β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the β-secretase enzyme
required for the production of the neurotoxic β-amyloid (Aβ) peptide that is widely
considered to have a crucial early role in the etiology of Alzheimer?s disease (AD). As a
result, BACE1 has emerged as a prime drug target for reducing the levels of Aβ in the AD
brain, and the development of BACE1 inhibitors as therapeutic agents is being vigorously
pursued. It has proven difficult for the pharmaceutical industry to design BACE1 inhibitor
drugs that pass the blood?brain barrier, however this challenge has recently been met and
BACE1 inhibitors are now in human clinical trials to test for safety and efficacy in AD
patients and individuals with pre-symptomatic AD. Initial results suggest that some of these
BACE1 inhibitor drugs are well tolerated, although others have dropped out because of
toxicity and it is still too early to know whether any will be effective for the prevention or
treatment of AD. Additionally, based on newly identified BACE1 substrates and phenotypes
of mice that lack BACE1, concerns have emerged about potential mechanism-based side
effects of BACE1 inhibitor drugs with chronic administration. It is hoped that a therapeutic
window can be achieved that balances safety and efficacy. This review summarizes the
current state of progress in the development of BACE1 inhibitor drugs and the evaluation of
their therapeutic potential for AD.
AlzheimeResearch.com | Finding a cure for Alzheimer's disease
Effect of Citalopram on Agitation in Alzheimer Disease The CitAD Randomized Clinical Trial
Importance Agitation is common, persistent, and associated with adverse consequences for patients with Alzheimer disease. Pharmacological treatment options, including antipsychotics are not satisfactory.
Objective The primary objective was to evaluate the efficacy of citalopram for agitation in patients with Alzheimer disease. Key secondary objectives examined effects of citalopram on function, caregiver distress, safety, cognitive safety, and tolerability.
Design, Setting, and Participants The Citalopram for Agitation in Alzheimer Disease Study (CitAD) was a randomized, placebo-controlled, double-blind, parallel group trial that enrolled 186 patients with probable Alzheimer disease and clinically significant agitation from 8 academic centers in the United States and Canada from August 2009 to January 2013.
Interventions Participants (n = 186) were randomized to receive a psychosocial intervention plus either citalopram (n = 94) or placebo (n = 92) for 9 weeks. Dosage began at 10 mg per day with planned titration to 30 mg per day over 3 weeks based on response and tolerability.
Main Outcomes and Measures Primary outcome measures were based on scores from the 18-point Neurobehavioral Rating Scale agitation subscale (NBRS-A) and the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC). Other outcomes were based on scores from the Cohen-Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory (NPI), ability to complete activities of daily living (ADLs), caregiver distress, cognitive safety (based on scores from the 30-point Mini Mental State Examination [MMSE]), and adverse events.
Results Participants who received citalopram showed significant improvement compared with those who received placebo on both primary outcome measures. The NBRS-A estimated treatment difference at week 9 (citalopram minus placebo) was −0.93 (95% CI, −1.80 to −0.06), P = .04. Results from the mADCS-CGIC showed 40% of citalopram participants having moderate or marked improvement from baseline compared with 26% of placebo recipients, with estimated treatment effect (odds ratio [OR] of being at or better than a given CGIC category) of 2.13 (95% CI, 1.23-3.69), P = .01. Participants who received citalopram showed significant improvement on the CMAI, total NPI, and caregiver distress scores but not on the NPI agitation subscale, ADLs, or in less use of rescue lorazepam. Worsening of cognition (−1.05 points; 95% CI, −1.97 to −0.13; P = .03) and QT interval prolongation (18.1 ms; 95% CI, 6.1-30.1; P = .01) were seen in the citalopram group.
Conclusions and Relevance Among patients with probable Alzheimer disease and agitation who were receiving psychosocial intervention, the addition of citalopram compared with placebo significantly reduced agitation and caregiver distress; however, cognitive and cardiac adverse effects of citalopram may limit its practical application at the dosage of 30 mg per day.
Refence: JAMA. 2014;311(7):682-691. doi:10.1001/jama.2014.93.
Clinical trial of an inhibitor of RAGE-Aβ interactions in Alzheimer disease
Objective: To examine safety, tolerability, and efficacy of PF-04494700, an inhibitor of the receptor for advanced glycation end products (RAGE), in mild to moderate Alzheimer disease (AD).
Methods: Double-blind, placebo-controlled trial at 40 academic centers (United States). Subjects with AD and Mini-Mental State Examination score 14–26 were randomized to PF-04494700 60 mg/day × 6 days, then 20 mg daily (high dose); 15 mg/day × 6 days, then 5 mg daily (low dose); or placebo, for 18 months. Clinical and laboratory measures were used to evaluate safety and tolerability. The primary efficacy measure was the Alzheimer's Disease Assessment Scale–cognitive (ADAS-cog). Secondary measures assessed clinical stage, function, behavior, MRI, and CSF biomarkers.
Results: A total of 399 subjects were randomized. In a prespecified interim analysis, when 50% of subjects had completed the 6-month visit, the high dose was associated with confusion, falls, and greater ADAS-cog decline and was discontinued. A second prespecified analysis compared low-dose and placebo groups for futility and safety approximately 12 months after all subjects were randomized. This analysis met criteria for futility, and treatment was discontinued. There were no safety concerns in the low-dose group. Analyses including post-futility data showed decreased decline on the ADAS-cog in the low-dose group at month 18. Other clinical and biomarker measures showed no differences between low-dose treatment and placebo.
Conclusions: PF-04494700 at 20 mg/d was associated with increased adverse events and cognitive decline. At 5 mg/d, PF-04494700 had a good safety profile. A potential benefit for this low dose on the ADAS-cog is not conclusive, because of high dropout and discontinuation rates subsequent to the interim analyses.
Classification of evidence: This study provides Class I evidence that in patients with AD high-dose PF-04494700 increased cognitive decline at 6 months and Class IV evidence that low-dose PF-04494700 slowed cognitive decline at 18 months.
Phase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer's Disease
BACKGROUND
Alzheimer's disease is characterized by amyloid-beta plaques, neurofibrillary tangles, gliosis, and neuronal loss. Solanezumab, a humanized monoclonal antibody, preferentially binds soluble forms of amyloid and in preclinical studies promoted its clearance from the brain.
METHODS
In two phase 3, double-blind trials (EXPEDITION 1 and EXPEDITION 2), we randomly assigned 1012 and 1040 patients, respectively, with mild-to-moderate Alzheimer's disease to receive placebo or solanezumab (administered intravenously at a dose of 400 mg) every 4 weeks for 18 months. The primary outcomes were the changes from baseline to week 80 in scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11; range, 0 to 70, with higher scores indicating greater cognitive impairment) and the Alzheimer's Disease Cooperative Study–Activities of Daily Living scale (ADCS-ADL; range, 0 to 78, with lower scores indicating worse functioning). After analysis of data from EXPEDITION 1, the primary outcome for EXPEDITION 2 was revised to the change in scores on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90, with higher scores indicating greater impairment), in patients with mild Alzheimer's disease.
RESULTS
Neither study showed significant improvement in the primary outcomes. The modeled difference between groups (solanezumab group minus placebo group) in the change from baseline was −0.8 points for the ADAS-cog11 score (95% confidence interval [CI], −2.1 to 0.5; P=0.24) and −0.4 points for the ADCS-ADL score (95% CI, −2.3 to 1.4; P=0.64) in EXPEDITION 1 and −1.3 points (95% CI, −2.5 to 0.3; P=0.06) and 1.6 points (95% CI, −0.2 to 3.3; P=0.08), respectively, in EXPEDITION 2. Between-group differences in the changes in the ADAS-cog14 score were −1.7 points in patients with mild Alzheimer's disease (95% CI, −3.5 to 0.1; P=0.06) and −1.5 in patients with moderate Alzheimer's disease (95% CI, −4.1 to 1.1; P=0.26). In the combined safety data set, the incidence of amyloid-related imaging abnormalities with edema or hemorrhage was 0.9% with solanezumab and 0.4% with placebo for edema (P=0.27) and 4.9% and 5.6%, respectively, for hemorrhage (P=0.49).
CONCLUSIONS
Solanezumab, a humanized monoclonal antibody that binds amyloid, failed to improve cognition or functional ability. (Funded by Eli Lilly; EXPEDITION 1 and 2 ClinicalTrials.gov numbers, NCT00905372 andNCT00904683.)
Disappointing Alzheimer’s trial yields new ideas
Dr. Stephen Salloway pulls no punches in describing the results of two clinical trials of the Alzheimer’s drug bapineuzumab that he helped to lead. The antibody failed to produce cognitive improvement for volunteers compared to a placebo, he and colleagues report Jan. 23 in the New England Journal of Medicine.
Looking for a breakthrough
“The biggest disappointment from this trial, was that if we had shown benefit with a drug like bapi, it would give people hope that Alzheimer’s is a treatable disease, that we can slow it down,” Salloway said.
That much needed breakthrough could come from new trials that apply the lessons researchers learned. It is likely that many of the participants, for example, had some form of dementia other than Alzheimer’s disease, Salloway said. A future trial should only include those with amyloid buildup confirmed by a PET scan and spinal fluid testing.
“We were surprised to find that overall 20 percent of participants in both the bapi and solanezumab trials did not meet the threshold for amyloid buildup,” Salloway said. “That proportion was higher for ApoE4 noncarriers.”
Also amyloid plays a more critical role early in the development of the disease, he said. Trials that administer the medication earlier could produce greater effects.
It would make sense, he said, to pair drugs like bapi with drugs such as a beta secretase inhibitor that maximize amyloid lowering. The safety of such a combination, or combination with drugs that address the tangles of tau proteins also found in Alzheimer’s, is not known, Salloway said, but needs to be carefully tested.
“Without taking strategic risks, we aren’t going to make the progress we need to move forward,” he said.
Testing drug combinations, however, may require pharmaceutical companies to pool resources and share data. He acknowledged that’s something competitors are usually reluctant to do. These partnerships are forming in the pre-competitive arena, he said, but need to be expanded into clinical trials.
“For the level of suffering with this disease and for our economy, we have to break down some barriers and come up with innovative approaches.”
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