ADHD Overview

• ADHD prevalence among 8- to 15-year-olds: 8.7% • Percentage of children with ADHD who have been treated consistently during the past year: 32% New(er) Treatments for • ADHD prevalence among 18- to 44-year-olds: 4.4% • Percentage of adults with ADHD who received treatment ADHD within the previous 12 months: 11% • Associated with high degrees of psychiatric comorbidity • Associated with impairment in multiple domains Timothy E. Wilens, MD • Associated with chronic course Chief, Division of Child and Adolescent Psychiatry • Circa 75% persistence from childhood into adolescence Co-Director, Center for Addiction Medicine • Circa 50% persistence from childhood into adulthood Massachusetts General Hospital Harvard Medical School ADHD = attention-deficit/hyperactivity disorder. Froehlich TE, et al. Arch Pediatr Adolesc Med. 2007;161(9):857-864. Kessler RC, et al. Am J Boston, Massachusetts Psychiatry. 2006;163(4):716-723. Wilens TE, et al. Postgrad Med. 2010;122(5):97-109. Network and Pathway Analysis Subgroup and Psychiatric Genomics Consortium. Nat Neurosci. 2015;18(2):199- 209.

Developmental Impact and Targets of Developing a Treatment Plan Treatment for ADHD

Academic difficulties Occupational failure • Educational /occupational evaluation and planning is critical Self-esteem issues Self-esteem • Parent/individual support and guidance (referral to support groups; Legal issues Relationship CHADD, ADDin) Behavioral Smoking problems • Cognitive-behavior therapy may be recommended initially if disturbance Injuries Injuries/accidents • ADHD symptoms are mild–moderate • Preschool Preschool Adolescent Adult • Pharmacotherapy is rejected School-age College-age • Pharmacotherapy is typically considered first-line • Once treatment is established, practitioner’s role Behavioral disturbance Academic failure • Coordinating with school or college student health service Academic difficulties Occupational difficulties Peer relationships Self-esteem regarding ADHD treatment Self-esteem issues Substance abuse • Preparing the patient (and family) for major transitions Injuries/accidents • Monitoring side effects • Monitoring progress

Pliszka S; AACAP Work Group on Quality Issues. J Am Acad Child Adolesc Psychiatry. Pliszka S; AACAP Work Group on Quality Issues. J Am Acad Child Adolesc Psychiatry. 2007;46(7):894-921. Canadian ADHD Resource Alliance (CADDRA). CADDRA Canadian ADHD Practice 2007;46(7):894-921. Brown TE, et al. Postgrad Med. 2010;122(5):42-51. Guidelines. www.caddra.ca/practice-guidelines/download. Accessed April 28, 2016.

Unmet Needs in : ADHD Pharmacologic Treatment Pharmacotherapy of ADHD FDA Approved  Effect size of nonstimulants  Stimulants > Nonstimulants for efficacy  Often need combination of nonstimulants + stimulants FDA Approved  Effectiveness throughout the day  Early morning symptoms Alpha agonists FDA Approved  After school, evening functioning Guanfacine (XR)  Improved executive functioning Clonidine (XR)  Behavioral self regulation (eg, moodiness, frustration) Guan XR or Clon XR + stimulants FDA Approved  Cognitive tasks (organization, planning, shifting, executing)  Effectiveness for frequent Sx, traits, or comorbidity(ies) , mood, tics, oppositionality Tricyclics  Safety in substance use disorders, low misuse/diversion  Tolerability  Ease of use Misc  Low side-effect burden Adler LA, et al. Attention-Deficit/Hyperactivity Disorder in Adults and Children. Cambridge University Press; 2015. Adler LA, et al. Attention-Deficit/Hyperactivity Disorder in Adults and Children. Cambridge University Press; 2015. Methylphenidate (MPH) in ADHD: (AMPH) in ADHD: Optimizing Dosing Optimizing Dosing

Maximum Dose* Duration Medication Starting Dose Usual Dosing Maximum Dose* Medication Starting Dose Duration ® 2.5–5 mg QD 1.5 mg/kg/day 6 hr / BID Usual Dosing Adderall XR® 2.5–5 mg QD 12 hr / QD Ritalin IR® 5 mg QD/BID 2 mg/kg/day 4 hr /BID Vyvanse® 30 mg QD 12–14 hr / QD Focalin® 2.5 mg QD/BID 1 mg/kg/day 4–5 hr / BID–TID Focalin XR® 5 mg QD 1 mg/kg/day 10–12 hr QD 3–5 hr / BID–QID Daytrana® 10 mg 6–16 hr Dexedrine Tablets® 2.5–5 mg BID 1.5 mg/kg/day

Concerta® 18 mg QD 2 mg/kg/day 12 hr / once Evekeo® 2.5–5 mg BID 3–5 hr / BID–QID

Metadate CD® 20 mg QD 8 hr / once Dexedrine Spansule® 5 mg QD 6 hr / QD–BID Ritalin LA® 20 mg QD 8 hr /once ® Dyanavel XR™ Quillivant <10 mg QD 12 hr /once 2.5–5 mg QD 1.5 mg/kg/day 12 hr / QD (suspension) Quillichew™ <10 mg QD 8 hr /once Adzenys XR™ 6.3–12.5 mg QD Not established 12 hr / QD (disintegrating tab) *May exceed FDA approved dose (eg, > 20 to 30 mg/day). *May exceed FDA approved dose. Wilens TE, et al. CNS News. 2007. Wilens TE, et al. Postgrad Med. 2010;122(5):97-109. Wilens TE, et al. Postgrad Med. 2010;122(5):97-109. www.drugs.com. www.drugs.com.

Extended-Release MPH Solution and AMPH Oral Disintegrating Tablets Chewable Preparations (Adzenys XR™) for Pediatric ADHD

Quillivant XR® QuilliChew ER™ Newly approved mixed AMPH Suspension Chewable tablet (3 to 1 ratio of d- to l-amphetamine) 12 hour duration 8 hour duration Duration of action to 12 hours 25 mg/5 cc (tsp) 20 mg scored, 30 mg scored, 40 mg tablets Equivalent Dosing Dosing to 60 mg daily Dosing to 60 mg daily AMPH ER disintegrating 3.1 mg 3.1 mg 9.4 mg 12.5 mg 15.7 mg 18.8 mg Approved in pediatrics Approved in pediatrics (Adzenys XR™) Mixed AMPH salts ER 5 mg 10 mg 15 mg 20 mg 25 mg 30 mg (Adderall XR®)

US Food and Drug Administration. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. US Food and Drug Administration. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

AMPH Suspension (Dyanavel XR™) for D,L AMPH (Evekeo®) for Pediatric ADHD Pediatric ADHD

Newly approved AMPH suspension Newly approved mixed AMPH Composition: 3.2 to1 ratio of d- to l-amphetamine Composition: 50% d- and l-amphetamine Dosing: 2.5 to 5 mg QD Duration of action to 10 hours Duration of action: 12 hours Dosing: 5 and 10 mg tablets

Laboratory classroom SKAMP-Combined scores. Lower scores denote more change. SKAMP = Swanson, Kotkin, Agler, M-Flynn, and Pelham. US Food and Drug Administration. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Childress AC, et al. J Child Adolesc Psychopharmacol. 2015;25(5):402-414. The Ventromedial PFC: Guanfacine XR in ADHD Emotional Regulation

Ventromedial PFC is thought to regulate emotion

Ventromedial

Basal PFC Ganglia Effect Size: 0.41–0.89

Amygdala

Hypothalamus Impairment may lead and Brainstem to aggressive and *3 weeks titration oppositional behavior 3 weeks maintenance (endpoint) 3 weeks taper *, + P < .05 PFC = prefrontal cortex. Anderson SW, et al. Nat Neurosci. 1999;2(11):1032-1037. Arnsten AF, et al. J Child Adolesc N = 324 (51 sites); 6 weeks active*. Mean Age = 11 ± 3 years. Psychopharmacol. 2007;17(4):393-406. Price JL, et al. Prog Brain Res. 1996;107:523-536. Sallee FR, et al. J Am Acad Child Adolesc Psychiatry. 2009;48(2):155-165.

Guanfacine XR Has Similar Efficacy Guanfacine XR in Adolescent ADHD with AM or PM Administration

Total Score Hyper/Imp • Objective: Despite the continuity of attention-deficit/hyperactivity disorder (ADHD) into adolescence, little is known regarding use of nonstimulants to treat ADHD in adolescents. This phase 3 trial evaluated the safety and efficacy of guanfacine extended release (GXR) in adolescents with ADHD. • Method: This 13-week, multicenter, randomized, double-blind, placebo-controlled trial evaluated once-daily GXR (1–7 mg per day) in adolescents with ADHD aged 13 to 17 years. The primary endpoint was the change from baseline in the ADHD Rating Scale–IV (ADHD-RS-IV) total score; key secondary endpoints included scores from the Clinical Global Impressions–Severity of Illness (CGI-S), and Learning and School domain and Family domain scores from the Weiss Functional Impairment Rating Scale–Parent Report (WFIRS-P) at week 13. • Results: A total of 314 participants were randomized (GXR, n = 157; placebo, n = 157). The majority of participants received optimal doses of 3, 4, 5, or 6 mg (30 [22.9%], 26 [19.8%], 27 [20.6%], or 24 [18.3%] participants, respectively), with 46.5% of participants receiving an optimal dose above the Inattention currently approved maximum dose limit of 4 mg. Participants receiving GXR showed improvement in ADHD-RS-IV total score compared with placebo (least-squares mean score change, –24.55 [GXR] versus –18.53 [placebo]; effect size, 0.52; P < .001). More participants on GXR also showed significant improvement in CGI-S scores compared with placebo (50.6% versus 36.1%; P = .010). There was no statistically significant difference between treatments at week 13 in the 2 WFIRS-P domains. Most treatment-emergent adverse events were mild to moderate, with sedation-related events reported most commonly 6–12 years, dosing 1–4 mg/day. Samples size of GXR AM (n = • Conclusion: GXR was associated with statistically significant improvements in ADHD symptoms in 107), GXR PM (n = 114), or adolescents. GXR was well tolerated, with no new safety signals reported. placebo (n = 112). • Clinical Trial Registration Information: Dose-Optimization in Adolescents Aged 13-17 Diagnosed With Attention-Deficit/Hyperactivity Disorder (ADHD) Using Extended-Release Guanfacine HCl; Newcorn JH, et al. J Am Acad http://ClinicalTrials.gov/; NCT01081132. Child Acad Psychiatry. 2013; 52(9):921-930. Wilens TE, et al. J Am Acad Child Adolesc Psychiatry. 2015;54(11):916.e2-925.e2

Guanfacine XR in Adolescent ADHD Guanfacine XR in Adolescent ADHD

Percentage of responders (full analysis set). Response was defined as a percentage reduction from the baseline visit in the ADHD-RS-IV total score of ≥30% and a CGI–Improvement of 1 or 2. Wilens TE, et al. J Am Acad Child Adolesc Psychiatry. 2015;54(11):916.e2-925.e2 Wilens TE, et al. J Am Acad Child Adolesc Psychiatry. 2015;54(11):916.e2-925.e2 Before School Functioning Questionnaire (BSFQ) Before School Functioning Questionnaire (BSFQ) Investigator-Rated Component (6 AM to 9 AM) Past Week (continued)

Did your child have difficulty with: None Mild Moderate Severe Did your child have difficulty with: None Mild Moderate Severe

1. Listening (to parents, other caregivers, siblings) 0 1 2 3 11. Hyperactivity (excessive motor activity, running around in morning) 01 2 3 2. Following Directions (coming to breakfast, getting dressed, picking up 01 2 3 necessary things) 12. Talkativeness (talking excessively) 01 2 3

3. Overall Organization (morning routines, getting things together, time 13. Interrupt/Blurt Out (interrupting/intruding, blurting out before question 01 2 3 01 2 3 awareness) is completed) 4. Dressing (putting on shirts, blouse, pants, shoes, coats) 01 2 3 14. Silliness (goofiness, silliness, joking around) 01 2 3 5. Attention (focusing on morning routines or activities) 01 2 3 15. Awaiting Turn (at breakfast, in line for bus or ride, bathroom time) 01 2 3 6. Being Quiet (loud, cannot occupy self unless with TV/ electronics) 01 2 3

16. Breakfast (not sitting down to eat, distracted while eating) 0 1 2 3 7. Distraction (easily off task, distracted by objects, noise, others) 01 2 3 17. Hygiene (washing, combing hair, brushing teeth) 01 2 3

8. Procrastination (waiting until last moment to complete morning tasks) 01 2 3 18. Independence (ability to perform tasks by him/herself) 01 2 3

9. Forgetfulness (memory of specific items; gym clothes, instrument, 01 2 3 19. Time Awareness (not using time correctly, taking too long) 01 2 3 equipment)

20. Getting to School (missing bus, disruptive car/bus ride, walking to 01 2 3 10. Misplacing/Losing Items (book bag, lunch tickets, school work/projects) 01 2 3 school, tardy)

Summary: Effect of MPH Transdermal Delivery Reliability and Validity of the BSFQ System on Investigator-Rated BSFQ

• Reliability – Self-rated BSFQ scores • Low internal homogeneity and test-retest reliability – Investigator-rated BSFQ scores • High internal homogeneity AND good test-retest reliability • Validity – Self-rated BSFQ scores **P < .01 • Poor concurrent validity, no treatment effects – Investigator-rated BSFQ scores • Significant concurrent validity, strong treatment effects

MTS = methylphenidate transdermal system; PTS = placebo transdermal system. Faraone SV, et al. J Atten Disord. 2015 Jan 9;[Epub ahead of print]. Wilens TE, et al. J Clin Psychiatry. 2010;71(5):548-556.

Effect of Guanfacine XR on Combination of Atomoxetine Plus Parent-Rated BSFQ Stimulants in the Treatment of ADHD

• Qualitative analysis of existing studies • N = 3 prospective (1 RCT) + 7 retrospective reports • Predominately children/adolescent with inadequate response to stimulants • Most often used = MPH • Conclusions – Small sample sizes –“Existing evidence suggests, but does not confirm, that this drug combination may benefit some, but not all, patients who have tried several ADHD medications without success.”

*P < .02 + psychostimulant. Wilens TE, et al. J Atten Disord. 2013 Sep 26;[Epub ahead of print]. Treuer T, et al. J Child Adolesc Psychopharmacol. 2013;23(3):179-193. Combination of Guanfacine XR Plus Combination of Guanfacine XR Plus Stimulants in the Treatment of ADHD Stimulants in the Treatment of ADHD

• Multisite, controlled 9-week trial • Dosing: 1 to 4 mg daily; mean = 3.2 mg (0.1 mg/kg) • Inclusion: Stimulant partial responders (> 4 week use with improvement; ADHD-RS-IV > 24 and CIG > 3) ages 6–17 years • Exclusion: Other psych, CV abnormal, weight < 55 lb or > 176 lb • Design: 5-week optimization and 3-week dose maintenance period (visits 7–10) • Primary outcome: ADHD-RS-IV (Investigator)

N = 455. N = 455. Wilens TE, et al. J Am Acad Child Adolesc Psychiatry. 2012;51(1):74.e2-85.e2. Wilens TE, et al. J Am Acad Child Adolesc Psychiatry. 2012;51(1):74.e2-85.e2.

Combination of Guanfacine XR Plus Combination of Clonidine XR Plus Stimulants in the Treatment of ADHD Stimulants for ADHD

Adverse effects Study of clonidine XR co- • Most common adverse effect ≥ sedation/somnolence administration to partial responders on stimulants (> ADHD-RS-IV 26 score) • Serious adverse effects—all unrelated to medication: • Dosing to 0.4 mg daily 1) syncope, 2) poison ivy, 3) emotional outbursts (in 0.2 mg BID dosing) • Duration: 5 weeks (then taper) • Cardiovascular indices at endpoint – Heart rate: -5.6 bpm – Systolic blood pressure: -2.2 mm Hg – Diastolic BP: -1.2 mm Hg – No ECG abnormal, no QT prolongation

Wilens TE, et al. J Am Acad Child Adolesc Psychiatry. 2012;51(1):74.e2-85.e2. Kollins SH, et al. Pediatrics. 2011;127(6):e1406-e1413.

Memantine for ADHD: MGH Open Trial

Adult ADHD Self Report Scale Total

Total Score

Inattention

Hyperactive/impulsive

N = 34 adults (LOCF) 12-week trial Titrated to 10 mg BID

Sonuga-Barke EJ, et al. Am J Memantine is not FDA approved for the treatment of ADHD. Psychiatry. MGH = Massachusetts General Hospital. 2013;170(3):27 Surman CB, et al. World J Biol Psychiatry. 2013;14(4):291-298. 5-289. Omega-3/Omega-6 Fatty Acids Adjunct Fish Oils in ADHD: for ADHD MGH Preliminary Results 35 ADHD-Rating Scale • Meta-analysis of 10 studies; N = 699 children 30 25 – Examined EPA, DHA (omega-3), and g-linoleic acid 20 (omega-6) 15 – Indicating mild improvement in ADHD overall with good 10 tolerability (ES = 0.28 monotherapy; 0.18 adjunct) 5 – Potential dose-response effect of EPA (omega-3) 0 Week 0 Week 4 Week 6 Week 9 Week 12 – May be useful for mood symptoms in ADHD (under study) 75 BRIEF-Emotional Control Subscale (T-Score) •Dosing 65

– High EPA to DHA or g-linoleic acid (omega-6) Improvement More 55 – < 1000 mg/day 45 – Preparations, brands vary dramatically 35 Week 0 Week 4 Week 6 Week 9 Week 12 EPA = eicosapentaenoic acid; DHA = docosahexaenoic acid. N = 8. Raw Data LSCF Bloch MH, et al. J Am Acad Child Adoles Psychiatry. 2011;50(10):991-1000. Wozniak J, et al. Eur BRIEF = Behavior Rating Inventory of Executive Function. Neuropsychopharmacol. 2007;17(6-7):440-447. Wilens TE, et al. Unpublished data 2016.

Nighttime Administered MPH for ADHD

New Medication Development in ADHD

Pharmacokinetic study of a single 7 PM evening dose of HLD200 (54 mg) in 11 children and 18 adolescents

Childress A, et al. Presented at: American Professional Society of ADHD and Related Disorders Annual Meeting; January 16-18, 2015; Washington, DC.

New ADHD Medications in Nighttime Administered MPH for ADHD Development

Oradur®-Methylphenidate SR • Mechanism: DAT/NET inhibitor • Status: Phase 3 [Orient Pharma, Taiwan] • Company: Durect • Description: New technology release converts short- acting oral capsule dosages into sustained-release products • Oradur® appears to facilitate delivery of MPH while reducing the potential for abuse via non-medically 6-week open study (presented) followed by controlled trial (not shown) approved modalities of administration (eg, N = 43 children aged 6 to 12 years insufflation). [This technology has already been employed Findings: Improvement in ADHD-RS-IV, BSFQ, DPREMB for oxycodone into what is known as Remoxy®.] Adverse effects: Stimulant like—no major effects on sleep DAT = transporter; NET = transporter. DPREMB = Daily Parent Rating of Evening and Morning Behavior Scale. Mental Health Daily. http://mentalhealthdaily.com/2015/09/14/new-adhd-medications-in-the-pipeline- Wigal S, et al. Presented at: American Professional Society of ADHD and Related Disorders Annual 2015/. Accessed April 28, 2016. Meeting; January 15-17, 2016; Washington, DC. ClinicalTrials.gov Identifier: NCT02450890; NCT02704390. New ADHD Medications in for ADHD in Adults Development

Dasotraline for the Treatment of Attention-Deficit/Hyperactivity Disorder: A Randomized, Dasotraline (SEP-225289) Double-Blind, Placebo-Controlled, Proof-of-Concept Trial in Adults • Company: Sunovion Koblan KS, Hopkins SC, Sarma K, Jin F, Goldman R, Kollins SH, LoebelA. • Mechanism: Triple reuptake inhibitor (, DAT/NE) Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by • Status: Phase 2/3 symptoms of inattention, hyperactivity, and impulsivity associated with clinically significant impairment in functioning. ADHD has an early onset, but frequently persists, with a prevalence estimate of 4% in adults. Dasotraline is a novel compound that is a potent inhibitor of dopamine • Comments: It appears as though the drug has a and norepinephrine transporters that achieves stable plasma concentrations with once-daily dosing. In this study, adult outpatients meeting DSM-IV-TR criteria for ADHD were randomized to significantly greater affinity for the DAT than the SERT. For 4 weeks of double-blind, once-daily treatment with dasotraline 4 and 8 mg/day or placebo. The this reason, researchers suspected that it would likely be primary efficacy end point was change from baseline at week 4 in the ADHD Rating Scale, Version IV (ADHD RS-IV) total score. Secondary efficacy end points included the Clinical Global better suited for the treatment of attentional deficits than Impression, Severity (CGI-S) scale, modified for ADHD symptoms. Least squares (LS) mean improvements at week 4 in ADHD RS-IV total score were significantly greater for dasotraline depressive symptoms. It is also suggested that the drug is 8 mg/day vs placebo (−13.9 vs −9.7; P = 0.019), and nonsignificantly greater for 4 mg/day (−12.4; a potent inhibitor of NET and affects levels of P = 0.076). The LS mean improvements in modified CGI-S were significantly greater at week 4 for dasotraline 8 mg/day vs placebo (−1.1 vs −0.7; P = 0.013), and for 4 mg/day vs placebo (−1.1 norepinephrine to a greater extent than serotonin. vs −0.7; P = 0.021). The most frequent adverse events reported were , decreased appetite, , and dry mouth. Discontinuations due to treatment-emergent adverse events SERT = . were 10.3% and 27.8% of patients in 4 and 8 mg/day treatment groups, respectively. This study Mental Health Daily. http://mentalhealthdaily.com/2015/09/14/new-adhd-medications-in-the-pipeline- provides preliminary evidence that once-daily dosing with dasotraline, a long-acting, dual 2015/. Accessed April 28, 2016. monoamine reuptake inhibitor, may be a safe and efficacious treatment for adult ADHD. ClinicalTrials.gov Identifier: NCT02428088; NCT02276209; NCT02457819; NCT02734693; NCT02160262; NCT01692782. Koplan KS, et al. Neuropsychopharmacology. 2015;40(12):2745-2752.

Dasotraline for ADHD in Adults Dasotraline for ADHD in Adults Incidence of TEAEs (%) (Safety Population; Incidence ≥ 3% and 2-Times Placebo) Dasotraline Dasotraline Placebo 4 mg/day 8 mg/day (n = 111) (n = 116) (n = 111) Insomnia 15.5 34.5 45.0

Decreased appetite 2.7 10.3 22.5

Dry mouth 2.7 7.8 17.1

Anxiety 1.8 9.5 9.0

Nausea 2.7 6.0 9.9

Dizziness .9 6.9 8.1

Palpitations 0 5.2 2.7

Weight decreased .9 2.6 5.4

Tension headache 0 5.2 0 Double-blind, placebo controlled study of 0, 4 mg, and 8 mg dasotraline .9 0 3.6 Any TEAE rated as ‘severe’ 0 6.0 13.5

TEAE = treatment-emergent adverse event. Koplan KS, et al. Neuropsychopharmacology. 2015;40(12):2745-2752. Koplan KS, et al. Neuropsychopharmacology. 2015;40(12):2745-2752.

New ADHD Medications in in ADHD Development

Edivoxetine A Randomized Trial of Edivoxetine in Pediatric Patients with Attention- Deficit/Hyperactivity Disorder • Mechanism: NET inhibitor • Company: Eli Lilly Lin DY, Kratochvil CJ, Xu W, Jin L, D'Souza DN, Kielbasa W, Allen AJ. • Status: Phase 3 OBJECTIVE: The purpose of this study was to assess the efficacy and safety of edivoxetine (LY2216684), a selective norepinephrine reuptake inhibitor, in • Edivoxetine (LY-2216684) is a drug under development for pediatric patients with attention-deficit/hyperactivity disorder (ADHD). the treatment of ADHD. The drug had previously undergone clinical trials as an adjunct treatment for depression, METHOD: A fixed-dose, randomized, double-blind, 8 week study was conducted in patients 6-17 years of age, who were randomized by two strata: 1) Patients ultimately failed to get FDA approval in 2012. The drug with prior stimulant use randomized to placebo, edivoxetine 0.1 mg/kg/day, functions primarily as a selective NET reuptake inhibitor, 0.2 mg/kg/day, or 0.3 mg/kg/day arms in a 1:1:1:1 ratio; 2) Stimulant-naïve increasing extracellular concentrations of norepinephrine. patients randomized to placebo, edivoxetine 0.1mg/kg/day, 0.2 mg/kg/day, Some reported side effects associated with the drug include: 0.3 mg/kg/day, or osmotic-release oral system methylphenidate (OROS MPH) (18-54 mg/day based on body weight) arms in a 1:1:1:1:1 ratio. The primary headaches, nausea, constipation, dry mouth, and efficacy measure was baseline-to-week 8 change of ADHD Rating Scale (ADHD- insomnia—all of which are common with other RS) total score for edivoxetine 0.2 mg/kg/day and 0.3 mg/kg/day. norepinephrine reuptake inhibitors.

Mental Health Daily. http://mentalhealthdaily.com/2015/09/14/new-adhd-medications-in-the-pipeline- 2015/. Accessed April 28, 2016. Lin DY, et al. J Child Adolesc Psychopharmacol. 2014;24(4):190-200. Edivoxetine in ADHD Edivoxetine in ADHD

RESULTS: A total of 340 patients were randomized to placebo (n = 78); edivoxetine 0.1 mg/kg/day (n = 76), 0.2 mg/kg/day (n = 75), or 0.3 mg/kg/day (n = 75); or OROS MPH (n = 36). In the stimulant-naïve stratum, the positive control, OROS MPH, was significantly superior to placebo in mean ADHD-RS total score change at end-point (- 19.46, P = 0.015). The edivoxetine 0.2 mg/kg/day and 0.3 mg/kg/day arms had statistically significantly greater improvement than the placebo arm in mean ADHD- RS total score change at end-point (placebo -10.35; edivoxetine 0.2 mg/kg/day - 16.09, P < 0.010; edivoxetine 0.3 mg/kg/day -16.39, P < 0.010) and Clinical Global Impressions-Improvement score (placebo 3.05; edivoxetine 0.1 mg/kg/day 3.01, P = 0.860; edivoxetine 0.2 mg/kg/day 2.54, P = 0.013; edivoxetine 0.3 mg/kg/day 2.53, P = 0.013). In the overall efficacy-analyses data set (n = 270), the effect size estimates for edivoxetine doses 0.1 mg/kg/day, 0.2 mg/kg/day and 0.3 mg/kg/day at the week 8 time point were 0.17, 0.51, and 0.54, respectively (for the stimulant-naïve stratum, the effect size estimate for OROS MPH was 0.69). Compared with placebo, edivoxetine treatment was associated with statistically significant increases in blood pressure and pulse (P < 0.050), and a smaller increase or slight decrease in weight.

CONCLUSIONS: Edivoxetine at doses of 0.2 mg/kg/day and 0.3 mg/kg/day demonstrated efficacy in ADHD treatment, despite the presence of a sizeable placebo response. No unexpected adverse events were identified. Clinical Trial Registry identifier: NCT00922636

Lin DY, et al. J Child Adolesc Psychopharmacol. 2014;24(4):190-200. Lin DY, et al. J Child Adolesc Psychopharmacol. 2014;24(4):190-200.

New ADHD Medications in Metadoxine in ADHD (Adults) Development

Metadoxine ER

• Mechanism: 5-HT2B selective agonist / GABA modulator • Company: Alcobra RCT, phase 2 study • Status: Phase 3 1400 mg/d • Metadoxine is a drug primarily used to treat alcohol N = 120 adults with ADHD. Efficacy measures = Conners’ Adult ADHD intoxication in Europe, but has also demonstrated efficacy for Rating Scale-Investigator Rated the treatment of ADHD. The drug is unique to other ADHD (CAARS-INV) medications in that it is comprised of an ion pair salt of pyridoxine (Vitamine B6) and L-pyroglutamate. The drug appears to function as a 5-HT2B selective agonist and has a high affinity for the GABA transporter, thereby preventing GABA degradation. Its mechanism of action is novel in that it doesn’t significantly alter monoamines (serotonin, norepinephrine, and dopamine). It solely acts on the 5-HT2B receptor as an agonist, and modulates GABA. GABA = γ-aminobutyric acid. Mental Health Daily. http://mentalhealthdaily.com/2015/09/14/new-adhd-medications-in-the-pipeline- 2015/. Accessed April 28, 2016. ClinicalTrials.gov Identifier: NCT02477748. Manor I, et al. J Clin Psychiatry. 2012;73(12):1517-1523.

Metadoxine in ADHD (Adults) Metadoxine in ADHD (Adults)

Efficacy of Metadoxine Extended Release in Patients with Predominantly RESULTS: There was a significant decrease in CAARS-INV Total ADHD Inattentive Subtype Attention-deficit/Hyperactivity Disorder. Symptoms scores in patients with ADHD-PI taking metadoxine ER (40%) compared with those taking placebo (21%) (P < 0.05), while the decrease for Manor I, Newcorn JH, Faraone SV, Adler LA. patients with ADHD-CT was not significant (27% vs 26%). Similarly, there was a OBJECTIVES: To compare the effects of metadoxine extended release (ER) with significant decrease in IA scores in patients with ADHD-PI (metadoxine ER, 50% those of placebo on inattentive (IA) versus hyperactive-impulsive (H-I) symptoms vs placebo, 23%; P < 0.005), while the change in patients with ADHD-CT was not and predominantly inattentive (PI) versus combined type (CT) subtype in adults significant. There was no significant difference in percent decreases seen in H-I with attention-deficit/hyperactivity disorder (ADHD). scores for patients with PI or ADHD-CT. Significantly higher response rates at both cutoffs (ie, 25% and 45% improvement) were seen in the metadoxine ER METHODS: This was a 1:1 randomized, double-blind, parallel-design study of group compared with the placebo group in CAARS-INV Total ADHD Symptoms metadoxine ER 1400 mg/day for 6 weeks in 120 adults with ADHD. Efficacy scores in patients with ADHD-PI, but not those with ADHD-CT. Test of Variables measures were baseline to end-of-treatment changes in Conners’ Adult ADHD of Attention ADHD scores were significantly decreased in the metadoxine ER Rating Scale-Investigator Rated (CAARS-INV) Total ADHD Symptoms scores group compared with the placebo group for patients with ADHD-PI, but not those with adult ADHD prompts, the Test of Variables of Attention ADHD scores, and with ADHD-CT. response rates (≥ 25% or ≥ 40% improvement in CAARS-INV Total ADHD Symptoms score). CONCLUSION: These data suggest that metadoxine ER is selectively efficacious for treating IA symptoms in adults with ADHD-PI. TRIAL REGISTRATION: www.ClinicalTrials.gov identifier NCT01243242.

Manor I, et al. Postgrad Med. 2013;125(4):181-190. Manor I, et al. Postgrad Med. 2013;125(4):181-190. New ADHD Medications in Metadoxine in ADHD (Adults) Development

Centanafadine • Mechanism: DAT > NET > 5-HT uptake inhibitor SAN DIEGO -- October 27, 2014 -- (triamine) Metadoxine extended release (ER) produced positive but not statistically • Company: Neurovance Bioscience significant effects on ADHD symptoms in • Status: Phase 2 adult patients, according to results of a • is a drug that is being developed for the phase 3, modified intention-to-treat (ITT) trial presented at the 61st Annual Meeting treatment of ADHD; and perhaps executive dysfunction of the American Academy of Child and within ADHD Adolescent Psychiatry (AACAP). • The drug functions primarily as a DAT/NET/5-HT reuptake inhibitor and is being examined for core ADHD, comorbid ADHD, and executive functioning issues.

Adler L, et al. Presented at: American Academy of Child and Adolescent Psychiatry 61st Annual Meeting; October 20-25, 2014; San Diego, CA. www.firstwordpharma.com/node/1242627#axzz45ojQiR5P. Accessed April 28, 2016. ClinicalTrials.gov Identifier: NCT02547428.

Open Trial of Centanafadine SR in Clinical Scales of Executive Functioning Adults with ADHD (BRIEF-A) with Centanafadine

Total Score Over Total Period1 Baseline Endpoint

100 45 S B1 B2 *P < .0001 vs Baseline 2 40 P < .0001 P < .0001 P = .0029 P < .0001 P = .0005 P < .0001 P < .0001 P < .0001 P < .0001 80 35 30 * 60 25 Centanafadine SR * 20 * *

40

15 Means T-Score 10

ADHD-RS-IV (Symptom Severity) (Symptom ADHD-RS-IV 5 ~ Scale floor 20 0 01234567 0 Week Inhibit Shift Emotional Self-Monitoring Initiate Working Plan/Organize Task Monitor Organization Control Memory of Materials

N = 37. Behavioral Regulation Metacognition S = screen evaluation; B1 = baseline 1 evaluation; B2 = baseline 2 evaluation (final). N = 37. Wilens TE, et al. Presented at: American Academy of Child and Adolescent Psychiatry 61st Annual Wilens TE, et al. Presented at: American Academy of Child and Adolescent Psychiatry 61st Annual Meeting; October 20-25, 2014; San Diego, CA. Meeting; October 20-25, 2014; San Diego, CA.

Most Common Adverse Events New ADHD Medications in Defined as ≥ 5% (≥ 2) Development

Preferred Term Patients (N = 41) Percent Number of Patients w/o AEs 7 17% AR-08 Number of Patients w/ AEs 34 83% • Mechanism: Adrenergic receptor agonist Diarrhea 12* 29% • Company: Arbor Pharmaceuticals Dry Mouth 7 17% • Status: Phase 2 Headache 7 17% • AR-08 is a drug under development for the treatment of Decreased Appetite 6 15% ADHD among children and adolescents (between ages 6 Dyspepsia 4 10% and 17 years). While its exact mechanism of action hasn’t Insomnia 4 10% been made publicly available, it is known that AR-08 Irritability 4 10% functions as an adrenergic receptor agonist. In other Abnormal Dreams 3 7% words, it stimulates specific receptors of norepinephrine, Anxiety 3 7% leading to increased psychomotor activation. Middle Insomnia 3 7% Upper Respiratory Tract Infection 3 7% Vomiting 3 7% *2 on placebo; 7 mild; 3 moderate; no patients discontinued due to diarrhea. Mental Health Daily. http://mentalhealthdaily.com/2015/09/14/new-adhd-medications-in-the-pipeline- Wilens TE, et al. Presented at: American Academy of Child and Adolescent Psychiatry 62nd Annual 2015/. Accessed April 28, 2016. Meeting; October 26-31, 2015; San Antonio, TX. ClinicalTrials.gov Identifier: NCT01876719. New ADHD Medications in New ADHD Medications in Development Development

Eltoprazine SPN-810 (Molindone HCl)

• Mechanism: 5-HT1A/1B partial agonist • Mechanism: Indole-derivative; D2 receptor selective antagonist • Company: Amarantus Bioscience • Company: Supernus Pharmaceuticals • Status: Phase 2 • Status: Phase 3 • Eltoprazine is a drug that was originally developed as an anti- • Supernus Pharmaceuticals has taken the typical aggressive agent. It is classified as a phenylpiperazine drug and molindone and repackaged it as chemical “SPN-810.” It is was intended to be used as a serenic agent, attenuating being tested (in Phase 3 clinical trials) for the specific treatment aggressive behaviors and impulses. of “impulsive aggression” associated with ADHD. It is not anticipated that SPN-810 would be first-line; however, it would • The drug functions primarily as a 5-HT1A and 5-HT1B partial be used as an adjunct for impulsive aggression. This agent agonist, but acts as a 5-HT2C receptor antagonist. It is primarily may be helpful for conduct +ADHD. It is thought to function under investigation for the treatment of levodopa-induced dyskinesia as a result of Parkinson’s disease, but is also in Phase primarily as a selective D2 receptor antagonist to minimize 2 clinical trials for the treatment of adult ADHD. Thus far, the drug aggression, hyperactivity, and psychotic symptoms. It also has is considered safe, well-tolerated, and has been tested in nearly a moderate affinity for cholinergic and adrenergic receptors, 700 humans. with a low affinity for D1 receptors. Mental Health Daily. http://mentalhealthdaily.com/2015/09/14/new-adhd-medications-in-the-pipeline- Mental Health Daily. http://mentalhealthdaily.com/2015/09/14/new-adhd-medications-in-the-pipeline- 2015/. Accessed April 28, 2016. 2015/. Accessed April 28, 2016. ClinicalTrials.gov Identifier: NCT02618408; NCT02618434; NCT02691182.

New ADHD Medications in Experimental Pharmaceuticals* Development

SPN-812 • Not Generally Demonstrated Efficacious for ADHD • Mechanism: NET inhibitor – Prohistaminergic agents (Herring WJ, et al. J Clin Psychiatry. • Company: Supernus Pharmaceuticals 2012;73(7):e891-e898.) – Cholinesterase inhibitors (Wilens TE, et al. J Child Adolesc • Status: Phase 2/3 Psychopharmacol. 2005;15(6):947-955. Biederman J, et al. J Clin • SPN-812 contains an active ingredient tested in Europe Psychopharmacol. 2006;26(2):163-166.) as an . The drug functions as a NET – Nicotinic partial agonist (Wilens TE, et al. J Am Acad Child Adolesc inhibitor, meaning it is considered a nonstimulant. Phase Psychiatry. 2011;50(1):79.e1-84.e1. Bain EE, et al. J Clin Psychiatry. 1/2 adult ADHD studies are completed and Phase 2/3 2012;73(6):783-789.) pediatric ADHD studies are underway. – Mixed catecholamine inhibitor (Wilens TE, et al. Behav Brain Funct. 2008;4:24.) – NET/DAT uptake inhibitor (ClinicalTrials.gov Identifier: NCT01458340) – Ampakines-mixed (Adler L, et al. APSARD. 2011) – Amino acids (Reimherr FW, et al. Am J Psychiatry. 1980;137(1):73-75. Reimherr FW, et al. Psychiatry Res. 1984;11(1):71-78.) Mental Health Daily. http://mentalhealthdaily.com/2015/09/14/new-adhd-medications-in-the-pipeline- 2015/. Accessed April 28, 2016. ClinicalTrials.gov Identifier: NCT01107496; NCT02633527; NCT02736656. *Not FDA approved for ADHD.

Summary

• Many existing medications and/or medication combinations that are FDA approved; and non-FDA approved for ADHD • New stimulant preparations are now available and being developed for ADHD • Nonstimulant medications continue to be developed with catecholamine and indoleamine reuptake inhibition as a general profile; though derivatives of older class agents are also being tested • Stay tuned—newer treatments may assist in the management of non-responsive or partially responsive ADHD