Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

ABSTRACT

Introduction: Phosphodiesterase (PDE) inhibitors improve signaling pathways in brain circuits by increasing intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). In the last decade, the first clinical studies investigating selective PDE inhibitors in Alzheimer’s disease (AD) have been initiated, based on their positive effects on cognitive processes and neuroprotection in numerous animal studies.

Areas covered: This article reviews the clinical studies investigating the pro-cognitive/neuroprotective effects of PDE inhibitors in patients with AD, as well as in age-associated memory impaired elderly and patients with mild cognitive impairment (MCI), the prodromal stage of AD. PDE inhibitors will also be discussed with respect to adverse effects including safety and tolerability.

Expert opinion: The limited available data of clinical studies with PDE inhibitors tested in different populations of AD patients do not allow the drawing of any concrete conclusion yet. Currently, studies with a PDE3 (cilostazol) or PDE9 inhibitor (BI 409,306) are still ongoing in patients with MCI or AD, respectively. Studies with PDE4 inhibitors (HT-0712, roflumilast and BPN14770) in healthy elderly and elderly with age-associated memory impairments indicate that the optimum dose and/or inhibiting the most relevant PDE isoform hold great promise when tested in the appropriate population of patients with MCI or AD eventually.

KEYWORDS:

• Alzheimer’s disease
• cAMP
• cGMP
• cognition
• mild cognitive impairment
• neuroprotection
• phosphodiesterase

Article highlights

• The limited amount of clinical studies with rather high doses and non-isoform selective PDE inhibitors tested in AD patients do not allow to draw any concrete conclusion yet.

• The future for an AD-specific PDE inhibitor lies in the development of isoform selective inhibitors that are most effective for cognitive enhancement and neuroprotection with limited side-effect profiles.

• It is of utmost importance to know the expression levels of the separate PDE splice variants in relevant brain areas of patients with MCI or AD, especially PDE splice variants with high or increased expression are interesting to inhibit.

• A low dose of a PDE inhibitor might be beneficial for cognitive enhancement and neuroprotection, while not inducing any unwanted side-effects.

• When testing a PDE inhibitor the appropriate population, i.e. age-associated cognitive impaired elderly, MCI patients or patients at different stages of AD, needs most careful consideration.

• First results with PDE4 inhibitors suggest that indeed the optimum dose and/or inhibiting the appropriate PDE isoform hold great promise when tested in the right population of patients with MCI or AD eventually.

This box summarizes key points contained in the article.

Declaration of interest

P Heckman is financially supported by the Human Enhancement and Learning (HEaL) initiative of Maastricht University, which stimulates research into cognitive enhancement to improve the quality of life. A Blokland and J Prickaerts have a proprietary interest in the PDE4 inhibitor roflumilast. J Prickaerts also has a proprietary interest in selective PDE4D inhibitors, including GEBR-32a. For the last three years A Blokland has been performing contract research into cognitive enhancing properties of specific drugs in humans for Takeda and Nootrobox. For the last three years the following activities of J Prickaerts can be disclosed: A grant was received from the Dutch Alzheimer Foundation (Alzheimer Nederland) to investigate cAMP-specific PDE inhibitors as a potential therapeutic target for cognitive decline in AD (project number WE.03-2016-07). Consultancy services have been performed for Takeda and Lundbeck. Finally, contract research has been conducted into cognitive enhancing properties of specific drugs in humans and/or animals for Takeda, Dart Neuroscience, Natural Stacks, Tetra Discoveries and Bayer. 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.