preliminary results from a phase 2, 14-week clinical trial that investigated the safety and efficacy of nabilone in patients with moderate to severe Alzheimer disease at the 2018 Alzheimer’s Association International Conference (AAIC) in Chicago, Illinois. The trial compared 6 weeks of nabilone 0.5 mg to 2 mg to 6 weeks of placebo, with a 1-week washout between phases in 39 participants.

“Treating agitation, currently, is very challenging,” Lanctôt said. “We know that the medications that are on the market that have the best results for efficacy also have the biggest problems for safety, so we’re excited if we can open a new therapeutic group to help treat these very challenging behaviors.”

The primary outcome of the trial was agitation measured by the Cohen Mansfield Agitation Inventory (CMAI), while secondary outcomes included safety, overall neuropsychiatric symptoms (Neuropsychiatric Inventory [NPI] total), cognition (standardized MMSE [sMMSE]), Severe Impairment Battery, and global impression (Clinician’s Global Impression of Change [CGIC]). In addition, researchers assessed subjects’ pain with the Pain Assessment in Advanced Dementia scale, nutritional status with the Mini-Nutritional Assessment-Short Form, and safety.

Preliminary results demonstrated significant differences in CMAI (P = .003), the NPI’s agitation/aggression domain (b value = —1.5; 95% CI, –2.3 to –0.6; P = .001), NPI total (b value = —4.6; 95% CI, –7.5 to –1.6; P = .004), and sMMSE (b value = 1.1; 95% CI, 0.1-2; P = .026) in favor of nabilone, providing rationale for the feasibility of a larger, confirmatory phase 3 trial.³ Lanctôt stressed the importance of closely monitoring sedation, as it was experienced by 45% of participants.

Not only were the preliminary results of this proof-of-concept trial positive, but the benefits of nabilone went beyond the patients, as caregiver distress was significantly reduced. Larger trials and replication of the findings are needed to provide confirmatory evidence regarding the safety of nabilone and make recommendations to change clinical practice.

“Because this is a synthetic version of [tetrahydrocannabinol], it doesn’t tell you anything about what medical marijuana would do, so these results should not encourage you to use medical marijuana or recreational marijuana to try and treat these symptoms in Alzheimer disease,” Lanctôt explained. “We hope that this trial opens the door for evaluating this particular group of medications for future treatment of agitation.”

Another agent being studied for agitation is Avanir Pharmaceuticals’ AVP-786, which was designed as a second-generation version of dextromethorphan/quinidine (Nuedexta). AVP-786 is a combination of dextromethorphan and quinidine, but unlike Nuedexta, it also contains deuterium. Researchers hypothesize that the penetration of this molecule into the brain leads to the activation and repression of certain neuronal pathways, leading to a reduction of agitation. In 2015, AVP-786 was granted a fast track designation by the FDA for treatment of agitation in patients with Alzheimer disease.

Currently, AVP-786 is being studied in the TRIAD program for agitation, which includes 2 placebo-controlled phase 3 clinical trials: TRIAD-1 (NCT02442765) and TRIAD-2 (NCT02442778). The phase 3 studies will evaluate 2 doses of AVP-786 versus placebo administered orally twice daily for 12 weeks in participants with agitation secondary to dementia of the Alzheimer type.

TRIAD-1 is expected to enroll 380 participants in 60 centers in the United States and has an estimated completion date of April 2019. TRIAD-2 is expected to be completed December 2019 with 470 participants enrolled in 75 centers. The primary outcome measure in both studies is change from baseline to week 12 in the CMAI, with secondary outcomes including the agitation/aggression domain of NPI, other domains of NPI, measures of global clinical change, measures of caregiver burden and quality of life, and standard safety measures.

In addition to these 2 US-based trials, additional global trials will be conducted as part of the TRIAD program. A long-term phase 3 extension study (NCT02446132) of AVP-786 is currently recruiting participants who have successfully completed TRIAD-1 (NCT02442765), TRIAD-2 (NCT02442778), or an earlier phase 2 study of AVP-923 (NCT01584440). Approximately 700 participants will be enrolled at 135 centers in North America for roughly 56 weeks total, however, those who have a follow-up visit 3 months after their last dose will be enrolled for 64 weeks total. Participants will receive either a low or high dose of AVP-786.

Primary outcome measures include the number of participants with any treatment-emergent AEs or serious AEs; any abnormal, clinically significant clinical laboratory value, 12-lead electrocardiography value, physical and neurological examination finding, vital sign value; changes in the Sheehan Suicidality Tracking Scale (S-STS) score, the MMSE score, Alzheimer’s Disease Assessment Scale-Cognitive Subscale score, the Timed Up and Go Test score, and the Epworth Sleepiness Scale score. The extension study is expected to be completed March 2021.

ITI-007 (lumateperone, Intracellular Therapies), an atypical antipsychotic with both serotonin and dopamine effects, is another candidate under investigation as a potential treatment option for agitation in patients with dementia, including Alzheimer disease. The first-in-class molecule provides selective and simultaneous modulation of serotonin, dopamine, and glutamate—3 neurotransmitter pathways implicated in mental illness.

The unique pharmacological features of ITI-007 predict enhancement of sleep and reduction of agitation and aggression at lower doses and antipsychotic and antidepressant efficacy at higher doses, Andrew Satlin, MD, the chief medical officer with Intra-Cellular Therapies, told NeurologyLive.

The safety, tolerability, and pharmacokinetics were first assessed in healthy older volunteers and patients with dementia in a dose-escalation phase I/II trial (NCT02078310).⁴ The agent was shown to be safe and well tolerated across a range of low doses among the patient population, showing clinical signs for improved cognition and no clinically significant impact on the extrapyramidal, endocrine, and cardiovascular systems. Study results confirmed no cognitive impairment by ITI-007 and demonstrated clinical signals for improved cognition with only 1 week of treatment.⁵

ITI-007 is currently being investigated in a phase 3 clinical trial (NCT02817906) to evaluate its safety and efficacy versus placebo in participants with a clinical diagnosis of probable Alzheimer disease and clinically significant symptoms of agitation. The 9-mg dose being studied is administered to participants as a solid oral formulation once daily for 4 weeks. The primary outcome is treatment efficacy, measured by the CMAI-community form; secondary outcomes include efficacy measures using the CGIS.

Underrecognized and Undertreated Neuropsychiatric Symptoms

Although the cognitive symptoms associated with Alzheimer disease are the most recognized, the neuropsychiatric symptoms are often the greatest challenge. If left untreated, these symptoms can accelerate decline and significantly impact the quality of life.

For Marwan Sabbagh, MD, director of the Cleveland Clinic Lou Ruvo Center for Brain Health, there is an incredible amount of pressure to address this challenge that has implications for patients, caregivers, and families alike.

“It’s a big deal. When we really talk about the dementia state now, we draw down on staging it as mild, moderate, and severe, and we start to see the emergence of the neuropsychiatric features in the late mild, early moderate stage, and oftentimes they can eclipse the entire disease,” Sabbagh told NeurologyLive. “After a while, patients and family don’t care about the forgetfulness, they care about the wandering, the paranoia, the delusion, the agitation, the trouble sleeping, and that really starts to take over the disease. And so it becomes a huge amount of the burden of the disease.”

Sabbagh added that while physicians have tried to address these issues through off-label uses of drugs, there is still no clear consensus or guidelines. “We’re winging it when it comes to managing neuropsychiatric features,” he said. Although he did point out that there are therapies being developed for behavioral symptoms, some of which are close to achieving FDA approval.

“I suspect we’ll see more drugs approved to treat behavioral symptoms within a year or 2,” he said. “That is a huge area of unmet need, and I suspect we’ll see some drugs to fill the gap.”

REFERENCES

1. Ballard C, Banister C, Khan Z, et al. Evaluation of the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer’s disease psychosis: a phase 2, randomized, placebo-controlled, double-blind study. Lancet Neurol. 2018;17(3):213-222. doi: 10.1016/S1474-4422(18)30039-5.

2. Ballard C, Youakim JM, Coate B, Stankovic S. Pimavanserin in Alzheimer’s disease psychosis: efficacy in patients with more pronounced psychotic symptoms. JPAD. 2018;1(3):1-7.

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: 10.14283/jpad.2018.30.

3. Ruthirakuhan M, Herrmann N, Abraham E, et al. A randomized, placebo-controlled, cross-over trial investigating nabilone as a treatment for agitation in patients with moderate-to-severe Alzheimer’s disease: blinded, interim safety results. Alzheimers Dement. 2017;13(7):1254.

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4. Intra-Cellular Therapies announces topline safety results from

phase

I/II clinical trial for ITI-007 in healthy geriatric subjects and patients with dementia [news release]. New York, NY: Intra-Cellular Therapies; October 13, 2014. ir.intracellulartherapies.com/news-releases/news-release-details/intra-cellular-therapies-announces-topline-safety-results-phase. Accessed September 15, 2018.

5. Intra-Cellular Therapies announces additional results from phase I/II clinical trial for ITI-007 in healthy geriatric subjects and patients with dementia [news release]. New York, NY: Intra-Cellular Therapies; November 21, 2014. ir.intracellulartherapies.com/news-releases/news-release-details/intra-cellular-therapies-announces-additional-results-phase-iii. Accessed September 15, 2018.