What’s Next for Alzheimer’s Medications?
Abstract
The pipeline for Alzheimer’s disease treatment is still filled with drug candidates targeting beta-amyloid, but the clinical research has shifted to a much earlier stage of the disease before symptoms appear.
Experimental treatments that block the aggregation of beta-amyloid in the brain have repeatedly failed to demonstrate clear efficacy in clinical trials of Alzheimer’s disease (AD) over the past decade. However, scientists are not ready to abandon beta-amyloid as a viable target of new therapies, given that the amyloid theory is still the best understood part of AD’s pathology supported by genetics and imaging data.
One example of continued development of anti-beta-amyloid therapy is solanezumab, a monoclonal antibody that binds to beta-amyloid peptides to prevent the formation of plaques. Although it failed two large phase 3 clinical trials, Eli Lilly has continued with its development after subgroup analysis suggested that it might have efficacy during the early stage of AD.
Currently, solanezumab is being tested in a couple of clinical trials in people who have prodromal AD or no clinical symptoms of dementia but who have signs of beta-amyloid pathology on brain scans. The hope is that if beta-amyloid aggregation can be halted early, AD can be prevented or at least delayed.
At the Alzheimer's Association International Conference (AAIC) held in Toronto in July, research into beta-amyloid, tau tangles, and inflammatory processes all garnered attention in the hunt for cures.
Work on Anti-Beta-Amyloid Candidates Continues
Similar to Eli Lilly’s approach with solanezumab, Roche has revived the clinical development of its anti-amyloid antibody gantenerumab after it failed to meet expected efficacy in previous trials. The company is collaborating with Eli Lilly to conduct a phase 2/3 trial that tests both gantenerumab and solanezumab for the prevention of AD in people with a dominant genetic mutation known to cause AD.
Meanwhile, Biogen has two anti-beta-amyloid drug candidates in development: aducanumab in phase 3 trials in collaboration with Neurimmune and BAN2401 in phase 2 trials with Eisai.
Some researchers believe beta-secretase 1 (BACE1) inhibitors, which block the enzyme that makes beta-amyloid peptides, are a key therapeutic target for AD. Several BACE1 inhibitors currently in testing include E2609 developed by Eisai and Biogen and MK-8931 by Merck and Co., both in phase 2 development, and CNP520, co-developed by Novartis and Amgen.
In addition, Novartis and Amgen are co-developing CAD106, which is said to induce the immune system to produce anti-beta-amyloid antibodies for AD treatment. The companies believe the approach could prove useful for delaying the disease onset and progression of AD.
Effectiveness of Anti-Tau Drugs Examined
While the role of aggregated tau protein in the pathology of dementia is much less understood than beta-amyloid, researchers have become increasingly interested in tau as a target for treating Alzheimer’s.
At AAIC, TauRx Pharmaceuticals announced the results from its double-blind, placebo-controlled phase 3 trial of its tau aggregation inhibitor known as LMTX (the first anti-tau drug to reach this stage of development). The active ingredient of LMTX is methylthioninium, or methylene blue, a commonly-used staining agent.
The results were disappointing; LMTX did not achieve the primary endpoints in the improvements of cognition and daily function in AD patients with mild and moderate symptoms after 18 months of treatment. Some benefits were reported in a small subgroup of patients who took LMTX monotherapy, but not in the majority of other patients, who took LMTX in combination with currently available AD treatments. The company is also conducting a trial of LMTX to treat frontotemporal dementia, and the results are expected later this year. The future development of LMTX is unclear at this stage.
Other research suggests that methylene blue could delay or reduce symptoms in people in the early stages of disease.
Axon Neuroscience based in Slovakia is also conducting phase 2 studies on AADvac1, an anti-tau-protein vaccine.
Other Approaches Widen the Search
Beta-amyloid and tau are not the only targets of Alzheimer’s therapies in development.
At AAIC, Anavex Life Sciences Corp. announced early results from an ongoing phase 2a study, in which ANAVEX 2-73, a sigma-1 receptor agonist, was given to 32 patients with mild to moderate AD. The open-label study was primarily intended to identify the maximum tolerated dose using an adaptive trial design. While the company reported that the study participants experienced a flat or slight decline in cognitive and functional indicators after 31 weeks, they noted it remains unclear how the drug will stack up in a randomized, placebo-controlled study.
Bryostatins—a group of naturally occurring molecules discovered in a species of marine organisms that act on protein kinase C—are also being tested for the treatment of AD, Fragile X syndrome, cancer, and other diseases. Neurotrope Bioscience is conducting a phase 2 study to compare bryostatin 1 with placebo in patients with moderate to severe AD.
AC-1204 is an oral drug that induces mild ketosis in the brain. There is evidence to suggest that ketones, which offer an alternative energy source to glucose in the brain and inhibit neuronal stress, may offer protection against some brain diseases. The medication is being tested in a phase 2/3 trial by Accera Inc. Top-line results are expected to be announced in December. ■
