Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Disappointing clinical trial results and genetic studies reinforce need for better schizophrenia treatments.

In January, Roche announced that two of its Phase III studies evaluating its investigational bitopertin (RG1678) to treat persistent, predominant negative symptoms of schizophrenia in adults failed to meet their primary endpoints. In the studies, adding bitopertin to antipsychotic therapy did not significantly reduce negative symptoms at 24 weeks compared to placebo. Bitopertin was generally well tolerated and its overall safety profile was similar to that seen in the previously reported Phase II trial (NN20372).

A third Phase III study evaluating the drug for these symptoms of schizophrenia continues, as do three Phase III studies investigating bitopertin for suboptimally controlled symptoms of schizophrenia. Suboptimally controlled symptoms, such as hallucinations and delusions, are symptoms that do not resolve despite treatment with an antipsychotic.

And new treatments are critically needed. Current drugs cause difficult side effects, as brilliantly depicted by Russell Crowe in the film A Beautiful Mind. In the 2002 movie, Crowe plays John Forbes Nash, Jr., a brilliant mathematician who came up with the game theory of economics and won the Nobel Prize in 1994. But at age 31, he developed schizophrenia, suffered a mental breakdown, and was treated with antipsychotics. In the film, he stops taking the drugs after finding that they dull his senses, emotions, and sex drive, and appears to overcome his illness through “sheer force of will.”

Experts credited Crowe with “a brilliant job of portraying the mannerisms and some of the behaviors of a schizophrenic—the best I have ever seen on the screen,” Ken Davis, M.D., chairman of psychiatry at Mount Sinai School of Medicine in New York, told ABC News. “On the other hand, the notion that willpower can really overcome schizophrenia is ludicrous.”

The reality is that most affected persons do not recover from this debilitating disease.

Commenting on Roche’s failed drug trials, Sandra Horning, M.D., Roche’s CMO and head of global product development, noted, “These results are disappointing for people with negative symptoms because more effective treatments are needed for these debilitating effects of schizophrenia. We will await data from the remaining bitopertin studies in schizophrenia before deciding on next steps.”

A Splitting of the Mind

Schizophrenia occurs in 1% of the general population, but it occurs in 10% of people who have a first-degree relative with the disorder such as a parent, brother, or sister. People who have second-degree relatives (aunts, uncles, grandparents, or cousins) with the disease also develop schizophrenia more often than the general population. The risk is highest for an identical twin of a person with schizophrenia. He or she has a 40 to 65% chance of developing the disorder.

Debilitating effects of the disease, which afflicts about 26 million people worldwide and is usually diagnosed between the ages of 16 and 25, include positive, negative, and cognitive symptoms. Positive symptoms include hallucinations, delusions, and suspiciousness; negative symptoms social withdrawal, lack of motivation, and reduced emotional reactivity; and cognitive deficits include difficulty concentrating and memory problems.

Positive symptoms have historically been treated with antipsychotic drugs such as Thorazine. But while effective in alleviating positive symptoms, they cause significant cognitive dulling and involuntary movements, and do not improve negative symptoms such as apathy, decreased motivation, and lack of emotional expressiveness.

In 1989, a new class of antipsychotics—atypical antipsychotics—was introduced that produced fewer of the neurological side effects of older medications, which often include such symptoms as muscular rigidity, painful spasms, restlessness, or tremors. But Clozaril, another “atypical” antipsychotic, proved effective where other antipsychotics failed and caused fewer neurological side effects. It did, however, cause agranulocytosis (decrease in the number of white cells), necessitating blood counts need to be monitored every week during the first six months.

And the market for effective agents to treat “negative” symptoms would prove significant. Research and consulting firm Decision Resources said, in a 2012 survey of U.S. psychiatrists, the doctors questioned said they would prescribe Roche/Chugai’s bitopertin to 28% of their patients with negative symptoms of schizophrenia, which is equivalent to a patient share of approximately 17% of the diagnosed schizophrenia population.

Decision Resources forecast at the time that bitopertin would earn a 15% patient share in the U.S. schizophrenia market by 2020, owing to its efficacy in the treatment of negative symptoms of the disorder. Clinical data and interviewed thought leaders, the firm said, indicated that bitopertin, Eli Lilly’s pomaglumetad methionil, Targacept’s TC-5619, Envivo Pharmaceuticals/Bayer’s EVP-6124, and Shire’s Vyvanse each demonstrated the potential to partially fulfill this unmet need.

“Due to the availability of at least eight atypical antipsychotics in most major markets, positive symptoms in approximately two-thirds of drug treated schizophrenia patients are at least adequately addressed,” said Decision Resources analyst Anne-Elise Tobin, Ph.D. “Therefore, the opportunities in this indication lie in developing therapies with new mechanisms of action that could be used in patients who are poorly controlled by their therapy and/or therapies that are effective at treating the negative or cognitive symptoms associated with schizophrenia.”

Decision Resources had predicted that bitopertin would be the first therapy approved as an adjunctive treatment for negative symptoms. If successful, the schizophrenia medicine could have generated as much as 2 billion Swiss francs ($2.19 billion) in annual sales, according to Andrew Weiss, an analyst for Bank Vontobel in Zurich.

But patients and their physicians will remain without these options any time soon as schizophrenia drug development remains risky for drug companies. Last May Shire said it had cancelled its Phase III program looking at Vyvanse for the treatment of negative symptoms of schizophrenia following “a review and prioritization of Shire’s development portfolio and taking into account investment requirements for recent acquisitions.”

And Targacept in December 2013 announced top-line results from a Phase IIb trial of TC-5619 as an augmentation therapy for the treatment of negative symptoms of schizophrenia. In the trial, TC-5619 did not meet the primary outcome measure, change from baseline on the Scale for the Assessment of Negative Symptoms (SANS) after 24 weeks versus placebo. In addition, TC-5619 did not demonstrate improvement on the key secondary measures of cognitive function. TC-5619 exhibited a benign safety and tolerability profile in the study.

Commenting on the findings, Stephen A. Hill, M.D., Targacept’s president and CEO, said, “The development of new and innovative treatments for patients suffering from central nervous system disorders is challenging, and the results of this study highlight the risks inherent in trying to address the unmet medical needs that remain in schizophrenia.”

The Schizophrenic Genome

A spate of recent research reports confirm the complexity of the disease and underscore Dr. Hill’s point, indicating why the disease remains such an intractable target for drug developers. In studies published in Nature in 2013, Steffanson et al., reported that individuals who carry high-risk genetic variants for schizophrenia and autism have impairments resembling those associated with disorders such as dyslexia, even when they do not yet have a mental illness.

The authors noted that research on pathogenesis of schizophrenia has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. And although, they say, schizophrenia has been considered a separate disease for over a century, its diagnosis has been based on signs and symptoms due to the absence of clear biological markers. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is, the authors say, that its genetic basis does not necessarily conform to “classical nosological disease boundaries.” Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders.

For their search for sequence variants associated with schizophrenia, the investigators performed a genome-wide scan of 2,663 schizophrenia cases and 13,498 controls from eight European locations (England, Finland [Helsinki], Finland [Kuusamo], Germany [Bonn], Germany [Munich], Iceland, Italy, and Scotland; collectively called SGENE-plus) using the Illumina HumanHap300 and HumanHap550 BeadChips. In total, 314,868 SNPs were included in an allelic association analysis.

By combining SNP data from several large genome-wide scans and following up the most significant association signals, the authors found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. They noted that their findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory, and cognition.

And in other findings, reported by assistant professor at Emory Jennifer Mulle and a large collaborating group of international scientists, a 1.4 megabase duplication on chromosome 7 (7q11.23) was identified that increases the risk for schizophrenia over 10 times, or to a 100-out-of-1,000 chance (10%). This finding suggests that identified gene variants that are rare in the population but, when present, more substantially increase the risk for developing schizophrenia.

“We also found it interesting that three different disorders (schizophrenia, autism, and intellectual development) that strike at different times and present in different ways have genetic links to this same region on chromosome 7,” commented Mulle. “Our findings support the notion of a neurodevelopmental link between these disorders.”

University of Bologna neuropsychiatrist Alessandro Serrett has framed the enormous challenge the study results, saying, “This study for the first time clearly states what has been previously suggested. There are so many variants that predispose to schizophrenia that it explains why, after more than 20 years of research, no single one has been unequivocally identified. There is a problem of heterogeneity in such large studies. But it paves the way for a future when we will create an individual profile of risk combining the thousands of genetic risk factors for each subject.”

And, physicians faced with treating the disease say, in view of the heterogeneity of the risk factors and the illness progression of individual patients, the use of multifaceted illness management programs consisting of different combinations of physical, psychological, and social interventions might be efficient and effective in improving recovery.

Patricia Fitzpatrick Dimond, Ph.D. ([email protected]), is technical editor at Genetic Engineering & Biotechnology News.

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