Results from the INCREASE study shed light on the value of the pharmacist in medication therapy management.
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Alzheimer disease, the fifth leading cause of death among adults 65 years or older, is a progressive type of dementia that affects an individual’s memory, thinking, and behavior.1,2 The condition can be characterized by the presence of amyloid-β (Aβ) plaques and neurofibrillary tangles harboring the potential to interfere with neurotransmitter signaling.3 In 2020, approximately 6 million individuals in the United States had Alzheimer disease, and although death rates for diseases such as heart disease and cancer are on the decline, death rates for those with Alzheimer disease are increasing.4,5 Keeping these statistics in mind, let’s take a look at the current treatment landscape.
Because there is no cure for Alzheimer disease, traditional treatments have the goal of improving symptoms and slowing down disease progression.6 The first treatment approach involves acetylcholinesterase inhibitors to increase acetylcholine concentrations in synaptic clefts to improve communication between nerve cells.6 The next treatment approach is the use of N-methyld-aspartate (NMDA) receptor antagonists to inhibit the action of glutamate, the excitatory neurotransmitter.6 When found in excess, glutamate contributes to the death of brain cells by causing an accumulation of calcium, which can negatively affect an individual’s ability to learn and retain information.6 Both acetylcholinesterase inhibitors and NMDA receptor antagonists have remained the traditional standards of care since 2003, a fact that contributed to much of the excitement about the novel medication class designed to treat the disease.6
After nearly 2 decades of relying on the traditional standards of care, the newest class of medications used to treat patients with Alzheimer disease is monoclonal antibody treatments. The first to hit the market was aducanumab-avwa (Aduhelm; Biogen Inc), which received FDA approval in 2021.7,8 Through intravenous administration, aducanumab enters the brain and binds to soluble and insoluble forms of Aβ to cause an immune response.7,9 The Aβ plaques are degraded after being recognized as foreign.7,9 A second monoclonal antibody treatment, lecanemab-irmb (Leqembi; Eisai Co, Ltd), was approved in January 2023.10 There are more antibody treatments in development; however, despite the excitement for this medication class, it is valuable to review some of the controversies regarding the approval of the first monoclonal antibody treatment for the disease.
These controversies can be traced back to 2 identical phase 3 studies evaluating aducanumab: EMERGE (NCT02484547) and ENGAGE (NCT02477800).11 These trials were terminated early after investigators, using a futility analysis, determined that the antibody treatment was not likely to meet its primary end point of a change from baseline to week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB) scale, which assesses 6 domains of cognitive and functional performance.11,12 However, 7 months after the termination of both trials, investigators determined that aducanumab did indeed reduce cognitive decline in the subset of patients in EMERGE who received the highest dose of aducanumab included in the study when compared with placebo.11 Questions were raised regarding why one trial achieved this outcome whereas the other did not if the trials were identical to one another.
Per investigators, this development was thought to be the result of the ENGAGE trial not studying the highest dose of aducanumab for a sufficient period.13 Initially, statistical analyses indicated a low probability of the trials reaching the desired outcome, which was determined by the results collected from the patients who enrolled early on in the studies.11,13 However, changes made to the study protocols allowed the patients in EMERGE who enrolled later on to reach the higher aducanumab dose, which is the dose that showed a reduction in cognitive decline.13 Despite the acknowledgment of the protocol changes, there remained clinical efficacy concerns, and an advisory committee voted almost unanimously against the approval of aducanumab due to inconclusive evidence that the drug was effective—nonetheless, the FDA approved aducanumab.8,14 As a result of this decision, 2 members of the advisory board resigned.14
The drugs were initially granted approval through the FDA’s accelerated approval pathway based on a surrogate end point.8,15 Approval was granted based on the idea that the reduction of Aβ plaques is a biomarker that is reasonably likely to predict the slowing of cognitive decline.8,15,16 It should also be stated that in July 2023, the accelerated approval of lecanemab was converted to a traditional FDA approval based on the Peripheral and Central Nervous System Drugs Advisory Committee’s unanimous agreement that there is evidence of lecanemab’s clinical benefit for patients with Alzheimer disease.17,18 The traditional approval of lecanemab is the first verification that a drug that targets the underlying process of Alzheimer disease can provide clinical benefit to patients.17 And although there was excitement for the phase 4 confirmatory trials to prove aducanumab’s clinical benefit, Biogen decided in January 2024 to terminate the trials and to discontinue the drug’s development and commercialization.19 The company stated that this decision was due to a reprioritization of funds toward Biogen’s Alzheimer disease pipeline, such as the continued advancement of lecanemab, and not based on investigators’ safety or efficacy concerns.19
Aducanumab is not the only monoclonal antibody impacted by recent trial terminations. In January 2024, Roche decided to terminate the development of gantenerumab despite promising published results of 2 trials, GRADUATE I (NCT03444870; n = 985) and GRADUATE II (NCT03443973; n = 980), in November 2023.20,21 Gantenerumab was a fully human, anti-A β IgG1 with a higher affinity for aggregated Aβ than any previously tested monoclonal antibody treatment.22 In the GRADUATE trials, participants were aged 50 to 90 years; they included patients with mild cognitive impairment or mild dementia due to Alzheimer disease.21 Additionally, participants had evidence of amyloid plaques based on cerebrospinal fluid testing or PET.21 The primary outcome of the trials was a change in the CDR-SB scale from baseline to week 116.21
The decision to terminate the GRADUATE trials was based on the results of a preplanned safety and efficacy analysis.20 However, it should be noted that when compared with placebo, gantenerumab reduced the amount of Aβ in the brain, but there was no association with a clinically significant cognition decline in both trials.21 In GRADUATE I, the change from baseline in the CDR-SB score in gantenerumab-treated vs placebo-treated patients was 3.35 and 3.65, respectively (difference, –0.31; 95% CI, –0.66 to 0.05; P = .10).21 For GRADUATE II, the change from baseline in the CDR-SB score was 2.82 and 3.01 for gantenerumab-treated vs placebo-treated patients, respectively (difference, –0.19; 95% CI, –0.55 to 0.17; P = .30).21 Lon Schneider, MD, director of the USC California Alzheimer’s Disease Center and the DellaMartin Chair in Psychiatry and Neuroscience at the Keck School of Medicine and Leonard Davis School of Gerontology of the University of Southern California, suggested that the trial outcomes could be the result of either splitting the trials into 2 separate studies, which may have negatively impacted the results, or not allowing the trials to last for a sufficient length of time, as both trials were only 2 years in duration.23 However, given the previous controversies surrounding both approvals and the utility of monoclonal antibody treatments for Alzheimer disease, the investigators’ decision to terminate the GRADUATE trials only further supports the need for additional research into the relationship between Aβ and cognitive decline.20
The clinical knowledge and expertise of pharmacists, particularly community pharmacists, are key for those wanting to support the older adult population.24 In a recent study analyzing potential modifiable risk factors for Alzheimer disease and related dementias, researchers describe a medication therapy management (MTM) protocol for a patient-centered team with the overall goal of delaying disease onset.25 In the phase 1 INCREASE study (NCT02849639), pharmacists and nonpharmacist clinicians collaborated on making recommendations for prescription and OTC medications while evaluating the overall acceptability of the interventions.25
The INCREASE study was a randomized controlled trial that enrolled adults 65 years and older (n = 90) taking at least 1 potentially inappropriate medication as defined by Beers Criteria.25 Stratification to treatment groups was based on amyloid burden.25 Those in the control group received educational pamphlets on medication appropriateness for older adults and risks associated with polypharmacy.25 In addition to the pamphlets, those in the MTM intervention treatment group met with a board-certified geriatric pharmacy specialist and a nonpharmacist study clinician to discuss medication recommendations and receive education on risks, benefits, and therapy alternatives.25 Additionally, members of the group provided their beliefs and preferences about medications and treatment goals.25
To evaluate the effect of MTM interventions, a 3-step process was implemented.25 First, a pharmacist identified a potential medication-related problem while providing initial recommendations for prescription and OTC medications, vitamins, and supplements.25 The team then reviewed all the initial recommendations while providing possible revisions before final recommendations were given.25 Finally, the participants’ responses to the recommendations were recorded.25
With a total of 602 recommendations made (an average of 7 recommendations per participant), the most common recommendations pertained to the following types of medications: cardiometabolic (23%), gastrointestinal (17%), pain management (15%), anticholinergics (13%), vitamins and supplements (13%), neuropsychiatric (11%), and other (9%).25 Recommendations pertaining to OTC medications were for proton pump inhibitors, vitamins and supplements, antihistamines, nonsteroidal anti-inflammatory drugs, and histamine type 2 receptor antagonists.25 The most common recommendations included dose adjustments, switches to preferred agents, advice pertaining to drug and disease monitoring, and drug discontinuations and initiations.25 Nearly half the time (46%), participants indicated a willingness to make the proposed changes, or they indicated the need to first discuss the recommendation with a primary care provider (38%).25 A refusal to abide to the recommendation occurred infrequently (6%).25 The remaining recommendations (10%) were deemed no longer clinically relevant.25
The results from INCREASE continue to highlight the important role pharmacists fulfill in the management of Alzheimer disease, as many of the adopted recommendations were for vitamins, supplements, and anticholinergic agents that required a therapeutic switch.25 OTC stewardship and pharmacists’ ability to discuss the risks and benefits of all medications with patients optimizes therapeutic decisions and prioritizes patients’ quality of life, especially for populations more susceptible to various forms of dementia, and in particular for Alzheimer disease.24,25
Brittany N. Galloway, PharmD, RPh, serves as a drug information specialist for an online comprehensive medication database and provides ambulatory care services with Outcomes, a medication therapy management pharmacy team. She is also an incoming medical communications research fellow with Cencora, Inc (formerly Xcenda).
Another important takeaway from INCREASE is that the multidisciplinary decision-making process optimizes the strength of pharmacist MTM recommendations.25 The opportunity for a pharmacist to directly engage with patients and prescribers while having access to relevant clinical information allows for meaningful conversations and increased patient acceptability of recommendations.24,25 Although pharmacists continue to uplift interprofessional collaborative approaches to address potential modifiable risk factors for cognitive decline, there is continued hope for new approaches to treating patients with Alzheimer disease. Of note, in 2023, there were 36 agents in 55 phase 3 trials for the disease.26 Despite the persistent unknowns about the disease and the terminations of highly anticipated clinical trials, it is valuable to acknowledge the continued various treatment possibilities that undoubtedly remain.
