Neurocrine Biosciences, Inc. Announces Phase II Results of VMAT2 Inhibitor NBI-98854 for Treatment of Tardive Dyskinesia

SAN DIEGO, March 26, 2012 /PRNewswire/ -- Neurocrine Biosciences, Inc. (NASDAQ: NBIX) today announced efficacy and safety results from a Phase II trial of NBI-98854 in 37 tardive dyskinesia patients. For the final analysis, data from one site was removed due to the inconsistent and incorrect application of the efficacy assessment protocol. With this site removed, the results showed a significant reduction in tardive dyskinesia symptoms at end of two weeks of active treatment with 50mg once-daily doses of NBI-98854.

“This Phase II trial was extremely informative. NBI-98854 displayed the efficacy and safety data we expected to see in both the 12.5mg and 50mg doses,” said Chris O’Brien, Chief Medical Officer of Neurocrine Biosciences. “While we had data inconsistencies at one site, this study has provided us with the necessary information and confidence to move forward into the larger Phase IIb trials as planned.”

After database lock and unblinding of study data, the pre-specified statistical assessment was conducted and the normal quality control evaluation of the output performed. An inconsistent pattern of Abnormal Involuntary Movement Scale (AIMS) scores emerged at one of the eight sites that was not evident during the blinded data review. Potential errors in randomization and drug exposure as causes for this data inconsistency were ruled out. However, a review of videotaped AIMS assessments at this single site noted discrepancies between the clinical score and the video record which were well outside of the variability associated with the AIMS. Additionally, videotaped AIMS assessments were reviewed at other sites and found to be administered appropriately.

Based on these findings, the AIMS data from this single site was removed and the statistical assessment was repeated. This post-hoc analysis demonstrated a clinically meaningful and statistically significant improvement in tardive dyskinesia symptoms for the subjects while receiving the 50mg once-daily dose. These subjects had a significant reduction in tardive dyskinesia symptoms at the end of two weeks of active treatment vs. the end of two weeks of placebo (difference in LS mean of 4.2 for the 50mg period vs. the placebo period, p-value=0.002). As expected, the 12.5mg dosing group was not statistically better during the active treatment period than during the placebo period (difference in LS mean of 0.4 for the 12.5mg period vs. placebo period, p-value=0.68).

The improvement in symptomology is also evidenced by the significant improvement in AIMS scores over baseline levels relative to placebo, excluding the one site. NBI-98854 reduced the average baseline AIMS score by 9.2 points in the 50mg period (p-value=0.0004) vs. a reduction of 4.9 points in the 12.5mg period and 4.7 for the placebo periods. A responder analysis also showed improvement in both the investigator reported Clinical Global Impression-Tardive Dyskinesia and the patient reported Patient Global Impression of Change.

When including the data from the site in question, this study did not meet the pre-specified primary endpoint of reducing the AIMS scores during active treatment periods. The efficacy results from the entire study population showed a non-significant reduction in tardive dyskinesia at the end of two weeks of active treatment vs. the end of two weeks of placebo (difference in LS mean of 1.1 for the 50mg period vs. the placebo period (n=15), p-value=0.42) (difference in LS mean of 0.7 for the 12.5mg period vs. placebo period (n=17), p-value=0.59).

The tables below summarize the primary endpoint as well as the responder analyses for all clinical sites as well as the post-hoc analysis.

Safety Profile

NBI-98854 was generally safe and well tolerated; the frequency of treatment-emergent adverse events was 17% during the placebo period and 24% and 32% in the 12.5mg and 50mg treatment periods, respectively. There were no serious adverse events during the treatment period. The most common adverse event was headache and one subject in the 50mg group discontinued due to akathisia. The underlying psychiatric state of subjects was monitored using the Brief Psychiatric Ratings Scale (BPRS) and shown to be stable or improved across study groups declining from 32 at baseline to 28 at the end of the study. There were no drug-drug interactions identified in subjects who were utilizing a range of psychotropic and other concomitant medications.

“While not ideal, this study served its primary purpose of informing the larger Phase IIb studies. The 50mg once-daily dose of NBI-98854 provided tardive dyskinesia sufferers with a remarkable improvement of symptoms, coupled with an excellent safety and tolerability profile,” said Kevin C. Gorman President and Chief Executive Officer of Neurocrine Biosciences. “We will apply additional controls in future studies to ensure appropriate scoring of AIMS.”

Trial Design

This trial was a randomized, double-blind, placebo controlled, cross-over, Phase II clinical trial utilizing NBI-98854 in tardive dyskinesia patients at eight investigator sites. This 37 subject study assessed once-daily NBI-98854 (12.5mg and 50mg) over a two week dosing period. The primary endpoint of the study was a comparison of placebo vs. active scores utilizing the Abnormal Involuntary Movement Scale (AIMS).

Next Steps for NBI-98854

A placebo controlled, double-blind, parallel design, multiple dose, twelve week Phase IIb study is planned to assess six-week dosing of NBI-98854 against placebo, followed by six weeks of active treatment with NBI-98854. The study will incorporate a capsule formulation of NBI-98854 and will be initiated in mid-2012, with top-line data anticipated by year-end.