Current Topics: Review
Clinical Pipelines for Alzheimer’s Disease Psychosis and Agitation
2024 年 72 巻 7 号 p. 610-617
詳細
2024 年 72 巻 7 号 p. 610-617
Agitation and psychosis are key behavioral and psychological symptoms of Alzheimer’s disease (AD). For family and caregivers of patients, such symptoms are critical factors of distress and increased burden, but medication to treat them is limited. In most cases, drugs for other neuropsychiatric diseases have been used to manage these symptoms in an off-label manner. Due to the complex pathological background of AD and limited clinical data, obtaining proof of concept for the treatment of these symptoms is challenging. However, in 2023, the U.S. Food and Drug Administration approved brexpiprazole as the first and only drug to treat agitation in AD. Several other compounds have been evaluated in clinical situations. This review highlights recent pipelines being developed for agitation and psychosis for patients living with AD.
Agitation and psychosis are common behavioral and psychological symptoms of dementia (BPSD) including Alzheimer’s disease (AD). These symptoms are critical factors that negatively impact the quality of life of patients and increase caregiver burden.1,2) Psychosis, mainly defined as delusion and hallucination,3) is a clinically relevant neuropsychiatric symptom that increases the risk of patient hospitalization and institutionalization.4) Symptoms of agitation are, for example, excessive or abnormal motor activity, verbal aggression, and physical aggression. Collectively these agitation symptoms increase the use of healthcare resources.5) According to the WHO, more than 55 million people suffer from dementia, and 60–70% of these patients have been diagnosed with AD.6) In Japan, dementia is estimated to affect more than 5 million people, 50% of whom are thought to have been diagnosed with AD.7) The prevalence of psychosis in these AD patients is estimated to be about 40%8,9) and the prevalence of agitation to be 30–50%.10,11) Some non-pharmacological interventions may work, but the efficacy is limited.12)
Despite the burden on patients and caregivers, therapies for psychosis and agitation are limited. There are no approved drugs to treat psychosis and agitation in Japan, creating a huge unmet medical need. To manage these symptoms, antipsychotics, antidepressants and other classes of drugs prescribed for different indications such as schizophrenia and depression, have been used in an off-label manner in clinical practice.13) For example, atypical antipsychotics such as risperidone, olanzapine and quetiapine have been used to control AD-associated psychosis or agitation.14) While typical antipsychotics, also known as first-generation antipsychotics, antagonize dopamine receptors including the dopamine D2 receptor (D2R), this causes extrapyramidal symptoms such as akathisia, dystonia or parkinsonism. Thus, atypical antipsychotics (second-generation antipsychotics) have reduced affinity for D2R to mitigate such adverse effects, while having increased affinity for serotonin receptors to sustain their efficacy.15) However, the efficacy and benefit/risk balance of off-label drugs are not satisfactory for treating dementia patients displaying psychosis and agitation as evidenced from clinical trials and systematic analyses.16,17)
The aim of this review is to provide key updates on clinical pipelines for agitation and psychosis of patients living with AD. Currently, approximately 150 drugs are listed in the pipeline for AD, but most of them focus on disease-modifying therapy (DMT) and only 7% of them target neuropsychiatric symptoms including agitation and psychosis.18) The former drugs aim to slow down the progression of AD and address cognitive impairment or memory loss, which may potentially reduce behavioral symptoms.19) However, ameliorating neuropsychiatric symptoms requires a straightforward approach to provide immediate relief to caregivers. Therefore, in this review, we specifically highlight compounds that are being developed to treat psychosis and/or agitation in AD patients.
Chart 1 presents selected clinical pipelines, being developed for the treatment of agitation associated with AD.
Brexpiprazole is a third-generation atypical antipsychotic for treatment of schizophrenia and adjunctive therapy in major depressive disorder, developed by Otsuka and Lundbeck as a successor to aripiprazole.20) This is the first and only drug approved by the U.S. Food and Drug Administration (FDA) for agitation in AD patients.21) It is a partial agonist of 5-hydroxytryptamine type 1A (5-HT1A), D2, and D3 receptors and an antagonist of 5-HT2A, 5-HT2B, 5-HT7, adrenergic α1A, α1B, α1D, and α2C. Its pharmacological profile is similar to that of aripiprazole. However, compared with aripiprazole, brexpiprazole has minimal intrinsic activity for D2R, which contributes to the reduction of certain side effects (potential akathisia and extrapyramidal symptoms).22) In addition, brexpiprazole displays higher potency for 5-HT1A, 5-HT2A, and α1B receptors. Clinical trials of aripiprazole showed modest efficacy in the treatment of psychosis in AD.23) However, a randomized double blind placebo-controlled study in nursing home patients with AD indicated that aripiprazole could be effective for related psychological and behavioral symptoms of agitation, anxiety and depression rather than psychosis.24) Given these results and its similar but modified properties compared to aripiprazole, brexpiprazole has been anticipated to be a potent drug for the treatment of psychosis and agitation in AD.
For the treatment of agitation in AD, two clinical trials (NCT01862640, NCT01922258)25,26) suggested that a 2 mg/d dose of brexpiprazole would be efficacious on the Cohen–Mansfield agitation inventory (CMAI)27) score with good tolerability.28) Furthermore, in an additional phase 3 trial (NCT03548584),29) groups of 2 and 3 mg/d dosing met the primary endpoint of mean change in the CMAI total score compared with the placebo at week 12. After positive votes by the FDA advisory committee, it was approved as the first and only drug for agitation associated with AD in the U.S. in May 2023.21)
2.2. AVP-786 and AVP-923AVP-786, a combination of deuterated dextromethorphan and quinidine for the indication of AD-associated agitation, was developed by Avanir and Otsuka.30) Dextromethorphan is a widely-used cough suppressant. It is an N-methyl-D-aspartate (NMDA) receptor antagonist and a σ1 agonist,31) suppressing glutamate excitotoxicity. However, it also has several pharmacological activities related to neuromodulator-associated receptors and transporters in the brain; its mechanism of action has not been fully clarified.32) Quinidine inhibits CYP2D6, a primary metabolizer of dextromethorphan, contributing to its improved pharmacokinetics (PK). A fixed dose combination of dextromethorphan and quinidine is known as AVP-923, the predecessor of AVP-786, and is sold under the brand name of Nuedexta® for the treatment of pseudobulbar affect.33) Clinical studies of AVP-923 suggested relevant efficacy for agitation in AD, but developers have conducted further clinical trials with AVP-786.34) Deuterated dextromethorphan has been expected to show better PK than AVP-923.35) The first study of TRIAD-1 (NCT02442765) showed positive results,36) but the second study of TRIAD-2 (NCT02442778) did not meet the primary endpoint of the CMAI composite score and key secondary endpoints.37) To pursue the therapeutic possibilities of AVP-786, the developers began a third phase 3 study (NCT03393520) in 2017.38) In addition, they started two additional phase 3 studies in 2020 (NCT04408755, NCT04464564),39,40) estimated to be completed at the end of 2024. In February 2024, they announced that the topline result of a phase 3 study (NCT03393520) showed no statistically significant difference on the primary efficacy endpoint of the CMAI total score.41)
2.3. AXS-05Axsome Therapeutics has developed a combination therapy using dextromethorphan and bupropion (AXS-05, Auvelity™)42) for the treatment of agitation in AD. This is a similar strategy to those of AVP-923 and AVP-786 as bupropion also inhibits CYP2D6, thus inhibiting the metabolism of dextromethorphan. However, bupropion is also an antidepressant acting as a noradrenaline and dopamine reuptake inhibitor and a nicotinic acetylcholine receptor antagonist.43) In addition, metabolites of bupropion have pharmacological activities.44) For example, the metabolite hydroxybupropion is a nicotinic acetylcholine receptor antagonist.45) Thus, not only pharmacokinetic but also pharmacological synergistic effects are expected for its clinical outcome.
In 2020, Axsome announced a positive topline result of AXS-05 from a phase 2/3 study, ADVANCE-1 (NCT03226522).46) It reduced the CMAI total score by 15.4 points at week 5, compared with the 11.5 for the placebo. Its phase 3 study of ACCORD (NCT04797715) consisted of open-label treatment of AXS-05 for all subjects, and the responders were randomized to continue AXS-05 or to switch to the placebo.47) In 2022, Axsome announced that the study met the primary endpoint of delaying the time to relapse of agitation associated with AD when compared with the placebo.48) They also started another phase 3 trial of ADVANCE-2 (NCT05557409),49) which is estimated to be completed in 2025.
2.4. BXCL-501BXCL501 is an orally dissolving sublingual film formulation of dexmedetomidine developed by BioXcel Therapeutics. It was approved for the acute treatment of agitation in schizophrenia, and bipolar I or II disorder in 2022, being distributed to patients under the brand name of IGALMI™.50) Dexmedetomidine is a selective α2 adrenergic agonist, and itself had been approved in 1999 for postoperative sedation in the intensive care unit.51) It acts on presynaptic α2 receptors, suppressing emission of noradrenaline.52) A low dose of dexmedetomidine is not expected to cause drowsiness and is anticipated to treat agitation.53) In 2022, BioXcel announced the first dosing of BXCL501 for acute treatment of agitation in patients with AD in a phase 3 trial of TRANQUILITY III (NCT05665088),54) which is expected to be completed in early 2024.55)
2.5. EscitalopramEscitalopram (brand name Lexapro®) is an oral selective serotonin re-uptake inhibitor used for the treatment of depression and anxiety, developed by Lundbeck. It is the (S)-enantiomer of citalopram, which is more active than the (R)-enantiomer.56) Dysfunction of the serotonergic system has been reported in cognitive impairment and BPSD.57) Escitalopram enhances functional serotonergic neurotransmission, compensating for the loss of serotonin, and is expected to treat psychiatric symptoms including agitation. In a CitAD study (NCT00898807),58) citalopram improved agitation-related scores when compared with the placebo, but adverse cardiovascular and cognition effects may limit sufficient dosing for AD patients.59) Another clinical trial of escitalopram, S-CitAD60) (NCT03108846),61) is ongoing and is expected to be completed in 2024.
2.6. DronabinolCannabinoids have been tested as therapeutic targets for agitation in AD. Dronabinol, a synthetic cannabinoid also known as tetrahydrocannabinol (THC), is a psychedelic compound found in cannabis. There are several studies using dronabinol in the clinic to evaluate the reduction of agitation in AD. Selected initial trials include a placebo-controlled crossover design study with 15 patients,62) an open-label pilot study for nighttime agitation,63) and two studies using Namisol®, a new formulation tablet of THC (NCT01302340, NCT01608217).64–67) There are no convincing findings that dronabinol could provide a positive benefit for agitation in AD and additional studies are needed to prove its efficacy.68) Currently, a trial of dronabinol to treat agitation in AD is ongoing at Johns Hopkins University; it is expected to be completed in May 2024.69,70) Another candidate is SCI-110, a combination of dronabinol and palmitoylethanolamide, which could reduce the side effects of dronabinol.71) In November 2023, the developer, SciSparc, announced a positive topline result from a phase 2a study of SCI-110, albeit an open-label study.72)
2.7. IGC-AD1IGC-AD1 is a combination of THC and melatonin, being developed by IGC Pharma.73) THC could induce increased blood pressure, but IGC-AD1 did not have an impact on blood pressure or blood pressure variability in a preliminary safety study.74) While the specifics are uncertain, this might be influenced by the effect of melatonin.75,76) A pilot study involving small numbers of patients indicated that it has the potential to alleviate agitation (NCT04749563).71,77) In January 2024, IGC Pharma announced the first dose of IGC-AD1 to a participant in its phase 2b trial, anticipated to be finished in 2025 (NCT05543681).78,79)
2.8. NabiloneNabilone is also a synthetic cannabinoid, which mimics the structure of THC and acts as a partial agonist at cannabinoid receptors (CBs), which may have therapeutic potential for the treatment of agitation in AD patients. CBs are localized in the hippocampus, striatum and cingulate cortex of important regions for cognitive and emotional functions.80) In a randomized placebo-controlled trial (NCT02351882),81) nabilone improved agitation and some secondary measurements, albeit sample size and study duration were limited.82,83) Also, sedation caused by the drugs and potential regulatory hurdles for these derivatives could be an issue.84) To evaluate the safety and benefit of nabilone for treatment of agitation, another study (NAB-IT) is being conducted with estimated completion in 2025 (NCT04516057).85)
2.9. PrazosinPrazosin is a selective antagonist of α1-adrenergic receptors.86) As there is a significant loss of noradrenergic neurons in AD patients, increasing the activity of the remaining noradrenergic neurons could compensate for their function.87) Patients who display agitation and aggression could have a heightened reactivity to noradrenaline in the brain.88) Thus, prazosin, an α1-blocker is thought to reduce the symptoms.89) There have been several clinical studies using prazosin for agitation and aggression in AD, but the findings are not consistent. A pilot randomized placebo-controlled study of 24 patients revealed that prazosin may be effective for agitation and aggression (NCT00161473).90,91) There have been subsequent trials testing the efficacy of prazosin (NCT01126099, NCT03710642),92,93) but due to small sample sizes, no conclusion has been reached on the efficacy of prazosin for treating agitation and aggression in AD.
Clinical pipelines for the treatment of Alzheimer’s disease psychosis (ADP) are shown in Chart 2.
Pimavanserin, sold as Nuplazid®, is an antipsychotic drug developed by Acadia.94) It has been used as the first FDA-approved medication for the treatment of Parkinson’s disease psychosis (PDP) since it was approved in 2016. Pimavanserin is an inverse agonist and antagonist of the serotonin 5-HT2A receptor, and it also has relatively weaker binding affinity for 5-HT2C receptor.95) It is of note that pimavanserin has no appreciable affinity for D2R, resulting in reduced motor side effects.96)
During clinical trials of PDP, a greater score change (e.g., the Scale for the Assessment of Positive Symptoms for Parkinson’s Disease Psychosis (SAPS-PD)) was observed for patients with cognitive impairment than unimpaired subjects,97,98) indicating it might be effective for patients with Parkinson’s disease dementia (PDD). In addition, in a phase 2 randomized-placebo controlled study of AD patients, pimavanserin reduced the Neuropsychiatric Inventory Nursing Home Version (NPI-NH), a psychosis score, more than the placebo at week 6, although statistical significance was not observed at week 12 (NCT02035553).99,100) A subsequent phase 3 randomized-placebo controlled study of pimavanserin (HARMONY, NCT03325556) has been conducted to assess the risk of relapse for pimavanserin responders with several subtypes of dementia including AD.101,102) Acadia submitted a new drug application of pimavanserin for dementia-related psychosis (DRP), however, the FDA declined its approval because of insufficient evidence due to the small number of patients with less common subtypes.103) Acadia, then resubmitted sNDA for ADP with existing data, but the FDA again rejected its application,104) noting the limited interpretability of the phase 2 study of ADP and that the positive phase 3 study could have been driven by the robustly positive results in the PDD subgroup. The FDA recommended that another phase 3 trial has to be conducted for pimavanserin.
3.2. KarXTKarXT is a combined drug of xanomeline and trospium. Xanomeline is an agonist of muscarine M1 and M4 identified and developed by Novo Nordisk and Eli Lilly.105,106) It had been considered to treat cognitive impairment of AD and improved the scores of Alzheimer’s Disease Assessment Scale, cognitive subscale (ADAS-cog) and Clinician’s Interview-Based Impression of Change Plus caregiver input (CIBIC-Plus).107) In addition, xanomeline also ameliorated behavioral symptoms including psychosis. However, its side effects of cholinergic syndrome were an obstacle to further development. Karuna Therapeutics combined xanomeline with trospium, an FDA-approved peripheral restricted muscarinic receptor antagonist. Trospium contributes to reducing side effects of xanomeline in plasma, but does not disturb its efficacy in the central nervous system.108) KarXT led to positive effects on psychosis and cognitive deficits for schizophrenia.109–111) A phase 3 study of KarXT for ADP is on-going (ADEPT-1, NCT05511363),112) which is estimated to be completed in early 2025, and two more phase 3 studies of ADEPT-2 and ADEPT-3 were initiated in 2023.113)
In addition to the candidates mentioned above, some agents are being considered to treat agitation and psychosis in AD, and are expected to be evaluated in proof-of-concept (PoC) studies. Acadia Pharmaceuticals identified a new chemical entity of ACP-204, a 5-HT2A antagonist, in their pipeline. It is a successor of pimavanserin, reducing the risk of QT prolongation with optimized profiles.114) Sumitomo Pharma is developing DSP-0038, a 5-HT2A receptor antagonist and 5-HT1A receptor agonist, which does not impact D2R. DSP-0038 is in a phase 1 clinical trial assessing its impact on Alzheimer’s disease psychosis and other BPSD symptoms such as agitation.115) Intra-Cellular is developing ITI-1284, a deuterated molecule of lumateperone, as an orally disintegrating sublingual tablet.116) Lumateperone is a third-generation atypical antipsychotic, named CAPLYTA®, approved for schizophrenia and bipolar I and bipolar II depression.117) It is a 5-HT2A antagonist and presynaptic D2R partial agonist. It also acts on dopamine D1 receptors and serotonin transporters.118) Intra-Cellular has announced its topline results for phase 1 and future plans for its phase 2 trial for CNS disease including DRP.
Due to complex and multifactorial mechanisms of AD and translational gaps, obtaining PoC for its symptoms has been a huge challenge.119) In addition, most patients living with AD are elderly and tend to have comorbidities, such as diabetes and cardiovascular disease, increasing the difficulty of drug development.120) Most agents, introduced in this review, have been developed for certain CNS diseases such as schizophrenia, bipolar disorder, or depression that occur in younger patients than those with BPSD. Testing drugs for such indications and collecting evidence could be a strategy to expand their usage to symptoms and diseases including agitation and psychosis in AD. Using such a strategy, the PoC of a few molecules have been revealed in clinical trials. Currently, molecules with several mechanisms of action are being tested for agitation and psychosis. Given the diversity of pathological backgrounds, there are several directions for drug discovery campaigns: (i) aim for a drug covering patients of diverse pathological backgrounds, (ii) aim for a drug treating broad symptoms including agitation and psychosis, (iii) aim for a very effective drug addressing a specific symptom. Polypharmacological strategies or combinations of drugs could be potential solutions for the first two approaches as indicated by brexpiprazole and AXS-05. The third strategy currently seems more challenging because of limited clinical evidence. However, emerging clinical data for approved and developing drugs should provide insights for the relevance of targets and segments of patients. Intensive research from various perspectives, including current pipeline compounds by academia and other pharmaceutical companies, should clarify relevant mechanisms and identify optimal approaches to tackle the symptoms and provide suitable drugs for patients suffering from psychosis, agitation, and other BPSD in AD.
The authors thank Dr. Shuji Yonezawa for providing invaluable feedback on this manuscript, Dr. Judy Noguchi for proofreading the manuscript, and Dr. Tasuku Tsukamoto for the drawing the graphical abstract.
T.O. and K.J. are employees of Shionogi & Co., Ltd.
