A Pilot Study of a Novel Monoamine Triple Inhibitor, Centanafadine (EB-1020) SR, In the Treatment of Attention- Deficit Hyperactivity Disorder in Adult Males1 Timothy Hsu, MD1, Andrew J. Cutler, MD2, Ann Childress, MD3, Randall D. Marshall, MD4, Mark Bradshaw, PhD5, Frank P. Bymaster, MS6, Anthony A. McKinney7, Stephen W. Hurt, PhD8, Catherine M. O'Brien1, Brigitte A. Robertson MD1, Timothy E. Wilens, MD7 1Clinical Development, Neurovance Inc., Cambridge, MA, 2Psychiatry, Florida Clinical Research Center, LLC, Bradenton, FL, 3Psychiatry, Center for Psychiatry and Behavioral Medicine, Las Vegas, NV,4Executive Medical Director, Neuroscience Therapeutic Area Lead, Retrophin, Inc. Cambridge, MA,5Biostatistics, Global Consulting Partners In Medical Biometrics, LLC, New York, NY, 6Pharmacology, Neurovance Inc., Cambridge, MA, 7Massachusetts General Hospital, Boston, MA, 8Psychiatry, Weill Cornell Medical College, New York, NY

ABSTRACT METHODS continued RESULTS continued DISCUSSION

Background: This pilot study was designed to evaluate centanafadine (EB- Figure 1. Study Design Table 1. Summary of demographics Figure 2. Total symptom severity scores, Results for this study of the triple reuptake inhibitor centanafadine SR in the 1020) SR as a novel non- treatment option for adult attention-deficit as assessed by the adult ADHD-RS-IV treatment of adult males with ADHD show that centanafadine SR appears ALL ENROLLED SUBJECTS to be effective and well tolerated at the doses tested. For the primary hyperactivity disorder (ADHD). Centanafadine SR is a - CHARACTERISTICS STATISTICS N (%)* preferring triple reuptake inhibitor with IC values for human transporter Age (yrs) N 41 efficacy endpoint of change from Baseline-2 (start of centanafadine SR 50 Mean 37.71 reuptake inhibition of 6 nM, 38 nM, and 83 nM ,for norepinephrine (NE), SD 11.87 treatment) in ADHD symptoms to Treatment Week 4 there was a Median 39.00 statistically significant decrease in the mean (SD) score for ADHD (DA) and (5HT), respectively. Minimum 19 Methods: A total of 41 adult males with well-characterized ADHD enrolled in Maximum 55 symptoms. Similar decreases were observed for the mean (SD) scores in

this 4-week, single-blind study with a 1-week placebo run-in. Centanafadine 18 - 35 19 (46.34 %) the subscales of inattentive symptoms and hyperactive/impulsive 36 - 50 13 (31.70 %) SR was given twice daily and titrated to a target dose of 500 mg daily over 10 51 + 09 (21.95 %) symptoms. Centanafadine SR also appears effective in treating executive Gender Male 41 (100 % ) function in adult males at the maximum dose studied, and appears to be days. Outcomes assessed included ADHD symptoms, executive function, *Percentages are based on the number of subjects enrolled and and tolerability. treated. well tolerated with no increase in suicidality observed at any of the dose Results: 37 subjects completed the trial. Centanafadine SR produced a 21- Data on file.2 BL1=baseline1; BL2=baseline 2 levels studied. Results from the secondary efficacy endpoints are This delayed return to baseline is distinct from consistent with the findings from the primary endpoint. While a direct point reduction on the adult ADHD Rating Scale-IV (ADHD-RS-IV) (endpoint At the end of single-blind placebo treatment, the ADHD-RS-IV with adult prompts was mean score = 17, p<0.0001) including significant reductions in inattentive re-administered. Patients who showed ≥30% improvement over baseline values were Data on file.2 comparison of centanafadine SR with other agents was not performed in this study, an indirect review of data from the published literature indicates (p<0.0001) and hyperactive/ impulsive symptoms (p<0.0001). Overall, 68% of removed from the study and offered 4 weeks of centanafadine SR treatment based on Figure 3: Changes from Baseline-2 to Figure 4: CGI-I % responders per week subjects were considered responders using the Clinical Global Impressions- clinical judgment. Those who showed <30% improvement on placebo from Baseline-1 treatment week 4 in mean scores for that centanafadine SR had comparable effectiveness to lisdexamfetamine 3,4 Improvement scale (CGI-I) (much/very much improved). Clinically and to Baseline-2 scores continued in the study. All subjects completed informed consent ADHD symptoms, as assessed by the in both ADHD symptoms and executive function changes. statistically significant improvements in overall and specific domains of including description of the single blind nature of the study but were not informed of the adult ADHD-RS-IV Based on these results, randomized, controlled studies of centanafadine SR executive function using the Behavioral Rating Inventory of Executive exact timing of the switch to active study drug. are warranted. Function—Adult Version (BRIEF-A) were observed (overall p<0.0001). No clinically meaningful trends in adverse events, laboratory values, vital signs, or Primary objective: To compare the change from Baseline-2 (start of REFERENCES th ECG parameters were noted. centanafadine SR treatment) in ADHD symptoms to Week 4 after 1. Wilens TE, Cutler AJ, Childress A, et al. Poster presented at: 54 annual conference of the investigational product administration, as assessed by the adult ADHD-RS-IV. American Society of Clinical Psychopharmacology; 2014 June 16-19; Hollywood, FL. Conclusions: Centanafadine SR appears effective in treating ADHD and 2. Data on file (Centanafadine SR Clinical Study Report), Neurovance Inc., Cambridge, executive function deficits in adult males. The maximum dose studied appears Other important secondary outcomes: The change from Baseline-2 on the Massachusetts inattentiveness and hyperactivity/impulsivity subscales of the ADHD-RS–IV at 3. Brown TE, Brams M, Gao J, et al. Postgrad Med. 2010 Sep;122(5):7-17. to be well tolerated. Based on these results, randomized, controlled studies of 4. Adler LA, Dirks B, Deas PF, et al. J Clin Psychiatry. 2013 Jul;74(7):694-702. centanafadine SR appear warranted. Weeks 1, 2, 3, 4, and 6; change from Baseline-2 on the BRIEF-A at Week 4; and outcome as measured by the responder rate utilizing the Clinical Global DISCLOSURES INTRODUCTION Impressions-Severity (CGI-S) and CGI-I scales at Weeks 1, 2, 3, 4 and the Timothy Wilens, MD: Grant support: NIH (NIDA) and Shire; Consultant: Euthymics/Neurovance, follow-up visit (Week 6). Shire, Theravance, Tris, Bay Cove Human Services (clinical services), National Football Despite the availability of both FDA-approved and other agents for the 2 Safety and tolerability: Assessed by occurrence of adverse events Data on file. CGI-I Response ≤2 is marked Improvement; a League/ERM Associates and Major/Minor League Baseball treatment of ADHD, a number of individuals either cannot tolerate or do not ≥30% reduction in symptoms by ADHD-RS-IV is throughout the study, clinical laboratory (hematology, blood chemistry, and Ann Childress, MD: Research support: Abbott Laboratories, Bristol-Myers Squibb, Ironshore, respond optimally to existing compounds, necessitating the development of defined as responder. Data on file.2 urinalysis) test results at Weeks 2 and 4 and the follow-up visit (Week 6), vital Johnson & Johnson Pharmaceutical Research & Development, Lilly USA, LLC, Neos alternative agents. Interest has arisen in the role of monoamine triple Therapeutics, Neurovance, Noven, NextWave Pharmaceuticals, Novartis, Ortho-McNeill Janssen signs and 12-lead electrocardiograms (ECGs) at each visit, and a Columbia Figure 5: T-Score change (baseline to Figure 6: Improvement in nearly reuptake inhibitors in the treatment of ADHD. Scientific Affairs, Otsuka, Pfizer, Rhodes, Sepracor, Shionogi, Shire, Somerset, Sunovion and Suicide Severity Rating Scale (CSSRS) at each visit. endpoint) in EF measured using the three all domains** of the WFIRS after Theravance; Consultant and speaker: Shire, Novartis and Pfizer; Speaker: Bristol-Myers Squibb, One monoamine transport inhibitor, centanafadine (1R,5S)-1-(naphthalen-2- domains of the BRIEF-A 4 weeks GlaxoSmithKline, Shionogi and Somerset; Consultant: Ironshore; Advisory board member: yl)-3-azabicyclo[3.1.0]hexane HCl), (EB-1020), may provide benefit for the RESULTS Shionogi treatment of adult patients with ADHD, because it combines robust NE uptake A total of 41 patients were enrolled at baseline-2 and 37 adult males Andrew Cutler, MD: Research grants: AbbVie (including Solvay), Acadia, Akili Interactive, inhibition with moderate DA uptake inhibition. Centanafadine SR, a sustained- completed this study and were considered evaluable for efficacy (Table 1). Alkermes, Arbor Pharmaceuticals, AstraZeneca, Avanir, Boehringer Ingelheim, Bristol-Myers release formulation developed for clinical use, is being investigated as a Squibb, DOV, Forest (including PGxHealth and Trovis), Genentech (Roche), GlaxoSmithKline, The ADHD-RS-IV scores for the patients were stable during the screening and potential treatment for ADHD in adults. The aim of this pilot study was to Janssen (including Ortho-McNeil), Jazz, JDS, Johnson & Johnson PRD, Lilly, Lundbeck, the two baseline visits with only 1 patient being dropped during the placebo evaluate centanafadine SR as a novel treatment for ADHD in adults. We MediciNova, Memory, Merck (including Organon and Schering-Plough), Neurovance, Novartis, run-in phase. Centanafadine SR produced a 21-point reduction on the ADHD- hypothesized that significant improvement in both primary ADHD and Orexigen, Otsuka, Pfizer (including Wyeth), Purdue, Rhodes, Sanofi (including Sanofi-Synthelabo RS-IV (endpoint mean score = 17, p<0.0001) and a delayed return to baseline and Sanofi-Aventis), Shionogi (including Addrenex and Sciele), Shire, Sunovion (including DSP ADHD/executive functioning outcomes would be demonstrated, as well as (Figure 2). Treatment with centanafadine SR also resulted in significant and Sepracor), Supernus, Takeda, Targacept, Teva (including Cephalon), Theravance, UCB and favorable tolerability observed, in patients on the after 4 weeks of reductions in inattentive (p<0.0001) and hyperactive impulsive symptoms Vanda; Consultant and speaker: AbbVie (including Solvay), Arbor Scientia, AstraZeneca, Avanir, treatment compared to baseline. Bracket (including UBC, Concordant, Pharmastar, Bioniche), Bristol-Myers Squibb, Forest (p< 0.0001) (Figure 3). The average % of the standard error of the mean Red line highlights a T-score ≥ 65 indicating a deficit **Of the 37 patients only a fraction (8) were in (including PGxHealth and Trovis), Genentech (Roche), GlaxoSmithKline, Janssen (including METHODS divided by the mean total score was about 11%, a low level of variability, in executive function. Data on file.2 school; p-value=0.0529. Data on file.2 Ortho-McNeil), Lilly, Lundbeck, Merck (including Organon and Schering-Plough), Novartis, indicating that the mean reduction in scores was not driven by a few patients. Otsuka, Pfizer (including Wyeth), Shionogi (including Addrenex and Sciele), Shire, Sunovion Table 2: Most common adverse events defined as ≥ 5% (occurring in 2 or This was a 4-week, Phase 2a, flexible-dose, single-blind, study with a one- (including DSP and Sepracor), Takeda and Vanda; Consultant: Akili Interactive, Alkermes, Overall, 68% of subjects were considered responders using the CGI-I more patients) week placebo run-in. A total of 41 adult males aged 18-55 years with well- (much/very much improved) (Figure 4). Clinically and statistically significant Arbor Pharmaceuticals, CeNeRX, Cypress, DOV, Genomind, Neos Therapeutics, Neuronex, characterized ADHD were enrolled in the trial. To be considered for inclusion improvements in overall and specific domains of executive function using the Neurovance, NextWave, Purdue, Rhodes, Sanofi (including Sanofi-Synthelabo and Sanofi- in this study, subjects were required to have an ADHD-RS-IV score ≥28 and Aventis), Supernus, Targacept, Teva (including Cephalon) and Theravance BRIEF-A were also found (overall p<0.0001) (Figure 5). Clinically and Randall Marshall, MD: Employee of Retrophin, Inc no other major medical or current psychiatric comorbidity. Centanafadine SR statistically significant improvements in emotional dysregulation using the was given twice daily and titrated to a target dose of 500 mg daily over seven Mark Bradshaw, PhD: Euthymics Bioscience, Neurovance Wender-Reimherr scale were observed (p<0.0001). Similarly, statistically Stephen Hurt, PhD: Eisai, Taisho, Euthymics Bioscience, Neurovance days (Figure 1). The trial was single-blind in that patients were not informed of significant improvement in function were observed on the Weiss Functional Frank Bymaster: Employee of Neurovance the exact timing of the centanafadine SR vs. placebo treatment to maintain Impairment Rating Scale (WFIRS) (p<0.0001) (Figure 6). No clinically Anthony McKinney: Employee of Neurovance the blinded nature of the placebo treatment and reduce potential placebo meaningful findings in adverse events, laboratory values, vital signs, or ECG Catherine O’Brien: Employee of Neurovance effects while on active study drug. The relatively short duration of the trial parameters were noted (Table 2). Notably, no increase in suicidality was Brigitte A. Robertson MD: Employee of Neurovance was chosen because of limitations in supportive toxicological testing available Timothy Hsu, MD: Employee of Neurovance observed with centanafadine SR at any dose level studied. *Two on placebo; 7 mild; 3 moderate; no patients at the initiation of the trial. 2 discontinued due to diarrhea. Data on file. This study was sponsored by

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