Research Highlights from Padmaja Genesh - May 2021
FDA Places Gene Therapy LX1001 on Fast Track
The therapy is designed to deliver a version of the APOE gene, called APOE2, to cells in the central nervous system (the brain and spinal cord) using an engineered viral vector.
Every person inherits two copies of the APOE gene, one from each biological parent. There are three versions of the APOE gene, called alleles — APOE2, APOE3, and APOE4 (often abbreviated to E2, E3, and E4). The E2 allele is associated with lower Alzheimer’s risk, whereas the E4 allele is linked to increased disease risk. As such, LX1001 is designed to deliver the protective allele (APOE2).
Lexeo is currently funding an open-label Phase 1 clinical trial (NCT03634007) to test the therapy in 15 Alzheimer’s patients, 50 or older, who have two copies of the E4 allele. Participants will be given different doses of the therapy.
The trial’s main goals are to examine LX1001’s safety profile and to determine a maximum-tolerated dose (the highest dose that can be given without unacceptable safety risks). The study will also assess the effect of the gene therapy on the APOE protein.
The trial is currently enrolling Alzheimer’s patients with mild cognitive impairment at Weill Cornell Medicine in New York City. Early data are expected by the end of the year, at which point all participants are expected to have been dosed with the therapy.
Longeveron’s Stem Cell Therapy Shows Potential in Phase 1 Trial
Longeveron’s Lomecel-B, an investigational bone marrow-derived medicinal signaling cell (MSC), showed an ability to slow cognitive decline and the loss of daily life abilities in patients with mild Alzheimer’s disease relative to those given a placebo in a Phase 1 clinical trial, the company announced.
Treatment with Lomecel-B was deemed safe, with the therapy meeting the trial’s primary safety goal and also improving patients’ quality of life.
The levels of several biomarkers for generating new arteries and anti-inflammatory markers also increased significantly with Lomecel-B treatment.
Results of the Phase 1 trial support the potential of Lomecel-B for Alzheimer’s patients. A follow-up Phase 2 study is scheduled to begin by the end of this year, according to Longeveron.
Longeveron’s Lomecel-B MSCs are stem cells derived from the bone marrow of young, healthy donors. This type of cell is thought to promote tissue repair, organ maintenance, and immune system function. As such, Longeveron believes that Lomecel-B can address multiple features of Alzheimer’s, including reducing brain inflammation, improving the function of arteries in the brain, reducing brain damage due to disease progression, and promoting regenerative responses.
Long-term Effects of Cholinesterase Inhibitors on Cognitive Decline and Mortality
The objective of the study was to investigate whether cholinesterase inhibitors (ChEIs) are associated with slower cognitive decline in Alzheimer dementia and decreased risk of severe dementia or death.
Patients with Alzheimer dementia from the Swedish Dementia Registry starting on ChEIs within 3 months of the dementia diagnosis were included and compared to non-treated patients with Alzheimer dementia.
Results The matched cohort included 11,652 ChEI users and 5,826 nonusers. During an average of 5 years of follow-up, 255 cases developed severe dementia, and 6,055 (35%) died. ChEI use was associated with higher MMSE score at each visit (0.13 MMSE points per year). ChEI users had a 27% lower risk of death compared with nonusers. Galantamine was associated with lower risk of death and lower risk of severe dementia and had the strongest effect on cognitive decline of all the ChEIs (0.18 MMSE points per year).
Conclusions ChEIs are associated with cognitive benefits that are modest but persist over time and with reduced mortality risk, which could be explained partly by their cognitive effects. Galantamine was the only ChEI demonstrating a significant reduction in the risk of developing severe dementia.
Classification of Evidence This study provides Class III evidence that for patients with Alzheimer dementia ChEIs decrease long-term cognitive decline and risk of death and that galantamine decreases the risk of severe dementia.
Dual Sensory Impairment and Cognitive Impairment in the Korean Longitudinal Elderly Cohort
Objective: To investigate the effects of single sensory impairment (SSI; visual or auditory) or dual sensory impairment (DSI; visual and auditory) on dementia and longitudinal changes of neuropsychological test scores.
In this nationwide, prospective, community-based elderly cohort study, KLOSCAD (the Korean Longitudinal Study on Cognitive Aging and Dementia), 6,520 elderly individuals (58–101 years) representing the general population were included. 932 had normal sensory function, 2,957 had an SSI, and 2,631 had a DSI. Demographic and clinical variables including cognitive outcomes were evaluated every 2 years over 6 years.
Results At baseline, DSI was significantly associated with increased dementia prevalence compared to normal sensory function, but SSI was not. During the 6-year follow-up, the incidence of dementia was significantly higher in the DSI group than in the normal sensory function group and neuropsychological scores significantly decreased.
Conclusions The results suggest that coexisting visual and hearing impairments facilitate dementia prevalence, dementia incidence, and cognitive decline, but visual or hearing impairment alone do not. Visual and hearing impairment may lead to dementia or cognitive decline independent of Alzheimer pathology.
Insufficient Evidence of Aducanumab Efficacy, ICER Draft Report Finds
A draft report from the Institute for Clinical and Economic Review, known as ICER, found that there is insufficient evidence to determine whether the investigational therapy aducanumab will provide health benefits to people with Alzheimer’s disease.
ICER is an independent non-profit research institute that works to assess the effectiveness and value of medicines and other medical services.
Notably, the institute’s Draft Evidence Report represents the midpoint of ICER’s assessment of the evidence on aducanumab — not a final decision.
Annovis Seeks Orphan Drug Status for ANVS401 for Down Syndrome Patients
Annovis Bio is seeking orphan drug status for its investigational therapy ANVS401, known as Posiphen, for treating Alzheimer’s disease in people with Down syndrome (DS-AD). Orphan drug designation is a way to help promising rare disease therapies reach market faster through certain development incentives.
The two Phase 2a trials are assessing the therapy’s safety and tolerability, as well as changes in disease-related biomarkers. Changes in the participants’ functional impairment, and cognitive, mental, and other neuropsychiatric symptoms also are being evaluated.
The DISCOVER study (NCT02925650) was designed to involve up to 24 adults with early Alzheimer’s at six locations within the United States.
A dose-finding and biomarker evaluation study (NCT04524351) is enrolling up to 68 participants, ages 45 and older, at 13 sites across the U.S. This trial includes both Alzheimer’s and Parkinson’s patients.
Posiphen is designed to reduce the formation of toxic clumps of misshapen proteins that damage nerves in both Alzheimer’s and Parkinson’s. In Alzheimer’s, it targets the beta-amyloid and tau aggregates, or clumps, that form in patients’ brains. It also targets the alpha-synuclein clumps that form in the brains of people with Parkinson’s.
Interim results from the DISCOVER study showed that Posiphen led to improvements in patients’ speed and coordination. The first three patients recruited into the combined Alzheimer’s and Parkinson’s study recently received their first doses of ANVS401.
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