Dementia is a syndrome composed

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1 Intense Focus Yet Many Setbacks for Alzheimer s Disease Drug Development Troy Kish, PharmD, BCPS 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 Dr. Kish is an Associate Professor of Pharmacy Practice at Long Island University, LIU Pharmacy (Arnold and Marie Schwartz College of Pharmacy and Health Sciences), in Brooklyn, New York. (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 Table 1. 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. 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. Gantenerumab 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 cellmediated 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. Treatment with gantenerumab was associated with an increase in amyloidrelated 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 234 P&T April 2018 Vol. 43 No. 4

2 Table 1 Current FDA-Approved Medications for Alzheimer s Disease Treatment 11,37 Drug Manufacturer Aricept (donepezil) Eisai, Inc. Razadyne (galantamine) Janssen Exelon (rivastigmine) Novartis Namenda (memantine) Allergan Namzaric (memantine/donepezil) Allergan Mechanism AChEI AChEI AChEI NMDA receptor antagonist Combination AChEI and NMDA receptor antagonist Approved Use severe AD IR: mild to TD: severe AD Moderate to severe AD Moderate to severe AD Formulations Dosing AWP 37 (30-Day Supply at Maximum Dose) Brand Generic* IR: 5-mg, 10-mg, and 23-mg tablets ODT: 5-mg and 10-mg tablets IR: 4-mg, 8-mg, and 12-mg tablets ER: 8-mg, 16-mg, and 24-mg tablets OS: 4 mg/ml IR: 1.5-mg, 3-mg, 4.5-mg, and 6-mg capsules TD: 9.5-mg and 13.3-mg patches IR: 5-mg and 10-mg tablets ER: 7-mg, 14-mg, 21-mg, and 28-mg capsules OS: 2 mg/ml ER: 7 mg/10 mg, 14 mg/10 mg, 21 mg/10 mg, and 28 mg/10 mg capsules Mild AD: 5 10 mg Severe AD: mg IR: 8 12 mg twice daily ER: 8 24 mg OS: 8 12 mg twice daily IR: 3 6 mg twice daily TD: mg IR and OS: 10 mg twice daily ER: 28 mg 28 mg/10 mg IR: $607 ODT: N/A IR or ER: $384 OS: N/A IR: $413 TD: $777 IR: $534 ER: $509 *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. IR: $312 ODT: $210 IR: $127 ER: $183 OS: $375 IR: $242 TD: $486 IR: $95 ER: N/A OS: OS: $635 $1,032 $507 N/A the placebo, 105-mg, and 225-mg groups, respectively. 14 Crenezumab 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- 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. 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 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 dosedependent 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. Vol. 43 No. 4 April 2018 P&T 235

3 Table 2 Therapies for Alzheimer s Disease Currently in Late-Stage Development 11 Medication Developer(s) Mechanism of Action Targeted Indication Route and Dose Gantenerumab Anti-Aβ mab Subcutaneous injection, Roche/MorphoSys dose TBD Crenezumab Roche/Genentech Aducanumab Neurimmune/ Biogen Flebogamma/ Albutein Grifols Biologicals Verubecestat Merck Elenbecestat Eisai/Biogen Lanabecestat AstraZeneca/ Eli Lilly Azeliragon vtv Therapeutics Nilvadipine Archer Pharmaceuticals Anti-Aβ mab Anti-Aβ mab IVIG albumin combination IV, 60 mg/kg or 180 mg/kg every four weeks IV, 3 mg/kg, 6 mg/kg, or 10 mg/kg every four weeks IV, with plasmapheresis, dose TBD BACE inhibitor Prodromal AD Oral, 12 mg or 40 mg BACE inhibitor BACE inhibitor Oral, 50 mg Oral, 20 mg or 50 mg Expected Price Strategy Anticipated U.S. Launch Date Priced in reference to aducanumab 2021 Priced in reference to gantenerumab 2023 Anticipated to be priced significantly above current AD therapy; likely to have first-to-market advantage Anticipated costs would be much higher than other therapies given the manufacturing process and procedures needed Expected to be priced higher than current therapies, but similar to other in-class medications Expected to be priced higher than current therapies, but similar to other in-class medications Expected to be priced higher than current therapies, but similar to other in-class medications RAGE inhibitor Mild AD Oral, 5 mg Expected to be priced at a large premium over currently available small-molecule therapies Dihydropyridine calcium-channel antagonist Oral, 8 mg Expected to be priced above current small-molecule therapies, but lower than immunotherapies 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 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. 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. 19 Flebogamma/Albutein 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 anti bodies 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-. 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 humanderived product. Verubecestat 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- and 236 P&T April 2018 Vol. 43 No. 4

4 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 Lanabecestat 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 Elenbecestat 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 in more than 1,300 patients with prodromal AD or early with a projected completion in late. 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 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 Novartis is developing CNP520 for the prevention of AD in patients determined to be high risk based on their age, apolipo protein 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 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 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 and is expected to be completed in 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 Nilvadipine 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. Intepirdine Axovant Sciences candidate intepirdine, an antagonist of serotonin receptor 6 (5-HT 6 ), was being evaluated in the treatment of mild-to- 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 , 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-HT 2A 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. CONCLUSION The pipeline for AD is filled with many potential candidates from varying therapeutic classes. While the prospect Vol. 43 No. 4 April 2018 P&T 237

5 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. REFERENCES 1. Prince M, Albanese E, Guerchet M, Prina M. World Alzheimer Report 2014: Dementia and Risk Reduction An Analysis of Protective and Modifiable Factors. London, United Kingdom: Alzheimer s Disease International (ADI); Centers for Disease Control and Prevention. National vital statistics report: deaths: final data for June 30, Available at: nvsr/nvsr65/nvsr65_04.pdf. Accessed December 21, 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, February Available at: gov/nchs/data/series/sr_03/sr03_038. pdf. Accessed December 21, Alzheimer s Association Alzheimer s disease facts and figures. Alzheimers Dement 2017;13: Alzheimer s Association. 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