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The history of Alzheimer’s Disease (AD) has followed a long and winding road from the earliest days of investigation by Dr. Alois Alzheimer to the recent controversial approval of Aduhelm. Despite the low success rate for AD therapies, scientific understanding of AD has advanced significantly and researchers are applying this knowledge to ongoing investigations.
Realization that toxic oligomers are the cause
Research as far back as the mid-1990s identified toxic oligomers as a source of neurotoxicity, although the findings were diluted by other work in the field that implicated other forms of amyloid-beta. Many candidates were repeatedly put to the test with antibodies broadly targeting all types of amyloid-beta such as solanezumab, bapineuzumab, gantenerumab and others. However, the efforts failed as the mechanism did not center on toxic oligomers.
As more non-specific approaches were being applied to amyloid-beta, investigators began to realize the key role that amyloid-beta oligomers play in toxicity and propagation. It isn’t the monomers or plaques that damage neurons but the small toxic oligomers that cause the injury that leads to AD.[i] This realization has allowed pioneers in the space to pursue therapies that specifically target these misfolded proteins in an effort to neutralize them and stop AD.
While biomarkers have been used to evaluate health from time immemorial, it was not until the ‘80s and ‘90s that laboratories, devices and collection techniques became sufficiently sophisticated to measure the wide variety of biological parameters that indicate health and complex disease. Biomarkers can be used for screening, diagnosis, monitoring, therapeutic interventions and patient response in clinical studies. They also offer utility as prognostic indicators.
In 2018, the FDA began to accept biomarker use for surrogate endpoints in AD clinical trials. FDA Guidance described a pathway for accelerated approval based on a biomarker thought to be reasonably likely to predict clinical benefit, coupled with a post-approval plan to gather evidence on clinical outcomes. Full approval is reliant upon demonstrating a drug-placebo difference as a clinical outcome.
Some of the Players
Several sponsors are advancing candidates that address the underlying cause of AD and the specific species of amyloid-beta behind neurodegeneration. mAbs targeting toxic oligomers include Acumen Pharmaceuticals’ (ABOS) ACU193 and ProMIS Neurosciences (PMN) PMN310. These programs recognize the importance of selecting the right target (toxic oligomers), avoiding damaging side effects (ARIA) and employing biomarkers to get the right drug to the right patient. Eli Lilly’s (LLY) donanemab targets both oligomers and plaque and is another leading contender in the space.
ACU193 is a humanized IgG2 mAb in development by Acumen Pharmaceuticals. It selectively binds to soluble amyloid-beta oligomers. The candidate is enrolling Alzheimer’s patients with mild cognitive impairment or mild dementia in a Phase I clinical trial designated INTERCEPT-AD. Preclinical studies in a mouse model demonstrated behavioral deficits improvements in open field and maze evaluations. These non-clinical data support the toxicity of amyloid-beta oligomers and the selective binding of ACU193 to these proteins.
The Phase I study’s primary goal is to determine safety and proof of mechanism. The trial is also comparing ACU193 against patients in a placebo arm which may provide cognition and biomarker data. Topline data are expected in 2023.
Another next-generation candidate that exhibits specificity and minimizes the risk of ARIA-E is on the cusp of starting a Phase I study. ProMIS Neurosciences’ lead candidate, PMN310, is preparing for a Phase I clinical trial, with completion of IND-enabling work expected soon. PMN310 uses the IgG1 isotype backbone, which is in contrast to ACU193’s IgG2 isotype. IgG1 has effector function, which promotes clearance of unwanted amyloid-beta, with minimal concern regarding ARIA risk since PMN310 does not bind to plaques. The nominal risk of ARIA should also allow higher dosing and potentially better efficacy than predecessors.
ProMIS differentiates itself from its neurodegenerative peers with its discovery platform[ii] which identifies epitopes unique to misfolded proteins, allowing for target specificity. Its antibodies have demonstrated selective binding to oligomers and maintenance of short term memory in an animal model.
Lilly’s donanemab is a humanized IgG1 monoclonal antibody (mAb) which contrasts with other amyloid-beta approaches by its use of pyroglutamate as a target. Pyroglutamate is a target for monoclonal antibody therapies given its unique signature. It is a natural amino acid derivative and it participates in an intermediate step in the production of glutathione, a potent anti-oxidant. Pyroglutamylated amyloid-beta is associated with amyloid-beta misfolding into more toxic aggregates.[iii],[iv] It accelerates the aggregation of amyloid-beta[v] and can also be found in plaque.
Eli Lilly is conducting a Phase III trial investigating donanemab in an ongoing randomized, placebo-controlled, double-blind, multi-center study. Lilly has started a rolling submission of a BLA to the FDA based on success of its Phase II trial that showed an improvement in cognition and daily function in patients that took the drug.
What does the Future Hold?
Despite the limited successes that have been experienced over the last decades, much has been learned and medical research is better positioned to target the source of disease and develop drugs to fight it. While early therapies in AD were only able to treat symptoms and later candidates indiscriminately targeted a broad spectrum of amyloid beta species, new prospects in active development are more selective for toxic oligomers and in some cases go even further to employ new structures to engage the immune system. Subsequent approaches, such as the use of intrabodies, may advance the field even further and rapidly evolving techniques such as gene therapy may take the baton from today’s leaders in the future.
For extended version of this article please click here.
See the previous chapters in A Tale of Tangles:
A Tale of Tangles We Weave / Extended Version
What’s Behind Alzheimer’s Disease? / Extended Version
The Desert Expanse / Extended Version
Image Credit: Tkgd2007, Wikimedia Commons
[i] Benilova, I. et al. The toxic Abeta oligomer and Alzheimer's disease: an emperor in need of clothes.
[ii] The computational platforms are called ProMIS and Collective Coordinates.
[iii] Galante D, et al. A critical concentration of N-terminal pyroglutamylated amyloid beta drives the misfolding of Ab1-42 into more toxic aggregates. Int J Biochem Cell Biol. 2016 Oct; 79():261-270.
[iv] Perez-Garmendia, R., Gevorkian, G. Pyroglutamate-Modified Amyloid Beta Peptides: Emerging Targets for Alzheimer´s Disease Immunotherapy. Current Neuropharmacology, 2013, 11, 491-498
[v] Lee J, et al. Role of the fast kinetics of pyroglutamate-modified amyloid-beta oligomers in membrane binding and membrane permeability. Biochemistry. 2014 Jul 22; 53(28):4704-14.