The potential of solanezumab and gantenerumab to prevent Alzheimer’s disease in people with inherited mutations that cause its early onset

ABSTRACT

Introduction: The recent failure of several clinical trials on anti-β-amyloid (Aβ) drugs in Alzheimer’s disease (AD) suggested earlier intervention in the disease course. Secondary prevention trials have been started in autosomal-dominant AD (ADAD) individuals without cognitive dysfunction and in cognitively healthy subjects at risk of developing sporadic AD (SAD).

Areas covered: Herein, the authors discuss prevention trials in ADAD and SAD, with a focus on the anti-Aβ monoclonal antibodies solanezumab and gantenerumab presently in Phase III clinical development. These therapies are also being tested in the Dominantly Inherited Alzheimer’s Network Trials Unit (DIAN-TU).

Expert opinion: Anti-Aβ monoclonal antibodies are being tested in subjects at the preclinical stage of ADAD and even in symptom-free subjects at risk of developing SAD. The subsequent DIAN-TU Adaptive Prevention Trial is a 4-year study that will assess whether such biomarker effects may stop the progress of the AD process, preventing cognitive symptoms. The hope is to interfere in the disease course when it is not too late. A clinical success of these prevention trials would represent the proof of the Aβ hypothesis of AD.

KEYWORDS:

• Monoclonal antibodies
• solanezumab
• gantenerumab
• prevention trials
• DIAN-TU trials
• API trials
• Alzheimer’s disease
• dementia
• BAN2401

Article highlights

• The brain deposition of the β-amyloid (Aβ) peptide is considered to be an early biological process of Alzheimer’s disease (AD).

• In recent years, early intervention with anti-Aβ drugs during the preclinical stages of AD is being pursued with the objective of blocking the disease process before it become untreatable.

• Anti-Aβ monoclonal antibodies, particularly solanezumab and gantenerumab, are mainly being tested in prevention trials in subjects at preclinical stage of ADAD or even in subjects without clinical symptoms at high risk of developing SAD.

• The Dominantly Inherited Alzheimer’s Network Trials Unit (DIAN-TU) Biomarker Trial is a 2-year study that will evaluate the effects of gantenerumab on brain Aβ deposition and of solanezumab on cerebrospinal fluid levels of Aβ_1-42 in asymptomatic individuals with presenilin or amyloid precursor protein mutations causing dominantly inherited AD.

• The subsequent 4-year DIAN-TU Adaptive Prevention Trial has the aim to assess the effects of gantenerumab and solanezumab on the DIAN-TU cognitive composite score.

• The success or failure of the DIAN-TU prevention trials will say a definite word on the Aβ cascade hypothesis of AD.

This box summarizes key points contained in the article.

Declaration of interest

BP Imbimbo is an employee of Chiesi Farmaceutici. They 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 article. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this article have no relevant financial or other relationships to disclose

Additional information

Funding

This study was supported by the ‘Ministero della Salute’, I.R.C.C.S. Research Program, Ricerca Corrente 2015-2017, Linea n. 2 ‘Malattie complesse e terapie innovative’, by the ‘5 x 1000’ voluntary contribution, and by the Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale (PRIN) 2009 Grant 2009E4RM4Z.