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Intense Focus Yet Many Setbacks for Alzheimer’s Disease Drug Development
Dementia is a syndrome composed of a variety of neurological deficits and impairments that affect memory, problem-solving, and/or language skills, which ultimately impact a patient’s ability to function. Several forms of dementia exist, such as vascular dementia and dementia with Lewy bodies; however, Alzheimer’s disease (AD) is by far the most common, accounting for 50% to 75% of cases.1 The Centers for Disease Control and Prevention reports AD as the sixth leading cause of death and a major cause of institutionalization; 50% of all nursing home residents have AD or other forms of dementia.2,3 With approximately 5.5 million people diagnosed in the U.S., the costs of caring for patients with AD has been estimated at $175 billion, 68% of Medicare and Medicaid’s total costs.4,5
The pathophysiology behind the development of AD is complex and still being researched. One of the leading theories centers on the accumulation of beta-amyloid (Aβ) fibrils that form plaques and lesions within the brain. Destabilization of microtubules resulting in cell death has also been attributed to the creation of neurofibrillary tangles from hyperphosphorylated tau proteins and may represent another disease pathway. Imbalances of neurotransmitters, such as glutamate, acetylcholine, serotonin, and norepinephrine, have also been demonstrated in patients with late stages of AD. Lastly, indirect inflammatory changes from the body’s attempt to clear the Aβ plaques have also been suggested as a potential causative factor.6 All of these different pathways provide a wealth of potential drug targets.
Currently available treatments for AD come from two main classes of medications: acetylcholinesterase inhibitors (AChEI) and N-methyl-D-aspartate (NMDA) receptor antagonists. These medications focus on managing neurotransmitter imbalances and can only stabilize a patient’s mental decline; they have not been shown to reverse symptoms of dementia. The role of these medications has been an area of debate given their associated costs, minimal therapeutic effects, and adverse effects, such as gastro intestinal issues, dizziness, or headache. A summary of these medications can be found in
The pharmaceutical industry has focused intensely on developing new treatments for AD, but it has been met with many setbacks over the past several years. Failures of major clinical trials have been seen with various therapeutic classes. In November 2016, Eli Lilly announced its monoclonal antibody (mAb) candidate solanezumab failed to meet its primary endpoint in the large phase 3 EXPEDITION-3 trial, and the company will not pursue the drug’s approval for treating mild AD.7 Prior to that, Pfizer’s bapineuzumab also failed in two phase 3 trials, which led that company to terminate all other ongoing studies.8 In September 2017, Axovant released negative topline results from its phase 3 trial evaluating intepirdine, a small-molecule therapy, and subsequently abandoned further development of this agent.9 This pattern highlights the complexity of this disease state, the difficulties associated with appropriate patient selection, and the appropriate timing of therapy.10
Despite this precedent, the pipeline of medications aiming to treat AD is robust as each company hopes to be the first to bring an effective therapy to market. Clinical trials are focusing both on treating the progression of AD and managing the symptoms associated with advanced dementia, such as agitation. Medications targeting AD management can be categorized as either small-molecule drugs or as larger, protein-based therapies. The following is a discussion, in no particular order, of several upcoming medications that are in late-phase development for AD.
Roche has two potential biological products coming to market—gantenerumab and crenezumab. Gantenerumab is a fully humanized mAb that works against Aβ fibrils in the brain and facilitates their clearance through cell-mediated responses.11 Clinical findings with gantenerumab have been mixed, and the SCARLET ROAD trial, which evaluated 797 patients with prodromal AD, was discontinued due to futility in its primary endpoint of change in clinical dementia rating (CDR). However, the trial suggested potential benefit in a subgroup analysis for patients who were likely to be fast progressors and received higher doses.12 Another phase 3 trial, MARGURITE ROAD, that was evaluating patients with mild disease has stopped recruiting patients and is continuing to monitor outcomes with no results yet reported. Based on the subgroup findings, additional phase 3 trials (GRADUATE 1 and 2) are being planned to evaluate higher doses of gantenerumab in patients with prodromal to mild AD.
Treatment with gantenerumab was associated with an increase in amyloid-related imaging abnormalities (ARIA), such as encephalopathy (ARIA-E) and hemosiderin deposition (ARIA-H). These abnormalities can be seen with all amyloid-targeting mAbs. ARIA-E is associated with edema, typically developing in the parietal, occipital, or frontal lobes, which can be asymptomatic or result in confusion or altered mental status. ARIA-H is thought to come from deposits of iron in the form of hemosiderin in the brain as a result of a small leakage of blood into adjacent tissue.13 The development of these adverse effects may present problems in future trials that are evaluating higher doses of gantenerumab because the incidence of ARIA-E appeared to be dose-dependent with rates of 0.8%, 6.6%, and 12.3% in the placebo, 105-mg, and 225-mg groups, respectively. ARIA-H occurred with a frequency of 10.9%, 19.2%, and 13.1% in the placebo, 105-mg, and 225-mg groups, respectively.14
Crenezumab is an mAb with affinity for multiple aggregated forms of Aβ as well as monomers and oligomers, and it is hypothesized that crenezumab’s ability to bind multiple forms of Aβ provides a lower risk for patients developing ARIA-E. Results from the phase 2 ABBY and BLAZE trials provided divergent results. ABBY evaluated 431 patients with mild-to-moderate AD who received differing doses of crenezumab every two or four weeks. This trial failed to demonstrate any significant reduction in the Alzheimer’s Disease Assessment Scale–Cognitive 12 (ADAS–cog12) or CDR–Sum of Boxes (CDR–SOB), which was the primary endpoint. An exploratory analysis of patients with only mild disease suggested a possible benefit in ADAS–cog12 decline (35% reduction; P = 0.036) but not in CDR–SOB (19% reduction; P = 0.42).15 The BLAZE trial evaluated changes in biomarkers such as Aβ levels in the brain and cerebrospinal fluid (CSF). This trial also failed to meet its primary endpoint of Aβ levels in the brain, but was able to produce slight but significant increases in CSF concentrations, which are suggestive that crenezumab is interacting with brain plaques.16 Initial safety data suggest crenezumab is well tolerated with no reports of ARIA-E in a dose-escalation study conducted in 52 patients. There were six cases of ARIA-H, but they did not require discontinuation of the medication.11
Based on the data from these phase 2 trials, Roche is moving forward with two phase 3 clinical trials. CREAD1 and CREAD2 are ongoing studies of 60 mg/kg intravenous (IV) crenezumab every four weeks versus placebo to evaluate the efficacy in patients with prodromal to mild AD. The estimated completion date is 2022 for these trials.17 It will be important to see if crenezumab is able to maintain its initial safety profile in these larger clinical trials.
Aducanumab is a recombinant human mAb derived from natural Aβ-specific antibodies. As a treatment, it is reported to bind to oligomers and insoluble fibrils of Aβ but not monomers. The ongoing phase 1b PRIME study was designed to evaluate the pharmacokinetics and pharmacodynamics of multiple doses of aducanumab while also evaluating Aβ plaque formations in the brain. Results from a 36-month follow-up were released in August 2017 that showed that amyloid plaques decreased in a time- and dose-dependent manner almost to the point of nondetection as demonstrated through positron emission topography scans. Results also suggested benefit in the patients’ rate of decline in CDR–SOB and Mini-Mental Status Exam scores. While these data are encouraging, it must be noted that these findings are based on 143 patients, and there were reports of ARIA-E in 46 patients, though this mostly did not result in discontinuation of the drug.18 These reports have generated a lot of excitement from key opinion leaders, but some remain skeptical until further safety and cognitive efficacy data are reported.
Biogen and Neurimmune are conducting two phase 3 trials, ENGAGE and EMERGE, to evaluate the role of monthly infused doses of aducanumab for the treatment of early to mild AD. Each of these trials is anticipated to evaluate 1,350 patients across 150 centers in the U.S., Europe, Australia, and Asia and to reach its primary completion date in 2020.19
Grifols Biologicals is developing a combination product containing 5% IV immune globulin (IVIG) (Flebogamma 5% DIF) and 20% human albumin (Albutein). The rationale behind this approach stems from observational studies showing that IVIG may contain antibodies against Aβ and thus may have a role in disease treatment or prevention. Data have been conflicting. Retrospective analyses have suggested a reduced risk of AD in patients receiving IVIG for other indications, but phase 2 or 3 trials were unable to demonstrate an impact in patients with mild-to-moderate AD.20 Reasons for these discrepancies include the various doses of IVIG studied, the timing of treatment initiation, and the formulations of IVIG used. The AMBAR trial is evaluating the role of long-term plasmapheresis with Flebogamma/Albutein following an initial plasma exchange procedure. The trial has finished enrolling patients, but preliminary results have not been released.21 Concerns about this treatment method include the patient inconvenience of requiring regular plasmapheresis, need for specialized staff and equipment at facilities, and maintaining a sufficient supply of IVIG, a human-derived product.
Another potential target for small molecules is the beta-secretase 1 cleaving enzyme (BACE), a key enzyme in initiating the formation of Aβ plaques in the brain.22 Medications in this class would be used as preventive therapy for preclinical patients or for those with early stages of AD. Verubecestat is a BACE inhibitor that demonstrated the ability to produce a greater than 90% reduction of Aβ in the CSF of healthy volunteers in three phase 1 trials. Following these initial successes, Merck proceeded with two phase 3 trials, EPOCH and APECS, which evaluated patients with mild-to-moderate AD and prodromal AD, respectively. However, in February 2017, Merck terminated the EPOCH study after an interim analysis concluded there was no chance of finding a positive clinical effect.23 The APECS trial was discontinued in February 2018 after an external data monitoring committee concluded that it was unlikely that positive benefit/risk could be established if the trial continued.24
AstraZeneca and Eli Lilly are co-developing lanabecestat, also a BACE inhibitor, for the treatment of AD. Following extensive phase 1 trials, lanabecestat was shown to reduce CSF concentrations of Aβ in a dose-dependent manner. Larger studies, such as the phase 3 DAYBREAK and phase 2/3 AMARANTH trials, are currently under way to evaluate the use of lanabecestat in patients with early AD with anticipated end dates of 2021 and 2019, respectively.25,26 Data from phase 1 studies demonstrated a 76% or greater reduction in CSF Aβ levels following multiple doses of 50 mg daily with no major safety concerns observed in the small sample sizes.27
A third BACE inhibitor, elenbecestat, is being developed by Eisai and Biogen. Similar to the other agents in this class, elenbecestat has demonstrated the ability to substantially reduce concentrations of Aβ in the CSF and was well tolerated with only mild adverse effects of headache and dizziness. Two phase 3 trials are under way, MISSION AD1 and MISSION AD2, that are evaluating 50 mg elenbecestat once daily in more than 1,300 patients with prodromal AD or early mild AD with a projected completion in late 2020.28
Future BACE Inhibitors
Two additional BACE inhibitors are also in development, but on longer timelines than previously mentioned agents.
Janssen and Shionogi are developing JNJ-54861911 for the treatment of asymptomatic patients who are at risk of developing AD. This BACE inhibitor is being evaluated in the phase 2/3 EARLY trial, but because the primary outcome is prevention of disease, the trial will last longer than other ongoing trials and is expected to be complete in 2023.29
Novartis is developing CNP520 for the prevention of AD in patients determined to be high risk based on their age, apolipoprotein E genotype, and presence of elevated amyloid levels. One trial, GENERATION S2, is comparing CNP520 with placebo in these high-risk patients.30 The other trial, GENERATION S1, is being conducted in collaboration with Amgen to evaluate CNP520 and Amgen’s CAD106 immunotherapy to assess the impact of these different therapies on preventing the onset of AD. It is anticipated that CNP520 would not launch until 2025.31
A proposed future role for the BACE inhibitor class is use in combination with immunotherapy treatments; however, large-scale clinical studies would need to be conducted to justify this therapeutic combination.
Azeliragon (vTv Therapeutics) is in development to inhibit the receptor for advanced glycation end products (RAGE) pathway to treat AD. The stimulation of RAGE by Aβ has been observed to drive amyloid plaque formation. A phase 3, placebo-controlled trial, STEADFAST, is evaluating azeliragon 5 mg daily in combination with an AChEI with or without memantine in 800 patients with mild AD and is expected to be completed in 2018.32 A phase 2 trial that compared higher doses of 20 mg azeliragon per day with 5 mg per day and placebo found higher rates of confusion (8.1% versus 4.5%) and falls (10.3% versus 6.1%) as well as greater cognitive decline in the 20-mg group compared with the placebo group.11
The dihydropyridine calcium-channel blocker nilvadipine is under evaluation by Archer Pharmaceuticals. Nilvadipine helps to maintain calcium homeostasis within the brain and promotes clearance of soluble amyloid peptides to prevent their deposition into plaques. A large phase 3 trial evaluating 511 participants across nine European countries was completed in December 2016, but results are still pending publication.33 In a small safety analysis in 86 patients with AD (56 received nilvadipine and 30 received placebo), the development of orthostatic hypotension was seen in 84% of patients in the treatment arm.34 This safety aspect may be of concern given the increased risk of falls present in elderly patients with dementia.
Axovant Sciences’ candidate intepirdine, an antagonist of serotonin receptor 6 (5-HT6), was being evaluated in the treatment of mild-to-moderate AD in the MINDSET study. Results from this trial showed no difference between intepirdine and placebo in the patients’ ADAS–cog or ADAS–Activities of Daily Living scores.9 Axovant will continue to evaluate other doses of intepirdine in the treatment of other diseases, such as dementia with Lewy bodies. The outcome of the MINDSET trial was similar to previous results for other medications in this class. Idalopirdine was a candidate that produced promising phase 2 results but subsequently had negative results in three phase 3 trials. Pfizer discontinued its candidate, PF-05212377, after a phase 2 trial determined futility.35,36 This string of failures suggests that this may not be a viable therapeutic class in AD.
Older medications, such as pioglitazone and the combination of cromolyn plus ibuprofen, are being evaluated for their impact on modifying AD, but expectations are low for these therapies to have a major impact or gain much market share.11
Other clinical trials are evaluating medications to manage symptoms associated with AD. Brexpiprazole (Rexulti, Otsuka America Pharmaceutical, Inc.) and aripiprazole are two currently approved medications being evaluated for the management of agitation in AD and would be expected to enter the market for this indication in 2018 and 2019, respectively. Novel agents for the management of agitation include Avanir/Otsuka’s AVP-786, a modified formulation of the current medication dextromethorphan hydrobromide/ quinidine sulfate (Nuedexta, Avanir) and Intra-Cellular Therapies’ lumateperone tosylate, a 5-HT2A receptor antagonist.11 These therapies may prove beneficial, but they may struggle to gain market share because they would likely enter behind brexpiprazole and aripiprazole.
The pipeline for AD is filled with many potential candidates from varying therapeutic classes. While the prospect of finding a viable treatment is exciting, practitioners will likely be skeptical until robust clinical trial data are available given the recent history of initial promise but ultimate disappointment with several agents.
Current FDA-Approved Medications for Alzheimer’s Disease Treatment
||AChEI||Mild to severe AD||IR: 5-mg, 10-mg, and 23-mg tablets
ODT: 5-mg and 10-mg tablets
|Mild AD: 5–10 mg once daily
Severe AD: 10–23 mg once daily
||AChEI||Mild to moderate AD||IR: 4-mg, 8-mg, and 12-mg tablets
ER: 8-mg, 16-mg, and 24-mg tablets
OS: 4 mg/mL
|IR: 8–12 mg twice daily
ER: 8–24 mg once daily
OS: 8–12 mg twice daily
|IR or ER: $384
||AChEI||IR: mild to moderate AD
TD: severe AD
|IR: 1.5-mg, 3-mg, 4.5-mg, and 6-mg capsules
TD: 9.5-mg and 13.3-mg patches
|IR: 3–6 mg twice daily
TD: 9.5–13.3 mg once daily
||NMDA receptor antagonist||Moderate to severe AD||IR: 5-mg and 10-mg tablets
ER: 7-mg, 14-mg, 21-mg, and 28-mg capsules
OS: 2 mg/mL
|IR and OS: 10 mg twice daily
ER: 28 mg once daily
||Combination AChEI and NMDA receptor antagonist||Moderate to severe AD||ER: 7 mg/10 mg, 14 mg/10 mg, 21 mg/10 mg, and 28 mg/10 mg capsules||28 mg/10 mg once daily||$507||N/A|
*AWP for lowest-price generic drug at the time of writing.
AChEI = acetylcholinesterase inhibitor; AD = Alzheimer’s disease; AWP = average wholesale price; ER = extended release; IR = immediate release; N/A = not available; NMDA = N-methyl-D-aspartate; ODT = orally disintegrating tablet; OS = oral solution; TD = transdermal.
Therapies for Alzheimer’s Disease Currently in Late-Stage Development
||Mechanism of Action||Targeted Indication||Route and Dose||Expected Price Strategy||Anticipated U.S. Launch Date|
||Anti-Aβ mAB||Prodromal to mild AD||Subcutaneous injection, dose TBD||Priced in reference to aducanumab||2021|
||Anti-Aβ mAB||Prodromal to mild AD||IV, 60 mg/kg or 180 mg/kg every four weeks||Priced in reference to gantenerumab||2023|
||Anti-Aβ mAB||Prodromal to mild AD||IV, 3 mg/kg, 6 mg/kg, or 10 mg/kg every four weeks||Anticipated to be priced significantly above current AD therapy; likely to have first-to-market advantage||2020|
||IVIG–albumin combination||Mild to moderate AD||IV, with plasmapheresis, dose TBD||Anticipated costs would be much higher than other therapies given the manufacturing process and procedures needed||2023|
||BACE inhibitor||Prodromal AD||Oral, 12 mg or 40 mg once daily||Expected to be priced higher than current therapies, but similar to other in-class medications||2020|
||BACE inhibitor||Prodromal to moderate AD||Oral, 50 mg once daily||Expected to be priced higher than current therapies, but similar to other in-class medications||2021|
||BACE inhibitor||Prodromal to mild AD||Oral, 20 mg or 50 mg once daily||Expected to be priced higher than current therapies, but similar to other in-class medications||2020|
||RAGE inhibitor||Mild AD||Oral, 5 mg once daily||Expected to be priced at a large premium over currently available small-molecule therapies||2020|
||Dihydropyridine calcium-channel antagonist||Mild to moderate AD||Oral, 8 mg once daily||Expected to be priced above current small-molecule therapies, but lower than immunotherapies||2018|
AD = Alzheimer’s disease; anti-Aβ mAB = anti-amyloid-beta monoclonal antibody; BACE = beta-secretase; IV = intravenously; IVIG = intravenous immune globulin; RAGE = receptor for advanced glycation end products; TBD = to be determined.
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- Centers for Disease Control and Prevention. Long-term care providers and services users in the United States: data from the National Study of Long-Term Care Providers, 2013–2014 February 2016; Available at: www.cdc.gov/nchs/data/series/sr_03/sr03_038.pdf. Accessed December 21, 2017
- Alzheimer’s Association. 2017 Alzheimer’s disease facts and figures. Alzheimers Dement 2017;13:325–373.
- Alzheimer’s Association. Fact sheet: costs of Alzheimer’s to Medicare and Medicaid March 2017; Available at: http://act.alz.org/site/DocServer/2012_Costs_Fact_Sheet_version_2.pdf?docID=7161. Accessed December 23, 2017
- Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med 2010;362;(4):329–344. Erratum in:
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- Eli Lilly and Company. Lilly announces detailed results of solanezumab phase 3 EXPEDITION3 study at the Clinical Trials on Alzheimer’s Disease (CTAD) 2016 meeting December 8, 2016; Available at: https://investor.lilly.com/releasedetail.cfm?ReleaseID=1003490. Accessed January 12, 2018
- Pfizer, Inc. Pfizer announces co-primary clinical endpoints not met in second phase 3 bapineuzumab study in mild-to-moderate Alzheimer’s disease patients who do not carry the Apoe4 genotype August 6, 2012; Available at: http://press.pfizer.com/press-release/pfizer-announces-co-primary-clinical-endpointsnot-met-second-phase-3-bapineuzumabstu. Accessed January 12, 2018
- Axovant Sciences. Axovant announces negative topline results of intepirdine phase 3 MINDSET trial in Alzheimer’s disease September 26, 2017; Available at: http://investors.axovant.com/news-releases/news-release-details/axovantannounces-negative-topline-results-intepirdine-phase-3. Accessed January 12, 2018
- Mehta D, Jackson R, Paul G, et al. Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010–2015. Expert Opin Investig Drugs 2017;26;(6):735–739.
- PharmaPoint: Alzheimer’s Disease–Global Drug Forecast and Market Analysis to 2026 New York, New York: GlobalData. September 2017;
- Ostrowitzki S, Lasser R, Dorflinger E, et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther 2017;9;(1):95
- Sperling RA, Jack CR
Jr Black SE, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement 2011;7;(4):367–385.
- Lasser R, Ostrowitzki S, Scheltens P, et al. Efficacy and safety of gantenerumab in prodromal Alzheimer’s disease: Results from Scarlet Road—a global, multicenter trial. Alzheimers Dement 2015;11;(7):P331– P332.
- Roche. Roche announces phase II clinical results of crenezumab in Alzheimer’s disease July 16, 2014; Available at: www.roche.com/investors/updates/inv-update-2014-07-16.htm. Accessed January 8, 2018
- Clinical Neurology News. Crenezumab posts lackluster imaging, biomarker data November 21, 2018; Available at: www.mdedge.com/clinicalneurologynews/article/88921/alzheimers-cognition/crenezumab-posts-lackluster-imaging/page/0/1. Accessed January 8, 2018
- ClinicalTrials.gov. A study of crenezumab vs. placebo to evaluate the efficacy and safety in participants with prodromal to mild Alzheimer’s disease. NCT03114657 October 25, 2017; Available at: https://clinicaltrials.gov/ct2/show/NCT03114657?term=Crenezumab&rank=2. Accessed January 9, 2018
- Biogen. Biogen reports new data from the phase 1b study of investigational Alzheimer’s disease treatment aducanumab August 28, 2017; Available at: http://media.biogen.com/press-release/neurodegenerative-diseases/biogen-reports-new-data-phase-1b-study-investigational-alzh. Accessed January 8, 2018
- ClinicalTrials.gov. Phase 3 study of aducanumab (BIIB037) in early Alzheimer’s disease (EMERGE). NCT02484547 October 3, 2017; Available at: https://clinicaltrials.gov/ct2/show/NCT02484547?term=Aducanumab&rank=2. Accessed January 8, 2018
- Relkin N. Clinical trials of intravenous immunoglobulin for Alzheimer’s disease. J Clin Immunol 2014;34;(suppl 1):S74–S79.
- ClinicalTrials.gov. A study to evaluate albumin and immunoglobulin in Alzheimer’s disease. NCT01561053 August 2, 2017; Available at: https://clinicaltrials.gov/ct2/show/NCT01561053?term=flebogamma&cond=Alzheimer+Disease&rank=4. Accessed January 8, 2018
- Vassar R. BACE1: the beta-secretase enzyme in Alzheimer’s disease. J Mol Neurosci 2004;23;(1–2):105–114.
- Merck and Co., Inc.. Merck announces EPOCH study of verubecestat for the treatment of people with mild to moderate Alzheimer’s disease to stop for lack of efficacy February 14, 2017; Available at: http://investors.merck.com/news/press-release-details/2017/Merck-Announces-EPOCH-Study-of-Verubecestat-for-the-Treatment-of-People-with-Mild-to-Moderate-Alzheimers-Disease-to-Stop-for-Lack-of-Efficacy. Accessed January 5, 2018
- Merck and Co., Inc.. Merck announces discontinuation of APECS study evaluating verubecestat (MK-8931) for the treatment of people with prodromal Alzheimer’s disease February 13, 2018; Available at: www.mrknewsroom.com/news-release/research-and-development-news/merck-announces-discontinuation-apecs-study-evaluating-ve. Accessed February 14, 2018
- ClinicalTrials.gov. A study of lanabecestat (LY3314814) in participants with mild Alzheimer’s disease dementia (DAYBREAK- ALZ). NCT02783573 January 9, 2018; Available at: https://clinicaltrials.gov/ct2/show/NCT02783573?term=Lanabecestat&rank=7. Accessed January 12, 2018
- ClinicalTrials.gov. An efficacy and safety study of lanabecestat (LY3314814) in early Alzheimer’s disease (AMARANTH). NCT02245737 January 9, 2018; Available at: https://clinicaltrials.gov/ct2/show/NCT02245737?term=Lanabecestat&rank=5. Accessed January 12, 2018
- Cebers G, Alexander RC, Haeberlein SB, et al. AZD3293: pharmacokinetic and pharmacodynamic effects in healthy subjects and patients with Alzheimer’s disease. J Alzheimers Dis 2017;55;(3):1039–1053.
- ClinicalTrials.gov. A 24-month study to evaluate the efficacy and safety of E2609 in subjects with early Alzheimer’s disease (MissionAD1). NCT02956486 December 27, 2017; Available at: https://clinicaltrials.gov/ct2/show/NCT02956486?term=elenbecestat&rank=3. Accessed January 4, 2018
- ClinicalTrials.gov. An efficacy and safety study of JNJ-54861911 in participants who are asymptomatic at risk for developing Alzheimer’s dementia (EARLY). NCT02569398 December 15, 2017; Available at: https://clinicaltrials.gov/ct2/show/NCT02569398?term=JNJ-54861911&rank=3. Accessed January 12, 2018
- ClinicalTrials.gov. A study of CNP520 versus placebo in participants at risk for the onset of clinical symptoms of Alzheimer’s disease (Generation S2). NCT03131453 December 5, 2017; Available at: https://clinicaltrials.gov/ct2/show/NCT03131453?term=CNP520&rank=1. Accessed January 8, 2018
- ClinicalTrials.gov. A study of CAD106 and CNP520 versus placebo in participants at risk for the onset of clinical symptoms of Alzheimer’s disease (Generation S1). NCT02565511 December 5, 2017; Available at: https://clinicaltrials.gov/ct2/show/NCT02565511?term=CNP520&rank=3. Accessed January 8, 2018
- ClinicalTrials.gov. Evaluation of the efficacy and safety of azeliragon (TTP488) in patients with mild Alzheimer’s disease (STEADFAST). NCT02080364 June 1, 2017; Available at: https://clinicaltrials.gov/ct2/show/NCT02080364?term=Azeliragon&rank=2. Accessed January 4, 2018
- ClinicalTrials.gov. A phase III trial of nilvadipine to treat Alzheimer’s disease (NILVAD). NCT02017340 March 6, 2017; Available at: https://clinicaltrials.gov/ct2/show/NCT02017340. Accessed January 4, 2018
- Kennelly SP, Abdullah L, Paris D, et al. Demonstration of safety in Alzheimer’s patients for intervention with an anti-hypertensive drug nilvadipine: results from a 6-week open label study. Int J Geriatr Psychiatry 2011;26;(10):1038–1045.
- H. Lundbeck A/S. Lundbeck annual report 2016 February 8, 2017; Available at: http://files.shareholder.com/downloads/AMDAGGC00/3834947744x0x926925/C05FC4E6-75BB-4467-881D-53786BFBE2DD/LUNDBECK_ANNUAL_REPORT_2016.pdf. Accessed January 4, 2018
- ClinicalTrials.gov. Study evaluating the safety and efficacy of PF-05212377 or placebo in subjects with Alzheimer’s disease with existing neuropsychiatric symptoms on donepezil. NCT01712074 March 20, 2017; Available at: www.clinicaltrials.gov/show/NCT01712074. Accessed January 4, 2018
- Red Book Online Ann Arbor, Michigan: Truven Health Analytics. Accessed February 19, 2018