Neurocrine Biosciences Inc. announced that NBI-98854, a small molecule VMAT2 inhibitor, showed a statistically significant and clinically meaningful reduction in tardive dyskinesia symptoms in the Phase IIb Kinect 2 study. The pre-specified primary endpoint was the change from baseline in the Abnormal Involuntary Movement Scale (AIMS) at week six as assessed by central blinded video raters. At week six, AIMS scores were reduced by 2.6 points in the NBI-98854 intention to treat (ITT) group compared to a reduction of 0.2 points in the placebo arm (p<0.001).

Additionally, the responder rate (>= 50% improvement from baseline) was 49% in the NBI-98854 ITT group compared to 18% in placebo (p=0.002). In the per-protocol (PP) group AIMS scores were reduced by 3.3 points for those subjects taking NBI-98854 (p<0.001), with a corresponding responder rate of 59% (p<0.001). The improvement in week six AIMS was also corroborated by the Clinical Global ImpressionTardive Dyskinesia (CGI-TD).

Treating clinicians determined that approximately 67% of the subjects taking NBI-98854 were ‘much improved' or ‘very much improved' at week six compared to only 16% of the placebo subjects (p<0.001) in this pre-specified key secondary efficacy endpoint. The pre-specified statistical analysis plan included three data sets: a safety set an ITT set and a PP set. Subject Profile: The Kinect 2 study randomized 102 subjects.

At week six, the ITT population included 44 placebo subjects and 45 subjects who were randomized to NBI-98854. By week six, approximately 70% of the ITT population, randomized to NBI-98854, were titrated to the 75 mg dose, approximately 20% were titrated to the 50mg dose and the remaining subjects received 25 mg of NBI-98854. At week six the PP population consisted of 44 placebo subjects and 34 subjects randomized to NBI-98854.

The PP week six final titrated dose level of NBI-98854 was similar to that of the ITT population. The PP population excluded eleven subjects whose plasma concentrations of NBI-98854 were below the lower limit of quantitation. Given the timing of serum samples collections and the pharmacokinetic profile of NBI-98854, it was determined that these subjects had not ingested the study drug.

The subjects in the Kinect 2 study had moderate to severe tardive dyskinesia with a mean baseline video AIMS score of 8.0. Similar to previous studies, the average age of the trial participants was 56 years with an average age at onset of tardive dyskinesia of 49 years. Approximately 60% of the subjects were male. Safety Profile: In this study NBI-98854 was generally safe and well tolerated.

During the six-week treatment period the frequency of treatment-emergent adverse events was 33% for placebo and 43% for NBI-98854. There were no drug related serious adverse events. The most common treatment emergent adverse events were fatigue in five subjects (9.8%) randomized to NBI-98854 vs.

two subjects (4.1%) in the placebo group, and headache reported by four subjects (7.8%) on NBI-98854 vs. two subjects (4.1%) on placebo. Discontinuation rates were similar in both the NBI-98854 and placebo treatment groups with five per study arm.

Participants were assessed utilizing the Barnes Akathisia Ratings Scale for akathisia and the Simpson-Angus Scale for parkinsonism. Both of these scales documented minimal symptoms at baseline and there was no worsening during the six weeks of treatment. Clinical hematology, chemistry and ECG monitoring indicated no emergent safety signals.

There were no drug-drug interactions identified in subjects who were utilizing a range of psychotropic and other concomitant medications. Next Steps for NBI-98854: Data from the Kinect 2 study will be integrated with the Kinect study data to inform the ultimate design of the next study, Kinect 3. The company will work with its consultants and scientific advisors to expand and refine the pharmacokinetic/pharmacodynamic models as well as to complete the remaining safety and efficacy analyses from both Kinect and Kinect 2. These data will form the basis for an End of Phase II briefing package along with the proposed Phase III protocol. Kinect 2 Study Design: The Kinect 2 Study was a randomized, parallel, double-blind, placebo-controlled, dose titration Phase IIb clinical trial utilizing the capsule formulation of NBI-98854 in moderate to severe tardive dyskinesia patients with an underlying mood disorder, schizophrenia or schizoaffective disorder, or a gastrointestinal disorder with exposure to metoclopramide.

This 100 subject study assessed once daily NBI-98854 over a six week placebo controlled dosing period. Half of the randomized subjects received placebo and half received NBI-98854. The NBI-98854 dosing regimen began with a once-daily dose of 25 mg for the initial two weeks.

At the completion of the initial two weeks of dosing, based on certain efficacy and safety criteria, patients were titrated to a once-daily 50 mg dose, or continued on the once-daily 25 mg dose for the following two-week period. At the completion of the second two weeks of treatment another efficacy and safety assessment was performed and patients were eligible to be titrated to a once daily 75 mg, 50 mg or 25 mg dose for the final two weeks of treatment. The primary endpoint of the study was a comparison of placebo vs.

active scores utilizing the AIMS at the end of week six by blinded central raters.