Research Highlights from Padmaja Genesh - July 2021
FDA Approves Aduhelm, First Targeted Alzheimer’s Therapy
On June 8, 2021, US Food and Drug Administration (FDA) approved Aduhelm, an Alzheimers’ drug developed by Eisai and Biogen under the name Aducanumab, as a disease-modifying therapy to slow down the progression of mild cognitive impairment (MCI) due to Alzheimer’s disease and early/mild Alzheimer’s disease. This makes Aduhelm (Aducaumab) the first drug to obtain approval in the last 20 years.
However, this approval has come against the recommendation of an independent advisory committee to the FDA that reviewed Phase 3 study findings and concluded that there is insufficient evidence of Aducanumab’s efficacy and benefits to persons with Alzheimer’s disease. As it was developed to slow progression in persons with MCI, it is not an option for persons with moderate or advanced disease since it is unlikely to benefit them. It is a conditional approval in the U.S. with an obligation of the drug manufacturer to continue to study the drug for benefits and harms, post-approval. It is expected to cost $56,000 per year of treatment.
Cholinesterase Inhibitors Found to Slow Long-term Cognitive Decline
A recent study fond that cholinesterase inhibitors, a class of drug used for treating Alzheimer’s disease, are linked to long-term reductions in cognitive decline and in the risk of death among patients.
In fact, the cognitive benefits and reduced mortality lasted for up to five years after diagnosis.
Folks receiving cholinesterase inhibitors showed an association with higher cognition at their follow-up, with Razadyne presenting the largest effect size (0.18 MMSE points change). There were no significant differences among different cholinesterase inhibitors’ effects on cognition.
Of the 17,478 patients in total in the analysis, cholinesterase inhibitor users had 27% lower mortality than non-users. Razadyne (Galantamine) users had the largest decrease (29%) in mortality compared with non-users, while those on Aricept had a 22% reduction, and those taking Exelon a 14% decrease. Additionally, among the three cholinesterase inhibitors evaluated, Razadyne (Galantamine) was the only one that significantly reduced the risk of developing severe dementia among Alzheimer’s patients.
The study was among the first to investigate the effects of cholinesterase inhibitors on cognition and to evaluate the therapies’ overall long-term impact, according to investigators.
Gosuranemab Fails TANGO Trial; Biogen Stops Development
Gosuranemab, previously known as BIIB092, was designed for diseases characterized by the build-up of toxic clumps (aggregates) of the tau protein. The antibody binds to a specific domain in the tau protein, called the N-terminal, which would reduce the spread of the abnormal form of this molecule within nerve cells, potentially slowing disease progression.
In previous studies, Gosuranemab was shown to bind to its target in the cerebrospinal fluid, which is the liquid that surrounds the brain and spinal cord.
In the international TANGO Phase 2 study (NCT03352557), TANGO had recruited 654 adults, ranging in age from 50 to 80, with mild Alzheimer’s or mild cognitive impairment (MCI) due to the disease. However, Biogen has announced that the study failed to meet its primary and exploratory efficacy goals.
Now, the TANGO trial has been terminated and Biogen will cease the clinical development of Gosuranemab as a potential therapy for Alzheimer’s disease patients.
Dosing Starts in Phase 3 Trial of ALZ-801 in Patients with APOE Variant
The first patient has been dosed in APOLLOE4, a Phase 3 trial testing the efficacy and safety of ALZ-801, an investigational oral treatment by Alzheon for people carrying a specific genetic variant linked to early onset, rapidly progressive Alzheimer’s disease.
This investigative treatment is for patients who carry a specific variant in the apolipoprotein E gene (APOE), known as APOEE4, linked to an earlier age of disease onset and an increased risk of rapid progression. It is thought that people with two copies of APOE4/4 — estimated to be about 15% of all Alzheimer’s patients — may benefit most from an anti-amyloid therapy like ALZ-801.
ALZ-801 is a small molecule designed to prevent the formation and clustering of harmful Beta-amyloid protein that play a role in the development of Alzheimer’s. It does this by releasing Tramiprosate, a compound that protects nerve cells by blocking the formation of soluble small protein fragments that damage those cells and are associated with the onset of Alzheimer’s cognitive symptoms and progression.
APOLLOE4 (NCT04770220) aims to enroll 300 people, ages 50 to 80, with early Alzheimer’s and carrying two copies of APOE4 across about 85 sites in the U.S., Canada, and Europe. Patients will receive either 265 mg of ALZ-801 or a placebo tablet twice a day for 78 weeks (about one and a half years). More information can be found here; information on non-U.S. sites is not yet available, but may be gained by emailing firstname.lastname@example.org
Gantenerumab Lowers Key Protein Levels in Early-onset Disease Trial
A rare and inherited form of early onset Alzheimer’s, also known as dominantly inherited Alzheimer’s, is caused by a mutation in the PSEN1, PSEN2, or APP genes. People with these mutations experience a decline in thinking and memory starting in their 30s or 40s.
The investigational therapy Gantenerumab was found to significantly lower levels of established biomarkers in the inherited form of early-onset Alzheimer’s disease, despite failing to slow cognitive decline or memory loss in symptomatic and asymptomatic patients, according to data from a Phase 2/3 clinical trial.
Based on these results, enrolled patients may choose to continue, or start, on Gantenerumab as part of an open-label extension study.
Another possible treatment evaluated in the trial, Solanezumab, failed to either prevent cognitive decline or show an improvement in these biomarkers.
With New Trial Data, Lecanemab Wins FDA Breakthrough Status
Based on new evidence from an ongoing Phase 2b clinical trial, the U.S. Food and Drug Administration (FDA) has granted breakthrough therapy designation to Lecanemab, also called BAN2401, an investigational antibody for treating early Alzheimer’s disease.
The FDA’s decision was based on clinical evidence from Study 201, a Phase 2b (NCT01767311) trial that enrolled patients who had mild cognitive impairment or dementia and a confirmed presence of beta-amyloid deposits in the brain.
Results from Study 201 showed that, when given at the highest dose (10 mg/kg every other week), Lecanemab reduced deposits of beta-amyloid in the brain and slowed clinical decline. However, the trial failed to meet its main goal.
Compiled by Padmaja Genesh, Learning Specialist.
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