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.”