Prothena’s Promise: Revolutionizing Alzheimer’s Treatment with a Breakthrough Therapy

• PRX012, a next-generation subcutaneous antibody, has the potential to eliminate treatment obstacles due to its unique pharmacological properties and improved binding profile compared to conventional amyloid-beta targeting medicines.
• PRX123, targeting the hallmarks of Alzheimer’s, Aβ plaque, and tau tangles, has the potential to revolutionize the treatment regime, and offers a beacon of hope for Alzheimer’s prevention.

The Alzheimer’s drugs market has made significant progress, especially in the last half-decade, with more amyloid beta-protein-targeted monoclonal antibodies entering the market space. With the evolving paradigm  of “amyloid hypothesis”, there are many hopes and dreams for finding disease-modifying therapies for Alzheimer’s. 

At the recently concluded American Academy of Neurology Annual Meeting (2024), in Denver, Prothena presented results from its two transformative assets, PRX012, which targets amyloid beta (Aβ), and PRX123, a novel dual amyloid beta-tau (Aβ-Tau) vaccine. 

In the abstract titled “Binding Characteristics of PRX012 Surrogate Demonstrate Potent Engagement of Toxic Amyloid Beta Protofibrils and Robust Clearance of Pyroglutamate-modified Amyloid Beta”, Prothena described evaluations that compared the binding of a PRX012 surrogate and lecanemab to Aβ protofibrils, characterized by surface plasmon resonance. It also compared the ability of PRX012 and donanemab to induce microglial clearance of pyroglutamate-Aβ from Alzheimer’s disease plaques.

PRX012, a next-generation subcutaneous antibody targeting epitope at the N-terminus of Aβ, outperformed LEQEMBI, by having a 20 times higher affinity to Aβ soluble protofibrils. It also removed pyroglutamate-modified Aβ, a component of senile plaques and vascular amyloid, at lower quantities than Eli Lilly’s donanemab.  Aβ plaque reduction, neutralization of toxic Aβ protofibrils, and clearance of pyroglutamate-modified Aβ in plaques, all correlate with slowing clinical decline in Alzheimer’s.

Prothenas’s PRX012, a US FDA-designated drug, neutralizes and clears aggregated forms of amyloid beta, such as protofibrils and plaques, at low doses due to its high binding avidity. Its unique pharmacological attribute along with a superior binding profile, is an almost perfect recipe to reduce barriers to treatment and establish it as a potential best-in-class anti-Aβ immunotherapy at a low volume, with infrequent subcutaneous dose. 

Prothena also presented results from the preclinical studies evaluating the in vivo efficacy of PRX123, in a transgenic mouse model expressing human amyloid precursor protein and with aggressively high Aβ pathology in an abstract titled “ Dual Amyloid Beta/Tau Vaccine PRX123 Surrogate Results in Robust Clearance of Amyloid Plaques in Brains of Aggressive APP/PS1 Mouse Model.”

Accumulation of Aβ plaque and tau tangles throughout the brain are hallmarks of Alzheimer’s disease.  Clinical evidence demonstrates that N-terminal anti-Aβ antibodies capable of robustly reducing Aβ plaques in the brain, mostly slow cognitive decline in Alzheimer’s, while anti-MTBR-tau antibodies suppress the pathogenic spatiotemporal spread of tau. It is therefore hypothesized that simultaneously disrupting these pathologic processes has the potential to address the major unmet of Alzheimer’s treatment and provide the much-needed preventive treatment.

Vaccines that target Aβ and tau may prevent or delay the clinical manifestation of Alzheimer’s by generating responses capable of intercepting both pathologic processes simultaneously. Attempts were made earlier as well to develop vaccines but were shelved after enrolled participants developed a brain inflammation known as meningoencephalitis. 

PRX123 generated robust immunogenic responses, producing antibodies that help remove Aβ plaques and neutralize MTBR-tau. It generated robust antibody titers strong enough to bind structural elements of Aβ plaques and tau tangles in post-mortem Alzheimer’s brain tissue, reaching concentrations comparable to those found in plasma (0.3%). Immunohistochemical analysis of brain tissue from vaccinated APP/PS1 mice established a significant reduction in cortical Aβ plaques compared with a nonsense peptide control group. The degree of plaque clearance achieved with PRX123s immunization was comparable to a plaque-clearing N-terminal monoclonal antibody, used as positive control.

A dual Aβ-Tau vaccine, PRX123, targets epitopes within Aβ and tau proteins, promoting amyloid clearance while blocking pathogenic tau interaction. This combination has the potential to not only treat but also prevent Alzheimer’s, offering a unique advantage not that only enhances its commercial viability but also underscores its potential to reach patients in need. The US FDA has cleared its IND application, with Phase I scheduled for 2024.

Despite all the positives, experimental vaccines still have a long and challenging path ahead, but breakthroughs in this space will be instrumental in driving growth and changing the Alzheimer’s treatment landscape, answering the unmet.