Tuesday, June 23, 2015 Poster Session I T1. THE ANTIDEPRESSANT ACTIVITY OF BASIMGLURANT, A NOVEL MGLU5-NAM; A RANDOMIZED, DOUBLE-BLIND, PLACEBO- CONTROLLED STUDY IN THE ADJUNCTIVE TREATMENT OF MDD Jorge Quiroz1, Dennis Deptula1, Ludger Banken2, Ulrich Beyer2, Paulo Fontoura2, Luca Santarelli2 1Roche Innovation Center NY, 2Roche Innovation Center Basel, Switzerland Abstract Background: Therapies targeting the glutamatergic system are known to be efficacious in the treatment of mood disorders. Antagonism of the post-synaptic mGlu5 receptor is a novel approach to indirectly modulate glutamatergic (NMDA) function and has shown efficacy in a number of preclinical behavioral models of depression. Basimglurant is a potent and selective negative allosteric modulator of the mGlu5 receptor which has been comprehensively profiled in Ph1 and Ph2a trials. The main objectives of this Ph2b trial were to evaluate the safety and efficacy of basimglurant modified release (MR) vs. placebo, as adjunctive therapy to ongoing antidepressant treatment in patients with major depressive disorder (MDD) who showed inadequate response to at least one but no more than three treatment failures within the current episode. Methods: In this 9-week study (6-week double-blind treatment, 3-week post-treatment follow- up), adult patients with DSM-IV-TR diagnosis of MDD were randomized to basimglurant 0.5 mg/d, 1.5 mg/d, or placebo (adjunctive to ongoing SSRI or SNRI). The primary endpoint was the mean change from baseline in the Montgomery-Åsberg Depression Rating Scale Sigma total score (MADRS), as rated by the clinician at week 6. Concomitantly, patient-rated MADRS scores were also collected and analyzed. Secondary endpoints included change in the Quick Inventory of Depressive Symptomatology (QIDS-SR16), MADRS response (≥ 50% reduction in score from baseline), MADRS remission (score of ≤ 10), and Clinician and Patient Global Impression scales (CGI-I, PGI-I and CGI-S). Exploratory endpoints included change in the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) and the Sheehan Disability Scale (SDS). Due to the exploratory nature of this study, one-sided p values were estimated with no adjustment for multiplicity. Completers (observed cases) ANCOVA and ITT MMRM statistical analysis were performed. Results: 333 male and female patients were randomized in to the study. The primary endpoint for the study (clinician-rated MADRS) was not met (p=0.127 ITT MMRM analysis); a trend for improvement was observed for basimglurant 1.5 mg vs. placebo (p=0.061 completers ANCOVA analysis) while statistical significance was reached utilizing the patient-rated MADRS (p<0.025 in both analyses). Regarding the secondary endpoints basimglurant 1.5 mg showed significant improvements vs. placebo in QIDS mean change from baseline (p=0.004 in both analyses), CGI-I mean score (p<0.039 in both analyses), PGI-I mean score (p<0.029 in both analyses). Significant improvements were also seen with in the patient-rated MADRS remission rate (p<0.024 both analyses), and to a lesser degree in the patient-rated MADRS response (p<0.1 both analyses). Lastly, significant improvements were observed in the Q-LES- Q-SF (p=0.011) and the SDS items 2-3 (p=0.047) (ITT MMRM). Basimglurant dosed at 0.5 mg showed no benefit over placebo in any of these measures. Withdrawal rates due to adverse events were 5.4%, 7.2% and 4.5% for basimglurant 0.5 mg, 1.5 mg, and placebo, respectively. The most common adverse event was dizziness (4%, 23%, and 6%), mostly transient and of mild intensity. Mania (spontaneously resolved) lead to withdrawal of 2 patients from the study in the 1.5 mg arm. Discussion: Adjunctive 1.5 mg/d basimglurant showed a consistent antidepressant effect across primary and secondary endpoints. Greater effects were seen in patient-rated endpoints such as the patient-rated MADRS and the QIDS, which statistically separated from placebo at several time-points including week 6, while clinician-rated MADRS only separated at earlier time- points but not at day 42. Basimglurant 0.5 mg/d was not effective compared to placebo. Study results should be considered in the context of the observed high placebo response in this trial (47% on the clinician- as a threshold that impedes observing statistical separation for active arms in adjunctive MDD treatment trials, minimizing the possibility of detecting true antidepressant effects. In this trial, nevertheless, basimglurant 1.5mg response rates were still consistently superior to placebo. Furthermore, basimglurant was overall safe and well tolerated in combination with SSRI/SNRI with mild transient dizziness as the most common emergent adverse event. These results warrant further investigation of basimglurant in the treatment of MDD both in the adjunctive as well as monotherapy settings. T2. DASOTRALINE: A NOVEL DRUG CANDIDATE FOR THE TREATMENT OF ADHD Robert Goldman1, Kenneth S. Koblan1, Seth C. Hopkins1, Antony Loebel2 1Sunovion Pharmaceuticals, Inc, Marlborough, MA and Fort Lee, NJ, 2Sunovion Pharmaceuticals, Inc. Abstract Several classes of drugs have demonstrated efficacy in the treatment of ADHD, including short- and long-acting stimulant and non-stimulant medications. However, there continues to be a need for additional treatment options that may offer a more differentiated clinical profile than current agents. Dasotraline [(1R,4S)-4-(3,4-Dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-amine], currently in development for adult and pediatric ADHD, is a potent inhibitor of human DA transporters (DAT; dopamine uptake IC50 3 nM) and NE transporters (NET; norepinephrine uptake IC50 4 nM), and a weaker inhibitor of human serotonin transporters (SERT; serotonin uptake IC50 15 nM; data-on-file, 2014). In humans, dasotraline has a tmax of 10-12 hours, a terminal elimination half-life (t½) of 47-77 hours, and achieves steady state plasma concentration by 2 weeks of daily dosing. A clinical trial has been completed in adults meeting DSM-IV-TR criteria for ADHD who were randomized, without titration, to 4 weeks of double-blind, once-daily treatment with fixed doses of dasotraline 4 mg/d (N=114), 8 mg/d (N=107), or placebo (N=110). On the ADHD Rating Scale, Version IV (ADHD RS-IV) total score, significant LS mean improvement was observed at Week 4 for dasotraline 8 mg/d versus placebo (-13.9 vs -9.7; P=0.019), with trend level significance for 4 mg/d (-12.4; P=0.076). LS mean improvement in a modified CGI-S scale was significantly greater at Week 4 for dasotraline 8 mg/d versus placebo (-1.1 vs -0.7; P=0.013), and for 4 mg/d (-1.1 vs -0.7; P=0.021). The most frequent adverse events reported were insomnia, decreased appetite, nausea, and dry mouth. The pharmacokinetic and pharmacodynamic characteristics of dasotraline suggest that it may have a favorable therapeutic profile for the treatment of ADHD, offering once-per-day dosing that provides sustained inhibition of DA and NE reuptake throughout the 24 hour dosing interval, with possible low risk of abuse potential due to its delayed tmax. The results of this first clinical trial provide preliminary evidence indicating that once-daily dosing with dasotraline, a long-acting, dual monoamine reuptake inhibitor, may be a safe and efficacious treatment for adult ADHD. Learning objectives: 1. Participants will learn about the efficacy and tolerability of dasotraline in adult patients diagnosed with ADHD 2. Participants will learn about the pharmacokinetic profile of a dasotraline, a new drug candidate for the treatment of ADHD T3. OPEN BOARD T4. NON-INVASIVE NEUROMODULATION WITH TRIGEMINAL NERVE STIMULATION IN MAJOR DEPRESSIVE DISORDER AND OTHER CNS DISORDERS Ian Cook1, Andrew Leuchter2, Christopher DeGiorgio1 1UCLA / NeuroSigma, 2UCLA Abstract Background: Modulation of brain activity via external Trigeminal Nerve Stimulation (eTNS) is an emerging therapy for CNS disorders, with an excellent safety profile and significant improvements in seizures, mood, cognition, and anxiety reported in preliminary open studies. Mechanistically, PET imaging findings showed acute, robust changes in cerebral perfusion in limbic and frontal regions. In a recently-completed dose ranging project, eTNS was examined under double-blind conditions in major depressive disorder (MDD) as an adjunct to pharmacotherapy. Methods: Forty-three adults with MDD (age 23-65, avg 43.0 (11.5 sd), ATHF 1-10) completed at least six weeks of the trial (primary endpoint). Subjects stimulated the trigeminal nerve for 8 hours each night at home using custom patch electrodes placed on the forehead. Clinical outcomes were assessed with scales including the Beck Depression Inventory (BDI), Inventory of Depressive Symptomology (IDS-SR) and Hamilton Depression Rating Scale (HDRS17). Medications remained constant throughout. Results: Symptom severity improved significantly for subjects receiving active stimulation (e.g., paired 2-tail t-test BDI 24.6 (8.5 sd) baseline vs 14.2 (7.3) week 6, p<0.00001). Subjects receiving active stimulation had significantly greater symptom improvement than subjects randomized to the control condition (e.g., BDI -41.7% vs -10.9% t=-2.61 2-tail p=0.013). Conclusions: Significantly greater symptom reductions were achieved in the 6 weeks of acute eTNS treatment than in our control condition. These findings replicate open trial results, extend them under double-blind controlled conditions, and justify further development. Symptom improvement did not differ across stimulation frequencies (‘doses’), suggesting that low doses of stimulation may lead to meaningful symptom improvement in MDD, and that the cumulative integration of stimulation events may be an important determinant of clinical effects. Trigeminal Nerve Stimulation is a unique form of neuromodulation because can be delivered at home using a non-invasive system, or may be deliverable with an implantable system that is under development. This novel approach to brain stimulation may have use as an adjunct to pharmacotherapy once efficacy and tolerability are confirmed with additional studies.