Concert Pharmaceuticals reported that its Phase 2 trial to evaluate CTP-692 as an adjunctive treatment in patients with schizophrenia did not meet the primary endpoint or other secondary endpoints. The company plans to focus internal resources on the advancement of CTP-543, which is currently in Phase 3 trials for the treatment of alopecia areata, as well as assessing additional pipeline candidates.
The Phase 2 trial double-blind, randomized, placebo-controlled study enrolled 325 patients already on a stable course of an antipsychotic medication. The patients were randomized to receive 1, 2 or 4-gram doses of CTP-692 or placebo once-daily. The primary endpoint of the trial was the change in the Positive and Negative Syndrome Scale (PANSS) total score at 12 weeks compared to baseline. CTP-692 did not show a statistically significant improvement over placebo at any of the doses. Additionally, no significant improvements were observed in either the positive or negative symptoms subscales of the PANSS scale at any of the CTP-692 doses evaluated. CTP-692 was generally well tolerated. The majority of adverse events were mild in severity and equally distributed across the dose groups, including placebo.
CTP-692 is a deuterium-modified form of D-serine. The underlying rationale of the current antipsychotic therapies for schizophrenia is that excessive dopaminergic neurotransmission and dysfunctional D2 receptor signaling are believed to play key pathophysiological roles in the disease, and consequently all approved typical and atypical antipsychotics possess some level of D2 antagonist activity. However, deficient glutamatergic neurotransmission mediated by the NMDA receptor is believed to be another underlying cause of schizophrenia. It has been reported that individuals with schizophrenia have low plasma and cerebrospinal fluid levels of D-serine, a key molecule that activates NMDA receptors in areas of the brain that are widely believed to play key roles in schizophrenia. CTP-692 administration may help enhance NMDA neurotransmission, potentially more safely than using unmodified D-serine.
Schizophrenia is a chronic neuropsychiatric disorder afflicting approximately 1% of the global population. 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. Currently available antipsychotic drugs offer some benefit for positive symptoms but are frequently associated with neurologic and metabolic adverse effects and are limited in their capacity to treat negative symptoms and cognitive dysfunction, which are related to poor functional outcomes.