Roche’s Investigational Antipsychotic Has Distinct MOA
Over at The Medicine Show (nice blog name, BTW), Forbes’s Matthew Herper showcases Roche’s antipsychotic in development, known currently by the catchy name RG1678 (or the even catchier RO4917838). The drug profile is prompted by Roche’s recent press release of phase 2 data and enthusiasm from psychiatrist Jeffrey Lieberman of Columbia University, lead author of the NIMH’s landmark CATIE project from several years ago.*
Lieberman’s evidently pumped because RG1678 has an MOA that is entirely different from that of existing antipsychotics—which generally block dopamine receptors.* The drug inhibits glycine reuptake, which may translate into better management of the so-called negative symptoms of schizophrenia, like apathy and withdrawal. Currently existing antipsychotics, of both the first- and second-generation varieties, are typically excellent at addressing the positive symptoms of schizophrenia, like hallucinations or paranoia; however, their historical downfall has been a lack of effect on negative symptoms. (The general, natural history of schizophrenia, a life-long disease, is an early burden of positive symptoms followed by a predominance of negative symptoms as the disease progresses.)
Data from Roche’s 8-week, placebo-controlled, phase 2 study (N = 323), which were presented at the very recent annual meeting of the ACNP in Miami (Umbricht et al), showed a “clinically meaningful” reduction of negative symptoms in patients who received RG1678 (10 or 30 mg) in combination with second-generation antipsychotics. Withdrawal of treatment for any reason (the most common of which historically, like in CATIE, is a lack of drug efficacy) was observed in 13%-20% of patients. Withdrawal rates did not appear to differ appreciably among treatment groups, according to the PR.
Roche’s Chief Medical Officer says a phase 3 program for the compound is underway. A search of the NIH’s clinical trials database for “RO4917838” reveals 3, longer (eg, 24-week), phase 3 trials that are recruiting. The studies will pit the investigational drug against placebo, without the use of concomitant antipsychotic therapy, and are expected to be completed in 2015.
MOA = mechanism of action; NIMH = National Institute of Mental Health.
* CATIE showed a relatively high rate of discontinuation (~70%) of antipsychotics in people with schizophrenia.
** Along with other pharmacodynamic properties, like effects on serotonin receptors. In the case of Roche’s compound, inhibition of glycine reuptake by neurons is intended to normalize glutamate transmission, the abnormality of which has been implicated in schizophrenia (along with a variety of other neurotransmission defects).