NBI-98854 - Vesicular Monoamine Transporter 2 Inhibitor (VMAT2).
To address the unmet medical needs of patients suffering from tardive dyskinesia (TD), Neurocrine is developing NBI-98854. NBI-98854 is a potent, highly selective, VMAT2 inhibitor that is effective in regulating the levels of dopamine release during nerve communication, while at the same time having minimal impact on the other monoamines. This selectivity may reduce the likelihood of “off target” side effects. Additionally, we have designed this novel compound to provide low, sustained, plasma and brain concentrations of the active drug to minimize the potential side effects associated with excessive dopamine depletion. With these features, NBI-98854 is anticipated to be well tolerated in patients.
During 2009, NBI-98854 completed a Phase I single ascending dose clinical trial in healthy male volunteers in Canada under an approved Clinical Trial Application with Health Canada. This trial showed NBI-98854 to be generally safe and well tolerated. There were no serious adverse events, clinically significant drug-related laboratory abnormalities or clinically significant electrocardiogram (ECG) findings. The characteristics of NBI-98854 met the pre-specified pharmacokinetic requirements for the trial: dose proportionality, low maximum concentration with adequate area-under-curve for drug exposure, low variability, and a half-life which supports once per day dosing.
During 2010, we completed a multiple, repeated dose Phase I study in healthy male volunteers. This trial also showed NBI-98854 to be generally safe and well tolerated, and again displayed the desired pharmacokinetic requirements. There were no serious adverse events, clinically significant drug-related laboratory abnormalities or clinically significant ECG findings. Based on the successful completion of this second Phase I study, we initiated a Phase IIa dose exploration study in patients with tardive dyskinesia in late 2010.
Upon successful completion of this open-label Phase IIa study, we filed an IND with the FDA to permit the initiation of larger Phase II studies in patients with tardive dyskinesia in the United States. In September 2011, we began a second Phase II study in tardive dyskinesia patients. This 32 patient placebo controlled, double-blind, randomized, cross-over study, used a within-subject comparison for safety and efficacy evaluation. Patients were randomized to either 12.5mg or 50mg doses of NBI-98854 for a two week dosing period, and also had a two week placebo dosing period. The primary efficacy endpoint of the study was a comparison of placebo versus active AIMS scores from the end each of the two dosing periods.
After database lock and unblinding of study data, 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. Based on these findings, the AIMS data from this single site was removed and a post-hoc analysis was completed which 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).
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).
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.
Data from this latest study was used to guide the dosing selection and design for larger Phase IIb studies in tardive dyskinesia patients that began in 2012.
Phase IIb Studies
The Kinect Study is a phase IIb randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy, safety and tolerability of two doses (50 and 100 mg) of NBI-98854 administered once daily (q.d.) for up to 2 weeks. This study will also allow evaluation of the efficacy of NBI-98854 50 mg q.d. for up to 6 weeks and the safety and tolerability of NBI-98854 50 mg q.d. for up to 12 weeks. Approximately 120 medically stable male and female subjects with schizophrenia or schizoaffective disorder who have moderate or severe tardive dyskinesia (TD) will be enrolled in the study. Eligible subjects will be randomized (1:1:2) to one of three treatment groups for the first 6 weeks of dosing: NBI 98854 50 mg q.d., NBI-98854 100 mg q.d. for 2 weeks followed by 50 mg q.d. for the remaining 4 weeks of the double-blind treatment period, or placebo. At the end of the 6-week placebo-controlled double-blind treatment period, subjects will continue in the study for an additional 6-week open-label period where all subjects who have completed the double-blind treatment period will receive NBI-98854 50 mg q.d. Two and four weeks after the last dose of study drug, follow-up assessments will be performed. Efficacy, safety, pharmacokinetics, and pharmacodynamics will be assessed at scheduled times throughout the study. To see examples of moderate and severe TD, please see the study YouTube advertisement at www.youtubeKinectstudy.com.
The Kinect2 study is a phase IIb, randomized, double-blind, placebo-controlled, dose-titration study to evaluate the efficacy, safety, and tolerability of NBI-98854 (titrated to subject’s optimal dose in the range of 25 to 75 mg) compared to placebo, administered once daily for a total of 6 weeks of treatment. Approximately 90 medically stable male and female subjects with one of the following clinical diagnoses will be enrolled: schizophrenia or schizoaffective disorder with neuroleptic-induced tardive dyskinesia (TD); mood disorder with neuroleptic-induced TD; or gastrointestinal disorder with metoclopramide-induced TD. Eligible subjects will be randomized (1:1) to NBI-98854 or placebo treatment. For subjects randomized to active treatment, the starting dose will be 25 mg NBI 98854, which may be escalated in increments of 25 mg every 2 weeks to a maximum of 75 mg to achieve an optimal dose of NBI-98854 for each subject. To maintain the study blind, subjects randomized to placebo will be subjected to the same dose escalation requirements but will receive only placebo during the treatment period. Efficacy, safety, pharmacokinetics, and pharmacodynamics will be assessed at scheduled times throughout the study.