Concert Pharmaceuticals Presents Preclinical Data on CTP-692, a Novel Drug Candidate for Schizophrenia, Supporting Potential to Improve Safety Profile of D-Serine
Findings Presented at
“Despite its therapeutic potential as an adjunctive medication for
schizophrenia, D-serine’s therapeutic potential has likely been limited
by renal safety concerns. As a result of the preclinical profile we have
observed with CTP-692 showing a potentially lower risk of renal toxicity
compared to non-deuterated D-serine, we believe it’s possible for us to
explore a wider exposure range to achieve optimal therapeutic dosing
levels of CTP-692,” said
In preclinical evaluation, CTP-692 and D-serine were shown to have similar functional activation of the NMDA receptor in the presence of glutamate. Relative to D-serine, CTP-692 showed increased metabolic stability in the preclinical study. CTP-692 provided greater exposure, based on area under the curve (AUC) analysis, and a longer half-life than corresponding doses of D-serine in vivo. Notably, in animal models, serum creatinine and blood urea nitrogen, important markers of kidney function, were highly elevated upon acute dosing with D-serine but stayed within the normal range with CTP-692.
A copy of the poster may be accessed in the Scientific Presentations section of the Company’s website at www.concertpharma.com.
CTP-692 is a deuterium-modified analog of endogenous D-serine. Based on documented effects of D-serine, the Company is pursuing the development of CTP-692 as a treatment of schizophrenia by potentially restoring NMDA receptor activity in key disease-related areas of the brain. 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. Concert is developing CTP-692 as an adjunctive therapy administered in addition to standard antipsychotic medicines with the potential 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 human NMDA synaptic co-agonist. 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 cerebrospinal fluid (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.
Cautionary Note on Forward Looking Statements
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plans and prospects, including statements about our expectations for the
clinical development of CTP-692 and other statements containing the
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