Psychiatric Drug Development: Hope Around the Corner?

Jeffrey A. Lieberman, MD


September 21, 2012

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This is Dr. Jeffrey Lieberman of Columbia University, speaking to you today for Medscape. I want to talk about some sobering news for the field of psychiatry: the termination of development programs for 3 psychotropic drugs. The first drug, called pomaglumetad, or LY2140023, is an mGluR2/3 agonist that inhibited the release of glutamate from neurons. This was being developed as a monotherapeutic or adjunctive treatment for schizophrenia, and it held great promise and expectations, but the development program has been stopped because in the phase 3 studies, the drug failed to meet the desired endpoints on interim analyses.

The other drugs were in the area of Alzheimer disease. These were monoclonal antibodies that either cleared or neutralized the formation of amyloid plaques. The first of these is bapineuzumab, and the other is solanezumab. These drugs were developed on the basis of the amyloid hypothesis. Both were in phase 2 trials that have been stopped because of failure to meet interim-analysis endpoints or study-termination endpoints.

This is sobering news and it reflects the fact, once again, that novel drug development for central nervous system disorders is not for the faint of heart. On the other hand, this is something that should not be entirely surprising and should not deter us -- and by "us," I mean our partners in the pharmaceutical and biotech sectors -- from continuing efforts to develop treatments for this range of brain diseases affecting mental function and behavior.

The brain is an organ that is orders of magnitude more complex than any other organ in the body. The brain has 100 billion cells. Each of the areas of the brain is organized cytoarchitecturally differently, and the cells connect via over 30 trillion synapses. Compare this to the heart, the liver, the gastrointestinal system, or the lungs, and there is no comparison in terms of complexity and intricacy. In addition, given the fact that we are developing treatments for brain disorders that affect mental function and behavior, the animal models that are an essential component of biomedical research and drug development are limited, because how can lower species like rodents model the complexity of human behaviors and mental disorders that we are trying to correct pharmacologically?

In addition, the biomarkers we use to signal the effect of the treatment or prove the target engagement of a molecule at the desired location in the brain or protein in the brain are still in development and not fully validated. Thus, the complexity of the brain and the limitations of existing tools make the prospects of certainty in drug development [for brain disorders] more questionable than in other organ systems and disease areas.

Certainly the research community and the National Institutes of Health (NIH) understand the importance of redoubling our efforts to develop treatments for this important group of disorders. The NIH has recently established a new Institute, NCATS, or National Center for Advancing Translational Science, which has as part of its core mission drug discovery and development. In addition, various other Institutes have put out RFAs [request for applications]; this includes the National Institute of Mental Health, which has initiated a series of what are called the "fast programs" to identify drugs that exist within the pharmaceutical industry and may no longer be under development, but can be repurposed for study for specific disorders. A quick, rigorous study using a fast-fail strategy can determine whether these agents have the potential for further development.

New efforts are coming from the biomedical research community as well as the NIH to spur drug development. I hope this will act as a catalyst for the pharmaceutical and biotech industries to not despair or back away from the risk of developing drugs in these areas, but rather to find the resources to support drug-development programs for these disorders.

What is the benefit? Anyone who works with psychiatric patients knows that there are tremendous unmet clinical needs, whether in schizophrenia, depression, bipolar disorder, autism, or Alzheimer disease. With these needs come tremendous market potential, so for those who stay the course and persevere, there will be very lucrative rewards. To me, this seems like a great opportunity, and I think our partners in the private sector should appreciate this. I look forward to partnering with them to try and work in a way that uses their precious resources most efficiently but still serves our scientific goals and the needs of our patients. Thank you for listening.