BOSTON—After focusing on antiamyloid medicines for many years, the pharmaceutical industry is making major investments in programs designed to discover tau-based therapeutics, according to an overview presented at the 2013 Alzheimer’s Association International Conference. Most major pharmaceutical companies with divisions dedicated to Alzheimer’s disease have established these discovery programs. Using various mechanisms of action, tau-based therapeutics have the potential to slow or prevent cognitive decline. Progress in drug development has been limited, however, and few such drugs are in clinical development. Only one tau-based medicine has progressed beyond phase I studies.
In addition, the past two years have witnessed the development of tau PET tracers, said Michael Hutton, PhD, Chief Scientific Officer for Neurodegenerative Diseases at Eli Lilly and Company in Basingstoke, United Kingdom. These imaging agents allow neurologists to monitor tau pathology in patients and may improve the development of tau-based therapeutics.
Tau-Based Therapeutics Have Various Targets
Drug-development programs are using various strategies to reduce tau pathology. Several companies have developed microtubule stabilizers to mitigate the loss of tau binding for the microtubules. The most advanced drug candidate in this class is Bristol-Myers Squibb’s epothilone D, which is in phase I trials. Epothilone D also is the only tau-based therapeutic being developed by a large pharmaceutical company. The molecule has a “remarkable” pharmacokinetic profile and can penetrate the brain, said Dr. Hutton. In vivo studies of transgenic models of tauopathy indicate that epothilone D reduces axonal degeneration and improves cognitive function. The small molecule also reduces tau pathology, but the mechanism by which it achieves this outcome is unknown, said Dr. Hutton.
Another approach is to develop drugs, such as kinases, that block tau phosphorylation. Drugs in this class, such as glycogen synthase kinase (GSK)-3 beta and cyclin-dependent kinase-5, could lower the amount of unbound tau that is available for aggregation and possibly slow the rate of aggregation. This approach, however, has been unsuccessful to date, largely because efforts have concentrated on key kinases that have many roles. As a result, it is difficult, if not impossible, to develop a safe GSK-3beta, said Dr. Hutton.
Ongoing attempts to develop medicines to improve tau clearance, or proteostasis, have faced similar hurdles. To date, it has been difficult to develop a safe and effective molecule that is sufficiently tolerated, said Dr. Hutton.
Efforts to create tau aggregation inhibitors continue to attract a lot of interest. The most clinically advanced tau-based therapeutic is methylthioninium, for which TauRx has begun phase III trials. The drug is designed to reduce levels of aggregated or misfolded tau proteins and to have high bioavailability and tolerability. The question facing developers of tau aggregation inhibitors “is whether it’s possible to get sufficient levels of the molecule to go into the brain and to achieve appropriate selectivity that allows us to block tau aggregation without a molecule getting sucked into the vast amounts of amyloid plaque,” said Dr. Hutton.
In addition to their clinical development programs, pharmaceutical companies have more than 30 ongoing preclinical programs focused on tau-based therapeutics. More than 10 of these programs are developing tau therapeutic antibodies and tau vaccines, and several of these candidates are expected to enter clinical trials by 2015, said Dr. Hutton.
Scientific Uncertainty Has Limited Tau Therapeutics’ Progress
Despite a large number of good clinical studies, the pharmaceutical industry has made relatively little progress in bringing tau-based therapies into clinical development. The most important reason for this limited success may be the continued uncertainty about the mechanism of tau pathogenesis, said Dr. Hutton. This uncertainty has limited what drug makers are willing to spend on developing these medicines and prevented researchers from focusing on a single drug target. But during the past three years, neurologists have begun to understand the mechanism of tau pathology more clearly, he added.
Another obstacle is that although available models of tau pathogenesis develop robust neurofibrillary pathology and may recapitulate many aspects of human disease, they are somewhat limited, said Dr. Hutton. The development of improved infusion models during the next few years may provide better tools for researchers.
Tau PET Tracers
A recent advance, however, could boost the success rate of efforts to develop tau-based therapeutics. A team led by Hartmuth Kolb, PhD, Senior Vice President of Research at Avid Radiopharmaceuticals, a wholly owned subsidiary of Lilly, developed a tau PET tracer called T-807. In their early clinical studies, Dr. Kolb and colleagues observed that increasing retention of T-807 in the brain correlated with increasing severity of Alzheimer’s disease symptoms. The distribution of the tau tracer signal also corresponded well with the brain regions where tau pathology is expected to occur.