Repurposed agents in the Alzheimer’s disease drug development pipeline

Abstract

Background Treatments are needed to address the growing prevalence of Alzheimer’s disease (AD). Clinical trials have failed to produce any AD drugs for Food and Drug Administration (FDA) approval since 2003, and the pharmaceutical development process is both time-consuming and costly. Drug repurposing provides an opportunity to accelerate this process by investigating the AD-related effects of agents approved for other indications. These drugs have known safety profiles, pharmacokinetic characterization, formulations, doses, and manufacturing processes. Methods We assessed repurposed AD therapies represented in Phase I, Phase II, and Phase III of the current AD pipeline as registered on ClinicalTrials.gov as of February 27, 2020. Results We identified 53 clinical trials involving 58 FDA-approved agents. Seventy-eight percent of the agents in trials had putative disease-modifying mechanisms of action. Of the repurposed drugs in the pipeline 20% are hematologic-oncologic agents, 18% are drugs derived from cardiovascular indications, 14% are agents with psychiatric uses, 12% are drug used to treat diabetes, 10% are neurologic agents, and the remaining 26% of drugs fall under other conditions. Intellectual property strategies utilized in these programs included using the same drug but altering doses, routes of administration, or formulations. Most repurposing trials were supported by Academic Medical Centers and were not funded through the biopharmaceutical industry. We compared our results to a European trial registry and found results similar to those derived from ClinicalTrials.gov. Conclusions Drug repurposing is a common approach to AD drug development and represents 39% of trials in the current AD pipeline. Therapies from many disease areas provide agents potentially useful in AD. Most of the repurposed agents are generic and a variety of intellectual property strategies have been adopted to enhance their economic value.

Anticancer drugs repurposed for Alzheimer’s disease: a systematic review

“…Drug repurposing may consent to optimize the efforts to develop new treatments for AD by exploring the AD-related effects of agents already approved for other clinical indications [ 16 ]. This approach is promising since many approved pharmacological agents have shown AD-relevant effects in animal models.…”

“…Moreover, it may significantly reduce the times and costs of drug development given that the repurposed drugs have already been tested in terms of safety/tolerability, thus rendering the conduction of further preclinical studies unnecessary [ 16 ]. In 2020, 53 clinical trials involving 58 FDA-approved agents acting on multiple therapeutic targets (e.g., neuroinflammation, neuroprotection, neurotransmitter modification) were registered in the ClinicalTrials.gov database, accounting for 39% of the overall AD pipeline [ 16 ]. In parallel, since 2019, the number of phase III studies targeting Aβ dropped by 20% [ 56 ].…”

“…The therapeutic implications of the complex relationship between cancer and dementia have instead been poorly investigated yet. Given the current therapeutic gap in AD, the scientific community is growingly investigating whether drugs approved for other diseases may be repurposed to slow down or even hamper AD course [ 15 , 16 ]. In this regard, some anticancer drugs have been shown to have a good permeability through the blood-brain barrier (BBB), thus potentially exerting relevant effects against AD pathology [ 17 , 18 ].…”

Recent advances on drug development and emerging therapeutic agents for Alzheimer’s disease

“…More than 3/4 th of these drugs are disease-modifying agents with the highest representation from hematologic-oncologic agents (20%), cardiovascular drugs (18%), antipsychotic agents (14%) and antidiabetic agents (12%). Some of the repurposed drugs in the pipeline for AD in the phase 3 clinical trials include escitalopram (SSRI, antipsychotic), brexipiperazole (Dopamine D 2 partial receptor agonist, schizophrenia), masitinib (anticancer), metformin (antidiabetic), guanfacine and losartan (cardiovascular) [ 16 ]. Corbett et al, in 2012 published an expert Delphi consensus review listing five potential classes of prioritized drugs for repurposing namely, minocycline (tetracycline antibiotic), losartan (angiotensin receptor blocker), nivaldipine (calcium channel blocker), liraglutide or semaglutide (glucagon- like peptides 1) and retinoid therapy for the treatment of AD [ 21 ].…”

Ethical Issues Which Have Prevented the U.S. from Maximizing Quality of Life Years

“…Both diseases are increasing rapidly in the population, while patients are able to live with the conditions for over a decade. Alzheimer's will not be discussed as there are excellent reviews of the issues [36][37][38], but in short it poses a problem in that there is no treatment on the horizon. Diabetes (type II) on the other hand is extremely targetable, with reduced caloric consumption and exercise literally at the patients finger tips.…”