On the Hunt for Breakthrough Therapies
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."