Clinical development of passive tau-based immunotherapeutics for treating primary and secondary tauopathies

ABSTRACT

Introduction

Tauopathies are clinicopathological entities with increased and pathological deposition in glia and/or neurons of hyperphosphorylated aggregates of the microtubule-binding protein tau. In secondary tauopathies, i.e. Alzheimer’s disease (AD), tau deposition can be observed, but tau coexists with another protein (amyloid-β). In the last 20 years, little progress has been made in developing disease-modifying drugs for primary and secondary tauopathies and available symptomatic drugs have limited efficacy.

Areas covered

The present review summarized recent advances about the development and challenges in treatments for primary and secondary tauopathies, with a focus on passive tau-based immunotherapy.

Expert opinion

Several tau-targeted passive immunotherapeutics are in development for treating tauopathies. At present, 14 anti-tau antibodies have entered clinical trials, and 9 of them are still in clinical testing for progressive supranuclear palsy syndrome and AD (semorinemab, bepranemab, E2814, JNJ-63733657, Lu AF87908, APNmAb005, MK-2214, PNT00, and PRX005). However, none of these nine agents have reached Phase III. The most advanced anti-tau monoclonal antibody for treating AD is semorinemab, while bepranemab is the only anti-tau monoclonal antibody still in clinical testing for treating progressive supranuclear palsy syndrome. Further evidence on passive immunotherapeutics for treating primary and secondary tauopathies will come from ongoing Phase I/II trials.

KEYWORDS:

• tau
• PSPS
• FTLD-Tau
• Alzheimer’s disease
• mild cognitive impairment
• monoclonal antibodies
• dementia
• tauopathies

Article highlights

• In primary tauopathies and Alzheimer’s disease (AD), a secondary tauopathy, aggregated and hyperphosphorylated protein tau is one of the main drivers of neurodegeneration.

• In primary and secondary tauopathies, anti-tau treatments are being developed to interfere with the aggregation process or to promote the clearance of tau protein.

• Tau-based passive immunotherapeutics in clinical trials mainly target extracellular tau, cutting its aggregation and intercellular spreading.

• At present, 14 anti-tau antibodies have entered clinical trials, and 9 of them are still in clinical testing for primary tauopathies and AD (semorinemab, bepranemab, E2814, JNJ-63733657, Lu AF87908, APNmAb005, MK-2214, PNT00, and PRX005).

• The most advanced anti-tau monoclonal antibody for treating AD is semorinemab, while bepranemab is the only antibody still in clinical testing for treating progressive supranuclear palsy syndrome.

• Five other anti-tau monoclonal antibodies have been discontinued for the treatment of primary/secondary tauopathies (gosuranemab, tilavonemab, zagotenemab, RG7345, and BIIB076).

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the Italian Ministry of Health, Progetto Malattie Croniche non Trasmissibili (MCnT) ad alto impatto sui sistemi sanitari e socio-assistenziali Grant PNRR-MAD-2022-12376656.