Riluzole and its prodrugs for the treatment of Alzheimer’s disease

Abstract

Current medications for Alzheimer’s disease help manage symptoms and behavioral problems. Nevertheless, they do not slow the progression of cognitive decline or dementia. A potential approach for treating Alzheimer’s disease is to target neurons that are sensitive to disease pathobiology such as glutamatergic neurons. Several patents disclosed methods for treating Alzheimer’s disease by administering riluzole or its prodrugs. Clinical trials revealed that 6 months treatment using riluzole or troriluzole is associated with a slower decline in the tomographic measures of the positron emissions of cerebral glucose metabolism in Alzheimer’s patients. The proposed strategy claims to prevent and/or slow the cognitive decline of Alzheimer’s patients and to enhance global functioning. These claims may also pave the way for other glutamate modulators to be used for Alzheimer’s disease.

Alzheimer’s disease is the most common cause of dementia (80% of cases are attributed to Alzheimer’s disease), an illness that affects more than 44 million people worldwide. In the USA, there are approximately 5.5 million Alzheimer’s patients. Of these, about 5.3 million are 65 years old and older and the rest are of younger ages with an early onset of Alzheimer’s disease. Alzheimer’s disease and dementia are least common in sub-Saharan Africa and most common in Western Europe. Research from the National Institute on Aging indicates that Alzheimer’s disease prevalence doubles every 5 years after the age of 65. In fact, by 2050, it is estimated that the number of people with Alzheimer’s disease in the USA will increase to about 16 million people. Importantly, the neuropathology of the brain in Alzheimer’s disease patients is biologically identified by the presence of extracellular deposition of diffuse and neuritic amyloid-β (Αβ) plaques and neuropil threads within dystrophic neurites that comprise hyperphosphorylated aggregated tau protein as well as intra-neuronal neurofibrillary tangles [1,2].

The primary pathogenesis model of Alzheimer’s disease suggests that cleavage of amyloid protein precursor (ΑPP) results in Αβ and hyperphosphorylated tau deposition, neurofibrillary tangles generation, neurons and synapses loss, immune response activation and eventually cognitive decline [1,2]. Therefore, there are several potential pharmacological targets for treating Alzheimer’s disease including ΑPP, Αβ, Apolipoprotein E, activated neuroimmune elements and the biochemical and biological pathways of each. Importantly, research has suggested that the cognitive weakening appears long after the disease starts, as demonstrated by the presence of Αβ and tau deposition as well as by innate immune activation long before cognitive decline, which complicates efforts to identify safe and effective treatments.

Currently, there are few medications approved by the US FDA to manage Alzheimer’s disease. These include memantine which is N-methyl-D-aspartate (NMDA) receptor modulator as well as rivastigmine, galantamine and donepezil, all of which are acetylcholinesterase inhibitors. While galantamine, rivastigmine and donepezil are used to manage the symptoms of mild to moderate Alzheimer’s disease, the rivastigmine patch, donepezil, memantine and donepezil/memantine combination are used to manage moderate to severe Alzheimer’s symptoms. Such medications may help to alleviate symptoms and may improve certain behavioral problems. Nevertheless, these drugs do not treat the underlying mechanism of disease. They can be useful for some patients for a limited time. Aducanumab is the first FDA-approved disease-modifying therapy to treat Alzheimer’s disease. Aducanumab may decrease amyloid deposits in the brain and slow the disease progression. However, it has not yet been shown to affect clinical outcomes such as cognitive decline or dementia progression [1,2]. Very recently, the FDA granted accelerated approval for lecanemab, a monoclonal antibody of the humanized version of mAb158, a mouse antibody, that identifies protofibrils and prevents Aβ deposition. Studies revealed that lecanemab administration is associated with a statistically significant, but minor, decrease in cognitive decline in patients group compared with a placebo group [3]. Accordingly, a crucial need exists to identify effective treatments for Alzheimer’s disease which can stop or reverse the disease in early stages.

Several molecules targeting various potential Alzheimer’s disease mechanisms did very well in animal models and were promising to undergo phase III trials, yet they failed to exhibit efficacy and safety in humans [1]. These include bapenizumab which is amyloid antibody that corrected behavioral problems in animals [4], LMTM which is a tau–targeting drug that cleared Αβ levels in mouse models and enhanced brain metabolism and spatial learning in rats [5], CNP520 which is a BACE inhibitor that decreased Αβ plaque deposition in mice and decreased Αβ levels in dogs and rats model of Alzheimer’s disease [6], and intravenous immunoglobulin that targets neuro-inflammatory response, protecting against memory deficit and Αβ pathology in a mice model of Alzheimer’s disease [7].

One possible new approach for treating Alzheimer’s disease is to focus on neurons that can be compromised by the disease pathology. Along these lines, glutamatergic dysregulation is involved in the pathophysiology of Alzheimer’s disease. The neocortical and hippocampal atrophy in Alzheimer’s disease brains exhibits degeneration, mainly in the large glutamatergic pyramidal neurons [8–10]. This indicates that such excitatory neurons are the most susceptible to neurodegeneration. Neuronal loss in Alzheimer’s disease has also been attributed to glutamate-mediated toxicity [11]. Furthermore, the Αβ plaques and neurofibrillary tangles formed of hyperphosphorylated tau, which are the Alzheimer’s neuropathophysiological hallmarks, are implicated in glutamatergic dysfunction.

New treatment: riluzole & its prodrugs

Riluzole is a benzothiazole derivative that acts as a glutamatergic modulator. It is indicated for the treatment of amyotrophic lateral sclerosis. Riluzole is a white yellowish powder that is very soluble in DMSO, methanol and DMF; sparingly soluble in 0.1 N HCl; freely soluble in dichloromethane; and very slightly soluble in water and in 0.1 N NaOH. Solubility of riluzole in supercritical CO₂ was also recently measured for the first time [12]. Riluzole is available as RILUTEK™, a 50 mg riluzole film-coated tablet and as TIGLUTIK™, an oral suspension containing 50 mg riluzole/10 ml of suspension.

Several animal studies have evaluated riluzole potential to treat pathologies associated with Alzheimer’s disease. For instance, riluzole has been shown to protect rodents against age-related cognitive decline through dendritic spines clustering [13], which strengthens neural communication [14,15]. Moreover, riluzole has been shown, in rodent models, to rescue gene expression profiles linked to aging and Alzheimer’s disease by modulating pathways related to neurotransmission and neuroplasticity [16]. Very recently, research indicated that riluzole prevented the decline of hippocampal-dependent spatial memory in an early-onset aggressive mice model of Alzheimer’s and inverted several gene expression changes pertaining to immune pathways [16]. Specifically, the reversals involved microglia-related genes that are critical to Alzheimer’s disease pathophysiology [16–21].

Along these lines, about 17 weeks of prodromal riluzole treatment in APP/PS1 mice was found to produce long-lasting procognitive effects and to attenuate glutamatergic tone. APP/PS1 mice treated with riluzole exhibited substantial improvement in long-term memory in comparison to vehicle-treated APP/PS1 mice similar to normal aging C57BL/6J control mice. Moreover, evoked glutamate release levels and basal glutamate concentration were restored, in APP/PS1 mice receiving prodromal riluzole treatment, to levels similar to those observed in age-matched C57BL/6J mice. Aβ plaque accumulation did not change with riluzole treatment. Importantly, this study suggested that targeting the glutamatergic system by riluzole during the early stages of Alzheimer’s disease progression may prevent cognitive decline, resulting in lasting effects on disease outcome [22]. In addition to glutamatergic pathway, neuroinflammation and oxidative stress can also contribute to Alzheimer’s disease. The downregulation of WNT/β-catenin pathway appears to be responsible for the dysregulation of the glutamatergic pathway, the enhancement of oxidative stress and neuroinflammation in Alzheimer’s patients. Accordingly, riluzole could be an interesting therapeutic strategy in Alzheimer’s disease because it activates the WNT/β-catenin pathway (Figure 1) [23].

Figure 1. . Potential mechanism of action of riluzole in Alzheimer’s disease.

Riluzole has been claimed as an effective treatment for Alzheimer’s disease via preventing and/or slowing the decline in cerebral glucose metabolism as determined by the use of FDA-approved biomarker fluorodeoxyglucose-PET (FDG PET), which substantially predicts cognitive function in mild to moderate Alzheimer’s disease. About 50–300 mg/day of riluzole has been claimed to be therapeutically effective for treating Alzheimer’s disease [24,25]. The disclosures revealed for the first time, in a randomized, double-blind, placebo-controlled trial, that 6 months of riluzole treatment (50 mg twice daily) leads to a slower decline of FDG PET measures of cerebral glucose metabolism in Alzheimer’s patients compared with placebo. The effect was observed in the lateral temporal cortex, precuneus, frontal cortex and the right hippocampus, yet it was most robust in posterior cingulate. A considerable correlation between cerebral metabolism in FDG PET and cognitive measures was discovered, which correlated cerebral glucose metabolism with cognition, an important measure of brain performance and function in Alzheimer’s disease [24,25].

Riluzole tablets have 60% bioavailability, given its extensive hepatic first pass metabolism (Figure 2). This has been attributed to metabolism by the heterogeneous hepatic enzyme of CYP1A2, which may also account for riluzole pharmacokinetics variability [26,27]. Moreover, riluzole has reduced bioavailability when taken with meals, resulting in recommending riluzole to be administered an hour before a meal or 2 h after it. Riluzole is also given twice a day and has dose-dependent effects on hepatic function tests. Other intrinsic limitations of riluzole include poor oral palatability, intense oral numbness upon direct administration to the oral mucosa, very low water solubility and pH-dependent chemical stability.

Figure 2. . The chemical structure of riluzole and its metabolism.

To address these problems, riluzole prodrugs were claimed to provide more effective Alzheimer’s disease treatments to patients. Patients are claimed to have an improved response in one or more areas including overall response rate, duration of response, delay of onset, quality of life, overall survival or patient reported outcome [28]. The prodrugs are to have the formula depicted in Figure 3 in which R²³ may be selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, CH₂CCH, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂OH, CH₂OCH₂Ph, CH₂CH₂OCH₂Ph, CH(OH)CH₃, CH₂Ph, CH₂(cyclohexyl), CH₂(4-OH-Ph), (CH₂)₄NH₂, (CH₂)₃NHC(NH₂)NH, CH₂(3-indole), CH₂(5-imidazole), acetic acid, propionic acid, acetamide and propionamide. These prodrugs are activated in vivo by peptidases to release riluzole, either directly or indirectly (Figure 3). One particular prodrug that was tested in a double-blind, randomized, placebo-controlled study was troriluzole (R²³ = H) [28,29]. Choosing this prodrug for testing has not been justified in the patents but synthetic feasibility can be a factor. The prodrug is associated with the advantages of potentially once daily oral dosing and of lower patient-to-patient variability of exposure, as opposed to the twice daily dosing and the large of patient-to-patient variability of the parent drug.

Figure 3. . The general structure of riluzole prodrugs.

Riluzole and its prodrugs have been claimed to slow and/or prevent the cognitive decline associated with Alzheimer’s disease progression. Conjugates offer gastrointestinal tract and metabolic stability. Troriluzole (R²³ = H) was chosen for testing. These prodrugs are activated in vivo by peptidases to release riluzole, either directly or indirectly.

In participants with mild-to-moderate Alzheimer’s disease, troriluzole demonstrated a numerical difference of a possible benefit at week 48 on the neuropsychiatric inventory (NPI). After 48 weeks, participants (N = 120) treated with troriluzole had an LS mean change of 2.3 points from the baseline on the NPI scale, whereas the placebo participants (N = 125) had an LS mean change of 3.8 points (difference -1.5, 95% Cl: -4.08, 1.10, p-value = 0.258). Troriluzole was also associated with numerical advantages at week 48 on the NPI scale across subgroups, including analyses consisting of only mild Alzheimer’s disease patients, only moderate Alzheimer’s disease patients, only ApoE4-negative patients and only ApoE4-positive patients. These results are indicative of the likely beneficial effects of troriluzole on decreasing the severity, as well as the frequency, of neuropsychiatric presentations of mild-to-moderate Alzheimer’s disease [28,29].

Moreover, a subgroup analysis of exclusively mild Alzheimer’s patients indicated that troriluzole displayed a numerical advantage at week 48 on the NPI exploratory measure, Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) co-primary measure, and hippocampal volumetric MRI secondary measure. After 48 weeks, troriluzole-treated patients with mild Alzheimer’s disease (N = 62) had an LS mean change from the baseline of 2.1 points on the NPI scale, versus 4.2 points for placebo participants (N = 63) (difference -2.1, 95% Cl: -5.99, 1.78, p-value = 0.286). After 48 weeks, troriluzole-treated participants with mild Alzheimer’s disease (N = 65) had an LS mean change of 4.2 points from the baseline (95% Cl: 2.7, 5.7) on the ADAS-Cog score, whereas the placebo-treated participants (N = 63) showed an LS mean change of 4.9 points from the baseline (95% Cl: 3.4, 6.4) (difference 0.7, 95% Cl: -1.4, 2.7, p-value = 0.5233). After 48 weeks, patients with mild Alzheimer’s disease (N = 48) who were treated with troriluzole had an LS mean percentage deformation change from the baseline hippocampal volume of -1.1% (95% Cl: -1.6, -0.6, p-value = 0.2240) versus -1.6% (95% Cl: -2.1, -1.0) for placebo participants (N = 49) (difference -0.5%, 95% Cl: -1.2, 0.3). These results are indicative of a potential disease-modifying effect associated with troriluzole, including the maintaining of hippocampal brain volumes, improving cognition and decreasing neuropsychiatric presentations in the initial phases of Alzheimer’s disease. Considering safety and tolerability, treatment with troriluzole was comparatively well-tolerated and exhibited a substantial safety profile similar to other studies [28,29].

Conclusion

Glutamate-mediated neurotoxicity has been implicated in the pathogenesis of Alzheimer’s disease. The amino acid glutamate is the most abundant excitatory neurotransmitter in the mammalian CNS. The glutamatergic hypothesis assumes that the cognitive decline seen in Alzheimer’s disease patients is attributed to the neuronal death triggered by the excessive stimulation of glutamatergic pathway(s). Furthermore, Αβ plaques and neurofibrillary tangles of tau protein have also been involved in glutamatergic excitotoxicity [30,31]. The effect of riluzole and its prodrugs, particularly troriluzaole, in Alzheimer’s disease has been described. Riluzole and troriluzole have been tested in phase II trials. The disclosures revealed that 6 months of riluzole treatment can slow the decline of FDG PET measures of cerebral glucose metabolism in Alzheimer’s patients compared with placebo [32]. The disclosures also indicated a potentially beneficial disease-modifying effect of troriluzole such as decreasing neuropsychiatric features and enhancing cognition in early stages of Alzheimer’s disease [28,29]. Details of primary end points and secondary outcome measures as well as the corresponding neuroimagings are available in [32]. Importantly, the potential of the claimed strategy and molecules is to be evaluated in advanced trials.

It is worth noting that the prodrug strategy has been leveraged in multiple reports before so as to address the drug development issues in Alzheimer’s disease. These have included ester/amide prodrugs, biooxidizable prodrugs, pleiotropic prodrugs, Mannich base prodrugs, linker-based prodrugs, peptide-based prodrugs and thiol-based prodrugs [33].

Future perspective

Alzheimer’s disease is the most common cause of dementia. Current medications for Alzheimer’s disease help manage the symptoms, but they do not prevent or slow the cognitive decline. Until now, no solution has been established for this problem. Riluzole and its prodrugs provide a novel platform for the development of safe and effective therapeutics to slow the cognitive decline in Alzheimer’s patients by targeting the glutamatergic neurons, the neurons that are most susceptible to the disease pathobiology. Testing other glutamate modulators such as ketamine, glycine, D-cycloserine, N-acetylserine, lamotrigine and topiramate can now be considered. For better outcomes, testing of glutamate modulators can be performed in combination with one or more of the currently approved drugs, in other words, memantine, donepezil, rivastigmine, galantamine or aducanumab.

Executive summary.

• Current medications for Alzheimer’s disease may help to alleviate symptoms and improve certain behavioral problems. Yet, they have not shown to slow the progression of cognitive decline or dementia.

• One possible approach for treating Alzheimer’s disease is to focus on neurons that are sensitive to disease pathobiology such as the glutamatergic neurons.

• The Αβ plaques and neurofibrillary tangles formed of hyperphosphorylated tau, which are the neuropathophysiological hallmarks of the disease, are implicated in glutamatergic dysfunction.

• The glutamate modulator riluzole and its prodrugs have been claimed to prevent and/or slow cognitive decline in Alzheimer’s disease.