2 Jun 2014
June 3, 2014. Several sessions at the Schizophrenia International Research Society 2014 meeting, held in Florence, Italy, April 5-9, discussed data from clinical trials testing novel antipsychotics and a variety of other drugs. Reading a description of every study presented could take as long as the wait to climb to the top of the city's iconic Basilica di Santa Maria del Fiore dome (Il Duomo); what follows is a subset of the clinical studies presented.
Drip, drip, drip
The April 6 afternoon session covering the latest from the schizophrenia pharmaceutical pipeline was, unfortunately, dominated largely by negative data. Speakers reported that several drugs failed to meet their primary endpoints, including a glycine transport inhibitor, a combination GABA agonist/dopamine antagonist, an alpha 7 nicotinic receptor agonist, a dopamine D1 agonist, and a D2/D3 partial agonist. However, the pipeline was not completely dry, and a few speakers presented promising efficacy data from Phase 2 studies.
Kimberly Vanover, Intra-Cellular Therapies, New York, discussed results from a trial of IT-007, a pharmacological jack-of-all-trades that acts as a serotonin 5-HT2A antagonist, a dopamine and glutamate phosphoprotein modulator, and a serotonin reuptake inhibitor (see SRF related conference report; SRF conference report). Compared to those given placebo, patients receiving the 60 mg (but not 120 mg) dose of IT-007 for one month had improved scores on the total Positive and Negative Syndrome Scale (PANSS) and on its positive symptom subscale. IT-007 improved symptoms across a variety of domains, consistent with a lessening of social impairment, said Vanover. It decreased negative symptoms in a subgroup of patients who had exhibited prominent negative symptoms at the start of the trial. In addition, in contrast to the active control risperidone, IT-007 improved some negative symptoms such as stereotyped thinking. Importantly, also unlike risperidone, it did not worsen other negative symptoms such as blunted affect. The drug was well tolerated, noted Vanover, and lacked many of the side effects such as metabolic syndrome and extrapyramidal symptoms that plague other antipsychotics.
Another compound with complex action was presented by Marc Cantillon of Reviva Pharmaceuticals, San Jose, California. He described his company's four-week Phase 2 REFRESH trial of the dopamine-serotonin system stabilizer RP5063 that balances partial agonism of D1, D2, D4, 5-HT1A, and 5-HT2A receptors with antagonism of 5-HT6 and 5-HT7 receptors. Cantillon reported clinically meaningful remission rates based on PANSS scores with all three doses tested (ranging from 34 percent to 46 percent), compared to 22 percent with placebo. Significant remission was also achieved using a second definition that combined PANSS and Clinical Global Impression (CGI) scale scores. Depression, anxiety, and cognitive symptoms also showed trends toward improvement, and the drug was safe and well tolerated at all three doses, he added.
Ilise Lombardo, FORUM Pharmaceuticals (formerly EnVivo Pharmaceuticals), Watertown, Massachusetts, reviewed the Phase 2b results of the nicotinic alpha 7 agonist encenicline for cognitive deficits in schizophrenia. She reported that treatment with the drug for four weeks improved global cognitive function, as measured by the CogState Battery and the PANSS cognitive scale. Encenicline also improved performance on a functional measure, the Schizophrenia Cognition Rating Scale (though only at the higher dose), and on the PANSS negative scale. A Phase 3 trial is currently underway.
Off label, but on target?
A drug repurposing session held on the final afternoon of the conference, a beautiful, sunny day in Florence, was attended by a few dedicated souls. Discussant Peter Buckley, Georgia Regents University, praised the session's speakers for their methodological rigor, and for the fact that their studies were rooted in biology.
Mark Weiser, Sheba Medical Center, Israel, presented a post-hoc analysis of a prior 16-week trial of aspirin, minocycline, and pramipexole as add-ons to antipsychotics in schizophrenia (see SRF related news report). A small but significant improvement on the total PANSS was observed with aspirin but not the other two drugs. When Weiser and colleagues divided subjects into thirds in a post-hoc analysis according to baseline levels of C-reactive protein (CRP), an acute marker of inflammation, those in the high CRP group showed a more substantial improvement on the PANSS positive subscale with aspirin. Harking back to the theme of the plenary session, these data suggest that only patients with high levels of inflammation should be included in further trials of aspirin.
The antibiotic minocycline has been proposed as an adjunctive treatment in chronic schizophrenia patients who are partially resistant to clozapine. Deanna Kelly, University of Maryland, Baltimore, discussed a pilot study showing that after 10 weeks of treatment, patients had significantly improved avolition, working memory performance, and anxiety/depressive symptoms, and trended toward a significant improvement in positive symptoms. She noted that nearly all patients wanted to continue minocycline after the trial ended and that the drug was well tolerated.
Jamie Hallak, University of Sao Paulo, Brazil, examined the role of nitric oxide (NO) in schizophrenia. In a preliminary acute study, patients on antipsychotics administered a single dose of the NO donor (and current treatment for high blood pressure) sodium nitroprusside displayed symptom improvement in as few as four hours (Hallak et al., 2013). This improvement on the Brief Psychiatric Rating Scale and the negative subscale of the PANSS was still present after four weeks. Hallak also described unpublished data from the same trial indicating that acute sodium nitroprusside also improved some domains of cognitive function.
In the final presentation of the session, Joshua Roffman, Massachusetts General Hospital, Boston, reviewed his earlier data demonstrating that, compared to those on placebo, patients taking folate and B12 (a cofactor in the folate metabolism pathway) supplements for 16 weeks showed an improvement in negative symptoms, but only when genetic variants in folate absorption were accounted for (see SRF related news report). In the second part of his talk, Roffman described unpublished MRI data from a subset of the original sample. After folate plus B12 treatment, patients displayed increased cortical thickness and in the mid-cingulate region; this was correlated with an improvement of negative symptoms. The supplements also increased activity in the frontoparietal control network. Roffman is currently conducting a clinical trial of the related compound L-methylfolate, with results expected later this year.—Allison A. Curley.