TABLE 12.
Summary descriptions of medications in the pipeline for neurocognitive disorders
| MEDICATION | MECHANISM OF ACTION | INDICATIONS BEING TESTED IN PHASE III | ROUTE AND DOSE | NOTES TO CLINICIANS (INCLUDING EFFECTS ON SEDATION, VITAL SIGNS, FALL RISK, AND QTc) |
|---|---|---|---|---|
| ACP-204 | Inverse agonist at 5-HT2A receptors.130,131 | Alzheimer’s disease-associated psychosis.130,131 | Oral, 30–60mg daily130,131 | Unlike pimavanserin, ACP-204 does not cause QTc prolongation.130,131 |
| AR1001 | Phosphodiesterase 5 (PDE5) inhibitor141 | Mild cognitive impairment and early Alzheimer’s disease141 | Oral, 30mg daily141 | No significant risk related to QTc prolongation and weight gain was reported. However, reports of fainting might increase fall risk.141 |
| Dextromethorphan-bupropion (Auvelity, AXS-05) | Dextromethorphan is an N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist. Bupropion is a norepinephrine-dopamine reuptake inhibitor that competitively inhibits CYP2D6, prolonging dextromethorphan half-life.143 | Agitation in Alzheimer’s disease; already approved in major depressive disorder142,143 | Oral 45mg dextromethorphan + 105mg bupropion once daily, then increase to twice daily after 3 days142 | Dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, and hyperhidrosis were reported.142,143 |
| Dapagliflozin (Farxiga) | Sodium-glycose co-transporter 2 (SGLT2) inhibitor, decreasing glucose reabsorption in blood152 | Cognitive impairment; symptoms of dementia and Alzheimer’s disease in patients with Type 2 diabetes152 | Oral, 10mg daily152 | United States Food and Drug Administration (FDA)-approved for treatment of Type 2 diabetes, heart failure, and symptoms of chronic kidney disease. Serious adverse effects (especially for those with Type 1 diabetes) include diabetic ketoacidosis, urinary tract infections, and genital yeast infections.152 |
| Donanemab | Antibody that targets accumulated deposits of amyloid beta peptides (N3pG)124,125 | Early stages of Alzheimer’s disease124,125 | Intravenous, 700–1,400mg every 4 weeks124,125 | No major concerns regarding fall risk, QTc interval change, weight change, sedation, or vital signs were noted. However, patients should be aware of potential adverse effects related to amyloid imaging. Cases of possible cerebral edema (amyloid-related) were observed with donanemab administration.124,125 |
| Gantenerumab (RO4909832) | Monoclonal antibody that targets amyloid plaques and degrades them through microglial recruitment and phagocytosis126 | Alzheimer’s disease126 | Subcutaneous, 120–1,200mg at varying intervals (minimum of 1 week)126 | Gantenerumab was granted breakthrough designation by the FDA in 2021. No significant concerns regarding weight loss, sedation, or fall risk were reported.126 |
| GV1001 | Gonadotropin releasing hormone receptor (GnRHR) activator147,148 | Alzheimer’s disease147 | Subcutaneous, 0.56–1.12mg weekly or every 2 weeks148 | No significant adverse effects related to QTc intervals, weight change, or fall risk were reported.147,148 |
| Latrepirdine (DMB-I, Dimebon) | H1 histamine receptor antagonist, NMDA receptor antagonist138 | Alzheimer’s disease138 | Oral,10–60mg daily138 | No significant risk of QTc prolongation, sedation, or falls were reported.138 |
| Levetiracetam low dose (AGB101, Keppra) | Synaptic vesicle glycoprotein 2A (SV2A) inhibitor139,140 | Mild cognitive impairment due to Alzheimer’s disease139,140 | Oral, 220mg daily139,140 | Levetiracetam is FDA-approved to treat partial seizures and epilepsy. In a Phase IIb trial, AGB101 did not statistically slow Alzheimer’s disease progression. Yet, its inhibitory effects on SV2A proteins hold promise, hypothesized to influence amyloid plaque formation. Phase II trials showed no significant risk of QTc interval change or weight gain, but falls were a common adverse effect.139,140 |
| Masitinib (Masivet) | Tyrosine kinase inhibitor157 | Alzheimer’s disease157 | Oral, 3–4.5mg/kg daily157 | No significant risk in QTc interval changes and vitals were reported. However, distinct adverse effects reported were neutropenia, hypoalbuminemia, and rash.157 |
| Masupirdine | 5-HT6 receptor selective antagonist135 | Alzheimer’s disease135 | Oral, 50–100mg daily135 | Commonly reported adverse effects to note include agitation, falls, and cases of atrial fibrillation.135 |
| Metformin extended release (metformin XR) | Acts on cognitive functioning using the gut-brain axis and regulates insulin levels by activating AMP protein kinase to avoid hyperinsulinemia, linked to neuroinflammation and amyloid beta plaque accumulation150 | Neurocognitive decline and dementia150 | Oral, 500–2,000mg daily150 | Previous studies have observed that metformin combats QTc prolongation and is able to reduce dispersion in low-to-medium doses.150 Some studies have observed insignificance or even risk of cognitive deterioration in patients with Type 2 diabetes.151 |
| Nabilone | Partial agonist at CB-1 and CB-2 cannabinoid receptors144,145 | Dementia144 | Oral, 0.5–1.5mg daily144,145 | Sedative effects after administration in some participants were observed. Furthermore, common reports of drowsiness might cause further fall risk.144 |
| Nilotinib (Tasigna) | c-Abl tyrosine kinase receptor inhibitor153 | Alzheimer’s disease153 | Oral, 84–112mg daily153 | There were no reports of QTc prolongation, weight change, or fall risk. Common adverse effects included mood swings, pain, and gastrointestinal discomfort.153,154 |
| Pimavanserin (Nuplazid) | 5-HT2A and 5-HT2C inverse agonist132,133 | Relapse prevention in dementia-related psychotic symptoms, residual psychotic symptoms in schizophrenia, and major depressive disorder132 | Oral, 20mg daily132 | Pimavanserin might prolong QTc intervals by 5–8ms.71 No significant concerns regarding weight gain, sedation, or fall risk were reported. It is currently approved for Parkinson’s disease psychosis only.132,133 |
| Remternetug | Antibody recognition of the pyroglutamated amyloid beta aggregated in amyloid plaques166 | Alzheimer’s disease | Subcutaneous, 700–2,800mg every 4 weeks | Higher than average amyloid-related imaging abnormalities were reported in early trials. No other significant adverse events were reported.166 |
| Sabirnetug (ACU193) | Monoclonal antibody developed to be selective for soluble amyloid beta oligomers, which accumulate in Alzheimer’s disease and cause neurodegeneration122,123 | Alzheimer’s disease122,123 | Intravenous infusion, 35mg/kg for the first 2 doses, followed by 50 mg/kg every 4 weeks122,123 | Phase I INTERCEPT-AD trial (NCT04931459) showed sabirnetug to be well tolerated with a favorable overall safety profile. Study results included statistically significant, dose-related amyloid plaque reduction similar to approved and in-review amyloid-directed therapies at similar time points, low overall levels of amyloid-related imaging artifacts (ARIA-E), and pharmacokinetic data confirming proof-of-mechanism.122,123 |
| Simufilam (PTI-125) | Filamin alpha-7 nicotinic acetylcholine receptor antagonist127 | Alzheimer’s disease (with and without dementia)127 | Oral, 100mg twice daily127,128 | While the drug is entering Phase III trials, there have been significant setbacks due to integrity of results, which is under investigation. No serious adverse health effects have been reported.127 |
| Suvorexant (Belsomra) | Antagonist at orexin-1 and orexin-2 receptors.136,137 | Dementia137 | Oral, 10mg nightly137 | Received United States Food and Drug Administration (FDA) approval in 2014 for the treatment of insomnia. Somnolence is a commonly reported adverse effect.136,137 |
| Tricaprilin (CER-0001) | Medium-chain triglyceride metabolized to act as ketogenic energy source for neural and physiological processes146 | Mild-to-moderate Alzheimer’s disease146 | Oral, 20g twice daily.146 | Commonly reported adverse effects included gastrointestinal discomfort and nausea.146 |
| Valiltramiprosate (ALZ-801) | Amyloid beta-42 aggregation inhibition through 3-SPA metabolism129 | Alzheimer’s disease129 | Oral, 265mg twice daily129 | Early trials showed adverse effects, such as nausea, dizziness (fall risk), and vomiting.129 |
| Xanomeline (Lumeron) | Muscarinic receptor agonist, selectively M1 and M4 receptors155 | Alzheimer’s disease and related cognitive deterioration155 | Oral, 75–225mg daily155 | Use of xanomeline was linked to weight gain in a limited number of individuals during clinical studies. Limited cases of increased QTc interval were reported after low dosage administration.155,156 |