Despite pharma's retreat and the many challenges in psychiatric drug development -- as detailed here -- the current psychiatric drug pipeline is not totally dry.
Cornell psychiatrist and New York Times contributor Richard Friedman, MD,1 recently lamented the lack of novel new drugs to treat psychiatric disorders. He blamed big pharmaceutical companies for the “crisis in drug innovation.”
In calendar year 2012, the FDA’s Center for Drug Evaluation and Research approved 39 new molecular entities (NMEs)-the highest number approved in more than a decade. Yet no psychiatric drugs were approved, although florbetapir F18 (Amyvid), Abbott’s compound for imaging of Î²-amyloid plaque in the brain, did receive a go-ahead. Most of the FDA’s approvals were for rare or “orphan” diseases (13) and for cancer (11). Among NMEs approved so far in 2013, no psychiatric drugs are on the list.2,3
“Even though 25% of Americans suffer from a diagnosable mental illness in any year, there are few signs of innovation from the major drug makers,” said Friedman, Professor of Clinical Psychiatry and Director of the Psychopharmacology Clinic at Weill Cornell Medical College.
“After a series of failed clinical trials in which novel antidepressants and antipsychotics did little or no better than placebos, the companies seem to have concluded that developing new psychiatric drugs is too risky and too expensive.” He noted that with rare exceptions, it is difficult to identify a truly novel psychotropic drug that has emerged in the past 30 years. “All of our current antidepressants, antipsychotics, and antianxiety drugs share the same molecular targets in the brain as their prototypes from the 1950s,” he said. The pharmaceutical industry is making a mistake, according to Friedman, “by running away from the brain just when things are getting interesting.” He cited the example of ketamine, an anesthetic agent that has been shown to have powerful antidepressant effects.
Other experts have also sounded the alarm. Steven Hyman, MD, former head of the NIMH and now director of the Stanley Center for Psychiatric Research at the Broad Institute, wrote that in the past 3 years, “the global pharmaceutical industry has significantly decreased its investment in new treatments for depression, bipolar disorder, schizophrenia, and other psychiatric disorders.”4 For example, GlaxoSmithKline has closed its psychiatric laboratories entirely, Pfizer has decreased the size of its research programs, and Astra Zeneca has stopped its internal research.
Problems, promises, partnering
The high cost and time involved in researching and developing psychotherapeutic drugs have thwarted the search for better drugs that can alter the disease process. Robert H. Lenox, MD, Professor of Pharmacology and Clinical Neuroscience at the University of New England College of Osteopathic Medicine, recently warned that drug discovery and development “is time and resource intensive.” The cost to develop a drug (including the cost of failures) is upwards of $1.5 to $2 billion. The Pharmaceutical Research and Manufacturers of America estimates that, on average, it takes about 10 to 15 years for a new medicine to complete the journey from initial discovery to the marketplace.
During his distinguished psychiatrist lecture at the American Psychiatric Association’s annual meeting in San Francisco, Lenox noted that drug failures occur even in phase 3 clinical trials and the number of failures is particularly high for CNS disorders. The failure rate for drug candidates entering phase 3 can be as high as 40% to 50%, with two-thirds of the failures due to lack of efficacy.
Psychiatric diseases are chronic and recurrent and have a complex etiology. These disorders “are neurodevelopmental and particularly vulnerable to the environmental factors,” Lenox said. “While there may be some understanding of the physiological dysfunction leading to symptoms, and we have had some success in symptomatic treatments, such as psychosis, we have very little understanding of the underlying disease process. Furthermore, we have very few animal models that have the validity to predict clinical efficacy.”
Particularly frustrating to Lenox is that “there is a dearth of valid new targets and novel drug candidates. Pharmaceutical companies often compete on the same poorly validated targets, wasting time and resources in the absence of early stage sharing of lead compounds and data . . . this is unsustainable as a business model.”
“DMS-5 does not reflect progress in our understanding of the shared pathophysiology of many of these neurobehavioral disorders, limiting translation of drug discovery data from animal models to humans,” according to Lenox. “We need to be looking at dimensional diagnosis, which DSM-5 has attempted to do. . . . So rather than looking at treating schizophrenia, I’m looking at treating anhedonia, cognition, or episodic memory; I’m looking at domains of brain dysfunction rather than treating that particular diagnosis.”
The Research Domain Criteria (RDoC) project of the NIMH was launched to define basic dimensions of functioning. “It is increasingly evident that mental illness will be best understood as disorders of brain structure and function that implicate specific domains of cognition, emotion, and behavior. RDoC is an attempt to create a new kind of taxonomy for mental disorders by bringing the power of modern research approaches in genetics, neuroscience, and behavioral science to the problem of mental illness.”5
Lenox explained that despite the problems involved in developing psychiatric and related drugs, there are some CNS disorders whose pathophysiology is currently more apparent for the pharmaceutical industry to explore. These include addiction, fragile X syndrome/autism, pain, and disorders of circadian rhythm. Brain imaging studies in animals and humans have implicated discrete circuits that mediate the stages of the addiction, including ventral striatum, limbic, and prefrontal regions of the brain. Recent studies in autism, he added, reveal the promise of modifying the disease process as well as the phenotypic expression of developmental brain disorders in childhood and may augur similar opportunities for altering disease progression in such psychiatric illnesses as schizophrenia.
Many pharmaceutical companies are “repurposing old drugs for new conditions,” such as duloxetine (Cymbalta) for depression, generalized anxiety disorder, and pain, said Lenox. The pharmaceutical industry is also beginning to shift risk of failure to earlier phases of drug development with the incorporation of novel translational biomarkers.
Some companies are moving from “blockbuster” drugs to “niche-buster” drugs and are concentrating on rare and orphan diseases for which there are market challenges but also genetic mutations that provide new drug targets with biological validity. A more collaborative approach to drug development is unfolding, according to Lenox. Pharmaceutical companies, for instance, are forming partnerships with researchers in government, academia, and smaller companies to support early-stage research, speed drug discovery, and facilitate funding.
“We cannot afford to waste time,” warned Lenox. “There should be a paradigm shift with more efficacious validation of targets and compounds in preclinical discovery based on a better understanding of pathophysiology. To this end, emerging biotechnology offers the promise of identifying functional networks in the brain that will permit novel pharmacological targeting of discrete pathways driving brain dysfunction associated with psychiatric disease.”
He continued, “We also need safer, more rapid, and earlier evidence of proof of concept. . . . And we need intellectual property and patent statutes that provide reasonable protections but that do not constrain efficient, innovative drug discovery and development. What’s more, we need FDA regulatory reforms with strong leadership.”
As regards psychiatry, “We must have the neurobiology to support our understanding of pathophysiology and the clinical descriptors that represent the disease process to better facilitate future drug discovery.” Lenox advised companies to design drug discovery programs to “effectively complement and enhance nonpharmacological treatment interventions” as new psychiatric drugs are developed. “We have other ways of accessing the brain,” he said, citing cognitive remediation, cognitive behavioral therapies, transcranial magnetic stimulation and vagus nerve stimulation. “We need to design drugs that work with these modalities, because ultimately we want to help our patients more effectively.”
1. Friedman RA. A dry pipeline for psychiatric drugs. New York Times. August 19, 2013. http://www.nytimes.com/2013/08/20/health/a-dry-pipeline-forpsychiatric-drugs.html?_r=0. Accessed September 8, 2013.
2. US Food and Drug Administration. 2012 Novel New Drugs Summary. January 2013. http://www.fda.gov/downloads/Drugs/DevelopmentApproval Process/DrugInnovation/UCM337830.pdf. Accessed September 9, 2013.
3. New Drugs at FDA: CDER’s new molecular entities and new therapeutic biological products of 2013. http://www.fda.gov/drugs/developmentapproval process/druginnovation/default.htm. Accessed September 9, 2013.
4. Hyman SE. Psychiatric drug development: diagnosing a crisis. 2013. http://www.dana.org/news/cerebrum/detail.aspx?id=41290. Accessed September 4, 2013.
5. Insel TR, Lieberman JA. DSM-5 and RDoC: shared interests. May 13, 2013. http://www.nimh.nih.gov/news/science-news/2013/dsm-5-and-rdoc-shared-interests.shtml. Accessed September 10, 2013.
6. Long G, Works J. Innovation in the biopharmaceutical pipeline: a multidimensional view. January, 2013. http://www.analysisgroup.com/uploadedFiles/Publishing/Articles/2012_Innovation_in_the_Biopharmaceutical_Pipeline.pdf. Accessed September 10, 2013.
7. Pharmaceutical Research and Manufacturers of America (PhRMA). Medicines in development: mental illnesses. 2012. http://phrma.org/sites/default/files/pdf/phrmamedsindevmentalillness2012.pdf. Accessed September 12, 2013.
8. Pharmaceutical Research and Manufacturers of America (PhRMA). Medicines in development: older Americans. 2013. http://www.phrma.org/sites/default/files/pdf/oac2013_0.pdf. Accessed September 12, 2013.