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The Drug Development Pipeline

A key part of NIH’s strategy for developing new treatments for Alzheimer’s and related dementias is to bolster the drug discovery and development pipeline. This section on prevention and treatment research focuses on the many NIH-supported clinical trials currently testing several different types of drugs for Alzheimer’s and related dementias. NIH’s strategy helps ensure scientists are addressing these multifaceted diseases through a wide range of approaches. The infrastructure for our drug discovery process to develop new medicines is described later in the Research Enterprise section, which highlights preclinical development.

Historically, the length of time required for researchers to discover a biological mechanism of disease, such as a gene variant that does not function normally, and then develop an effective treatment without toxic side effects has been 12 to 15 years. Additionally, very few drug candidates succeed through the pipeline to reach Food and Drug Administration (FDA) approval, because they are not found to be both safe and effective. To accelerate the discovery of effective treatments that will become broadly available to the public, NIH has developed programs to make data, knowledge, and research tools widely available to all researchers. Instead of competing with each other, stakeholders in industry, academia, and government are collaborating to reach a common goal: developing effective treatments for Alzheimer’s and related dementias.

Thanks to the substantial investment in Alzheimer’s and related dementias research over the past several years, NIH has increased drug discovery significantly. Of the many drug candidates in NIH-supported drug development programs for Alzheimer’s and related dementias, 10 have now matured through the preclinical development pipeline to reach the clinical trial stage. These 10 drug candidates target multiple aspects of the disease process, as shown in the chart below. Of these 10, three graduated to clinical testing in 2019. One (AV-1959) is a DNA vaccine against the amyloid deposits that build up in the brains of people with Alzheimer’s, another (AAV2- BDNF) is a gene therapy to deliver a nerve-protective protein to prevent nerve cell loss, and the third (NNI-362) is a drug that may stimulate new neurons to grow.

MW-151, also featured in the chart below, is an example of a drug candidate now in clinical trials that was developed with NIH support, including a Small Business Innovation Research (SBIR) grant. MW-151 is being tested in humans for the ability to lessen inflammation in the brain. Too much inflammation can damage brain cells and is one of the mechanisms leading to dementia.

10 NIH-Funded Drug Candidates Now Being Tested in Clinical Trials for Alzheimer’s and Related Dementias
Drug Candidate How it works
LM11A-31 Promotes nerve cell survival
Elayta (CT1812) Prevents beta-amyloid toxicity
BPN14770 Protects from losing neuron connections
Allopregnanalone Promotes nerve cell growth
MW151 Inhibits brain inflammation
MW150 Inhibits brain inflammation
PU-AD Promotes degradation of toxic proteins
NNI-362 Promotes new neuron growth
AV-1959 DNA vaccine Clears amyloid brain deposits
AAV2-BDNF gene therapy Prevents nerve cell loss

NIH’s SBIR and Small Business Technology Transfer (STTR) programs are an integral source of capital for early-stage U.S. small businesses that are creating innovative technologies to improve health. These programs help small businesses break into the federal research and development arena, create life-saving technologies, and stimulate economic growth. This funding helps the private sector bring promising technologies to the consumer market. Through these programs, NIH is leveraging the economic engine of small businesses to enhance scientific innovation. Before the increased funding for Alzheimer’s and related dementias (2010-2013), NIA awarded 69 SBIR/STTR grants to 62 small companies. After the increased appropriations (2016-2019), NIA more than tripled that achievement by awarding 231 SBIR/STTR grants to 221 companies for discovery and development of new treatments, as well as biomarker research and technologies for improving care and caregiving.

As potential drug candidates make it through the development pipeline to be tested in clinical trials, the NIA-Funded Active Alzheimer’s and Related Dementias Clinical Trials and Studies list is continuously updated on NIA’s public website. The sections are divided into categories of how the drug candidates target the disease process:

Active NIH-Supported Trials for Alzheimer's and Related Dementias. 39 early-stage drug trials. 10 late-stage drug trials. 65 care and caregiver intervention trials. 9 psychiatric symptom relief trials. 111 behavioral and lifestyle prevention trials. 234 total clinical trials as of April 2020.

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Phase 1 to Phase 4 Drug Trials

Most of the NIH-supported trials for Alzheimer’s and related dementias are in an early stage, which means Phase 1 or Phase 2 trials, but several Phase 3 trials are also in progress. According to FDA, with each successive phase, a longer period of time and more participants are needed to conduct the study.

  • Phase 1. Phase 1 trials typically involve 20 to 100 participants for several months. These trials are designed to answer questions about safety and dosage. About 70% of all drugs tested in Phase 1 proceed to Phase 2. It is important to keep in mind that FDA regulates many kinds of drugs, not just those for Alzheimer’s and related dementias, and these statistics refer to all drugs in the development pipeline.
  • Phase 2. The second phase of drug testing continues safety testing and can require up to several hundred participants for several months to two years. About 33% of all FDA-regulated drugs move from Phase 2 to Phase 3.
  • Phase 3. Hundreds to thousands of participants are needed over one to four years for Phase 3 trials. These larger, longer studies enable experts to evaluate how effective interventions are and to detect whether using the drug may cause long-term or rare side effects. Only about 25% of all FDA-regulated drugs move beyond Phase 3 in the drug development pipeline toward commercialization because the data provide evidence of treatment benefit without unacceptable side effects.

After a drug has been approved by FDA and is marketed, Phase 4 trials are sometimes conducted. In 2019, NIH funded a Phase 4 drug study called Pragmatic Evaluation of Events and Benefits of Lipid-Lowering in Older Adults (PREVENTABLE). Through this Phase 4 trial, researchers will examine the overall benefits and risks of a commercially available cholesterol-lowering drug known as atorvastatin in 20,000 adults age 75 or older without cardiovascular disease. The trial will help determine whether the drug can help prevent dementia and disability in this age group, as well as prevent heart attacks and other cardiovascular-related deaths, without increasing adverse health outcomes.

For a more in-depth look at the research implementation milestones in this area, including progress and accomplishments, visit research-pharmacological.

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