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Fast Forward to Drug Approval

Rare FDA decision expedites new drug developed by Northwestern neuropharmacologist

Psychiatrist Herb Meltzer sadly watched the agitated woman accuse her son of trying to poison her. Although not her physician, Dr. Meltzer certainly recognized the devastating effects of his mother-in-law’s Parkinson’s disease psychosis (PDP). Occurring in up to half of all patients with Parkinson’s, symptoms of the psychotic disorder may include hallucinations and delusions. The development of PDP often leads to institutionalization and increased mortality.

“I was on the sidelines,” explains Dr. Meltzer, professor of psychiatry and physiology and director of the Translational Neuropharmacology Program at Northwestern University Feinberg School of Medicine. “I told my brother-in-law it was the disease talking, not his mother.”

Ironically, Dr. Meltzer has been far from the sidelines and right on the PDP playing field for quite a while. In fact, he may soon see a drug he helped develop become the first approved treatment for the disorder. In early April, Dr. Meltzer celebrated, along with colleagues at ACADIA Pharmaceuticals in San Diego for which he has been a clinical advisor, the stunning announcement: the Food and Drug Administration (FDA) had expedited the company’s path to filing a new drug application (NDA) for pimavanserin, a selective serotonin 5-HT2Areceptor blocker. Typically, the FDA requires data from two successful pivotal Phase III clinical studies affirming a drug candidate’s safety and efficacy before the agency will even consider an NDA. Just as ACADIA was planning to launch another Phase III study this spring to fulfill this requirement, the FDA decided the company had amassed enough data to support an NDA filing.

Herbert Meltzer, MD, designed ACADIA Pharmaceutical's initial proof of concept trial of the drug pimavanserin to treat Parkinson's disease psychosis.

“This action on the part of the FDA is extremely unusual,” says Dr. Meltzer, who designed ACADIA’s initial proof-of-concept trial of pimavanserin, a drug he had initially suggested ACADIA develop to treat schizophrenia, with PDP as a secondary indication. “The FDA staff decided that results from my small clinical study and the first successful Phase III study were sufficient to establish efficacy and safety.”

Bringing a safe and effective drug to market is a monumental achievement. Pimavanserin is not yet there but has significantly moved within striking distance with this recent nod from the regulatory agency.

24 years in the making

The neuropharmacologist’s collaboration with ACADIA began in 2000. The company wanted to develop a drug targeting the serotonin 5-HT 2A receptor, a neurotransmitter ACADIA believed played a key role in schizophrenia based upon basic research from Meltzer and their own studies. A distinguished schizophrenia investigator, then at Case Western Reserve University, he welcomed ACADIA’s offer to translate his ideas about developing safer and more effective drug treatments for psychosis. Through his provocative and groundbreaking research, Dr. Meltzer originally championed the idea that blocking the 5-HT2A receptor would lead to better antipsychotic drugs with fewer side effects. Existing drugs often impaired motor function because they targeted the dopamine D2 receptor. Of the 14 different types of serotonin receptors in this complex area of study, Dr. Meltzer zeroed in on the 5-HT2A type—the same receptor that leads to hallucinogenic properties of LSD and mescaline. It was an ideal target to complement weak D2 receptor blockade in schizophrenia and as a standalone treatment for PD psychosis.

Pimavanserin structure (also known as ACP-103)

“In the 1980s, I identified the drug clozapine as the first antipsychotic for treatment-resistant schizophrenia,” says Dr. Meltzer, explaining what led him to propose the development of a drug like pimavanserin. Never approved in the United States, clozapine had been withdrawn as an antipsychotic in Europe due to toxicity issues. “I was interested in understanding the drug’s motor system effects. Clozapine was different from first-generation antipsychotics. Unlike the so called ‘typical’ drugs then in wide  use, clozapine didn’t produce Parkinsonian symptoms, such as  muscle stiffness, slowed movement and tremor, or tardive dyskinesia, abnormal involuntary muscle movements of the face, trunk and limbs.”

Prior to Dr. Meltzer’s research, the commonly accepted view was that the psychotic behavior of schizophrenia resulted mainly, if not exclusively, from excessive activity of the neurotransmitter dopamine stimulating one of its key receptors, the D2 type in the limbic brain. Similarly, PDP develops after initiating replacement therapy for the loss of dopamine neurons by administering the precursor of dopamine, L-DOPA. First-generation antipsychotic drugs work by blocking dopamine D2 receptors in the area of the brain involved in functions such as reality testing, reward, emotion, and memory. This action, however, results in the unwanted motor disturbance of antipsychotic drugs.

As co-PI for the single clinical study that led to the FDA-approval of clozapine for treatment-resistant schizophrenia, Meltzer dedicated his basic research effort to understanding why clozapine and other “atypicals” (called such because they don’t cause motor movement problems) worked. In 1988, in a widely cited landmark paper that generated 2,700 citations, the results of the clozapine trial in schizophrenia were published. In 1989, just a few months later, Dr. Meltzer and his colleagues published the results of their efforts to understand the pharmacologic basis for atypical antipsychotic drugs. The core concept?  Strong 5-HT2A and weaker D2 receptor blockade, a ratio which is also known as the “Meltzer Index.” In the same papers, he proposed that the psychotic component of schizophrenia was due to a combination of both excessive 5-HT2A and D2 receptor stimulation.

3-D model of drug pimavanserin, the development of which has been expedited by the FDA

“We found that the ‘atypical’ drugs, which produced little or no motor side effects, were more potent serotonin 5-HT2A than D2 receptors,” says Meltzer. “Eventually, we showed that clozapine could be an effective antipsychotic and tolerable to patients with PD psychosis at very low doses, which did not block D2 receptors but could block 5-HT2A receptors.”

His discoveries contributed to a rush to develop a new class of atypical antipsychotics. These “sons of clozapine,” rather than clozapine, became the dominant treatments for schizophrenia and other disorders, because the severity of clozapine’s side effects was off-putting to many prescribers and patients. Additionally, Dr. Meltzer’s serotonin-dopamine hypothesis wasn’t universally accepted.

“No one doubted clozapine’s effectiveness at treating dopamine-based psychosis,” says Bryan L. Roth, MD, PhD, professor of pharmacology at the University of North Carolina, who joined Case Western as a junior faculty member in the early ‘90s specifically because of Dr. Meltzer’s well-regarded pre-clinical and clinical neuropharmacology program in schizophrenia. “But there was debate about whether it was the action of 5-HT2A or some other receptor.” Agrees Dr. Meltzer, “My theory met with some resistance.  It wasn’t the only one advocated and was not immediately obvious the correct one.”

Then ACADIA called. The start-up company’s founder, scientist Mark Brann, believed that Dr. Meltzer was on to something good.

A receptive audience

“ACADIA had looked over the theories of schizophrenia and appropriate drug targets and thought that I had gotten it right with advocating for the role of the 5-HT2A,” recalls Dr. Meltzer, who in the summer of 1996 moved to Vanderbilt University as Douglas Bond Professor of Psychiatry and director of psychopharmacology in the Department of Psychiatry. His work with ACADIA led to the discovery of pimavanserin, a drug that holds much promise for the treatment of schizophrenia, bipolar disorder, and depression, as well as the psychosis of Alzheimer’s disease.

So 24 years later, Meltzer has seen his hypothesis come to light in a novel compound, in part, due to his unflagging belief in serotonin receptors and their role in psychosis. “He has single-mindedly studied this once trendy area through its ups and downs,” says Dr. Roth, an expert in molecular neuropharmacology. “Without the vast amount of data he has generated and his devotion over the years, it is safe to say this drug would not exist.”

Advancing novel research findings that bring the next breakthrough drug to market requires substantial investment of capital, as much as a billion dollars, by some industry estimates, when all is said and done. Clinical trials can cost as much as $150,000 per patient, and 600 subjects is the norm for a pivotal trial. Driven to pursue new knowledge, academia is full of people with great ideas. Interested in developing new therapeutics, pharmaceutical companies have the drug development and regulatory know-how, as well as the funding, to invest in ideas they believe will yield the best products. How academia and private industry come together isn’t an exact science but based on the successful collaboration of Dr. Meltzer and ACADIA, it is a relationship that can truly help to translate research into clinical practice.

“It’s critical to overcome the bias in academics and look for more ways to partner with industry,” says Dr. Meltzer, who plans to soon start conducting clinical trials for the use of pimavanserin in patients with schizophrenia. “If our medical center’s mission is to do the best for everyone, developing these types of relationships is the best way to achieve this goal.”

This model shows pimavanserin binding to the serotonin receptor. The seven loops are the folds of the 5-HT2A receptor protein in the cell membrane. Illustration by: Seva Katrich, Scripps

 

Advancing schizophrenia treatment

Risperidone is a widely used antipsychotic drug for schizophrenia patients experiencing a relapse of psychosis. In 2012 Dr. Meltzer published a study showing the benefits of combining pimavanserin with a sub-effective dose of risperidone to restore full 5-HT2A receptor blockade. Used together, the two drugs are more effective at alleviating schizophrenia-related psychosis and produce much fewer side effects than the standard dose of risperidone.

Dr. Meltzer hopes to test this concept in a clinical trial in the very near future. He says, “If successful, it will be another major milestone in our efforts to help people with severe mental illnesses.”