Alzheimer’s disease drug-development pipeline: few candidates, frequent failures

Abstract

IntroductionAlzheimer’s disease (AD) is increasing in frequency as the global population ages. Five drugs are approved for treatment of AD, including four cholinesterase inhibitors and an N-methyl-D-aspartate (NMDA)-receptor antagonist. We have an urgent need to find new therapies for AD.MethodsWe examined Clinicaltrials.gov, a public website that records ongoing clinical trials. We examined the decade of 2002 to 2012, to better understand AD-drug development. We reviewed trials by sponsor, sites, drug mechanism of action, duration, number of patients required, and rate of success in terms of advancement from one phase to the next. We also reviewed the current AD therapy pipeline.ResultsDuring the 2002 to 2012 observation period, 413 AD trials were performed: 124 Phase 1 trials, 206 Phase 2 trials, and 83 Phase 3 trials. Seventy-eight percent were sponsored by pharmaceutical companies. The United States of America (U.S.) remains the single world region with the greatest number of trials; cumulatively, more non-U.S. than U.S. trials are performed. The largest number of registered trials addressed symptomatic agents aimed at improving cognition (36.6%), followed by trials of disease-modifying small molecules (35.1%) and trials of disease-modifying immunotherapies (18%). The mean length of trials increases from Phase 2 to Phase 3, and the number of participants in trials increases between Phase 2 and Phase 3. Trials of disease-modifying agents are larger and longer than those for symptomatic agents. A very high attrition rate was found, with an overall success rate during the 2002 to 2012 period of 0.4% (99.6% failure).ConclusionsThe Clinicaltrials.gov database demonstrates that relatively few clinical trials are undertaken for AD therapeutics, considering the magnitude of the problem. The success rate for advancing from one phase to another is low, and the number of compounds progressing to regulatory review is among the lowest found in any therapeutic area. The AD drug-development ecosystem requires support.

Apolipoprotein E region molecular signatures of Alzheimer's disease

“…Despite considerable progress in research into genetic predisposition to ADs, with the greatest advances involving APOE research, progress in the development of therapeutic interventions has been slow, with a success rate of only 0.4% in clinical trials conducted between 2002 and 2012 (Cummings, Morstorf & Zhong, 2014). The corresponding 99.6% failure rate indicates that the mechanisms underlying the development of ADs remain poorly understood.…”

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

“…AD drugs developed with EOAD models were explored for use as human LOAD therapy, under an assumption that drugs effective on EOAD would also be effective in treating LOAD. More than 98% of drugs tested in EOAD rodent models were ineffective in human LOAD patients in clinical trials (Cummings, Morstorf, & Zhong, 2014), raising concerns on current drug targets and on the validity of the EOAD models for human LOAD.…”

Protein production is an early biomarker for RNA‐targeted therapies

“…There is a dire need to develop novel therapeutics for these conditions, as current FDA‐approved drugs are not adequately effective, and no treatments exist to reverse disease pathology. Despite promise of new therapies in preclinical models over the past 30 years, these compounds have failed in Amyotrophic Lateral Sclerosis (ALS) and Alzheimer's Disease (AD) clinical trials at rates greater than 95% and 99%, respectively 2, 3. One important way to improve the current treatment landscape is to focus on the development of novel methods to determine whether a therapeutic has engaged the intended target in human clinical trials.…”