The World Alzheimer Report 2013 paints a chilling picture of the scope of the disease with more than 35 million people worldwide currently living with the condition, a number that is expected to double by 2030 and more than triple by 2050.

The more than 5.1 million Americans suffering from the disease also moved the U.S. government to make a $156 million funding commitment last year and introduce a national plan to address Alzheimer’s disease. Their roadmap has the ambitious goal to prevent and effectively treat the condition by 2025.

This plan lays out a blueprint for expanding research in prevention and treatment and getting the most promising drugs from discovery into clinical trials.

There is no doubt that innovative medicines will be required in the wake of a number of high profile late-stage clinical trial disappointments including Eli Lilly and Co.’s candidate solanezumab, and Pfizer Inc. and Johnson & Johnson’s bapineuzumab, which originated with Elan Corp. plc.

“Setbacks in Alzheimer’s research are disappointing to many, including the scientists carrying out the studies, but these unsuccessful attempts are critical stepping stones to advancing our understanding of this extremely complex disease,” noted Pharmaceutical Research and Manufacturers of America (PhRMA) president and CEO John J. Castellani on the occasion of releasing the organization’s report, “Alzheimer’s Research: Setbacks and Stepping Stones,” last year.

The report found that between 1998 and 2011, 101 treatments failed to reach patients. In the same time period only three medicines were approved to treat symptoms of the disease.

Brighter Future

Despite numerous product failures, the future may be brighter judging by the level of activity taking place in academic circles and the early discovery research being conducted by biotech companies.

Scientists from the Icahn School of Medicine at Mount Sinai, in partnership with the New York Stem Cell Foundation (NYSCF), for example, have been awarded a multi-year grant from the National Institutes of Health (NIH) to study Alzheimer’s disease.

The research team will use several cellular and animal models to validate the actions of individual genes, as well as entire molecular networks predicted to drive the disease. The team will also employ a computational approach to test if any existing drugs currently used for other conditions are capable of modulating the Alzheimer’s networks and can, therefore, be repurposed for Alzheimer’s disease treatment or prevention.

The approach assumes that Alzheimer’s might best be explained and treated by focusing on genes that serve as “hubs” that interconnect a group of genes. These hubs are important because when they malfunction and develop Alzheimer’s, they cause predictable malfunctions of the entire group of connected genes.

“The fact that Alzheimer’s is a complex disease that is believed to result from a biological cascade probably triggered by multiple genetic and environmental factors has led to several drugs failing in late-stage clinical trials,” Eliseo Salinas, executive vice president and head of research & development at Stemcells Inc., told BioWorld Insight. “This is because the drugs were designed to target and act upon a single component, such as amyloid plaques or tau protein, in what we now know is a very complex disease.”

Stemcells is taking a different approach to the treatment of the disease. They are employing cell-based therapies, which they have found can influence several relevant biological targets rather than targeting a single mechanism in the disease cascade.

Preclinical research has shown that that transplantations of their purified human neural stem cells (HuCNS-SC) survive in the toxic environment of the Alzheimer’s disease brain and restore memory under the regulation of the host, Salinas said.

The company has just begun down the long road on its Alzheimer’s disease program thanks to the support of the California Institute for Regenerative Medicine (CIRM). The institute has agreed to provide approximately $19.3 million to the company in the form of a forgivable loan to help fund preclinical development and investigational new drug application-enabling activities, and Stemcells recently received an initial disbursement of $3.8 million. (See BioWorld Today, July 31, 2013.)

“We could not have undertaken such a high risk-high reward project without the funding that CIRM has made available to help us move towards the clinic,” Martin McGlynn, president and CEO of Stemcells, told BioWorld Insight.

The company will evaluate its HuCNS-SC cells in collaboration with researchers at the University of California, Irvine led by Frank LaFerla, a world-renowned researcher in the field. Already, in two animal models relevant to Alzheimer’s disease, they have demonstrated that the neural stem cells were able to restore memory and significantly enhanced synaptic function. Importantly, the therapeutic effect did not require a reduction in beta amyloid or tau that accumulates in the brains of patients with Alzheimer’s disease and account for the pathological hallmarks of the disease.

Salinas said the goal of the research will be to file an investigational new drug (IND) application with the FDA within four years.

Taupathies

Among the many other therapeutic approaches to treating Alzheimer’s, Oligomerix Inc., of New York, is focusing on the development of small-molecule drugs aimed specifically at inhibiting tau aggregation at the earliest phases of tau self-association into toxic oligomers in neurons. The company has discovered that tau becomes a proteolytic enzyme upon forming an oligomer structure that causes it and other proteins to fragment.

It recently received a two-year Small Business Innovation Research Phase IIb grant for $1.7 million from the National Institute on Aging to extend its research. The program will allow Oligomerix to evaluate its lead candidates in animal models of Alzheimer’s and related tauopathies, with the goal of selecting candidates for IND-enabling studies. (See BioWorld Today, Sept. 11, 2013.)

Also in the same area, researchers from Washington University in St. Louis have developed antibodies that, when administered to mouse models of tau pathology, improved the animals’ cognitive deficits. The antibodies target the protein tau, which is known to form tangles in Alzheimer’s disease and a number of other disorders that collectively go by the name tauopathies. Once tau forms tangles in one cell, those tangles can propagate from cell to cell, and the antibodies the authors tested blocked the extracellular tau tangles that are intermediates in the seeding process. The researchers concluded that “immunotherapy specifically designed to block transcellular aggregate propagation will be a productive treatment strategy” for tauopathies. (See BioWorld Today, Sept. 30, 2013.)

Editor’s Note: Part II of this article will be published next week.