Overview. Drugs that modulate neurotransmitter (NT) activity are targeted toward symptomatic relief of Alzheimer’s disease and are not considered disease-modifying therapies. Alzheimer’s disease is characterized by the broad loss of neurons — in addition to the loss of cholinergic neurons, Alzheimer’s disease results in the loss of other neurons essential to normal brain function, including monoaminergic neurons. Many companies are targeting a variety of receptors, such as serotonin (5-HT) and alpha-amino-3-hydroxγ-5-methylisoxazole-4-propionic acid (AMPA) receptors, in an attempt to upregulate the activity of the remaining neurons.
Sanofi-Aventis is also developing a variety of drugs for Alzheimer’s disease, including agents that target the 5-HTia and 5-HT4 receptors (SR-57746A [xaliprodene] and SL-65.0155, respectively). In addition to targeting their respective 5-HT receptors, these drugs appear to have neurotrophic-like effects on neurons — that is, in pre-clinical studies, these drugs were shown to maintain synaptic connections and induce neuronal repair in the degenerating cholinergic neurons. (Sanofi-Aventis’s SR-57667B appears to have properties similar to those of xaliprodene and SL-65.0155, although its mechanism of action is unclear.) These drugs have a novel and potentially promising therapeutic objective for the Alzheimer’s disease population. Glaxo-SmithKline and Roche are also developing drugs for Alzheimer’s disease that target serotonin receptors — more specifically, the 5-HT6 receptors — although these drugs are early in their clinical development.
Many other drugs are in the early stages of development, including Lilly’s LY-451395 and Servier’s S-18986, which target the AMPA receptor. Both of these drugs seek to modulate the levels of glutamate, an NT with essential broad roles in the brain, but lack of specificity in targeting AMPA receptors has resulted in problems with toxicity in previous AMPA-targeted drugs, and these drugs are unlikely to reach the market until these specificity problems are resolved.
Cortex Pharmaceuticals appeared to be making progress in this area of AMPA target specificity with its AMPAkine compound CX-717; however, in April 2006, the FDA required the company to halt clinical trials because of the agency’s concerns relating to preclinical studies. At this writing, the drug’s future is unclear. This section also discusses the results of trials with Cortex’s CX-516, for which trials have been discontinued.
Mechanism of Action. Loss of neuronal function can result in cognitive and behavioral changes in Alzheimer’s disease patients. An important role for monoamines (dopamine, norepinephrine, and serotonin) is to activate the cerebral cortex, which is associated with a variety of behaviors, including attention behavior and the ability to focus on tasks. A decline in the levels of these NTs is associated with a variety of issues, including loss of memory, depression, psychoses, and sleep disturbances. For Alzheimer’s disease patients, NT modulators have the potential to slow the cognitive and functional decline associated with the disease.
CX-717. In development by Cortex Pharmaceuticals and Servier Laboratories, the AMPAkines group of compounds has modulatory effects on the AMPA receptor. Lack of specificity in targeting AMPA receptors has resulted in problems with toxicity in previous AMPA targeted drugs, but the AMPAkines appear to have resolved some of these issues. CX-516 trials for mild cognitive impairment (MCI) have been discontinued in the United States, France, and the United Kingdom, following disappointing Phase II results in February 2004. The newer generation CX-717 is in Phase I trials for Alzheimer’s disease and MCI in the United States. In January 2005 the company received FDA approval to initiate Phase II studies for CX-717.
Glutamate binding to the AMPA receptor plays a key role in learning and memory. Specifically, glutamate binding results in the activation of the receptor, the opening of the receptor channel, and a flow of sodium ions (Na + ) across a concentration gradient, leading to membrane excitation and transmission of an action potential. A large concentration of glutamate receptors (GluR1) is found in the hippocampal region of the brain, an area significantly affected by Alzheimer’s disease pathology and vital for normal cognitive function. It is thought that strengthening excitatory synapses may compensate for the loss of synapses associated with Alzheimer’s disease neurodegeneration. CX-717 amplifies the activity of glutamate by modulating the kinetics of the AMPA channel and keeping the AMPA receptor from returning to its inactive state as rapidly as it does normally. CX-717 has an increased affinity for the nondesensitized state of the receptor, keeping the channel open longer and thus facilitating cognitive enhancement.
Because of the substantial financial commitment needed to develop and market AMPAkine drugs, Cortex has licensed the compounds for development in a variety of indications. NV Organon outlicensed the rights to the AMPAkine technology for schizophrenia and depression. Servier has obtained the development and commercialization rights to AMPAkines for the treatment of memory impairment associated with aging and neurodegenerative diseases in Europe, Asia, the Middle East, and certain South American countries. Indications in this agreement include, but are not limited to, Alzheimer’s disease, MCI, sexual dysfunction, anxiety disorders, and the dementia associated with Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis.
Originally, Servier and Cortex focused their development on the compound CX-516. The drug entered trials for Alzheimer’s disease, MCI, ADHD, schizophrenia, Fragile X syndrome, and sleep disorders. However, CX-516 failed to demonstrate significant treatment effect in MCI (Cortex Pharmaceuticals Inc., 2004). Cortex states that the drug’s failure in this trial was due largely to the one-hour half-life of the compound. Combined with the drug’s low potency, the short half-life of the drug would require patients to take several pills, three to four times per day. As a result, Cortex is now focusing on development of the second-generation AMPAkine compound CX-717, which the company states is more potent and has a longer half-life (approximately 9 hours) than CX-516. Neither Cortex nor Servier intends to perform further research or development with CX-516. Indeed, Servier is continuing its clinical development of AMPAkines by focusing on the agent S-18986-1, which the company states has a longer half-life and greater potency than CX-516.
Several Phase I trials of CX-717 were completed in 2004. Sleep deprivation will be the first indication to be tested in Phase II trials. As a precaution, CX-727 is being evaluated as a back-up candidate for CX-717, and toxicology testing of CX-727 is currently ongoing. Ultimately, Cortex plans to use data from these pilot Phase II trials to entice large pharmaceutical companies to outlicense CX-717 or CX-727.
The only clinical data available supporting AMPAkines’ efficacy for the treatment of Alzheimer’s disease is from trials with CX-516. A Phase I study presented at the Anti-Aging Therapies Conference in London in 2002 showed that CX-516 was well tolerated and was observed to enhance memory and learning of healthy young and elderly adults (). Participants received a single administration of CX-516 or placebo and were subsequently evaluated for their ability to recall nonsense words, a task that was quite difficult for the elderly people. A small improvement was observed in the young adults, and a dose-related increase in recall was noted in the elderly participants. At the highest doses tested, the recall of nonsense words in the elderly group was two and a half times better than baseline, raising it to almost the same level as the young group. In other Phase I trials, patients who received the drug three times daily (600-2, 700 mg) for four weeks experienced no significant side effects at low doses, but at higher doses CX-516 caused hypertension, a potential problem for aged patients ().
Xaliprodene (SR-57746A). Xaliprodene (SR-57746A) is a 5-HTiA receptor agonist in Phase III development in Europe by Sanofi-Aventis for the treatment of Alzheimer’s disease. The drug was originally developed as an anxiolytic and was most recently in development for amyotrophic lateral sclerosis (ALS), but the NDA filing in Europe was withdrawn in 2002 when the clinical trial results were not considered robust enough to meet regulatory requirements for approval.
Although preclinical studies have shown that xaliprodene has high affinity for the 5-HTia receptor, it is the drug’s secondary, neurotrophic mechanism of action that contributes to its potential as a disease-modifying agent for Alzheimer’s disease. Xaliprodene has been shown in vitro and in animal studies to have properties similar to those of nerve growth factor (nerve growth factor) and brain-derived nerve growth factor (BDNF), two neurotrophic factors; neurotrophic factors are vital ingredients to maintaining neuronal health and survival. nerve growth factor has been shown to increase the survival of cholinergic neurons, and in vitro studies have shown that cholinergic neurons will produce more acetylcholine in the presence of nerve growth factor. However, nerve growth factor does not cross the blood-brain barrier (BBB), making delivery of the neurotrophin to affected brain regions a significant problem. Therefore, a drug that acts like nerve growth factor or other growth factors and can cross the BBB would be very valuable in treating neurodegenerative diseases such as Alzheimer’s disease.
In in vitro studies, xaliprodene appears to function as a neuroprotectant, decreasing neuron death. The drug appears specific to cholinergic neurons: in preclinical studies xaliprodene appears to reduce cholinergic neuron death in an animal model of cholinergic neuron lesion. In vitro studies in cholinergic neurons have shown that xaliprodene increases neurogenesis (the generation of new neurons), which may enhance cognitive function in patients. Based on these mechanisms of action, Sanofi-Aventis hypothesizes that treatment with xaliprodene in Alzheimer’s disease patients could prevent the neurodegeneration of forebrain cholinergic neurons, preserve cholinergic pathways, and prevent memory deficits associated with the disease.
Two Phase III placebo-controlled, double-blind trials for Alzheimer’s disease involving 2, 400 patients began in September 2003. The patients were randomized to receive placebo or 0.5mg/day of xaliprodene orally for 18 months. Primary end points for the trials include tests for cognitive function and global functioning. In a subset of trial participants, investigators will also use MRI to measure any change in hippocampal volume. Secondary end points of the trials include changes in behavior symptoms, functional decline, and change in whole brain volume as measured by MRI.
Whether xaliprodene can cross the BBB in sufficient concentrations to be effective at drug target sites remains to be determined. Should this hurdle be overcome, a further challenge remains: the drug’s primary targets are the cholin-ergic neurons in the forebrain, yet xaliprodene binds to 5-HTia receptors, which are dispersed throughout the brain. Given the potential for this drug to cause the production of nerve growth factor in a wide variety of brain regions outside the forebrain, xaliprodene has the potential to produce undesirable side effects similar to those seen with nerve growth factor therapy. These effects include nonspecific neurite sprouting of nociceptive neurons (which led to severe back pain in nerve growth factor-treated patients) and depression of appetite centers (which resulted in significant weight loss in nerve growth factor-treated patients). Weight loss is a particularly troubling side effect in a drug targeted toward aged Alzheimer’s disease patients prone to frailty and poor eating habits. There is currently not enough data to provide evidence that xaliprodene can selectively target the cholinergic neurons of Alzheimer’s disease patients, so the potential for significant side effects is high. Furthermore, the drug would not curtail the accumulation of Aβ plaques or neurofibrillary tangles — hallmarks of the underlying disease process. Therefore, as a symptomatic drug, xaliprodene would likely be used as part of an add-on regimen should it come to market.
SR-57667B. SR-57667B is a compound similar to xaliprodene that is in development by Sanofi-Aventis; the drug is in Phase lib studies in France for the treatment of Alzheimer’s disease.
Although its mechanism of action is unclear, SR-57667B stimulates the expression of the mRNA for the endogenous neurotrophic factors nerve growth factor, brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) in cortical and hippocampal astrocytes in vitro. SR-57667B may thus function as a neutrophic and neuroprotective agent; indeed, the drug enhanced the survival of cholinergic neurons in culture and maintained afferent cholinergic synaptic connections in the hippocampus in vivo, after the lesion of the cholinergic septohippocampal pathway. Thus, by preventing the degeneration of forebrain cholinergic neurons, SR-57667B may delay or prevent the memory impairment seen in Alzheimer’s disease patients.
A double-blind, placebo-controlled Phase lib study (ALTIMMA) is under way in 500 patients with mild to moderate Alzheimer’s disease (MMSE scores between 12 and 26, inclusive) to evaluate the safety and efficacy of SR-57667B as an oral monotherapy (4 mg/day) or administered in combination with an AChEI. The frequency of administration has not been disclosed by Sanofi-Aventis. Primary efficacy measures include assessment of cognitive function and global decline at 52 weeks, likely using standardized neuropsychological tests commonly used in Alzheimer’s disease trials, such as the MMSE, ADAS-cog, CGIC, CIBIC, and NPI tests. Secondary outcomes include measures of functional decline and behavioral symptoms at 52 weeks.
SL-65.0155. SL-65.0155, a 5-HT4 receptor partial agonist/antagonist, is in development by Sanofi-Aventis. The drug is currently in Phase II trials in Europe; no development has been reported in the United States or Japan.
5-Hydroxytryptamine (serotonin [5-HT]) receptors have been shown to have a role in enhancing cognitive processes such as learning and memory () by potentiating the release of acetylcholine in the cortex and hippocampus (). 5-HT4 receptors are found in the CNS, the heart, and in the gastrointestinal (GI) tract. In the CNS, 5-HT4 receptor binding sites have been found in the neocortex and the hippocampus (). Up to eight variants of the 5-HT4 receptor have been identified in humans — none are brain specific, precluding the possibility of designing a 5-HT4 receptor agonist specific to the CNS (). Instead, the different types of 5-HT4 receptors in the nervous system and at the periphery raise the possibility that side effects may plague a drug targeting the 5-HT4 receptor.
In preclinical studies, SL-65.0155 has been shown to have a dual mechanism of action: the drug behaves as a partial 5-HT4 receptor agonist in the CNS and as a competitive 5-HT4 receptor antagonist in the periphery. Indeed, doses 1, 000-fold higher than those required for cognitive effects were administered to rats without eliciting peripheral side effects (cardiovascular or gastrointestinal). As a partial agonist to 5-HT4 receptors in the CNS, the drug targets the neocortex and hippocampus, regions of the brain associated with neurodegeneration during Alzheimer’s disease. In animal studies, activation of these receptors has stimulated acetylcholine release in the frontal cortex, a property that could potentially address the cholinergic deficit seen in Alzheimer’s disease patients. As a competitive antagonist in the periphery, the drug theoretically inhibits the activity of the 5-HT4 receptors and thereby avoids the side effects associated with binding and activation of 5-HT4 receptors outside of the CNS (such as increased heart rate and GI motility).
In addition, SL-65.0155 has been shown in preclinical studies to increase the expression of nerve growth factor (nerve growth factor), a neurotrophic factor necessary for the maintenance of neuronal health and survival. In vivo studies have shown that the drug improves neuronal repair after lesions of the cholinergic septohippocampal pathway, suggesting that treatment with SL-65.0155 in Alzheimer’s disease patients could prevent the neurodegeneration of forebrain cholinergic neurons, preserve cholinergic pathways, and prevent memory deficits associated with the disease. Finally, 5-HT4 receptors stimulate the secretion of nonamyloidogenic-soluble forms of amyloid precursor protein (sAPPa) in neuroblastoma cell cultures; the sAPPa form has been shown to have neuroprotective properties (Mattson MP, 1993; Robert SJ, 2001). Thus, the drug could shift amyloid precursor protein processing away from the insoluble Aβ-42 form to the nonamyloidogenic, soluble, and neuroprotective Aβ-40 form.
Phase I clinical data are not available, but preclinical studies have identified no side effects associated with the drug’s pharmacological profile as a partial agonist in the CNS and as a competitive antagonist in the periphery. SL-65.0155 appeared to improve memory in aged rats in the linear maze test and in memorγ-deficient mice as assessed by the Morris water maze ().
Based on information from the company Web site, a double-blind, placebo-controlled Phase lib study is currently ongoing to measure the efficacy of SL-65.0155 in patients with mild to moderate Alzheimer’s disease. Patients (n = 400) will be randomized to either placebo or 0.5, 2.0, or 8.0mg/day of SL-65.0155. The primary end points for the 12-week trial are the patients’ cognitive function and global decline, likely measured as compared with baseline scores. Secondary outcome measures for the study include functional decline and behavioral symptoms.
Should SL-65.0155 prove efficacious in clinical trials, its dual mechanisms of action suggest that the drug would act to both slow disease progression and modify the disease itself. In addition to side effects associated with binding to other serotonin receptors (such as sexual dysfunction and weight gain, which are less problematic in this patient population), this drug may potentially cause side effects from its binding to 5-HT4 receptors in the periphery, despite the drug acting as a 5-HT4 receptor antagonist in the periphery in animal models. Preclinical studies in animals suggest the drug does not cause peripheral side effects. However, until clinical trials provide compelling evidence in humans for the dosing responses, BBB permeability, and the use of the drug long term, it is possible that SL-65.0155 may be contraindicated in its target Alzheimer’s disease population because of its effects on the heart (potentially increasing heart rate — mediated either by peripheral 5-HT4 receptors or α1-adrenoceptors). The upregulation of nerve growth factor that has been noted in vitro and in vivo has yet to be demonstrated in clinical studies, and the potential side effects associated with nonspecific increases in neurotrophic factors can be severe (previous studies have shown that patients administered nerve growth factor into the ventricles of the brain suffered from neuronal sprouting, causing nonspecific pain and appetite suppression; both of these side effects would be significant in the Alzheimer’s disease population) ().
Finally, a reduction in 5-HT4 receptors has been reported in Alzheimer’s disease patients, with approximate reductions of 23% in the cortex and 66% in the hippocampus (). It is unclear, therefore, whether the drug will have a significant therapeutic effect when its target is reduced in Alzheimer’s disease patients.