On the Hunt for Breakthrough Therapies

Advances in understanding the genetic causes underlying psychiatric disorders and ongoing research and development by pharmaceutical companies in search of the next blockbuster promise to introduce exciting, new treatments in the coming years. But realizing gains from current scientific advances may take some time.

These days, drug companies appear to be a bit more risk-aversive and are looking to license drugs from other companies that may already have preliminary data. The increased cost of drug development and the current regulatory climate has had a chilling effect on taking risks and pursuing novel strategies. "It's a huge investment for a company to decide to go off in a truly novel direction," said Jeffrey Lieberman, M.D., in an interview with Psychiatric Times. Lieberman is professor and vice chairperson for research and scientific affairs in the department of psychiatry at the University of North Carolina School of Medicine.

Developing new drugs is an expensive and risky venture. Pharmaceutical companies spend an average of $802 million to get a new drug to market, according to the Tufts Center for the Study of Drug Development. That amount jumps to $897 million when including the cost of post-approval studies required by the U.S. Food and Drug Administration to determine long-term safety and effectiveness in a wider range of patients or in specific patient subgroups.

On average, it takes a compound 10 to 15 years to get from the lab to the pharmacy. Only five compounds out of 5,000 in preclinical tests get as far as human trials. And only one in five drugs that make it to clinical testing gets approved.

According to a report issued last year by the Pharmaceutical Research and Manufacturers of America (PhRMA), the drug industry has 99 medicines in development for treating mental illnesses involving 44 pharmaceutical and biotechnology companies (Figure). (Due to copyright concerns, this figure cannot be reproduced online. Please see p10 of the print edition--Ed.) These potential drugs are either in clinical trials or awaiting approval from the FDA.

"The new medicines in the pipeline offer hope of reducing the human and economic costs of mental illnesses," PhRMA reported. Those costs include $100 billion for directly treating mental illnesses in the United States and an additional $80 million in indirect costs.

The challenge that pharmaceutical companies face, Lieberman explained, is being able to develop new successful products-presumably more effective or safer and thus more desirable to use-while also generating profits. These companies have a range of strategies available for developing treatments from traditional, proven approaches to novel, innovative approaches.

This spectrum of drug development strategies can be viewed in the context of how much financial risk is involved, Lieberman said. Known ways of developing a drug or group of drugs is a low-risk strategy, but it also has lower potential gain. Novel strategies are higher risk but have higher potential gain. Companies have different development programs based on this continuum of risk.

The problem is that it is hard to find a novel strategy or mechanism of action that is going to be effective in treating an illness, according to Lieberman. For example, antipsychotic drugs have historically targeted the dopamine-2 receptor. Each new drug over the years has been a variation of that, first with the introduction of atypical antipsychotics and now with the introduction of aripiprazole (Abilify), which he said could possibly represent a new generation of antipsychotic drug.

Referred to by some researchers as a dopamine-serotonin system stabilizer, aripiprazole works on the dopamine-2 receptor. But while other atypicals act as a full antagonist, aripiprazole acts as a partial agonist-partially inhibiting the receptor at the same time that it partially stimulates it. Still, it is an iteration of an older mechanism, Lieberman said. A truly novel antipsychotic would have no dopamine-2 receptor activity. And while there have been some efforts to develop such a drug, none have been successful so far.

Currently, several companies are working to develop non-dopamine-based therapies, such as looking at serotonin-2A receptor antagonists, neurokinin-3 receptor antagonists and cannabinoid receptor antagonists.

"They're much more novel strategies but they're higher risk," Lieberman explained.

There's a similar phenomenon in the development of drugs for depression. Traditionally, these drugs have inhibited reuptake transporters, specifically serotonin or norepinephrine. "Now we're seeing the introduction of dual reuptake inhibitors and triple reuptake inhibitors," he said. For example, the newly approved duloxetine (Cymbalta) targets dopamine, norepinephrine and serotonin.

However, these innovations are not entirely novel. Rather than producing new paradigms for drug mechanisms of action, these drugs are iterations of a traditional approach, namely to develop molecules that work as catecholamine or indolamine uptake inhibitors, Lieberman said.

However, there are some novel strategies being pursued. A number of pharmaceutical companies are pursuing a neurokinin-1 receptor antagonist and corticotropin-releasing factor antagonists, among other novel molecules.

Beyond this, an ongoing approach is recognizing that any one treatment may not be able to alleviate all the dimensions of an illness, and combined treatments may be necessary, Lieberman said. For instance, antipsychotic drugs are the mainstay of treatment for schizophrenia, but existing antipsychotic drugs don't always work well on negative symptoms, cognitive deficits and prevention of mood-associated symptoms. "This may be because certain dimensions of the illness are related to other pathophysiological processes other than just dopamine hyperactivity," Lieberman said.

Consequently, there has been an effort to develop drugs that target systems believed to underlie these other symptom dimensions, he said. A prime example has been glutamate's role in cognition. There has been a tremendous effort to develop compounds that act on the glutamate system for treatments that might help against cognitive impairment, negative symptoms and behavioral deficits. "However, these treatments can't be used alone," Lieberman said. "These treatments in all likelihood would need to be used with an antipsychotic drug."

Unlocking the Genome

As researchers continue to unlock the secrets of the human genome, more advanced medicines that target specific genes can be expected. But it could take years for these kinds of advances to translate into pharmaceutical products.

The cancer treatment imatinib (Gleevec) was the first to emerge as a molecular designer drug. It selectively blocks cellular proliferation by inhibiting tyrosine kinase. Blocking the enzyme prevents the rapid growth of white blood cells that occurs in patients with chronic myeloid leukemia.

Similar successes are likely to be seen in treatments for Alzheimer's disease because the illness has a well-characterized neurobiology, Lieberman said.

It is hard to predict how long it will take for genetic breakthroughs to result in the development of successful therapeutic agents, he said. The gene for Huntington's disease, for example, was discovered in 1993 but has yet to result in a treatment.

The same holds true for disorders such as cystic fibrosis and Rett syndrome. While the genes behind these disorders have been discovered, effective treatments based on that genetic information have not.

The idea of applying genomics to identifying genes that can point to targets for drug development is a very powerful one, and ultimately will revolutionize the way that treatments are developed, Lieberman said. However, "it's not necessarily an easy process."

The pace of research is accelerating as different types of genetic-based technologies are developed.

Linkage and association studies, in which researchers painstakingly examine possible genetic origins for disorders within families or isolated populations, are giving way to powerful technologies such as gene multi-array chips, which can hold the code for thousands of genes. These microchips are hybridized with a patient's tissue--whether it's postmortem brain tissue, spinal fluid or blood--in order to examine gene expression and look for differences associated with a particular disorder.

Proteomics, another emerging technology, searches for gene products, usually proteins, in biologic fluids or specimens.

"These are powerful ways that can help to ultimately identify targets for drug development and ultimately may lead to individualization and selection of treatments for specific patients," Lieberman said.

NIMH Research

Most research begins in government-funded studies; the findings of which become public domain.

In September, the National Institute of Mental Health announced a new program that would expand its in-house research into the genetics of schizophrenia. "For the first time, we have half a dozen vulnerability genes to explore," NIMH Director Thomas Insel, M.D., announced in a press release.

Multidisciplinary research teams will examine how these genes work at molecular, cellular and systems levels to determine the "risk architecture" of schizophrenia and to examine changes in the brain that alter thinking and emotions in ways that are associated with the disorder. The work will involve everything from cell-culture models to brain imaging.

"Genes don't directly encode for the hallucinations, delusions and blunted affect of schizophrenia," said Daniel Weinberger, M.D., chief of the NIMH Clinical Brain Disorders Branch (CBDB). "Rather, there is a very complicated path between a gene's influence on the regulation and function of a protein and such psychiatric phenomena."

The studies--which will examine two versions of the COMT gene, as well as GRM3, DISC1, dysbindin and neuregulin--will attempt to identify biological tests for the disorder and ways to switch genes "on" and "off" in order to develop prevention and treatment strategies. "Such findings emerging from the fast-track intramural effort will serve to stimulate spin-off studies by extramural, or grant-supported, researchers," Insel added.

One gene identified by CBDB that looks like a risk factor for schizophrenia is COMT. The enzyme produced by COMT is one that already has a drug that can act on it, Lieberman said. This points to justification for developing drugs that act as COMT inhibitors.

In July, NIMH announced funding for the Center for Collaborative Genetic Studies on Mental Disorders at Rutgers University. The university's previous research center, also funded by NIMH, established more than 17,000 cell lines from blood samples and distributed more than 25,000 DNA samples to more than 100 investigators worldwide.

The new center will continue that work by enhancing research collaborations and developing novel methods for data analysis that will help in the replication of genetic discoveries, according to Steven Moldin, Ph.D., NIMH project director for the Center. "The Center's activities are expected to greatly accelerate gene discovery in mental disorders such as autism, mood disorders and schizophrenia, and lead to the identification of novel targets for new therapies," Molding stated in a press release. "Ultimately, we expect these results to revolutionize the diagnosis, treatment and prevention of these disorders."