The discovery of novel Alzheimer’s biomarkers is enabling better trial selection, earlier pipeline decision making and new targets for therapeutics.
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Alzheimer’s research is having a moment, and the discovery of novel biomarkers is enabling progress far beyond diagnostics.
Since their role in Alzheimer’s disease (AD) was first identified in the 1980s, amyloid beta and tau proteins have been the hallmark AD biomarkers. And while the anti-amyloid theory is regaining traction, researchers now understand there are many pathologies and co-pathologies involved in the disease.
Laura Nisenbaum, Ph.D., executive director of drug development at the Alzheimer’s Drug Discovery Foundation (ADDF), envisions a future of precision medicine, drug regimens tailored to each patient - as is currently the case in cancer therapeutics.
“Alzheimer’s is about 30 years behind where cancer research is,” she said.
Utilizing extensive biomarker testing, physicians could prescribe a combination of therapies based on the specific physiology of their patient’s unique disease.
Combining different therapies would allow us to “go beyond the type of effects that are beginning to be seen in the anti-amyloid base,” Nisenbaum said.
Novel Biomarkers Inform Trials
Historically, up to 30% of patients enrolled in AD drug trials didn’t actually have the disease, as defined by pathology, she said.
The advancement and accessibility of biomarker testing lends itself to more accurate diagnoses, enabling recruitment of the right people into the right trials.
Research suggests degeneration from AD begins 15-20 years before clinical manifestation, making early detection critical to treatment.
Backed by ADDF’s Diagnostics Accelerator, molecular diagnostics company DiamiR is developing CogniMIR, a blood-based assay that measures levels of specific microRNAs to detect synaptic dysfunction and neurodegeneration before clinical presentation. It can also predict disease progression.
Foregoing the needle, Israel-based NeuraLight is developing a platform to detect biomarkers in neurological diseases, including AD, utilizing oculometric measures.
NeuraLight’s platform monitors micro-movements of the eye.
"[This provides] a signature of the neurodegeneration of the brain…, the acuity of the disease and how much it has progressed,” Micha Breakstone, Ph.D., CEO and co-founder, told BioSpace.
The ocular markers are highly sensitive to indicate change. They also offer an objective marker that “reduces noise and variability” compared to other measurements that are more subjective and “questionable,” Breakstone said.
The technology not only opens the door for earlier, non-invasive diagnosis, but it can also detect efficacy early in clinical development, leading to less time lost on trial flops.
Biomarkers can help companies “make rigorous decisions about whether to continue to explore a particular therapeutic target or mechanism of action, or to move to another approach,” Nisenbaum said.
TDP-43 and ApoE4
As biomarkers evolve to improve clinical trial outcomes, they may also have a role in building the therapeutic pipeline.
The TDP-43 protein has already shown promise as a druggable biomarker for ALS, a neurodegenerative disease with some pathological connections to AD.
PrimeC, a combination therapy being developed by NeuroSense Therapeutics, reduced functional and respiratory deterioration and led to statistically significant changes in ALS-related biological markers in a Phase IIa study.
TDP-43 is known to cause neuroinflammation, and its characteristics suggest an interaction between this biomarker and amyloid beta or tau.
In January, NeuroSense released results from a biomarker study that showed the protein was elevated in AD patients compared with a control group.
Alon Ben-Noon, co-founder and CEO of NeruoSense, started the company to tackle ALS.
“Honestly, I didn’t think at the time about Alzheimer’s at all,” he told BioSpace. But, as the data progressed and the biomarker study revealed the huge potential, he deemed it worth the effort to try to advance another therapy in the AD space.
Based on the biomarker study, NeuroSense will commence a Phase II double-blind proof-of-concept study to test the therapy in AD in the first half of 2023. The company has partnered with NeuraLight to track ocular biomarkers in clinical trials.
Another prime biomarker for the development of Alzheimer’s disease is the apolipoprotein E (APOE)4 gene variant. While 15% of healthy people have the variant, it is present in over 50% of AD patients. APOE4 is considered to be the strongest risk factor gene for the disease.
Armed with that knowledge, Lexeo Therapeutics is developing LX1001, an AAV-based gene therapy, for patients with this mutation.
LX1001 is designed to work by delivering the apolipoprotein E2 (APOE2) gene into the central nervous system in an attempt to halt or slow disease progression.
The gene therapy is currently in Phase I/II trials.
