5HT6 Antagonists in the Treatment of Alzheimer’s Dementia: Current Progress

5HT6 Antagonists in the Treatment of Alzheimer’s Dementia: Current Progress Neurol Ther (2018) 7:51–58 https://doi.org/10.1007/s40120-018-0095-y REVIEW 5HT6 Antagonists in the Treatment of Alzheimer’s Dementia: Current Progress . . Megan Andrews Babak Tousi Marwan N. Sabbagh Received: February 15, 2018 / Published online: May 2, 2018 The Author(s) 2018 show a statistically significant improvement in ABSTRACT cognitive function. This article will provide a comprehensive review of 5HT6 antagonists in Alzheimer’s disease is an important condition drug development, including some that have with a considerable and unmet disease burden been recently discontinued. We will discuss in large need of continued research and more both the successes and failures of this drug class treatment options. The 5HT6 antagonists are a and provide rationale for their continued new class of medications to be offered. Because research and development. they are pro-cholinergic, these medications are to be used as adjuncts to acetylcholinesterase inhibitors (such as donepezil), further increas- Keywords: 5HT6 Antagonist; Alzheimer’s ing acetylcholine in the central nervous system disease; Cognition; Learning; Memory; Mood (CNS). Early trials of the 5HT6 antagonists disorders showed improvements in cognition and activi- ties of daily living when used as adjuncts to current therapies for Alzheimer’s dementia. INTRODUCTION However, recent phase III trials have failed to Enhanced content To view enhanced content for this Alzheimer’s disease is a progressive neurode- article go to https://doi.org/10.6084/m9.figshare. generative disorder affecting over 40 million people worldwide [1]. It is the most common form of dementia, and there is currently no M. Andrews cure. With the number of elderly increasing Creighton University School of Medicine, Phoenix, each year, Alzheimer’s dementia is a well- AZ, USA known and important disease in desperate need B. Tousi of new treatment options. Cleveland Clinic, Lou Ruvo Center for Brain Health, The current treatment approach has been Cleveland, OH, USA used for over a decade [2], offering a temporary M. N. Sabbagh (months) and modest improvement in cogni- Department of Neurology, Barrow Neurological tion. These medications include acetyl- Institute, Phoenix, AZ, USA cholinesterase inhibitors (donepezil, M. N. Sabbagh (&) rivastigmine, galantamine) and NMDA receptor Cleveland Clinic, Lou Ruvo Center for Brain Health, antagonists (memantine) [3]. Acetyl- Las Vegas, NV, USA cholinesterase inhibitors are meant to increase e-mail: Sabbagm@ccf.org 52 Neurol Ther (2018) 7:51–58 the amount of acetylcholine in the brain by symptomatic treatments such as neurochemical preventing degradation of the neurotransmit- enhancers, and Dimebon, have been evaluated ter, thus improving cognitive function [4]. but have not shown any demonstrable efficacy Memantine blocks the NMDA receptor on glu- for Alzheimer’s disease. Here we discuss the tamate neurons in conditions of excess gluta- class of 5HT6 antagonists. We highlight their matergic stimulation, Alzheimer’s disease being successes and failures and provide rationale for a condition of excessive glutamate stimulation their continued research and development. leading to neurotransmitter dysfunction [3]. This article is based on previously conducted Memantine therefore stabilizes glutamate neu- studies and does not contain any studies with rons [5]. human participants or animals performed by The cholinergic hypothesis of Alzheimer’s dis- any of the authors. ease postulates that destruction of cholinergic neurons in the CNS leads to decreased acetyl- Medications choline and declining cognitive function. By pro- tecting cholinergic neurons and increasing the The following sections discuss each 5HT6 amount of circulating acetylcholine in the CNS, antagonist and its current state in drug cognition improves, albeit temporarily. The development. cholinergic hypothesis does not account for the accumulation of beta-amyloid plaques or neu- Phase I rofibrillary tangles [4]. It also accounts for only one neurotransmitter, acetylcholine, which provides PRX-07034 too narrow an approach for such a complex CNS PRX-07034 is a selective 5HT6 receptor antago- disease. nist. Phase I trials showed PRX-07034 to be highly New research in Alzheimer’s dementia has selective for 5HT6 receptors over other 5HT focused on the 5HT6 receptor, a serotonin receptors and non-serotonin receptors. It has receptor found primarily in the CNS and local- similar brain penetration to other 5HT6 antago- ized in areas important in learning and memory. nists. In rats, PRX-07034 at 1 and 3 mg/kg was Selective serotonin re-uptake inhibitors have found to enhance delayed alternation, a mea- been the main pharmacological treatment for surement of improved short-term memory. At the depression and anxiety for the past two decades, same doses, it also enhanced switch strategy, a but target a different serotonin receptor subtype. measurement of improved cognitive flexibility 5HT6 antagonists are meant to serve as symp- [7]. There were no adverse effects. No phase II tomatic treatment for Alzheimer’s disease. These trials have been reported yet [6]. Notable side drugs block the 5HT6 receptor, which leads to a effects include decreased food intake and body decrease in striatal GABA interneurons. This weight, making it a drug candidate for use in decrease in inhibitory GABA allows for increases obesity as well as Alzheimer’s dementia [8]. in the release of acetylcholine and glutamate [6]. These drugs are likely to be taken in combi- nation with acetylcholinesterase inhibitors to AVN-322 further increase the amount of acetylcholine AVN-322 is a selective 5HT6 receptor antagonist centrally. Because the 5HT6 receptors are loca- manufactured by Avineuro Pharmaceuticals for use in cases of Alzheimer’s disease and ted in the CNS, peripheral side effects are min- imal [5]. As they are serotonin receptor schizophrenia. It is a sister drug to AVN-101 and AVN-211, two 5HT6 antagonists under devel- antagonists, 5HT6 antagonists may have the added benefit of a positive effect on depression opment for Alzheimer’s disease. Phase I trials showed AVN-322 to be well tolerated with no and anxiety, mood disorders often associated with the progression of Alzheimer’s disease [6]. adverse effects. It showed high selectivity for Several classes of disease-modifying drugs, the 5HT6 receptor and reversed the negative including monoclonal antibodies, gamma-sec- cognitive effects of scopolamine and MK-80 [9]. retase inhibitors, tau-aggregation inhibitors, No phase II trials have been reported yet. Neurol Ther (2018) 7:51–58 53 Phase II in animals undergoing elevated plus-maze, ele- vated platform, and open field tests [11]. This makes AVN-211 a good drug candidate for AVN-101 future research into mood disorders. AVN-101 is considered a multitarget serotonin antagonist. It blocks the 5HT7 serotonin recep- tor and, to a lesser extent, the 5HT6, 5HT2A, SAM-760 (synonyms: PF-05212377, WYE- 5HT2C, H1, and adrenergic receptors. AVN-101 103760) is unique to the 5HT6 antagonist drug class in SAM-760 is a selective 5HT6 antagonist. It was that it exhibits dual 5HT6 and 5HT7 antago- developed as a follow-up drug to cerlapirdine nism. These receptors share the same signal after cerlapirdine failed to show clinical efficacy transduction pathway and both are present in at any dose in phase II trials [6]. SAM-760 brain regions important to learning, memory, completed phase I trials with no adverse effects and anxiety. Phase I trials showed no adverse at doses of up to 50 mg daily. Pfizer terminated effects for doses of up to 20 mg/day. The drug a phase II trial after SAM-760 30 mg/day failed will start phase II trials for Alzheimer’s disease to produce an improvement in cognition in and anxiety [10]. patients already taking a stable dose of done- AVN-101 was developed as a multimodal pezil. This was an 18-week, randomized, double- drug in light of evidence that many serotonin blind, placebo-controlled, parallel assignment antagonists targeting a single receptor have study [12]. Development of SAM-760 has since failed to show clinical efficacy. AVN-101 is been discontinued. being researched primarily as a treatment for Alzheimer’s dementia, but has shown signifi- Phase III cant anxiolytic properties in mice undergoing elevated plus-maze, elevated platform, and Idalopirdine (synonyms: Lu AE58054, SGS518, open field platform experiments [10]. The pro- LY483518) gression of Alzheimer’s disease is associated Idalopirdine is a 5HT6 receptor antagonist with the development of anxiety, depression, originally developed for use in schizophrenia. and sleep disorders, so AVN-101 may offer the After showing a positive effect on cognition, the additional benefit of symptomatic relief from drug was entered into clinical trials for use in these associated mood disorders. This also Alzheimer’s dementia. By blocking the 5HT6 makes it a good drug candidate for further receptor, idalopirdine acts to increase the research into mood disorders [10]. amount of acetylcholine in the CNS. It further increases the amount of acetylcholine by AVN-211 (synonym: CD-008-0173) inhibiting CYP206, an enzyme involved in the AVN-211 is a selective 5HT6 antagonist origi- metabolism of donepezil, thereby increasing its nally developed for use in schizophrenia. Phase bioavailability [13]. I trials showed AVN-211 to be well tolerated, Idalopirdine completed phase I trials with no with a notable side effect of decreased body adverse effects and showed promising results in weight at 20 mg/kg [11]. Avineuro Pharmaceu- a randomized, double-blind, placebo-controlled ticals has discussed plans to begin clinical trials phase II study. In this 6-month trial, idalo- for its use in Alzheimer’s disease after phase II pirdine 90 mg daily was taken with donepezil trials for schizophrenia showed positive effects 10 mg daily. This regime showed a significant on cognition. Pre-clinical trial data show AVN- improvement in cognitive function as measured 211 to have pro-cognitive effects superior to by ADAS-cog, thereby meeting the phase II those of PRX-07034 and intepirdine in the passive avoidance test and the Morris water More information can be found in the entry ‘‘RIP: maze test. Its effects were comparable to those serotonin receptor 5-HT6 antagonist’’ on the ALZ- of donepezil and memantine [11]. AVN-211 has FORUM website: 2018. https://www.alzforum.org/ also been shown to have anxiolytic properties news/research-news/rip-serotonin-receptor-5-ht6- antagonist. Accessed 10 Feb 2018. 54 Neurol Ther (2018) 7:51–58 Table 1 Phase III Idalopirdine studies Trial Formulation Adjunct Result STARSHINE Idalopirdine 30 mg Donepezil Fail Idalopirdine 60 mg Donepezil Fail STARBEAM Idalopirdine 10 mg Donepezil Fail Idalopirdine 30 mg Donepezil Fail STARBRIGHT Idalopirdine 30 mg Acetylcholinesterase inhibitor Fail Idalopirdine 60 mg Acetylcholinesterase inhibitor Fail trial’s primary endpoint. Secondary endpoints, inhibitor (donepezil, rivastigmine, or galan- including ADLs and global cognitive status, tamine). As reported by Atri et al., STARSHINE, showed improvement, although these were not STARBEAM, and STARBRIGHT all failed to 2,3 statistically significant. improve cognition as measured by ADAS-Cog, Based on the phase II results, a phase III ADCS-ADL, and ADCS-CGIC [16]. program was started in 2013 which included three randomized, double-blind, placebo-con- Intepirdine (synonyms: SB-742457, RVT-101, trolled, parallel-group, 24-week trials. These GSK-742457) studies include STARSHINE, STARBEAM, and Intepirdine is a selective 5HT6 receptor antag- STARBRIGHT, all of which measured the effect onist that is being evaluated for use in Alzhei- of adding idalopirdine to an acetyl- mer’s dementia and Lewy body dementia. cholinesterase inhibitor [14] (Table 1). Phase III Intepirdine completed phase I trials with no trials showed weak efficacy as compared to adverse effects. Intepirdine was studied in three phase II trials, which may be explained by phase II studies as monotherapy and one phase underdosing. Phase II trials evaluated the use of II study as an adjunct to donepezil in mild to 90 mg daily (30 mg TID) as an adjunct to an moderate Alzheimer’s dementia. Monotherapy acetylcholinesterase inhibitor. Study investiga- studies showed intepirdine to be well tolerated tors decided to lower the dose of idalopirdine in but less likely to be efficacious in Alzheimer’s phase III trials based on receptor occupancy disease, as the results of these studies were analysis conducted by PET scan [15]. inconsistent. One study showed a statistically STARSHINE included one arm of idalopirdine significant change in global function but not 30 mg daily and a second arm with 60 mg daily, cognition [17] and the other two failed to show both as adjuncts to donepezil. STARBEAM any significant improvement [18], [19]. In con- included two arms of idalopirdine added to trast, intepirdine (15 mg or 35 mg) produced donepezil: one arm at 10 mg daily and the sec- improvements in cognition and ADLs for up to ond arm at 30 mg daily. STARBRIGHT also 48 weeks when used as an adjunct to a included two arms, 30 mg and 60 mg, of idalo- stable dose of donepezil. However, it did not pirdine as an adjunct to an acetylcholinesterase meet the overall criteria for success with the primary endpoint of Clinical Dementia Rating More information can be found in the entry for scale Sum of Boxes (CDR-SB), and did not yield idalopirdine on the ALZFORUM website: https://www. a statistically significant improvement [19]. alzforum.org/therapeutics/idalopirdine. Accessed 10 Feb A six-month, randomized, double-blind, Please see the press release from Lundbeck A/S: placebo-controlled phase III study called ‘‘Lundbeck’s Lu AE58054 meets primary endpoint in MINDSET was started in 2015 (Table 2). This large placebo-controlled clinical proof of concept study study evaluated the use of intepirdine 35 mg in people with Alzheimer’s disease’’ http://investor. daily in patients with Alzheimer’s disease lundbeck.com/releasedetail.cfm?ReleaseID=677436. already taking stable doses of donepezil [20]. In Accessed 9 Mar 2018. Neurol Ther (2018) 7:51–58 55 Table 2 Phase III Intepirdine studies Trial Formulation Adjunct Result MINDSET Intepirdine 35 mg Donepezil Fail MINDSET extension Intepirdine 35 mg Acetylcholinesterase inhibitor or memantine Fail Table 3 Phase III Latrepirdine studies Trial Formulation Adjunct Result CONCERT Latrepirdine 5 mg Donepezil Fail Latrepirdine 20 mg Donepezil Fail CONNECTION Latrepirdine 5 mg Fail Latrepirdine 20 mg Fail CONSTELLATION Latrepirdine 20 mg Memantine Fail CONTACT Latrepirdine 20 mg Donepezil Fail September 2017, Axovant announced that the have pro-cognitive effects, attributable to its drug had failed to improve cognition or ADLs. antagonism at the 5HT6 receptor in addition to A 12-month, open-label, extension study of the H1 receptor. Latrepirdine also appears to MINDSET using intepirdine 35 mg daily as an stabilize mitochondria, making it a neuropro- adjunct to either an acetylcholinesterase inhi- tective drug [21]. Based on these properties, bitor or memantine (unspecified) also failed to latrepirdine was entered into clinical trials for improve cognition [20]. use in both Alzheimer’s disease and Hunting- Intepirdine was also studied in a phase II ton’s disease in the 2000s [21]. study in DLB patients (HEADWAY) to compare A small pilot study established latrepirdine a 6-month course of 35 or 70 mg intepirdine to to be well tolerated at doses of up to 20 mg TID. placebo in terms of changes since baseline on A randomized, double-blind, placebo-con- the CIBIC? scale. The study did not meet its trolled phase II trial showed statistically signif- primary endpoint [21]. icant improvement in five outcomes measured in patients taking latrepirdine 20 mg TID com- pared to placebo. These outcomes included Latrepirdine (synonyms: Dimebon, dimebolin, improvements in ADAS-cog, MMSE, ADCS-ADL, PF-01913539) behavior (NPI), and by physician assessment Latrepirdine, more commonly known as Dime- (CIBIC-plus) [22]. bon, is an antihistamine originally developed Latrepirdine was subsequently entered into for allergic rhinitis. The drug was discovered to phase III trials which included CONCERT, More information is available in the entry for CONNECTION, CONSTELLATION, and CON- intepirdine on the ALZFORUM website: https://www. TACT (Table 3). Latrepirdine was taken with alzforum.org/therapeutics/intepirdine. Accessed 10 Feb stable donepezil in both the CONCERT and CONTACT trials. It was taken as monotherapy More information available in the press release ‘‘Axo- in the CONNECTION trial. In contrast, CON- vant announces negative results for intepirdine in phase 2b HEADWAY and pilot phase 2 gait and balance STELLATION evaluated latrepirdine as an studies; positive trends in efficacy seen in pilot phase 2 adjunct to memantine. Phase III trials were nelotanserin study’’ from Axovant: http://investors. axovant.com/news-releases/news-release-details/ axovant-announces-negative-results-intepirdine-phase- More information is available in the press release 2b-headway. ‘‘Pfizer and medivation initiate two phase 3 trials of 56 Neurol Ther (2018) 7:51–58 terminated due to a lack of clinical efficacy. antagonists have also been shown to improve Latrepirdine also failed to produce an improve- mood disorders such as anxiety and depression ment in phase III trials for Huntington’s disease, that are associated with the progression of Alz- and its development for use in these two neu- heimer’s dementia. They would provide the first rodegenerative disorders has since been dis- type of symptomatic treatment available for continued [21]. Alzheimer’s dementia [6]. Although current research has focused on symptomatic treatment of Alzheimer’s disease, SUVN-502 (company: Suven Life Sciences) Cirrito et al. suggest a role for serotonin antag- SUVN-502 is another selective 5HT6 receptor onists as possible disease-modifying agents [26]. antagonist. Phase I trials showed SUVN-502 to be Their research has shown an association well tolerated with no adverse effects [23]. The between the use of SSRIs and decreased amy- drug is currently in recruitment for phase IIa loid-beta plaques in mice. This association clinical trials in patients with moderate Alzhei- appears to translate to human subjects. In ret- mer’s disease who are already on stable doses of rospective studies, Cirrito et al. found decreased donepezil with memantine. This trial will be a levels of amyloid-beta in human subjects of multicenter, 28-week, randomized, double-blind, normal cognition taking a chronic SSRI [26]. placebo-controlled, parallel assignment study. These findings support further research into the The treatment group includes a low-dose SUVN- serotonin neurotransmitter system, especially 502 arm and a high-dose SUVN-502 arm [24]. The its relation to Alzheimer’s dementia. drug combination of SUVN-502, donepezil, and The use of 5HT6 receptor antagonists as memantine will increase the amount of acetyl- adjuncts to acetylcholinesterase inhibitors has choline and glutamate in the CNS [5, 25]. fostered much excitement, as they successfully completed phase I trials and showed cognitive DISCUSSION improvement in phase II studies. Despite their success in the early phases of drug develop- The 5HT6 antagonists target multiple neuro- ment, idalopirdine, intepirdine, and latre- transmitter systems, including acetylcholine, pirdine did not show clinical efficacy in larger glutamate, and serotonin. Blockage of the 5HT6 phase III clinical trials. The development of this receptor leads to increased acetylcholine and drug class seems to have slowed down consid- glutamate, which improves cognition. The use erably, with drugs such as SAM-760, inte- of these drugs as an adjunct to acetyl- pirdine, and latrepirdine being discontinued. cholinesterase inhibitors and memantine sup- Idalopirdine may be soon to follow [14]. ports the cholinergic hypothesis that increased Despite these disappointing results in phase levels of acetylcholine in the CNS promote III trials, it is important to remember that we still learning and memory. do not completely understand the mechanism The role of serotonin in Alzheimer’s disease involved in the 5HT6 receptor or the neuro- is not completely understood [2], although its transmitter pathways involved in Alzheimer’s importance in Alzheimer’s dementia and other dementia. The 5HT6 receptor is complex and cognitive disorders is becoming evident. In probably has multiple pathways of neurotrans- animal studies, overexpression of the 5HT6 mitter communication. For example, both ago- receptor has been shown to lead to cognitive nists and antagonists of the 5HT6 receptor have impairments, and blocking the 5HT6 receptor been shown to have pro-cognitive effects [6]. appears to promote learning [6]. The 5HT6 Further research will need to focus on the differ- ent pathways involved in this receptor system. As is evident from the failure of the phase III Footnote 6 continued dimebon in patients with moderate-to-severe Alzhei- trials of idalopirdine, these medications may mer’s disease’’ from Pfizer: http://press.pfizer.com/press- also be underdosed. In her review of the drug release/pfizer-and-medivation-initiate-two-phase-3- trials of idalopirdine, Hesselink calls attention trials-dimebon-patients-moderate-severe-alz. Accessed 9 to establishing medication dosing in phase II Mar 2018. Neurol Ther (2018) 7:51–58 57 trials and the mistake of changing a dosing NeuroTau. Advisory: Biogen, Lilly, VTV Thera- regime in phase III trials [15]. Although results peutics, Axovant, Grifols. CME: MedLearning from STARSHINE, STARBEAM, and STARB- Group, Miller Meded, Medscape, Rockpointe, RIGHT appear discouraging at first glance, Peerview Press. Research investigator: AC interpretation of this data should be done with Immune, Lilly, Biogen, Merck, VTV Therapeu- care and some skepticism, and conclusions tics, Roche, Avid, Axovant, Janssen, Suven, and about the utility of idalopirdine should not be Medivation (an investigator for dimebon and drawn until it is tested at doses comparable to Intepirdine). Megan Andrews and Babak Tousi those used in phase II trials. Similarly, increased have nothing to disclose. At the time of writing doses of the cholinesterase inhibitors and Marwan Sabbagh was affiliated with the Barrow memantine may be considered. Neurological Institute, Phoenix, AZ, USA. At the time of publication Marwan Sabbagh is affiliated with the Cleveland Clinic, Lou Ruvo Center for CONCLUSIONS Brain Health, Las Vegas, NV, USA. Alzheimer’s dementia is a complex disease Compliance with Ethics Guidelines. This likely involving multiple neurotransmitter sys- article is based on previously conducted studies tems in addition to beta-amyloid plaques, neu- and does not contain any studies with human rofibrillary tangles, and possibly other participants or animals performed by any of the pathological processes. The pathogenic mecha- authors. nism of Alzheimer’s disease is not completely understood. This article reviewed the class of Open Access. This article is distributed 5HT6 antagonists for use in Alzheimer’s under the terms of the Creative Commons dementia. Although phase III trials of idalo- Attribution-NonCommercial 4.0 International pirdine, intepirdine, and latrepirdine failed to License (http://creativecommons.org/licenses/ provide clinical efficacy, phase II trials for sev- by-nc/4.0/), which permits any non- eral 5HT6 antagonists showed improvement in commercial use, distribution, and reproduction cognition and ADLs. Further development of in any medium, provided you give appropriate these drugs may prove beneficial as our under- credit to the original author(s) and the source, standing of Alzheimer’s disease, neurotrans- provide a link to the Creative Commons license, mitter systems, and the 5HT6 receptor improve. and indicate if changes were made. ACKNOWLEDGEMENTS REFERENCES 1. Prince MJ. World Alzheimer Report 2016—im- Funding. No funding or sponsorship was proving healthcare for people living with dementia: coverage, quality and costs now and in the future. received for this study or the publication of this https://www.alz.co.uk/research/world-report-2016. article. Supported by the Barrow Neurological Accessed 9 Mar 2018. Foundation and NIA P30 AG019610. 2. Ramirez MJ. 5-HT6 receptors and Alzheimer’s dis- Authorship. All named authors meet the ease (5-hydroxytryptamine 6) (report). Alzheimers Res Ther. 2013;5:15. International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this 3. Anand R, Gill KD, Mahdi AA. Therapeutics of Alz- article, take responsibility for the integrity of heimer’s disease: past, present and future. Neu- the work as a whole, and have given their ropharmacology. 2014;76:27–50. approval for this version to be published. 4. Thompson S, Lanctot KL, Herrmann N. The benefits and risks associated with cholinesterase inhibitor Disclosures. 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5HT6 Antagonists in the Treatment of Alzheimer’s Dementia: Current Progress

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Neurol Ther (2018) 7:51–58 https://doi.org/10.1007/s40120-018-0095-y REVIEW 5HT6 Antagonists in the Treatment of Alzheimer’s Dementia: Current Progress . . Megan Andrews Babak Tousi Marwan N. Sabbagh Received: February 15, 2018 / Published online: May 2, 2018 The Author(s) 2018 show a statistically significant improvement in ABSTRACT cognitive function. This article will provide a comprehensive review of 5HT6 antagonists in Alzheimer’s disease is an important condition drug development, including some that have with a considerable and unmet disease burden been recently discontinued. We will discuss in large need of continued research and more both the successes and failures of this drug class treatment options. The 5HT6 antagonists are a and provide rationale for their continued new class of medications to be offered. Because research and development. they are pro-cholinergic, these medications are to be used as adjuncts to acetylcholinesterase inhibitors (such as donepezil), further increas- Keywords: 5HT6 Antagonist; Alzheimer’s ing acetylcholine in the central nervous system disease; Cognition; Learning; Memory; Mood (CNS). Early trials of the 5HT6 antagonists disorders showed improvements in cognition and activi- ties of daily living when used as adjuncts to current therapies for Alzheimer’s dementia. INTRODUCTION However, recent phase III trials have failed to Enhanced content To view enhanced content for this Alzheimer’s disease is a progressive neurode- article go to https://doi.org/10.6084/m9.figshare. generative disorder affecting over 40 million people worldwide [1]. It is the most common form of dementia, and there is currently no M. Andrews cure. With the number of elderly increasing Creighton University School of Medicine, Phoenix, each year, Alzheimer’s dementia is a well- AZ, USA known and important disease in desperate need B. Tousi of new treatment options. Cleveland Clinic, Lou Ruvo Center for Brain Health, The current treatment approach has been Cleveland, OH, USA used for over a decade [2], offering a temporary M. N. Sabbagh (months) and modest improvement in cogni- Department of Neurology, Barrow Neurological tion. These medications include acetyl- Institute, Phoenix, AZ, USA cholinesterase inhibitors (donepezil, M. N. Sabbagh (&) rivastigmine, galantamine) and NMDA receptor Cleveland Clinic, Lou Ruvo Center for Brain Health, antagonists (memantine) [3]. Acetyl- Las Vegas, NV, USA cholinesterase inhibitors are meant to increase e-mail: Sabbagm@ccf.org 52 Neurol Ther (2018) 7:51–58 the amount of acetylcholine in the brain by symptomatic treatments such as neurochemical preventing degradation of the neurotransmit- enhancers, and Dimebon, have been evaluated ter, thus improving cognitive function [4]. but have not shown any demonstrable efficacy Memantine blocks the NMDA receptor on glu- for Alzheimer’s disease. Here we discuss the tamate neurons in conditions of excess gluta- class of 5HT6 antagonists. We highlight their matergic stimulation, Alzheimer’s disease being successes and failures and provide rationale for a condition of excessive glutamate stimulation their continued research and development. leading to neurotransmitter dysfunction [3]. This article is based on previously conducted Memantine therefore stabilizes glutamate neu- studies and does not contain any studies with rons [5]. human participants or animals performed by The cholinergic hypothesis of Alzheimer’s dis- any of the authors. ease postulates that destruction of cholinergic neurons in the CNS leads to decreased acetyl- Medications choline and declining cognitive function. By pro- tecting cholinergic neurons and increasing the The following sections discuss each 5HT6 amount of circulating acetylcholine in the CNS, antagonist and its current state in drug cognition improves, albeit temporarily. The development. cholinergic hypothesis does not account for the accumulation of beta-amyloid plaques or neu- Phase I rofibrillary tangles [4]. It also accounts for only one neurotransmitter, acetylcholine, which provides PRX-07034 too narrow an approach for such a complex CNS PRX-07034 is a selective 5HT6 receptor antago- disease. nist. Phase I trials showed PRX-07034 to be highly New research in Alzheimer’s dementia has selective for 5HT6 receptors over other 5HT focused on the 5HT6 receptor, a serotonin receptors and non-serotonin receptors. It has receptor found primarily in the CNS and local- similar brain penetration to other 5HT6 antago- ized in areas important in learning and memory. nists. In rats, PRX-07034 at 1 and 3 mg/kg was Selective serotonin re-uptake inhibitors have found to enhance delayed alternation, a mea- been the main pharmacological treatment for surement of improved short-term memory. At the depression and anxiety for the past two decades, same doses, it also enhanced switch strategy, a but target a different serotonin receptor subtype. measurement of improved cognitive flexibility 5HT6 antagonists are meant to serve as symp- [7]. There were no adverse effects. No phase II tomatic treatment for Alzheimer’s disease. These trials have been reported yet [6]. Notable side drugs block the 5HT6 receptor, which leads to a effects include decreased food intake and body decrease in striatal GABA interneurons. This weight, making it a drug candidate for use in decrease in inhibitory GABA allows for increases obesity as well as Alzheimer’s dementia [8]. in the release of acetylcholine and glutamate [6]. These drugs are likely to be taken in combi- nation with acetylcholinesterase inhibitors to AVN-322 further increase the amount of acetylcholine AVN-322 is a selective 5HT6 receptor antagonist centrally. Because the 5HT6 receptors are loca- manufactured by Avineuro Pharmaceuticals for use in cases of Alzheimer’s disease and ted in the CNS, peripheral side effects are min- imal [5]. As they are serotonin receptor schizophrenia. It is a sister drug to AVN-101 and AVN-211, two 5HT6 antagonists under devel- antagonists, 5HT6 antagonists may have the added benefit of a positive effect on depression opment for Alzheimer’s disease. Phase I trials showed AVN-322 to be well tolerated with no and anxiety, mood disorders often associated with the progression of Alzheimer’s disease [6]. adverse effects. It showed high selectivity for Several classes of disease-modifying drugs, the 5HT6 receptor and reversed the negative including monoclonal antibodies, gamma-sec- cognitive effects of scopolamine and MK-80 [9]. retase inhibitors, tau-aggregation inhibitors, No phase II trials have been reported yet. Neurol Ther (2018) 7:51–58 53 Phase II in animals undergoing elevated plus-maze, ele- vated platform, and open field tests [11]. This makes AVN-211 a good drug candidate for AVN-101 future research into mood disorders. AVN-101 is considered a multitarget serotonin antagonist. It blocks the 5HT7 serotonin recep- tor and, to a lesser extent, the 5HT6, 5HT2A, SAM-760 (synonyms: PF-05212377, WYE- 5HT2C, H1, and adrenergic receptors. AVN-101 103760) is unique to the 5HT6 antagonist drug class in SAM-760 is a selective 5HT6 antagonist. It was that it exhibits dual 5HT6 and 5HT7 antago- developed as a follow-up drug to cerlapirdine nism. These receptors share the same signal after cerlapirdine failed to show clinical efficacy transduction pathway and both are present in at any dose in phase II trials [6]. SAM-760 brain regions important to learning, memory, completed phase I trials with no adverse effects and anxiety. Phase I trials showed no adverse at doses of up to 50 mg daily. Pfizer terminated effects for doses of up to 20 mg/day. The drug a phase II trial after SAM-760 30 mg/day failed will start phase II trials for Alzheimer’s disease to produce an improvement in cognition in and anxiety [10]. patients already taking a stable dose of done- AVN-101 was developed as a multimodal pezil. This was an 18-week, randomized, double- drug in light of evidence that many serotonin blind, placebo-controlled, parallel assignment antagonists targeting a single receptor have study [12]. Development of SAM-760 has since failed to show clinical efficacy. AVN-101 is been discontinued. being researched primarily as a treatment for Alzheimer’s dementia, but has shown signifi- Phase III cant anxiolytic properties in mice undergoing elevated plus-maze, elevated platform, and Idalopirdine (synonyms: Lu AE58054, SGS518, open field platform experiments [10]. The pro- LY483518) gression of Alzheimer’s disease is associated Idalopirdine is a 5HT6 receptor antagonist with the development of anxiety, depression, originally developed for use in schizophrenia. and sleep disorders, so AVN-101 may offer the After showing a positive effect on cognition, the additional benefit of symptomatic relief from drug was entered into clinical trials for use in these associated mood disorders. This also Alzheimer’s dementia. By blocking the 5HT6 makes it a good drug candidate for further receptor, idalopirdine acts to increase the research into mood disorders [10]. amount of acetylcholine in the CNS. It further increases the amount of acetylcholine by AVN-211 (synonym: CD-008-0173) inhibiting CYP206, an enzyme involved in the AVN-211 is a selective 5HT6 antagonist origi- metabolism of donepezil, thereby increasing its nally developed for use in schizophrenia. Phase bioavailability [13]. I trials showed AVN-211 to be well tolerated, Idalopirdine completed phase I trials with no with a notable side effect of decreased body adverse effects and showed promising results in weight at 20 mg/kg [11]. Avineuro Pharmaceu- a randomized, double-blind, placebo-controlled ticals has discussed plans to begin clinical trials phase II study. In this 6-month trial, idalo- for its use in Alzheimer’s disease after phase II pirdine 90 mg daily was taken with donepezil trials for schizophrenia showed positive effects 10 mg daily. This regime showed a significant on cognition. Pre-clinical trial data show AVN- improvement in cognitive function as measured 211 to have pro-cognitive effects superior to by ADAS-cog, thereby meeting the phase II those of PRX-07034 and intepirdine in the passive avoidance test and the Morris water More information can be found in the entry ‘‘RIP: maze test. Its effects were comparable to those serotonin receptor 5-HT6 antagonist’’ on the ALZ- of donepezil and memantine [11]. AVN-211 has FORUM website: 2018. https://www.alzforum.org/ also been shown to have anxiolytic properties news/research-news/rip-serotonin-receptor-5-ht6- antagonist. Accessed 10 Feb 2018. 54 Neurol Ther (2018) 7:51–58 Table 1 Phase III Idalopirdine studies Trial Formulation Adjunct Result STARSHINE Idalopirdine 30 mg Donepezil Fail Idalopirdine 60 mg Donepezil Fail STARBEAM Idalopirdine 10 mg Donepezil Fail Idalopirdine 30 mg Donepezil Fail STARBRIGHT Idalopirdine 30 mg Acetylcholinesterase inhibitor Fail Idalopirdine 60 mg Acetylcholinesterase inhibitor Fail trial’s primary endpoint. Secondary endpoints, inhibitor (donepezil, rivastigmine, or galan- including ADLs and global cognitive status, tamine). As reported by Atri et al., STARSHINE, showed improvement, although these were not STARBEAM, and STARBRIGHT all failed to 2,3 statistically significant. improve cognition as measured by ADAS-Cog, Based on the phase II results, a phase III ADCS-ADL, and ADCS-CGIC [16]. program was started in 2013 which included three randomized, double-blind, placebo-con- Intepirdine (synonyms: SB-742457, RVT-101, trolled, parallel-group, 24-week trials. These GSK-742457) studies include STARSHINE, STARBEAM, and Intepirdine is a selective 5HT6 receptor antag- STARBRIGHT, all of which measured the effect onist that is being evaluated for use in Alzhei- of adding idalopirdine to an acetyl- mer’s dementia and Lewy body dementia. cholinesterase inhibitor [14] (Table 1). Phase III Intepirdine completed phase I trials with no trials showed weak efficacy as compared to adverse effects. Intepirdine was studied in three phase II trials, which may be explained by phase II studies as monotherapy and one phase underdosing. Phase II trials evaluated the use of II study as an adjunct to donepezil in mild to 90 mg daily (30 mg TID) as an adjunct to an moderate Alzheimer’s dementia. Monotherapy acetylcholinesterase inhibitor. Study investiga- studies showed intepirdine to be well tolerated tors decided to lower the dose of idalopirdine in but less likely to be efficacious in Alzheimer’s phase III trials based on receptor occupancy disease, as the results of these studies were analysis conducted by PET scan [15]. inconsistent. One study showed a statistically STARSHINE included one arm of idalopirdine significant change in global function but not 30 mg daily and a second arm with 60 mg daily, cognition [17] and the other two failed to show both as adjuncts to donepezil. STARBEAM any significant improvement [18], [19]. In con- included two arms of idalopirdine added to trast, intepirdine (15 mg or 35 mg) produced donepezil: one arm at 10 mg daily and the sec- improvements in cognition and ADLs for up to ond arm at 30 mg daily. STARBRIGHT also 48 weeks when used as an adjunct to a included two arms, 30 mg and 60 mg, of idalo- stable dose of donepezil. However, it did not pirdine as an adjunct to an acetylcholinesterase meet the overall criteria for success with the primary endpoint of Clinical Dementia Rating More information can be found in the entry for scale Sum of Boxes (CDR-SB), and did not yield idalopirdine on the ALZFORUM website: https://www. a statistically significant improvement [19]. alzforum.org/therapeutics/idalopirdine. Accessed 10 Feb A six-month, randomized, double-blind, Please see the press release from Lundbeck A/S: placebo-controlled phase III study called ‘‘Lundbeck’s Lu AE58054 meets primary endpoint in MINDSET was started in 2015 (Table 2). This large placebo-controlled clinical proof of concept study study evaluated the use of intepirdine 35 mg in people with Alzheimer’s disease’’ http://investor. daily in patients with Alzheimer’s disease lundbeck.com/releasedetail.cfm?ReleaseID=677436. already taking stable doses of donepezil [20]. In Accessed 9 Mar 2018. Neurol Ther (2018) 7:51–58 55 Table 2 Phase III Intepirdine studies Trial Formulation Adjunct Result MINDSET Intepirdine 35 mg Donepezil Fail MINDSET extension Intepirdine 35 mg Acetylcholinesterase inhibitor or memantine Fail Table 3 Phase III Latrepirdine studies Trial Formulation Adjunct Result CONCERT Latrepirdine 5 mg Donepezil Fail Latrepirdine 20 mg Donepezil Fail CONNECTION Latrepirdine 5 mg Fail Latrepirdine 20 mg Fail CONSTELLATION Latrepirdine 20 mg Memantine Fail CONTACT Latrepirdine 20 mg Donepezil Fail September 2017, Axovant announced that the have pro-cognitive effects, attributable to its drug had failed to improve cognition or ADLs. antagonism at the 5HT6 receptor in addition to A 12-month, open-label, extension study of the H1 receptor. Latrepirdine also appears to MINDSET using intepirdine 35 mg daily as an stabilize mitochondria, making it a neuropro- adjunct to either an acetylcholinesterase inhi- tective drug [21]. Based on these properties, bitor or memantine (unspecified) also failed to latrepirdine was entered into clinical trials for improve cognition [20]. use in both Alzheimer’s disease and Hunting- Intepirdine was also studied in a phase II ton’s disease in the 2000s [21]. study in DLB patients (HEADWAY) to compare A small pilot study established latrepirdine a 6-month course of 35 or 70 mg intepirdine to to be well tolerated at doses of up to 20 mg TID. placebo in terms of changes since baseline on A randomized, double-blind, placebo-con- the CIBIC? scale. The study did not meet its trolled phase II trial showed statistically signif- primary endpoint [21]. icant improvement in five outcomes measured in patients taking latrepirdine 20 mg TID com- pared to placebo. These outcomes included Latrepirdine (synonyms: Dimebon, dimebolin, improvements in ADAS-cog, MMSE, ADCS-ADL, PF-01913539) behavior (NPI), and by physician assessment Latrepirdine, more commonly known as Dime- (CIBIC-plus) [22]. bon, is an antihistamine originally developed Latrepirdine was subsequently entered into for allergic rhinitis. The drug was discovered to phase III trials which included CONCERT, More information is available in the entry for CONNECTION, CONSTELLATION, and CON- intepirdine on the ALZFORUM website: https://www. TACT (Table 3). Latrepirdine was taken with alzforum.org/therapeutics/intepirdine. Accessed 10 Feb stable donepezil in both the CONCERT and CONTACT trials. It was taken as monotherapy More information available in the press release ‘‘Axo- in the CONNECTION trial. In contrast, CON- vant announces negative results for intepirdine in phase 2b HEADWAY and pilot phase 2 gait and balance STELLATION evaluated latrepirdine as an studies; positive trends in efficacy seen in pilot phase 2 adjunct to memantine. Phase III trials were nelotanserin study’’ from Axovant: http://investors. axovant.com/news-releases/news-release-details/ axovant-announces-negative-results-intepirdine-phase- More information is available in the press release 2b-headway. ‘‘Pfizer and medivation initiate two phase 3 trials of 56 Neurol Ther (2018) 7:51–58 terminated due to a lack of clinical efficacy. antagonists have also been shown to improve Latrepirdine also failed to produce an improve- mood disorders such as anxiety and depression ment in phase III trials for Huntington’s disease, that are associated with the progression of Alz- and its development for use in these two neu- heimer’s dementia. They would provide the first rodegenerative disorders has since been dis- type of symptomatic treatment available for continued [21]. Alzheimer’s dementia [6]. Although current research has focused on symptomatic treatment of Alzheimer’s disease, SUVN-502 (company: Suven Life Sciences) Cirrito et al. suggest a role for serotonin antag- SUVN-502 is another selective 5HT6 receptor onists as possible disease-modifying agents [26]. antagonist. Phase I trials showed SUVN-502 to be Their research has shown an association well tolerated with no adverse effects [23]. The between the use of SSRIs and decreased amy- drug is currently in recruitment for phase IIa loid-beta plaques in mice. This association clinical trials in patients with moderate Alzhei- appears to translate to human subjects. In ret- mer’s disease who are already on stable doses of rospective studies, Cirrito et al. found decreased donepezil with memantine. This trial will be a levels of amyloid-beta in human subjects of multicenter, 28-week, randomized, double-blind, normal cognition taking a chronic SSRI [26]. placebo-controlled, parallel assignment study. These findings support further research into the The treatment group includes a low-dose SUVN- serotonin neurotransmitter system, especially 502 arm and a high-dose SUVN-502 arm [24]. The its relation to Alzheimer’s dementia. drug combination of SUVN-502, donepezil, and The use of 5HT6 receptor antagonists as memantine will increase the amount of acetyl- adjuncts to acetylcholinesterase inhibitors has choline and glutamate in the CNS [5, 25]. fostered much excitement, as they successfully completed phase I trials and showed cognitive DISCUSSION improvement in phase II studies. Despite their success in the early phases of drug develop- The 5HT6 antagonists target multiple neuro- ment, idalopirdine, intepirdine, and latre- transmitter systems, including acetylcholine, pirdine did not show clinical efficacy in larger glutamate, and serotonin. Blockage of the 5HT6 phase III clinical trials. The development of this receptor leads to increased acetylcholine and drug class seems to have slowed down consid- glutamate, which improves cognition. The use erably, with drugs such as SAM-760, inte- of these drugs as an adjunct to acetyl- pirdine, and latrepirdine being discontinued. cholinesterase inhibitors and memantine sup- Idalopirdine may be soon to follow [14]. ports the cholinergic hypothesis that increased Despite these disappointing results in phase levels of acetylcholine in the CNS promote III trials, it is important to remember that we still learning and memory. do not completely understand the mechanism The role of serotonin in Alzheimer’s disease involved in the 5HT6 receptor or the neuro- is not completely understood [2], although its transmitter pathways involved in Alzheimer’s importance in Alzheimer’s dementia and other dementia. The 5HT6 receptor is complex and cognitive disorders is becoming evident. In probably has multiple pathways of neurotrans- animal studies, overexpression of the 5HT6 mitter communication. For example, both ago- receptor has been shown to lead to cognitive nists and antagonists of the 5HT6 receptor have impairments, and blocking the 5HT6 receptor been shown to have pro-cognitive effects [6]. appears to promote learning [6]. The 5HT6 Further research will need to focus on the differ- ent pathways involved in this receptor system. As is evident from the failure of the phase III Footnote 6 continued dimebon in patients with moderate-to-severe Alzhei- trials of idalopirdine, these medications may mer’s disease’’ from Pfizer: http://press.pfizer.com/press- also be underdosed. In her review of the drug release/pfizer-and-medivation-initiate-two-phase-3- trials of idalopirdine, Hesselink calls attention trials-dimebon-patients-moderate-severe-alz. Accessed 9 to establishing medication dosing in phase II Mar 2018. Neurol Ther (2018) 7:51–58 57 trials and the mistake of changing a dosing NeuroTau. Advisory: Biogen, Lilly, VTV Thera- regime in phase III trials [15]. Although results peutics, Axovant, Grifols. CME: MedLearning from STARSHINE, STARBEAM, and STARB- Group, Miller Meded, Medscape, Rockpointe, RIGHT appear discouraging at first glance, Peerview Press. Research investigator: AC interpretation of this data should be done with Immune, Lilly, Biogen, Merck, VTV Therapeu- care and some skepticism, and conclusions tics, Roche, Avid, Axovant, Janssen, Suven, and about the utility of idalopirdine should not be Medivation (an investigator for dimebon and drawn until it is tested at doses comparable to Intepirdine). Megan Andrews and Babak Tousi those used in phase II trials. Similarly, increased have nothing to disclose. At the time of writing doses of the cholinesterase inhibitors and Marwan Sabbagh was affiliated with the Barrow memantine may be considered. Neurological Institute, Phoenix, AZ, USA. At the time of publication Marwan Sabbagh is affiliated with the Cleveland Clinic, Lou Ruvo Center for CONCLUSIONS Brain Health, Las Vegas, NV, USA. Alzheimer’s dementia is a complex disease Compliance with Ethics Guidelines. This likely involving multiple neurotransmitter sys- article is based on previously conducted studies tems in addition to beta-amyloid plaques, neu- and does not contain any studies with human rofibrillary tangles, and possibly other participants or animals performed by any of the pathological processes. The pathogenic mecha- authors. nism of Alzheimer’s disease is not completely understood. This article reviewed the class of Open Access. This article is distributed 5HT6 antagonists for use in Alzheimer’s under the terms of the Creative Commons dementia. Although phase III trials of idalo- Attribution-NonCommercial 4.0 International pirdine, intepirdine, and latrepirdine failed to License (http://creativecommons.org/licenses/ provide clinical efficacy, phase II trials for sev- by-nc/4.0/), which permits any non- eral 5HT6 antagonists showed improvement in commercial use, distribution, and reproduction cognition and ADLs. Further development of in any medium, provided you give appropriate these drugs may prove beneficial as our under- credit to the original author(s) and the source, standing of Alzheimer’s disease, neurotrans- provide a link to the Creative Commons license, mitter systems, and the 5HT6 receptor improve. and indicate if changes were made. ACKNOWLEDGEMENTS REFERENCES 1. Prince MJ. World Alzheimer Report 2016—im- Funding. 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Neurology and TherapySpringer Journals

Published: May 2, 2018

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