HealthDay News — Xanthine dehydrogenase/oxidase blockers may reduce the risk for neurodegenerative diseases, according to a study published online May 17 in PLOS ONE.

Yizhe Song, from the Washington University School of Medicine in St. Louis, and colleagues conducted a population-based, case-control study of US Medicare beneficiaries in 2009 to identify prescription medications associated with a lower risk for 3 neurodegenerative diseases: Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis. The analysis included 42,885 patients with neurodegenerative disease and 334,387 randomly selected controls. All filled medications were categorized according to their biological targets and mechanisms of action of those targets using medication data from 2006 to 2007. The odds ratios were estimated for 141 target-action pairs and each neurodegenerative disease. For target-action pairs inversely associated with diseases, replication was attempted in a cohort, including an active comparator group.

The researchers found that the most consistent inverse association across all 3 neurodegenerative diseases was for xanthine dehydrogenase/oxidase blockers, tied to the gout medication allopurinol. In multinomial regression, allopurinol was associated with a 13 to 34% lower risk for each neurodegenerative disease group and a mean reduction of 23% overall compared with those not using allopurinol. In the replication cohort, there was a 23% reduction for neurodegenerative diseases observed in the fifth year of follow-up comparing allopurinol users versus nonusers; with an active comparator group, more marked associations were seen.

“The medication associations we studied relate to disease risk,” a coauthor said in a statement. “Further research will be necessary to examine whether this mechanism slows progression of these diseases.”

Abstract/Full Text

Alzheimer Dementia Treatments

The Food and Drug Administration (FDA) has granted Fast Track designation to ACI-24.060, an anti-amyloid beta (Abeta) active immunotherapy candidate for the treatment of Alzheimer disease.

By enhancing the formation of polyclonal anti-Abeta antibodies, ACI-24.060 is expected to inhibit plaque accumulation and increase plaque clearance, thereby potentially reducing or preventing Alzheimer disease progression.

The designation was supported by initial interim safety and immunogenicity data from the phase 1b/2 ABATE trial (ClinicalTrials.gov Identifier: NCT05462106), a double-blind, placebo-controlled study assessing ACI-24.060 in patients with prodromal Alzheimer disease.

Results showed that ACI-24.060 elicited an anti-Abeta antibody response in the low-dose cohort. Treatment was found to be safe and well tolerated with no serious safety concerns reported.

The anti-Abeta vaccine candidate is currently being investigated at a higher dose. Initial data on amyloid plaque reduction measured by PET imaging are expected in the first half of 2024.

“By inducing a polyclonal response including antibodies against both oligomeric Abeta and pyroglutamate-Abeta, ACI-24.060 targets the same toxic species as disease modifying anti-Abeta monoclonal antibodies that slowed AD progression in phase 3 clinical trials,” said Dr Andrea Pfeifer, CEO of AC Immune SA. “As ACI-24.060, created using our SupraAntigen^® platform, specifically targets the most toxic forms of Abeta, we believe it may offer best-in-class efficacy with all the potential advantages in safety, administration and distribution that can be expected from a vaccine.”

The ABATE study will also assess the effects of ACI-24.060 in adults with Down syndrome.

HealthDay News — Antipsychotics are more often used by older adults receiving home health care (HHC) services with Alzheimer disease and related dementias (ADRD) vs those without ADRD, and their use is associated with worse functional outcomes, according to a study published online September 6 in the Journal of the American Geriatrics Society.

Jinjiao Wang, PhD, RN, from the University of Rochester in New York, and colleagues conducted a secondary analysis of 6684 adults aged 65 years and older, with and without ADRD, receiving care from an HHC agency in 2019 to examine the prevalence and predictors of antipsychotic use and its impact on outcomes among those living with ADRD. The change in the composite activities of daily living (ADL) score from HHC admission to HHC discharge (functional outcome) was measured in 5833 patients, where a positive score indicates improvement and a negative score indicates decline.

The researchers found that among patients with and without ADRD, the point prevalence of antipsychotic use was 17.2 and 6.6%, respectively. Predictors of antipsychotic use among patients living with ADRD included having greater ADL limitations, taking more medications, having behavioral and psychological symptoms, and living alone. Antipsychotic use was associated with having less ADL improvement at HHC discharge among patients living with ADRD.

“Antipsychotic use in persons with dementia is a serious patient safety issue, and it should be regularly reviewed for opportunities of deprescribing, such as dose reduction until discontinuation, whenever possible,” Wang said in a statement.

Abstract/Full Text

Aduhelm received accelerated approval from the Food and Drug Administration (FDA) for this indication in 2021. In a company press release, Biogen stated that resources allocated to the Aduhelm program would instead be put toward advancing the development of another anti-amyloid beta treatment, Leqembi^® (lecanemab-irmb), as well as other new treatment modalities. Leqembi received traditional approval from the FDA in 2023 for the treatment of Alzheimer disease in patients with mild cognitive impairment or mild dementia stage of the disease, the population in which treatment was indicated in clinical trials.

According to the Company, the decision to discontinue Aduhelm was not related to any safety or efficacy concerns. The ENVISION study (ClinicalTrials.gov Identifier: NCT05310071), which was expected to verify the clinical benefit of Aduhelm, has also been terminated.

Commenting on the decision, Christopher A. Viehbacher, President and CEO of Biogen, said, “As a pioneer in Alzheimer’s disease, Biogen is reprioritizing resources to build a leading franchise to address the multiple pathologies of the disease and patient needs. We plan to further advance the launch of Leqembi, together with Eisai, and continue to bolster innovation with the development of the other assets in our pipeline.”

The Food and Drug Administration (FDA) has accepted for Priority Review the supplemental New Drug Application (sNDA) for brexpiprazole for the treatment of agitation associated with Alzheimer dementia (AAD).

The sNDA is supported by data from two 12-week, randomized, double-blind, placebo-controlled phase 3 studies (Study 331-12-283 [ClinicalTrials.gov Identifier: NCT01862640] and Study 331-14-213 [ClinicaTrials.gov Identifier: NCT03548584]) that evaluated the efficacy and safety of brexpiprazole, an atypical antipsychotic, in patients with AAD. Patients were randomly assigned to receive brexpiprazole or placebo. The primary endpoint for both studies was the change from baseline in the Cohen-Mansfield Agitation Inventory (CMAI) total score at week 12.

In Study 331-12-283, results showed that treatment with brexpiprazole 2mg/day significantly improved symptoms of agitation compared with placebo (P <.05) based on the mean change in CMAI total score from baseline to week 12. A statistically significant improvement was also observed with brexpiprazole 2mg/day and 3mg/day compared with placebo (P <.05) in Study 331-14-213.

The safety of brexpiprazole was consistent with its known profile. Treatment emergent adverse events that occurred in at least 2% of brexpiprazole-treated patients and more than with placebo were insomnia, somnolence, nasopharyngitis, and urinary tract infection.

A Prescription Drug User Fee Act target date of May 10, 2023 has been set for the application. The FDA is expected to hold an advisory committee meeting to discuss the application.

Brexpiprazole is currently available under the brand name Rexulti for use as an adjunctive therapy to antidepressants for the treatment of major depressive disorder. Rexulti is also indicated for the treatment of schizophrenia in adults and pediatric patients 13 years of age and older.

References

1. Otsuka and Lundbeck announce FDA acceptance and Priority Review of sNDA for brexpiprazole for the treatment of agitation associated with Alzheimer’s dementia. News release. Otsuka and Lundbeck. January 7, 2023. Accessed January 9, 2023. https://www.businesswire.com/news/home/20230107005003/en/Otsuka-and-Lundbeck-Announce-FDA-Acceptance-and-Priority-Review-of-sNDA-for-Brexpiprazole-for-the-Treatment-of-Agitation-Associated-With-Alzheimer%E2%80%99s-Dementia.
2. Otsuka Pharmaceutical and Lundbeck present positive data from multiple phase 3 studies showing brexpiprazole significantly improved symptoms of agitation in patients with Alzheimer’s dementia at the 2022 Clinical Trials for Alzheimer’s Disease Congress. News release. Otsuka. December 1, 2022. Accessed January 9, 2023. https://www.otsuka-us.com/news/otsuka-pharmaceutical-and-lundbeck-present-positive-data-multiple-phase-3-studies-showing.

HealthDay News — Cumulative use of proton pump inhibitors (PPIs) for more than 4.4 years is associated with an increased risk for dementia, according to a study published online August 9 in Neurology.

Carin Northuis, MPH, PhD, from the University of Minnesota in Minneapolis, and colleagues examined the associations between current and cumulative PPI use and risk for incident dementia in the Atherosclerosis Risk in Communities Study. PPI use was assessed at clinic visits 1 (1987 to 1989) to 5 (2011 to 2013) and reported annually. PPI use was classified according to current use at visit 5 and duration of use prior to visit 5 (zero days, one day to 2.8 years, 2.8 to 4.4 years, and >4.4 years).

The analysis included 5712 dementia-free participants at visit 5. The minimum cumulative PPI use was 112 days and maximum use was 20.3 years; median follow-up was 5.5 years. The researchers identified 585 incident cases of dementia over follow-up. Compared with those not using PPIs, participants using PPIs at visit 5 did not have an increased risk for developing dementia during subsequent follow-up. An increased risk for dementia was seen for those using PPIs for great than 4.4 cumulative years prior to visit 5 compared with those reporting no use. For lesser amounts of use, the associations were not significant.

“It is important that people taking these medications speak with their doctor before making any changes, to discuss the best treatment for them, and because stopping these drugs abruptly may result in worse symptoms,” coauthor Kamakshi Lakshminarayan, MBBS, PhD, also of the University of Minnesota and a member of the American Academy of Neurology, said in a statement.

Several authors disclosed ties to the pharmaceutical industry.

Abstract/Full Text (subscription or payment may be required)

Scott C. Zimmerman, MPH, from the University of California in San Francisco, and colleagues examined the association of terminating metformin treatment for reasons unrelated to kidney dysfunction with dementia incidence in a cohort study of metformin users. The final analytic sample included 12,220 early terminators and 29,126 routine metformin users.

The researchers found that compared with routine users, the early terminators had a significantly increased risk for dementia diagnosis (hazard ratio, 1.21). Contributions to this association by changes in hemoglobin A1c (HbA1c) level or insulin use varied from no contribution for insulin use at 5 years after termination to 0.07 years for HbA1c level at one year after termination in a mediation analysis, indicating that the association was mainly independent of HbA1c level changes and insulin use.

“Terminating metformin treatment was associated with increased dementia incidence, corroborating prior observational research that initiating metformin was associated with reduced risk of dementia,” the authors write. “This finding has important implications for the clinical management of diabetes.”

One author disclosed ties to the pharmaceutical industry.

Abstract/Full Text

AVP-786 is a combination of deudextromethorphan hydrobromide, an uncompetitive NMDA receptor antagonist and sigma-1 agonist, and quinidine sulfate, a CYP2D6 inhibitor. According to Otsuka, the deuterated form of the drug significantly reduces its susceptibility to cytochrome P450 (CYP2D6) enzyme metabolism thereby increasing bioavailability.

The randomized, double-blind, placebo-controlled, parallel-design study (ClinicalTrials.gov Identifier: NCT03393520) included over 600 patients aged 50 years and older with dementia due to Alzheimer disease who had clinically significant, moderate to severe agitation. Study participants were randomly assigned to receive AVP-786 or placebo orally twice a day for 12 weeks. 

Results showed treatment with AVP-786 did not significantly improve agitation associated with dementia due to Alzheimer disease vs placebo, based on the change from baseline in the Cohen-Mansfield Agitation Inventory total score (primary endpoint). As for safety, falls were reported with greater frequency in the AVP-786 groups (8.6% for AVP-786 high dose; 9.1% for AVP-786 low dose;  2.8% for placebo).

“While the result of this trial is disappointing, we plan to analyze the full data set to determine the future potential of AVP-786 in the treatment of agitation associated with dementia due to Alzheimer disease,” said John Kraus, MD, PhD, executive vice president and chief medical officer at Otsuka. 

Full study results will be submitted for scientific publication at a later date.

Khi Yung Fong, from the National University of Singapore, and colleagues conducted a systematic review of studies reporting comparisons of dementia incidence between patients treated with DOACs and warfarin for AF. Data were included for 10 studies with 342,624 patients.

The researchers found that compared with warfarin, DOACs were associated with a significantly lower risk for developing dementia (hazard ratio [HR], 0.88); the association was significant for Asian patients (HR, 0.81) but not non-Asian patients. In subgroup analyses, similar significance was seen for propensity score-matched studies and patients aged 65 to 75 years, but not for patients aged 75 years and older.

A lower mean age corresponded to significantly greater favoring of DOACs over warfarin. In a network meta-analysis, significant reductions were seen in dementia risk for rivaroxaban, apixaban, and dabigatran vs warfarin (HRs, 0.854, 0.881, and 0.871, respectively).

“The use of DOAC in AF significantly reduces dementia risk compared with warfarin, particularly in Asian patients. The possible reversal of this effect with increasing age merits further randomized trials with long-term follow-up,” the authors write.

One author disclosed ties to the pharmaceutical industry.

Abstract/Full Text

In patients with amyloid-positive early symptomatic Alzheimer disease, treatment with donanemab significantly slowed cognitive and functional decline, according to data presented at the 2023 Alzheimer’s Association International Conference (AAIC).

Donanemab is an investigational antibody therapy that targets a modified form of deposited amyloid-β peptide called N3pG. The randomized, double-blind, placebo-controlled TRAILBLAZER-ALZ 2 study (ClinicalTrials.gov Identifier: NCT04437511) evaluated the efficacy and safety of donanemab in adults 60 to 85 years of age with early symptomatic Alzheimer disease. Study participants were stratified by tau level into either a low/medium or high tau group.

Previous findings showed that among patients in the low/medium tau group (n=1182), donanemab was found to significantly slow clinical decline by 35% compared with placebo, based on the change from baseline on the integrated Alzheimer Disease Rating Scale (iADRS; primary endpoint) over 18 months (P <.0001). Donanemab also slowed clinical decline by 36% vs placebo on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; key secondary endpoint) over 18 months (P <.0001). Among all study participants (n=1736), treatment with donanemab significantly slowed decline by 22% on iADRS and 29% on CDR-SB.

New data presented at AAIC showed that among patients with mild cognitive impairment (n=214), donanemab slowed decline by 60% on iADRS and 46% on CDR-SB. The benefits of donanemab were also observed in patients with mild dementia due to Alzheimer disease (n=534); the treatment slowed decline by 30% on iADRS and 38% on CDR-SB in this patient population. A post-hoc subgroup analysis also demonstrated that among patients with low/medium tau, a greater benefit was seen in patients under 75 years of age treated with donanemab vs those aged 75 years and older.

Additionally, 47% of donanemab-treated patients with low/medium tau showed no decline on CDR-SB at 1 year vs 29% of patients who received placebo. In this population, treatment with donanemab was associated with a 39% lower risk of progressing to the next stage of disease over the 18-month trial.

Using amyloid positron emission tomography brain scan, findings showed significant reductions in brain amyloid plaque levels among patients in the donanemab arm as early as 6 months after initiating treatment. At 12 months, approximately half of all participants achieved predefined criteria of amyloid plaque clearance and were able to stop treatment. At 18 months, 7 of every 10 participants reached this threshold.

As for safety, amyloid-related imaging abnormalities of edema or effusion occurred in 24% and 2.1% of participants in the donanemab and placebo groups, respectively. Infusion-related reactions were reported in 8.7% of donanemab-treated patients and 0.5% of placebo patients.

Lilly has completed the submission of the application for donanemab with the Food and Drug Administration. A decision is expected by the end of the year.

Wenya Zhang, from the Chinese Academy of Medical Sciences & Peking Union Medical College in Beijing, and colleagues conducted a population-based cohort study using data from the UK Biobank to examine whether age at AF diagnosis is associated with risk of incident dementia and its subtypes. The main analysis included 433,746 participants.

The researchers found that compared to individuals without AF, the 30,601 with AF had increased risk of developing all-cause dementia and VD (adjusted hazard ratios, 1.42 and 2.06, respectively), but not AD. Younger age at AF onset was associated with increased risks of developing all-cause dementia, AD, and VD (adjusted hazard ratio per 10-year decrease, 1.23, 1.27, and 1.35, respectively). For developing all-cause dementia, the highest hazard ratio was seen for individuals with AF diagnosed before age 65 years, followed by AF diagnosed at age 65 to 74 years (adjusted hazard ratios, 1.82 and 1.47, respectively) after propensity-score matching; the hazard ratio for AF diagnosed at 75 years or older was not significant. Results were similar for AD and VD.

“The quantitative manifestation of the association between AF onset age and incident dementia highlights the importance of monitoring cognitive function among AF patients, especially those younger than 65 years at diagnosis,” the authors write.

Abstract/Full Text

The Food and Drug Administration (FDA) has accepted for Priority Review the supplemental Biologics License Application (sBLA) for lecanemab-irmb (Leqembi) to convert its accelerated approval status to a traditional approval for the treatment of Alzheimer disease.

Lecanemab is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. It reduces amyloid beta plaques in the brain, which is a defining pathophysiological feature of Alzheimer disease.

Lecanemab received accelerated approval in January 2023 based on data from a phase 2b trial (ClinicalTrials.gov Identifier: NCT01767311). The study showed that treatment with lecanemab resulted in a statistically significant reduction in brain amyloid plaque compared with placebo.

The sBLA is supported by data from the confirmatory, double-blind, placebo-controlled phase 3 Clarity AD trial (ClinicalTrials.gov Identifier: NCT03887455), which included 1795 patients with early Alzheimer disease. Patients were randomly assigned 1:1 to receive either lecanemab 10mg/kg via intravenous infusion once every 2 weeks or placebo. The primary endpoint was the change from baseline to 18 months in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score.

Findings demonstrated a statistically significant treatment difference in the CDR-SB score change (-0.45; [95% CI, -0.67, -0.23]; P <.001), indicating a reduction in clinical decline of 27% with lecanemab compared with placebo. Highly statistically significant changes in CDR-SB were observed as early as 6 months.

Results also showed statistically significant improvements in all key secondary endpoints compared with placebo (P <.001), including changes in amyloid levels in the brain (as measured by amyloid positron emission tomography), the AD Assessment Scale-Cognitive Subscale 14 (-1.44 [95% CI, -2.27, -0.61]), the AD Composite Score (-0.050 [95% CI, -0.074, -0.027), and the AD Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (2.0 [95% CI, 1.2-2.8]).

A Prescription Drug User Fee Act target date of July 6, 2023 has been set for the application.

References

1. FDA accepts Eisai’s filing of a supplemental Biologics License Application and grants Priority Review for traditional approval of Leqembi (lecanemab-irmb) for the treatment of Alzheimer’s disease. News release. Eisai. Accessed March 5, 2023. https://www.prnewswire.com/news-releases/fda-accepts-eisais-filing-of-a-supplemental-biologics-license-application-and-grants-priority-review-for-traditional-approval-of-leqembi-lecanemab-irmb-for-the-treatment-of-alzheimers-disease-301762846.html.
2. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. Published online January 5, 2023. doi:10.1056/NEJMoa2212948

HealthDay News — Older adults with cognitive impairment have limited eligibility for anti-β amyloid monoclonal antibodies when applying clinical trial criteria, according to a study published online August 16 in Neurology.

Rioghna R. Pittock, from the Mayo Clinic in Rochester, Minnesota, and colleagues applied the clinical trial eligibility criteria for lecanemab and aducanumab treatment to participants with early Alzheimer Disease from the population-based Mayo Clinic Study of Aging (MCSA). The study sample included 237 MCSA participants with mild cognitive impairment (MCI) or mild dementia and increased brain amyloid burden.

The researchers found that the sample was reduced to 112 participants (47.3%) with the lecanemab trial’s inclusion criteria and was further reduced to 19 (8%) with the trial’s exclusion criteria. Instead of applying additional cognitive criteria, modifying the exclusion criteria to include all participants with MCI resulted in 17.4% of participants with MCI being eligible for lecanemab. Overall, 104 participants met the clinical trial inclusion criteria for aducanumab (43.9%). The number of eligible participants was further reduced to 12 (5.1%) with the aducanumab trial’s exclusion criteria. Chronic conditions and neuroimaging findings were common exclusions.

“Our study results show only a small percentage of people with early Alzheimer’s disease may be eligible to receive treatment, mostly due to chronic health conditions and brain scan abnormalities common in older adults,” study author Maria Vassilaki, MD, PhD, also of the Mayo Clinic, said in a statement. “Additional research is needed to examine the safety and efficacy of monoclonal antibodies targeting amyloid-β plaques in larger, more diverse populations.”

Several authors disclosed ties to the pharmaceutical industry.

Abstract/Full Text (subscription or payment may be required)

Editorial (subscription or payment may be required)

Donanemab is an investigational antibody therapy that targets a modified form of deposited amyloid-β peptide called N3pG. The randomized, double-blind, placebo-controlled TRAILBLAZER-ALZ 2 study (ClinicalTrials.gov Identifier: NCT04437511) evaluated the efficacy and safety of donanemab in adults 60 to 85 years of age with early symptomatic Alzheimer disease. Study participants were stratified by tau level into either a low/medium or high tau group. 

Findings showed that regardless of tau level, a clinical benefit was observed with donanemab, especially among patients in earlier stages of Alzheimer disease (based on the change from baseline on the integrated Alzheimer Disease Rating Scale). Results also showed significant reductions in brain amyloid plaque levels among patients in the donanemab arm as early as 6 months after initiating treatment. At 12 months, approximately half of all participants achieved predefined criteria of amyloid plaque clearance and were able to stop treatment.

“We are confident in donanemab’s potential to offer very meaningful benefits to people with early symptomatic Alzheimer’s disease,” said Anne White, executive vice president of Eli Lilly and Company, and president of Lilly Neuroscience. “It was unexpected to learn the FDA will convene an advisory committee at this stage in the review process, but we look forward to the opportunity to further present the TRAILBLAZER-ALZ 2 results and put donanemab’s strong efficacy in the context of safety.”

The FDA has yet to set a date for the advisory committee meeting to discuss donanemab.

The Food and Drug Administration (FDA) has granted Fast Track designation to AVB-101 for the treatment of frontotemporal dementia (FTD) with mutations in the progranulin (GRN) gene.

FTD is an early-onset form of dementia that affects behavior, language, and movement. It is the leading cause of dementia in individuals younger than 65 years of age. GRN-related FTD is caused by a mutation in the GRN gene, which prevents the production of progranulin. Low levels of progranulin lead to neuronal cell death and subsequent loss in brain function. AVB-101 is an investigational gene therapy designed to restore progranulin levels in areas of the brain affected by FTD by delivering a functional copy of the GRN gene.

“We are using adeno-associated virus (AAV) technology and taking a novel approach to deliver a functional copy of the GRN gene directly to the brain via bilateral, MRI-guided intrathalamic infusion with the aim to restore normal levels of the progranulin protein,” said David Cooper, MD, Chief Medical Officer for AviadoBio. “Our preclinical program shows robust biodistribution to the brain areas where it is needed to restore levels of progranulin, potentially slowing or stopping the progression of FTD-GRN, with little to no progranulin in the rest of the body where it may have adverse effects.”

The Company has initiated the open-label, phase 1/2 ASPIRE-FTD study (ClinicalTrials.gov Identifier: NCT06064890) to evaluate AVB-101 in patients with FTD-GRN in Europe; the trial will open in the US in 2024. Study participants will receive a one-time treatment delivered into the thalamus via a stereotactic neurosurgical procedure. In addition to safety, the study will investigate whether AVB-101 can restore progranulin to at least normal levels and whether it can slow down or stop the progression of FTD-GRN.

“Receiving Fast Track designation underscores the significant need for treatment options for these patients, and we are eager to soon open US clinical trial sites and offer an innovative option for eligible patients with FTD-GRN,” said Lisa Deschamps, CEO.

The FDA previously granted Orphan Drug designation to AVB-101 for the treatment of FTD.

The Food and Drug Administration’s (FDA) Peripheral and Central Nervous System Drugs Advisory Committee (PCNS) voted unanimously (6 “yes” to 0 “no”) that lecanemab-irmb (Leqembi^®) shows clinical benefit as a treatment for Alzheimer disease (AD).

Lecanemab is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. In January 2023, the FDA granted accelerated approval to lecanemab for the treatment of AD based on data from a phase 2b trial (ClinicalTrials.gov Identifier: NCT01767311). In March 2023, lecanemab received Priority Review for its supplemental Biologics License Application seeking to convert its accelerated approval status to a traditional full approval.

The panel reviewed efficacy and safety data from the confirmatory phase 3 Clarity AD trial (ClinicalTrials.gov Identifier: NCT03887455), which included 1795 patients with early AD. Patients were randomly assigned 1:1 to receive either lecanemab 10mg/kg via intravenous infusion once every 2 weeks or placebo. The primary endpoint was the change from baseline to 18 months in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score.

Results showed a statistically significant treatment difference in the CDR-SB score change (-0.45; P =.00005), indicating a reduction in clinical decline of 27% with lecanemab over 18 months compared with placebo. Findings also showed statistically significant improvements in all key secondary endpoints compared with placebo (P <.001), including changes in amyloid levels in the brain (as measured by amyloid positron emission tomography), the AD Assessment Scale-Cognitive Subscale 14 (-1.44 [95% CI, -2.27, -0.61]), the AD Composite Score (-0.050 [95% CI, -0.074, -0.027), and the AD Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (2.0 [95% CI, 1.2-2.8]).

The most common adverse events reported with lecanemab were infusion reactions (26.4% vs 7.4% with placebo), amyloid related imaging abnormalities-hemosiderin deposition (ARIA-H; combined cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis: 17.3% vs 9.0% with placebo), ARIA-E (edema/effusion: 12.6% vs 1.7% with placebo), headache (11.1% vs 8.1% with placebo), and fall (10.4% vs 9.6% with placebo).

The panel members also discussed the use of lecanemab in specific subgroups, including apolipoprotein E (ApoE) ε4 homozygote patients, patients requiring concomitant anticoagulants, and those with cerebral amyloid angiopathy.

A regulatory decision is expected on July 6, 2023. Although not bound to the committee’s recommendations, the FDA does take them into consideration when making decisions on approval.

The Food and Drug Administration’s (FDA) Psychopharmacologic Drugs Advisory Committee and the Peripheral and Central Nervous System Drugs Advisory Committee voted 9 to 1 in favor of the use of brexpiprazole (Rexulti^®) for the treatment of agitation associated with Alzheimer dementia (AAD). The majority of the panel believed that the data provided were sufficient to allow for the identification of a population in whom the benefits of treating AAD with brexpiprazole outweighed the potential risks associated with use of atypical antipsychotics.

The FDA panel reviewed data from three 12-week, double-blind, placebo-controlled phase 3 studies (Study 331-12-283 [ClinicalTrials.gov Identifier: NCT01862640], Study 331-12-284 [ClinicalTrials.gov Identifier: NCT01922258], and Study 331-14-213 [ClinicaTrials.gov Identifier: NCT03548584]) in which patients with AAD were randomly assigned to receive either brexpiprazole or placebo. The primary endpoint for both studies was the change from baseline in the Cohen-Mansfield Agitation Inventory (CMAI) total score at week 12.

In Study 331-12-283, results showed that treatment with brexpiprazole 2mg/day significantly improved symptoms of agitation compared with placebo (P <.05) based on the mean change in CMAI total score from baseline to week 12. A statistically significant improvement was also observed with brexpiprazole 2mg/day and 3mg/day compared with placebo (P <.05) in Study 331-14-213. However, the primary endpoint was not met in Study 331-12-284.

An assessment of mortality risk across clinical trials showed that the effect of brexpiprazole appeared to be consistent with the risk associated with other antipsychotics used in elderly patients with dementia. Treatment emergent adverse events that occurred in at least 2% of brexpiprazole-treated patients and more than with placebo were insomnia, somnolence, nasopharyngitis, and urinary tract infection.

Although not bound by the committees’ recommendations, the FDA does take them into consideration when making decisions on approval. A Prescription Drug User Fee Act target date of May 10, 2023 has been set for the application. If approved, brexpiprazole would be the first medication indicated for AAD in the US.