Clinical Trial Perspective 5 Clinical Trial Perspective Alzheimer’s disease clinical trials: past failures and future opportunities Clin. Invest. (Lond.) Over a decade has elapsed since the US FDA has approved a medication for Alzheimer’s Roy Yaari*,1,2 & Ann Hake1,2 disease (AD) despite clinical trials of numerous agents over a wide array of mechanisms 1Eli Lilly & Company, Lilly Corporate including neurotransmitter modulation and disease modifying therapy targeting Center, Indianapolis, IN 46285, USA 2Indiana University School of Medicine, amyloid and tau. The failures of clinical trials in AD may be due to inadequate Department of Neurology, Indianapolis, understanding of mechanisms of action and/or poor target engagement; however, IN 46202, USA other factors could include inadequate study design, stage of AD along the continuum *Author for correspondence: studied, inclusion of participants without Alzheimer’s pathology into clinical trials Tel.: +1 317 651 6163 and limited power of endpoint measures. Future studies will need to carefully assess [email protected] these possible shortcomings in design of upcoming trials, especially as the field moves toward studies of disease modifying agents (as opposed to symptomatic treatment) of AD and to patients that are very early in the disease spectrum. Keywords: Alzheimer’s disease • Alzheimer’s disease biomarkers • amyloid • clinical trials • preclinical Alzheimer’s disease • tau US FDA approved medications continue to provide significant, but modest More than three decades ago, the choliner- symptomatic benefit[5–7] . gic hypothesis proposed that degeneration The compound memantine introduced a of cholinergic neurons in the basal fore- second mechanism for symptomatic treat- brain and the associated loss of cholinergic ment of AD into clinical practice. Meman- neurotransmission in the cerebral cortex, tine, an N-methyl-D-aspartate (NMDA) hippocampus and other areas contributed partial antagonist that regulates overstimu- significantly to the deterioration in cogni- lation of excess glutamate in the CNS, has tive function seen in Alzheimer’s disease also shown mild but statistically significant 3 (AD) [1] . In 1993, the first centrally act- improvement of symptoms in patients with ing cholinesterase inhibitor, tacrine, was moderate to severe AD [8]; and in 2003, it approved by the US FDA for treatment of was the last FDA-approved medication for AD based on evidence from three pivotal AD. Approval of new formulations and dos- 2015 studies [2–4] that showed statistically signifi- ing of these medications has subsequently cant, dose-related improvements on tests occurred, but no novel drugs. of cognition, clinician- and caregiver-rated Although these medications provide mod- global evaluations and quality-of-life mea- est benefit for the symptoms of AD in some sures. It was subsequently approved in sev- patients, they do not arrest or reverse the eral European countries. The adverse event underlying neurodegenerative disorder. Fur- profile of hepatotoxicity, nausea, vomiting, ther, not all patients respond to these treat- abdominal pain and diarrhea has limited ments, or their benefits are limited by intol- its use and it is no longer in production in erable side effects. Additional symptomatic the USA. Subsequent cholinesterase inhibi- treatment options are necessary, and thera- tors – donepezil, rivastigmine and galan- peutic interventions for AD that can decel- tamine – have been FDA-approved and erate or even prevent disease progression are part of 10.4155/CLI.14.127 © 2015 Future Science Ltd Clin. Invest. (Lond.) (2015) 5(3), 297–309 ISSN 2041-6792 297 Clinical Trial Perspective Yaari & Hake urgently needed. Numerous symptomatic as well as Glutamate-NMDA receptor modulators disease-modifying agents have been, and continue In addition to memantine, other NMDA receptor antag- to be, actively pursued. Treatments that slow or onists were tested without success including remacemide, stop disease progression remain a significant unmet EVT 101, D-cycloserine and neramexane [18–20] . medical need. Glutamate-AMPA receptor modulators Symptomatic therapy Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propio- Many investigative compounds have focused on nate (AMPA) receptors, which are another subgroup treating the cognitive symptoms of AD by modulat- of glutamate receptors, have also been tested as poten- ing neurotransmission disturbances resulting from tial therapeutic targets for AD. Compounds such as neurodegeneration. Ampalex and LY451395 have not shown success in clinical trials [20]. Acetylcholine The deficit of cholinergic function that follows the loss Serotonin of neurons in the basal forebrain has been extensively A number of serotonin receptors have been postulated studied and helped lead to development of the cur- to be potential therapeutic targets for the cognitive, rently available centrally acting cholinesterase inhibi- behavioral and affective symptoms of AD, but have tors. Other molecules designed to enhance cholinergic not yielded evidence of significant efficacy in clinical function have not been successful. trials thus far. Development of the 5HT1A antagonist Lecozotan was discontinued after Phase II due to Other cholinesterase inhibitors poor tolerability [21] . The 5-HT1A agonist xaliproden, In addition to the four cholinesterase inhibi- thought to be neuroprotective, was found to decrease tors that were approved by the FDA, several others loss of hippocampal volume in two Phase III stud- were investigated but were ultimately unsuccess- ies, but it lacked efficacy on cognitive endpoints [22]. ful due to lack of efficacy, intolerable side effects or The 5HT4 agonist PRX-3140, 5HT4 partial ago- impractical/ineffective dosing. These include velna- nists such as PF04995275 and RQ-9 and 5-HT6 crine [9], sustained-release physostigmine [10], eptas- antagonists including LU-AE58054, PRX-07034, tigmine [11], metrifonate [12] and huperzine A [13] . PF-05212365, SR57746 and SB742457 may be in Although the huperzine A study was negative on development [21,23]. its primary endpoint, a trend toward cognitive improvement was found on the higher dose. Histamine Latrepiridine, an antihistamine that was once used Nicotine receptor agonists in Russia, was thought to stabilize mitochondria and Augmentation of cholinergic function by stimulation therefore possibly have neuroprotective effects. Despite of cholinergic receptors was also attempted, with little robust findings in a Phase II study, it did not meet end- success thus far. Nicotine patches [14] and the partial points in two Phase III studies on primary or second- α7 agonists, ispronicline (AZD3480) [15], GTS-21, ary endpoints. MK-0249, an H3 receptor inverse ago- TC-5619, ABT-126 and MEM 3454 have been studied nist, showed no cognitive benefit in a 4-week, Phase II [16] . Other nicotinic agonists or modulators currently study in mild-to-moderate AD [24]. In a Phase II, under investigation are EVP-6124, MT-4666 and 16-week monotherapy trial in mild-to-moderate AD, MK-7622. GSK239512, an H3 receptor antagonist, did not meet primary cognitive endpoints [25]. Other agents target- Muscarinic agonists ing histamine, including ABT-288 and GSK189254, Development of both full and partial agonists of the have been unsuccessful. M1 muscarinic receptor has been limited due to adverse effects. In 3–6 month Phase II and III studies, study Other neurotransmitters drugs cevimeline (AF102B), milameline, xanomeline, A number of other agents targeting various neurotrans- sabcomeline (SB 202026), talsaclidine and alvameline mitter systems have been tested but, thus far, have been (LU 25–109) generally showed the parasympatho- unsuccessful. These include the GABA-B antagonist mimetic effects of gastrointestinal symptoms, hyper- SGS-742 and the phosphodiesterase-4 inhibitors MEM salivation, sweating and frequent urination, rendering 1414 and MK-0952 [23]. Although FDA-approved and them clinically inadequate [17] . ANAVEX 2–73 targets widely used for treatment of AD in the past, ergoloid sigma-1 and muscarinic receptors and is currently mesylates, a combination of three dehydrogenated ergot being studied. alkaloids that may stimulate dopaminergic and seroto- 298 Clin. Invest. (Lond.) (2015) 5(3) future science group Alzheimer’s disease clinical trials: past failures & future opportunities Clinical Trial Perspective nergic receptors, were unsuccessful in a pivotal trial [26]. between these two pathways, they may not be mutually A meta-analysis of 47 studies showed ergoloid mesylates exclusive of each other. to be very modestly more effective than placebo [27]. The amyloid hypothesis Antidiabetic agents The amyloid hypothesis posits that excess accumula- Insulin has been tested due to alterations in cerebral tion of brain amyloid beta (Aβ), the component of glucose metabolism observed in AD. A pilot study neuritic plaques which is one of the hallmark patho- suggested a cognitive benefit of intranasal insulin logic findings, causes AD. For over two decades, the in both mild cognitive impairment (MCI) due to amyloid hypothesis has been the main target for dis- AD and patients with mild-to-moderate AD [28]. A ease-modifying therapies. This hypothesis is supported larger intranasal insulin study is currently enrolling by: the presence of Aβ in neuritic plaques; the genetics 240 participants with MCI due to AD or mild AD. of dominantly inherited familial AD involving muta- Rosiglitazone lowers blood glucose by improv- tions of amyloid precursor protein