More Specificity is What the Doctor Ordered

Photo by Steven HWG on Unsplash

The following post was written and/or published as a collaboration between Benzinga’s in-house sponsored content team and a financial partner of Benzinga.

Alzheimer’s disease (AD) is one of human health’s most relentless adversaries.  In just a few years it is expected to be the highest cost disease Americans face, overtaking heart disease and cancer.  One of the driving factors for this shift is the lack of a cure.  

The last few years have been dramatic ones for the most prominent candidate in AD, Biogen’s BIIB Aduhelm.  With an early halt to its trial in 2019 and a tumultuous reversal of fortunes over the next two years, Biogen’s monoclonal antibody (mAb) was eventually approved by the FDA in June 2021.  While it does not work as well as many desired, it is providing patients hope.  Aduhelm’s approval was important as it shows the drug is doing some things right and provides a template for the next generation of candidates. 

First Generation Aβ AD Candidates

mAbs that were developed over the last decade and a half were mostly non-specific as to the type of amyloid β they targeted and frequently produced inflammatory side effects.  Some efficacy was observed in early trials, but the signal for most of these first generation candidates wasn’t enough to get approved.  Not only did these mAbs bind to toxic oligomers, which have strong scientific support as the cause of AD, but also to monomers and plaques which don’t.  Monomer and plaque binding siphoned away the drug and caused potentially fatal swelling in the brain. 

Source: https://commons.wikimedia.org/w/index.php?curid=16969598

Second Generation Candidates

To remedy the distraction by harmless forms of amyloid β, a successful candidate must selectively bind only to toxic oligomers.   It should also avoid binding to plaques and vascular deposits which contributes to brain swelling or ARIA.  ARIA limits dosing and restricts the amount of drug that can sequester and target misfolded toxic oligomers for destruction.  

Several new candidates that appear to offer better specificity and selectivity and also avoid ARIA are now emerging into later stages of development.  Three candidates that stand out the most include Eli Lilly’s LLY donanemab, Acumen Pharma’s ABOS ACU193 and ProMIS Neurosciences’ PMN PMN310, each of which addresses the main disadvantages of earlier amyloid β targeting mAbs.

Donanemab

Lilly’s donanemab, a humanized IgG1 mAb, singles out pyroglutamate which appears on amyloid β peptides and is a target for mAbs given its singular features.  It is a natural amino acid derivative and an intermediate step in the production of glutathione, a potent anti-oxidant.   Pyroglutamylated amyloid β is associated with amyloid β misfolding into more toxic forms.,  It accelerates the aggregation of amyloid β and can also be found in plaque.

Eli Lilly is conducting a Phase III trial investigating donanemab and has started a rolling submission of a BLA to the FDA which may receive approval by 2H:22.  The application was based on success of its Phase II trial that demonstrated an improvement in cognition and daily function in patients receiving the drug.  

ACU193

ACU193, a humanized IgG2 mAb in development by Acumen Pharmaceuticals, selectively binds to soluble amyloid β oligomers.  The candidate is enrolling Alzheimer’s patients with mild cognitive impairment or dementia in a Phase I trial.  Preclinical studies in a mouse model showed behavioral deficit improvements in various memory tests.  These non-clinical data support the toxicity of amyloid β 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.  

PMN310

Another next-generation candidate that exhibits specificity and minimizes the risk of ARIA is on the cusp of starting a Phase I study.  ProMIS Neurosciences’ lead candidate, PMN310, is preparing to enter the clinic with completion of investigational new drug (IND)-enabling work targeted for 2H:22.  PMN310 uses the IgG1 isotype backbone, which promotes clearance of unwanted amyloid β, with minimal concern regarding ARIA since PMN310 does not bind to plaques.  The nominal risk of ARIA will also allow higher dosing and potentially better efficacy.

ProMIS offers a powerful discovery platform which identifies unique features on misfolded proteins, allowing for target specificity.  Its antibodies have demonstrated selective binding to oligomers and maintenance of short term memory in an animal model.

View the full version of this article here.

The preceding post was written and/or published as a collaboration between Benzinga’s in-house sponsored content team and a financial partner of Benzinga. Although the piece is not and should not be construed as editorial content, the sponsored content team works to ensure that any and all information contained within is true and accurate to the best of their knowledge and research. This content is for informational purposes only and not intended to be investing advice.