Concert Pharmaceuticals has initiated the second Phase 1 clinical trial with CTP-692, a novel deuterium-modified form of D-serine being developed as an adjunctive treatment for schizophrenia. The Phase 1 single-ascending dose trial will evaluate the safety, tolerability, and pharmacokinetic profile of CTP-692 in healthy volunteers.
“For decades all approved schizophrenia drugs have acted predominantly by modulation of dopamine, or dopamine and serotonin receptors. By activating glutamatergic pathways as an NMDA co-agonist, CTP-692 has the potential to be a safe and effective new adjunctive treatment for schizophrenia, and treat positive and negative symptoms and cognitive dysfunction,” stated Roger Tung, Ph.D., President and Chief Executive Officer of Concert Pharmaceuticals, Inc. “We are excited about continuing our Phase 1 program and in the fourth quarter of 2019 are preparing to advance CTP-692 into a Phase 2 trial that is intended to support advancement into pivotal evaluation.”
The initial Phase 1 trial evaluated the safety, tolerability, and pharmacokinetics of a single oral dose of CTP-692 versus D-serine in a crossover study conducted in Australia. In individuals treated with both compounds, CTP-692 was found to have increased plasma exposure compared to D-serine. In addition, CTP-692 was found to be well tolerated in healthy volunteers and no serious adverse events were reported. Under its Investigational New Drug application in the United States, Concert will conduct this second study in the Phase 1 program to assess the safety, tolerability, and pharmacokinetics of single-ascending oral doses of CTP-692 in a double-blind, placebo-controlled trial. The Phase 1 single-ascending dose trial will also evaluate the effect of food on the pharmacokinetics of the compound. In addition, the Phase 1 program will include a double-blind, placebo-controlled, multiple-ascending dose trial assessing CTP-692 dosed orally over seven days. Topline data from the Phase 1 program is expected in the first half of 2019.
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The CTP-692 clinical program is supported by Concert’s preclinical studies which have shown the potential of CTP-692 to improve upon the safety profile of D-serine. D-Serine has been shown to cause nephrotoxicity in published preclinical studies. Concert’s preclinical studies have demonstrated that selective deuterium modification resulted in increased exposure of CTP-692 relative to a similar dose of D-serine, and administration of CTP-692 did not cause changes in serum creatinine and blood urea nitrogen at doses where D-serine caused substantial nephrotoxicity as assessed by these kidney function markers. These preclinical results were presented by Concert at the American College of Toxicology 2018 Annual Meeting in November 2018. 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 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 has been shown to have similar ability to bind to and activate human NMDA receptors relative 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.
An extensive body of evidence supports 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 believed to be 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.