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 and End of Phase II Meeting
The larger Phase IIb TD program began in 2012. The initial Phase IIb study (Kinect Study) was a randomized, parallel, double-blind, placebo-controlled, clinical trial utilizing the capsule formulation of NBI-98854 in moderate to severe TD patients with underlying schizophrenia or schizoaffective disorder. This 109 subject study assessed two doses of once-daily NBI-98854 over a six-week placebo-controlled dosing period. Approximately half of the randomized subjects received placebo and half received one of two doses of NBI-98854. The two NBI-98854 dosing groups consisted of a 50mg group for six weeks and a group that began at 100mg for the initial two weeks and then converted to 50mg for the final four weeks of placebo-controlled dosing period. Subsequent to the placebo-controlled dosing, all subjects were eligible to enter a six-week open label safety extension, whereby 50mg of NBI-98854 was administered once daily with additional AIMS assessments. The primary endpoint of the study was a comparison of placebo versus active scores utilizing the AIMS at the end of week six as assessed by the on-site AIMS assessors.
The 50mg dose of NBI-98854 did not reach statistical significance for the primary endpoint at week six; however, the 100mg dose, utilizing a blinded central video AIMS assessment, showed a statistically significant and clinically meaningful reduction in TD symptoms at week two (the end of the 100mg dose interval).
NBI-98854 was generally safe and well tolerated during the twelve weeks of the Kinect Study. During the six-week placebo-controlled treatment period the frequency of treatment-emergent adverse events was 37% for placebo and 26% for NBI-98854. There were no drug-related serious adverse events. The most common treatment emergent adverse event was mild and transient somnolence during the placebo-controlled portion of the study.