Concert Pharmaceuticals Announces Advancement of Novel Drug Candidate in Schizophrenia
Published: Feb 28, 2018
“We see neuropsychiatry as an area in which our team is well-positioned to broaden and expand our pipeline and apply our deuterium chemistry technology to create innovative medicines with differentiated therapeutic properties,” said Roger Tung, Ph.D., President and CEO of Concert Pharmaceuticals. “Our newest development candidate, CTP-692, represents an exciting opportunity to improve upon the existing standard-of-care with the potential to make a meaningful difference for patients with schizophrenia.”
Despite its therapeutic potential as an adjunctive antipsychotic medication, the development of D-serine has been limited by safety concerns. D-serine has been shown to cause nephrotoxicity in preclinical testing. In addition, laboratory findings suggesting a possible renal safety signal were observed in some patients who received D-serine in clinical studies.
CTP-692 has the potential to improve the safety profile of D-serine. In preclinical evaluation, Concert found that selective deuterium modification increased D-serine exposure and substantially reduced evidence of renal impairment. As a result, the Company believes that it can explore a wider exposure range to achieve optimal therapeutic levels in the clinic with a much lower risk of renal toxicity. These results support the further advancement of CTP-692.
About CTP-692 and Schizophrenia
CTP-692 is a deuterium-modified analog of endogenous D-serine. Based on documented effects of D-serine, the Company believes that CTP-692 has the potential to restore NMDA receptor activity in key areas of the brain and improve clinical outcomes in patients with schizophrenia. CTP-692 is expected to have similar pharmacology to D-serine with the potential for an improved safety profile and improved clinical outcomes in the treatment of schizophrenia. CTP-692 will be developed as an adjunctive therapy administered in addition to standard antipsychotic medicines to improve both positive and negative symptoms as well as cognitive function in patients with schizophrenia.
There is an extensive body of evidence supporting NMDA receptor hypofunction as a key underlying mechanism of schizophrenia. The NMDA receptor comprises two binding domains and, in addition to requiring glutamate binding, activation with a co-agonist such as D-serine or glycine is necessary for NMDA receptor activation. D-serine is the most important endogenous co-agonist for synaptic transmission in the human central nervous system. It has been postulated for some time that administration of NMDA co-agonists could benefit patients with schizophrenia since there is evidence that plasma and CSF levels of endogenous D-serine are reduced in patients with schizophrenia.
Schizophrenia is a chronic and devastating neuropsychiatric disorder that is ranked as a leading cause of disability worldwide. The disease afflicts nearly 1% of the world’s population, affecting both men and women equally, and striking all ethnic and socioeconomic groups with a similar level of prevalence. The illness is characterized by multiple symptoms that are categorized into three main clusters known as positive symptoms (hallucinations, delusional behaviors and thought disorder), negative symptoms (social withdrawal, flattened affect and poverty of speech), and cognitive dysfunction (diminished capacity for attention, working memory and executive function). The underlying basis of the current antipsychotic therapy is that excessive dopaminergic neurotransmission and dysfunctional D2 receptor signaling play key pathophysiological roles in the disease, and consequently all typical and atypical antipsychotics in clinical practice possess some level of D2 antagonist activity. Currently available antipsychotic drugs exhibit efficacy for positive symptoms, but are limited in their capacity to treat negative symptoms and cognitive dysfunction which are related to poor functional outcomes for these patients.