Lessons learned from the failure of solanezumab as a prospective treatment strategy for Alzheimer’s disease

ABSTRACT

Introduction

In the last decade, the efforts conducted for discovering Alzheimer’s Disease (AD) treatments targeting the best-known pathogenic factors [amyloid–β (Aβ), tau protein, and neuroinflammation] were mostly unsuccessful. Given that a systemic failure of Aβ clearance was supposed to primarily contribute to AD development and progression, disease-modifying therapies with anti-Aβ monoclonal antibodies (e.g. solanezumab, bapineuzumab, gantenerumab, aducanumab, lecanemab and donanemab) are ongoing in randomized clinical trials (RCTs) with contrasting results.

Areas covered

The present Drug Discovery Case History analyzes the failures of RCTs of solanezumab on AD. Furthermore, the authors review the pharmacokinetics, pharmacodynamics, and tolerability effect of solanezumab from preclinical studies with its analogous m266 in mice. Finally, they describe the RCTs with cognitive, cerebrospinal fluid and neuroimaging findings in mild-to-moderate AD (EXPEDITION studies) and in secondary prevention studies (A4 and DIAN-TU).

Expert opinion

Solanezumab was one of the first anti-Aβ monoclonal antibodies to be tested in preclinical and clinical AD showing to reduce brain Aβ level by acting on soluble monomeric form of Aβ peptide without significant results on deposits. Unfortunately, this compound showed to accelerate cognitive decline in both asymptomatic and symptomatic trial participants, and this failure of solanezumab further questioned the Aβ cascade hypothesis of AD.

KEYWORDS:

• Alzheimer’s disease
• Aβ monoclonal antibodies
• solanezumab
• preclinical
• secondary prevention
• disease-modifying therapies

Article highlights

• Amyloid-β(Aβ) is a peptide believed to play a key role in the pathogenicity of Alzheimer’s disease (AD).

• Solanezumab is a humanized monoclonal antibody whose target engagement are soluble Aβ peptides of central nervous system, acting less on Aβ plaques.

• In transgenic mice PDAPP, acute and sub chronic treatment with solanezumab attenuated or reversed memory and learning deficits.

• Solanezumab did not lead to significant therapeutic benefits at the earlier AD stages according to large clinical (EXPEDITION trials) and secondary prevention studies (DIAN-TU Adaptive Prevention trial and A4).

• In AD, the substantial failure of solanezumab suggested that increased Aβ deposits could represent mainly a host response to an upstream pathophysiological process.

List of acronyms

AD: Alzheimer’s disease; Aβ: amyloid-β; IgG1: immunoglobulin G1; ARIAs: amyloid-related imaging abnormalities; RCTs: randomized clinical trials; FDA: Food and Drug Administration; MCI: mild cognitive impairment; PET: positron emission tomography; CSF: cerebrospinal fluid; A4: Anti-Amyloid Treatment in Asymptomatic AD; DIAN-TU: Dominantly Inherited Alzheimer’s Network-Trials Unit; APP: amyloid precursor protein; MMSE: Mini Mental State Examination; ADAS-Cog14: 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale; ADCS-iADL: Alzheimer’s Disease Cooperative Study – instrumental Activities of Daily Living; MRI: magnetic resonance imaging; LEARN: Longitudinal Evaluation of Amyloid Risk and Neurodegeneration; ASOs: antisense oligonucleotides

Declaration of interest

The authors have no other 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This paper was supported by the Project “Development of an ensemble learning-based, multi-dimensional sensory impairment score to predict cognitive impairment in an elderly cohort of Southern Italy” funded by the European Union – Next Generation EU – NRRP M6C2 – Investment 2.1 Enhancement and Strengthening Biomedical Research within the NHS (Grant Agreement PNRR-MAD-2022-12376656).