At the 2019 International Congress on Alzheimer’s Disease (AD) and Parkinson’s disease (PD) in Lisbon, Portugal, scientists and researchesr presented the new opportunities and the lessons learnt in trials with monoclonal antibodies (mAbs).

This followed all the failures that affected the AD pipeline, especially in AD drugs targeting the amyloid pathways, such as Roche’s crenezumab and lastly Biogen/Eisai aducanumab, the most promising drug in the AD pipeline.

Several clinical trials of mAbs were conducted in the past few years with clear no success in terms of efficacy, the list include Pfizer’s bapinezumab and ponezumab, Eli Lilly’s solanezumab and donanemab, Roche’s crenezumab and gantenerumab and Biogen’s/Eisai’s aducanumab.

In all this trials scientists and researcher learnt that the most neurotoxic species of amyloid-beta (Aβ) is the soluble oligomer, which has emerged as the central target for disease modifying treatment (DMT) including mAbs.

Clearance of fibrillar Aβ is perhaps not an essential goal of treatment but may occur as an epiphenomenon to clearance of oligomers and reducing fibrillar Aβ at the cost of augmenting soluble species could actually be harmful. MAbs directed against the N-Terminus of Aβ may be most effective in clearing toxic aggregated species of Aβ (including oligomers and protofibrils).

In clinical trials of these amyloid-lowering therapies under development for AD, Amyloid-related imaging abnormalities-edema (ARIA-E) has been reported with increased incidence in patients with mild to moderate AD. Scientist hypothesized that if ARIA-E is caused by clearance of fibrillar Aβ from cerebral vessels, then mAbs with conformationally specific epitopes selective for soluble aggregated species (oligomers and protofibrils) may avoid ARIA-E. In fact if ARIA-E is more related to inflammation, then humanized mAbs lacking the microglia-activating the fragment crystallizable region (Fc) could emerge as promising therapies even though remain unclear whether the infrequency of ARIA-E with crenezumab is related to its IgG4 structure or its mid-domain epitope.

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At this moment there are still question to be answered as it is still unclear whether early interventions necessary for treatment benefit, for example, whether an Aβ cascade is initiated such that deterioration can no longer be slowed, or whether in the setting of advanced Aβ deposition, modest Aβ clearance is irrelevant. Empiric trial evidence for this viewpoint is limited in the post-hoc analyses from the Phase III solanezumab program and the phase II crenezumab trial.

Earlier intervention with a DMT, including mAbs, is advantageous and this is the reason why there are additional studies of pre-clinical AD to join the ongoing secondary prevention trials: Anti-Amyloid Treatment in Asymptomatic AD trial (A4) for solanezumab, AD Prevention Initiative (API) for crenezumab, and Dominantly Inherited AD Network (DIAN-TU) for solanezumab and gantenerumab.

Anti-amyloid mAbs bind different epitopes and conformations of Aβ and N-terminal antibodies have demonstrated safety but have failed in clinical endpoints in mild-dementia and prodromal AD. However, it remains unclear whether Aβ plaque clearance is a necessary feature of an effective anti-amyloid antibody and early interventions is necessary for any treatment benefit.

Lessons learnt from all mAbs trials taught that mild patients may respond better and ARIA occurs and must be monitored in mAbs trials. Clinical effects can be shown and more sensitive approach may be useful such as the AD Composite Score (ADCOMS). Design innovation, such as adaptive design can address some issue of AD drug development (dose, duration and adverse events management) and the use of biomarkers can support the downstream effect.

After the discontinuation of Biogen’s/Eisai’s aducanumab the hope for scientists and experts in the field is on Biogen’s/Eisai’s BAN2401, that entered phase III trial last week and is considered to be the most promising drug in the AD pipeline. Several clinical trials have been discontinued due to failure to reverse or even slow the cognitive decline associated with the disease, leading some researchers to question if they are pursuing the right target.

However, scientists and researchers have still hope in target amyloid as a potential treatment of AD even though they also think that amyloid should not be the only target but target in combination, and they agreed that the approval of a new drug for this indication is still far away. Future antibodies may be designed to dissociate efficacy and ARIA-E and combination of therapies can be seen as a more common trend in the field, namely mAb with bace inhibitors and combination of mAb and anti tau therapies.