Christopher F. O’Brien

KINECT 3: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial of Valbenazine for Tardive Dyskinesia

OBJECTIVE Tardive dyskinesia is a persistent movement disorder induced by dopamine receptor blockers, including antipsychotics. Valbenazine (NBI-98854) is a novel, highly selective vesicular monoamine transporter 2 inhibitor that demonstrated favorable efficacy and tolerability in the treatment of tardive dyskinesia in phase 2 studies. This phase 3 study further evaluated the efficacy, safety, and tolerability of valbenazine as a treatment for tardive dyskinesia. METHOD This 6-week, randomized, double-blind, placebo-controlled trial included patients with schizophrenia, schizoaffective disorder, or a mood disorder who had moderate or severe tardive dyskinesia. Participants were randomly assigned in a 1:1:1 ratio to once-daily placebo, valbenazine at 40 mg/day, or valbenazine at 80 mg/day. The primary efficacy endpoint was change from baseline to week 6 in the 80 mg/day group compared with the placebo group on the Abnormal Involuntary Movement Scale (AIMS) dyskinesia score (items 1-7), as assessed by blinded central AIMS video raters. Safety assessments included adverse event monitoring, laboratory tests, ECG, and psychiatric measures. RESULTS The intent-to-treat population included 225 participants, of whom 205 completed the study. Approximately 65% of participants had schizophrenia or schizoaffective disorder, and 85.5% were receiving concomitant antipsychotics. Least squares mean change from baseline to week 6 in AIMS dyskinesia score was -3.2 for the 80 mg/day group, compared with -0.1 for the placebo group, a significant difference. AIMS dyskinesia score was also reduced in the 40 mg/day group (-1.9 compared with -0.1). The incidence of adverse events was consistent with previous studies. CONCLUSIONS Once-daily valbenazine significantly improved tardive dyskinesia in participants with underlying schizophrenia, schizoaffective disorder, or mood disorder. Valbenazine was generally well tolerated, and psychiatric status remained stable. Longer trials are necessary to understand the long-term effects of valbenazine in patients with tardive dyskinesia.

Elagolix Treatment for Endometriosis-Associated Pain Results from a Phase 2, Randomized, Double-Blind, Placebo-Controlled Study

This Phase 2 study evaluated the safety and efficacy of elagolix for treating endometriosis-associated pain. A total of 155 women with laparoscopically confirmed endometriosis were randomized to placebo, elagolix 150 mg, or elagolix 250 mg once daily for 12 weeks. Placebo patients were rerandomized to elagolix and elagolix patients continued their dosing assignment for 12 additional weeks; the primary efficacy measure was changed from baseline in the monthly mean numerical rating scale for pain at week 12. Monthly mean (standard error of the mean) reductions were greater with elagolix versus placebo (−1.19 ± 0.18, −1.25 ± 0.18, and −0.88 ± 0.18 for elagolix 150 mg, 250 mg, and placebo, respectively); differences were not statistically significant. Monthly mean dysmenorrhea and nonmenstrual pelvic pain scores were reduced with elagolix, with significant differences for dysmenorrhea at weeks 8 and 12 versus placebo (P < .05). Minimal bone mineral density changes were observed with elagolix treatment. In women with endometriosis-associated pain, elagolix demonstrated an acceptable efficacy and safety profile in this Phase 2 study.

Elagolix, an oral GnRH antagonist, versus subcutaneous depot medroxyprogesterone acetate for the treatment of endometriosis: effects on bone mineral density.

This randomized double-blind study, with 24-week treatment and 24-week posttreatment periods, evaluated the effects of elagolix (150 mg every day, 75 mg twice a day) versus subcutaneous depot medroxyprogesterone acetate (DMPA-SC) on bone mineral density (BMD), in women with endometriosis-associated pain (n = 252). All treatments induced minimal mean changes from baseline in BMD at week 24 (elagolix 150 mg: −0.11%/−0.47%, elagolix 75 mg: −1.29%/−1.2%, and DMPA-SC: 0.99%/−1.29% in the spine and total hip, respectively), with similar or less changes at week 48 (posttreatment). Elagolix was associated with improvements in endometriosis-associated pain, assessed with composite pelvic signs and symptoms score (CPSSS) and visual analogue scale, including statistical noninferiority to DMPA-SC in dysmenorrhea and nonmenstrual pelvic pain components of the CPSSS. The most common adverse events (AEs) in elagolix groups were headache, nausea, and nasopharyngitis, whereas the most common AEs in the DMPA-SC group were headache, nausea, upper respiratory tract infection, and mood swings. This study showed that similar to DMPA-SC, elagolix treatment had minimal impact on BMD over a 24-week period and demonstrated similar efficacy on endometriosis-associated pain.

Elagolix, an oral GnRH antagonist for endometriosis-associated pain: a randomized controlled study

Objective The aim of this study was to estimate the efficacy of elagolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, for the treatment of endometriosis-associated pelvic pain. Methods This was a phase II, randomized, placebo-controlled parallel group study conducted at 37 US centers, consisting of an 8-week double-blind period followed by a 16-week open-label period. Patients were 137 women aged 18 to 49, with laparoscopically confirmed endometriosis and moderate to severe nonmenstrual pelvic pain and dysmenorrhea, who were administered elagolix 150 mg daily or placebo. The primary outcomes of the study were the daily assessment of dysmenorrhea, nonmenstrual pelvic pain and dyspareunia using a modified Biberoglu-Behrman scale. Results During the double-blind period, there were significantly greater mean reductions from baseline to week 8 in dysmenorrhea (-1.13 ± 0.11 vs. −0.37 ± 0.11, p<0.0001), nonmenstrual pelvic pain (-0.47 ± 0.07 vs. −0.19 ± 0.07, p = 0.0066), and dyspareunia scores (-0.61 ± 0.10 vs. −0.23 ± 0.10, p = 0.0070) in the elagolix group compared with placebo. Continued improvements were observed during the open-label treatment regardless of initial treatment allocation. Elagolix treatment was also associated with significant improvements in quality-of-life measures during the double-blind and open-label periods. The most common adverse events occurring with elagolix were nausea, headache and hot flush, each in 9.9% of patients. Conclusion Elagolix effectively reduced endometriosis-associated pelvic pain over a 24-week period and was well-tolerated.

The Effects of Valbenazine in Participants with Tardive Dyskinesia: Results of the 1-Year KINECT 3 Extension Study

BACKGROUND Valbenazine, a highly selective vesicular monoamine transporter 2 inhibitor, is approved for the treatment of tardive dyskinesia. This is the first report of long-term effects in adults with tardive dyskinesia. METHODS Participants with a DSM-IV diagnosis of schizophrenia, schizoaffective disorder, or a mood disorder who completed the 6-week, double-blind, placebo-controlled period of KINECT 3 were eligible to enter the 42-week valbenazine extension (VE) period and subsequent 4-week washout period. The extension phase was conducted from December 16, 2014, to August 3, 2016. Participants who received placebo and entered the VE period were re-randomized 1:1 to valbenazine 80 or 40 mg while others continued valbenazine at the KINECT 3 dose. Safety assessments included treatment-emergent adverse events (TEAEs) and scales for suicidal ideation/behavior, treatment-emergent akathisia or parkinsonism, and psychiatric symptoms. Efficacy assessments included the Abnormal Involuntary Movement Scale (AIMS) and Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD). RESULTS 198 participants entered the VE period, 124 (62.6%) completed treatment (week 48), and 121 (61.1%) completed the follow-up visit after washout (week 52). During the VE period, 69.2% of participants had ≥ 1 TEAE, 14.6% had a serious TEAE, and 15.7% discontinued due to a TEAE. During washout, 13.1% of participants experienced a TEAE. No apparent risk for suicidal ideation or behavior was found. Long-term valbenazine treatment did not appear to induce or worsen akathisia or parkinsonism. Participants generally remained psychiatrically stable during the study. AIMS and CGI-TD measures indicated sustained tardive dyskinesia improvement, with scores returning toward baseline after 4 weeks of valbenazine washout. CONCLUSIONS The long-term safety and tolerability of valbenazine were generally favorable, and maintenance of treatment effect was apparent with both doses during this long-term study. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02274558.

Differences in Dihydrotetrabenazine Isomer Concentrations Following Administration of Tetrabenazine and Valbenazine

BackgroundTetrabenazine (TBZ) activity is thought to result from four isomeric dihydrotetrabenazine (HTBZ) metabolites ([+]-α-HTBZ, [−]-α-HTBZ, [+]-β-HTBZ, [−]-β-HTBZ). Each isomer has a unique profile of vesicular monoamine transporter 2 (VMAT2) inhibition and off-target binding. Previously published data only report total isomer (α) and (β) concentrations. We developed a method to quantify the individual HTBZ isomers in samples from patients with Huntington’s disease receiving TBZ. For comparison, concentrations of [+]-α-HTBZ, the single active metabolite shared by valbenazine (VBZ) and TBZ, were determined in samples from patients with tardive dyskinesia receiving VBZ.MethodsA liquid chromatography–tandem mass spectrometry (LC-MS/MS) method was developed and validated for quantitation of the four individual HTBZ isomers. Concentrations were determined in serum from patients with Huntington’s disease administered TBZ and plasma from patients with tardive dyskinesia administered VBZ once daily.ResultsIn patients administered TBZ, [−]-α-HTBZ and [+]-β-HTBZ were the most abundant HTBZ isomers while [−]-β-HTBZ and [+]-α-HTBZ were present as minor metabolites. Only [+]-α-HTBZ was observed in patients administered VBZ.ConclusionsBased on relative abundance and potency, [+]-β-HTBZ appears to be the primary contributor to VMAT2 inhibition by TBZ, a finding in contrast with the generally held assertion that [+]-α-HTBZ is the major contributor. [−]-α-HTBZ, the other abundant TBZ metabolite, has much lower VMAT2 inhibitory potency than [+]-β-HTBZ, but increased affinity for other CNS targets, which may contribute to off-target effects of TBZ. In contrast, pharmacological activity for VBZ is derived primarily from [+]-α-HTBZ. Individual HTBZ isomer concentrations provide a more clinically relevant endpoint for assessing on- and off-target effects of TBZ than total isomer concentrations.

Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist: results from a phase 2, randomized controlled study

Purpose Elagolix is a novel, oral GnRH antagonist that dose-dependently suppresses estradiol levels. This study evaluated safety and efficacy of elagolix vs. leuprorelin acetate (LA) and placebo in women with endometriosis-associated pain. Methods In this multicenter, double-blind study, women with laparoscopically confirmed endometriosis were randomized to oral elagolix 150 or 250 mg once daily, placebo or 3.75 mg LA intramuscularly (i.m.) monthly for 12 weeks. Placebo and LA patients were re-randomized to elagolix, and elagolix patients continued treatment for another 12 weeks. Results Baseline demographics were similar among groups (mean age 31.7 years). Significantly greater reductions in monthly mean pelvic pain compared with placebo (p<0.05) were observed in both elagolix doses at week 4, elagolix 250 mg at week 8 and LA at weeks 4, 8 and 12. The mean (95% CI) percentage change in spinal bone mineral density (BMD) from baseline at week 12 was -1.05 (-1.68, -0.43), -0.80 (-1.53, -0.07) and -1.63 (-2.28, -0.99) for elagolix 150-mg, 250-mg and LA groups, respectively, compared with a mean percentage increase in placebo group (0.11 [-0.50, 0.71]). Headache was the most common adverse event for all treatment groups. Conclusions Both elagolix and LA reduced endometriosis-associated pain for up to 24 weeks of treatment and were associated with generally acceptable safety profiles in this study. Based on relatively small changes from baseline to week 12 in BMD, elagolix may offer a potential long-term treatment option for endometriosis-associated pain in affected women. Larger clinical studies with elagolix are warranted. Trial Registration Clinicaltrials.gov Identifier: NCT00797225.

Development and Validation of the Endometriosis Daily Pain Impact Diary Items to Assess Dysmenorrhea and Nonmenstrual Pelvic Pain

Daily diary-based dysmenorrhea and nonmenstrual pelvic pain impact items were developed and validated to measure efficacy in endometriosis clinical trial settings. Items were developed across 3 stages of qualitative research, and their psychometric properties were explored in a phase II randomized controlled trial. Eight focus groups, 20 semistructured telephone interviews, and 15 face-to-face concept elicitation and cognitive debriefing interviews constituted the qualitative phase of the research. Psychometric properties of reliability, convergent validity, and responsiveness of the dysmenorrhea and nonmenstrual pelvic pain daily items were examined quantitatively in a phase II clinical trial of an investigational endometriosis treatment. Both qualitative concept elicitation and cognitive debriefing research yielded wording for item response options that resonated with adult women with endometriosis. Daily assessment of dysmenorrhea and nonmenstrual pelvic pain impact was the preferred measurement approach among adult women with endometriosis. Quantitatively, correlations between the dysmenorrhea and nonmenstrual pelvic pain items and other measures of pain impact provided endorsement for the items’ convergent validity. Longitudinal measurement properties, involving test–retest reliability and sensitivity to change/responsiveness, offered evidence for the adequacy of the measurement properties of the daily diary-based dysmenorrhea and nonmenstrual pelvic pain impact items. Data from a phase II trial provided evidence that the daily dysmenorrhea and nonmenstrual pelvic pain impact items, developed and tested through qualitative research involving both focus groups and individual interviews, are well-defined, reliable, valid, and responsive for measuring the impact of pain in endometriosis to assess therapeutic response.