Chad Swanson, PhD, on the Promising Effect of BAN2401 on Alzheimer Disease Progression

November 15, 2018

The BAN2401 International Project Team Leader and Clinical Lead spoke about how the introduction of a novel, potentially disease modifying therapy would represent a paradigm shift in the field.

Chad Swanson, PhD

Just last month Eisai and Biogen announced additional topline data from Study 201 that explored the effect of BAN2401, their investigational anti-amyloid beta monoclonal antibody, on patients with Alzheimer disease.

The antibody demonstrated a statistically significant reduction in brain amyloid measured by positron emission tomography (PET) at 18 months (P <.0001). Additionally, BAN2401 displayed a significant slowing of clinical decline with those treated with the investigational agent, seeing a 30% greater slowing compared to placebo (P = .034), as measured by the Alzheimer’s Disease Composite Score (ADCOMS).1

To dive deeper, providing additional insight into the mechanism of action of the antibody and what differentiates it from other investigational therapies, NeurologyLive spoke with Chad Swanson, PhD, Senior Director, Neurology Business Group, BAN2401 International Project Team Leader and Clinical Lead, BAN2401-G000-201 Study Director, in an interview.

NeurologyLive: Can you talk about the mechanism of action for BAN2401?

Chad Swanson, PhD: BAN2401 is an anti-amyloid beta monoclonal antibody that has low affinity for amyloid-beta (Aβ) monomer and high affinity for large soluble aggregated Aβ species, which are sometimes referred to as protofibrils. BAN2401 is at least a thousand-fold more selective for protofibrils over the monomer. Now, among the aggregated species themselves, BAN2401 shows at least 10-fold preferential activity for protofibrils over insoluble fibrils, which make up amyloid plaque.

We’ve seen in preclinical studies that BAN2401 can both neutralize these large soluble aggregates and it can clear them from the brains of animals via phagocytosis. Moreover, we’ve shown in Study 201 that clearance of brain amyloid is correlated with slowing in disease progression in early Alzheimer disease as measured by multiple clinical outcome assessments, including Alzheimer’s Disease Composite Score (ADCOMS), Alzheimer’s Disease Assessment Scale-Cog (ADAS-Cog), and Clinical Dementia Rating Scale (CDR) Sum of Boxes (CDR-SB).

How does this therapy differ from other potential therapies?

CS: Currently, there’s nothing approved to delay disease progression in patients with early Alzheimer disease, which is defined as subjects who either have mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease dementia. Drugs on the market today such as donepezil are approved to provide symptomatic relief for patients with mild to severe Alzhemier disease dementia.

As mentioned, BAN2401 has low affinity for Aβ monomers and high affinity protofibrils, with at least a thousand-fold selectivity for protofibrils over monomers. Preclinical studies have shown that it is the protofibrils that are considered toxic to the synapse, whereas the monomers are considered to be far less toxic. The pharmacological profile of BAN2401 is different than many of the other anti-Aβ monoclonal antibodies that have been in development due to the fact that they have generally had higher affinity for monomer in addition to affinity for aggregated species. The high concentration of monomer in plasma may limit antibody engagement with aggregated species in the brain, and thus may significantly limit activity for antibodies with high affinity for monomers.

As a result, we believe BAN2401 has the potential to more substantially impact amyloid and particularly the toxic amyloid aggregated species, in the brain compared to other antibodies that have been tested in the past for Alzheimer disease, thereby having effects on clinical outcomes.

What is the clinical impact that BAN2401 could have on this patient population?

CS: There are currently no approved therapies for patients with early Alzheimer disease and, as such, introduction of a novel, potentially disease modifying therapy would represent a paradigm shift in the field.

Transcript edited for clarity.

REFERENCE

1. https://www.neurologylive.com/clinical-focus/ban2401-displays-promising-effect-alzheimer-disease-progression