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

Date Published: July 3, 2014

Publisher: BioMed Central

Author(s): Jeffrey L Cummings, Travis Morstorf, Kate Zhong.


Alzheimer’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.

We examined, 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.

During 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).

The 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.

Partial Text

Alzheimer’s disease (AD) is becoming increasingly common as the global population ages. It is estimated that currently 44 million victims of AD dementia exist in the world and that this will grow to more than 100 million cases by 2050 [1,2]. We urgently need to identify drugs that prevent, delay the onset, slow the progression, or improve the symptoms of AD. is a public website that records ongoing clinical trials of all diseases. The database began in 2000 [9]. In 2005, the International Committee of Medical Journal Editors (ICMJE) began to require trial registration in a public database as a condition of publication [10]. This greatly increased the number of registrants on Beginning in 2007, the FDA Amendments Act required registration of all clinical trials of drugs and devices subject to FDA regulation [11]. Registration is required no later than 21 days after enrollment of the first participant. provides reliable data on clinical trials starting from this 2007 date.

Table 1 provides an overview of the total number of trials registered over the decade of 2002 through 2012 on The 413 trials include 124 Phase 1 trials, 206 Phase 2 trials, and 83 Phase 3 trials. These 413 trials represent 244 unique compounds, with many compounds having more than one trial and some present in more than one phase. More Phase 2 trials were conducted than any other trial type, and fewer Phase 3 trials. Taking the years since 2007 when registration was required, 157 Phase 2 trials and 54 Phase 3 trials were performed. The total number of trials was highest in 2008 (61) and 2009 (72) and has remained approximately stable (45 to 51) over the past 3 years.

This study used the publically available database to assess the historic trends of AD drug development and to put the current pipeline of agents in perspective. The results demonstrate that detailed interrogation of can provide insight into longitudinal trends in drug development. A comprehensive database of all clinical trials registered in, the Aggregate of (AACT), has become available [12] and may facilitate further analyses. provides a remarkable resource of information regarding drug development for AD and other disorders. Trends in AD drug development over time can be seen, and the movement of the drugs through the pipeline can be monitored. has provided comprehensive information since 2007, when registration of clinical trials was required by the FDA. The analyses demonstrate that the number of clinical trials has been declining since the 2008 through 2009 period. The pharmaceutical industry sponsors most drug development for AD, whereas NIH accounts for a relatively small percentage of drug development. The United States has the largest number of clinical trials of any single country, but more clinical trials are conducted outside of the United States than inside of the United States.

AD: Alzheimer’s disease; Aß: amyloid beta protein; FDA: Federal Drug Administration; ICMJE: International Committee of Medical Journal Editors; MCI: mild cognitive impairment; MMSE: Mini-Mental State Examination; NIH: National Institutes of Health; NMDA: N-methyl-D-aspartate; U.S.: United States.

Dr. Cummings has provided consultation to Acadia, ADAMAS, Avanir, Boehinger-Ingleheim, Bristol Myers Squibb, Eisai, EnVivo, Genentech, General Electric Healthcare, GSK, Lilly, Lundbeck, Medavante, Merck, Novartis, Otsuka, Pfizer, Prana, QR Pharma, Resverlogix, Servier, Sonexa, Suven, Takeda, and Toyama pharmaceutical companies. TM and KZ have no disclosures.

JLC conceived the project, participated in analyses of the database, reviewed the database for accuracy, reviewed the statistical calculations, drafted the manuscript, and approved the final manuscript. TM constructed the database, participated in analyses of the database, revised the manuscript, and approved the final manuscript. KZ reviewed the database, participated in analyses of the manuscript, participated in revising the manuscript, led the statistical analyses, and approved the final manuscript.