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Tourette’s Disorder and TicsChild and Adolescent Psychopharmacology:
What’s New?
March 16, 2019Barbara J. Coffey, MD, MS
Division Chief, Child and Adolescent Psychiatry
Professor, Department of Psychiatry and Behavioral Sciences
University of Miami Miller School of Medicine
Director, UHealth Tics, OCD and Related Problems Program
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Disclosures
My spouse/partner and I have the following relevant financial relationship with a commercial interest to disclose:
• Abide Therapeutics: Scientific Advisory Board• American Academy of Child and Adolescent Psychiatry: Honoraria• Bracket: Honoraria• Cincinnati Children’s Hospital: Honorarium• Harvard Medical School: Honoraria• Neurocrine Biosciences: Research Support• Nevada Psychiatric Association: Honorarium• NIMH: Research Support• Partners Healthcare: Honoraria• Teva/Nuvelution: Research Support; Scientific Advisory Board• Tourette Association of America: Co-Chair, Medical Advisory Board; TAA-CDC Partnership
Off-label indications will be discussed
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Tourette’s Disorder and Tics:Learning Objectives
• At the end of this session, the participant should be able to:
–Review approved and off label treatments for Tourette’s and tic disorders
–Preview potential new drugs in the pipeline for treatment of tics
– Interpret relevance of clinical trial findings for application to treatment of youth with tics and Tourette’s Disorder
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The Challenges of Treating Tics!
Roessner, V. et al. Eur Child Adolesc Psychiatry (2011); 20:173-196
……
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Tics/Tourette’s Disorder: Pharmacotherapy Overview
Only formally approved (labeled) treatments for TD: – D2 dopamine antagonists: conventional neuroleptics– Haloperidol (Haldol) and pimozide (Orap)– Aripiprazole (Abilify) (Physicians Desk Reference, 2016)Haloperidol: effective for tics, superior to placebo(Shapiro et al. 1968, 1978)Pimozide: effective for tics, superior to placebo and
haloperidol (Shapiro et al. 1983, 1984; Sallee et al. Am J Psych. 1997)
**Aripiprazole: effective for tics, superior to placebo (Yoo et al; 2013)
Other interventions– Psychoeducation; referral to the Tourette Association – *Habit reversal therapy (Comprehensive Behavioral
Intervention for Tics)– Individual/ family therapy; educational consultation
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Daily Doses of Frequently Prescribed Tic Medications(Egolf, A. Coffey, B. Current Pharmacotherapeutic Approaches to the Treatment of
Tourette Syndrome: Drugs Today; 2014 Feb; 50 (2):159-79. doi: 10.1358/dot.2014.50.2.2097801).
Medication Range of daily dosing
Haloperidol 0.25-4.0mg
Pimozide 0.5-8.0mg
*Risperidone 0.125-3.0mg
Aripiprazole 1.0-15.0mg
*Clonidine 0.025-0.4mg
*Guanfacine 0.25-4.0mg
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Quezada, J. Current Approaches and New Developments in the Pharmacological Management
of Tourette Syndrome. 2018.
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Why A Need for New Psychopharmacological Treatments for Tourette’s?
Labeled for indication: D2 dopamine blockers have potential major adverse effects.
First generation neuroleptics: extrapyramidal effects
Second generation antipsychotics: metabolic effects
Off label agents: alpha adrenergic agonists: less effective; response moderated by ADHD. Fatigue, somnolence, and cardiovascular effects.
Comprehensive Behavioral Intervention for Tics (CBIT): lack of trained therapists; duration of treatment
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Novel Agents For Tourette’s: So Where are We Going……?
This is one of the most exciting periods in decades for investigation of novel treatments for Tourette Syndrome………!!
• Several novel compounds are currently under investigation or in the pipeline:
• VMAT2 Inhibitors
• D1 Dopamine Receptor Antagonist
• Serine Hydrolase
• Cannabis Related/Cannabinoid Compounds
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• VMAT-2 inhibition depletes dopamine, reducing involuntary movements• Clinically validated by efficacy of VMAT-2 inhibitors (reserpine, tetrabenazine)
Mechanism of VMAT2 Inhibition in Hyperkinetic Movement
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Fusar-Poli P et al. Am J Psychiatry 2012;169:264-272.
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Deutetrabenazine in Tics associated with Tourette syndrome. Jankovic J, Jimenez-Shahed J, Budman C, Coffey B. et al.
Tremor Other Hyperkinet Mov. 2016; 6.doi: 10.7916/D8M32W3H
*• Background: SD-809 (deutetrabenazine), an inhibitor of vesicular
monoamine transporter type 2 (VMAT2), depletes presynaptic DA and may have utility in treatment of various hyperkinetic movement disorders, including tics.
• Aims: Explore safety, tolerability and preliminary efficacy of SD-809 in adolescents with tics associated with Tourette Syndrome (TS).
• Methods: In an open-label design, TS patients (age 12-17 years) were titrated over 6 weeks to a dose up to 36 mg/day. Titration phase was followed by a maintenance phase at this dose for 2 weeks.
• An independent, blinded rater assessed tic severity with the Yale Global Tic Severity Scale (YGTSS) and tic impact with the TS-Clinical Global Impression (TS-CGI).
• Safety was assessed by monitoring adverse events (AEs), vital signs, physical examination, 12-lead ECGs, clinical laboratory tests and safety scales.
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Deutetrabenazine in Tics associated with Tourette syndrome. Jankovic J, Jimenez-Shahed J, Budman C, Coffey B. et al.
Tremor Other Hyperkinet Mov. 2016; 6.doi: 10.7916/D8M32W3H
*• Methods: Adolescent patients (mean age 16 years; range: 12-18) with moderate-to-severe tics associated with TS
• Open-label treatment x 8 weeks (dosage: 6-36 mg/day)
• Mean dose at Week 8 = 32.0 mg (Range: 18-36 mg)
_
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Deutetrabenazine in Tics associated with Tourette syndrome. Jankovic J, Jimenez-Shahed J, Budman C, Coffey B. et al.
Tremor Other Hyperkinet Mov. 2016; 6.doi: 10.7916/D8M32W3H
• Results: N= 23 patients received SD-809 and had at least 1 post-baseline YGTSS assessment.
• Mean (SD) YGTSS Total Tic score at baseline was 31.6 (7.9) which decreased by 11.6 (8.2) at endpoint, a 37.6% reduction in tic severity (p<0.0001).
• PGIC results at week 8 indicated that more than 75% of subjects described themselves as much or very much improved, compared to before treatment.
• Mean dose at endpoint was 32.1 mg/day.
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Deutetrabenazine in Tics associated with Tourette syndrome. Jankovic J, Jimenez-Shahed J, Budman C, Coffey B. et al.
Tremor Other Hyperkinet Mov. 2016; 6.doi: 10.7916/D8M32W3H
• Results: One week after withdrawal of SD-809, statistically significant increases were observed in a number of YGTSS component scores.
• No serious or severe AEs were reported. • One subject withdrew from the study for an AE of irritability
that was unrelated to study drug.• Conclusion: SD-809 was well tolerated and associated with
clinically meaningful improvement in tic severity. • Results support further development of SD-809 for treatment
of TS. A large Phase II/III global trial will take place soon. Investigator meeting for flexible dose randomized controlled trial took place January 25-27 in Houston, so this trial is good to go!!!
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Deutetrabenazine in Tics associated with Tourette syndrome. Jankovic J, Jimenez-Shahed J, Budman C, Coffey B. et al.
Tremor Other Hyperkinet Mov. 2016; 6.doi: 10.7916/D8M32W3H
• Treatment-Emergent Adverse Events: 15/23 (65.2%)• Most common AEs were headache, fatigue, irritability and
somnolence• None serious or severe
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Under Investigation: Alternative in Reducing Tics in Tourette Syndrome(ARTISTS) 1 & 2
Deutetrabenazine: (TV50717) Phase 2/3Sponsor: Teva/Nuvelution
• Key Inclusion: Children and adolescents ages 6-16; tics must cause significant distress and/or impairment
• Primary Outcome Measure: Change in Total Tic Score (TTS) on Yale Global Tic Severity Scale (YGTSS)
• What is New? Patients randomized by weight and CYP2D6 impairment; randomized withdrawal period during open label extensionStrengths: Phase 1 results positive; compound was tolerable. Open label extension and follow up. Dyskinesia unlikely!
• Location: Global: US; Europe: Russia; Latin and South America; South Korea; Australia; New Zealand
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Under Investigation: Phase 2/3Efficacy and Safety of NBI-98854 (Valbenazine) in Pediatric Subjects With
Tourette Syndrome
Sponsor: Neurocrine Biosciences
► Design: Randomized, double blind, placebo controlled trial to assess safety/efficacy of NBI-98854 (valbenazine; VMAT 2 inhibitor) administered once daily for up to 12 weeks. Dose is optimized followed by randomized withdrawal (weeks 8,10, or 12)
► N=180 subjects ages 6-17 years with Tourette Syndrome
► Primary Outcome Measure: Change in YGTSS TTS
► Key inclusion: Tics must cause significant distress and/or impairment
► What Is New? Open label initiation with randomized withdrawal; no TTS threshold score for enrollment
► Strengths: Study design should facilitate recruitment; dyskinesia unlikely. Open label extension and long term follow up.
► Location: 37 US sites
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In the Pipeline: Ecopipam (Phase 2/3)
Sponsor: Emalex Biosciences
• Emalex Biosciences recently acquired Psyadon Pharmaceuticals and exclusive rights to develop, register and market ecopipam, with orphan drug designation for treatment of pediatric Tourette Syndrome (TS) in patients under 16 years of age.
• Ecopipam: a potent, selective antagonist of D1 receptor family; a first-in-class drug that selectively blocks the actions of dopamine at its receptor.
• Theoretical models suggest nigrostriatal DA “drives” movement in BG via both activating direct (D1 receptor, “net excitatory”) and inhibiting indirect (D2 receptor, “net inhibitory”) pathways. Based on this model, blocking either pathway should reduce tics.
• D1-receptor super-sensitivity may be a mechanism for the repetitive behaviors associated with Tourette Syndrome.
• What is new? First in class drug; positive results in early phase studies.Strengths: May provide new insight into dopamine receptor system involvement in TS and/or OCD.
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Ecopipam, a D1 Receptor Antagonist, for Treatmentof Tourette Syndrome in Children: A Randomized,
Placebo-controlled Crossover Study (Gilbert, D. et al.Movement Disorders, Vol. 33, No. 8, 2018; 1272-1280)
• Method: Forty youth aged 7 to 17 years with Tourette syndrome and Yale Global Tic Severity Scale – total tic score of ≥20 were enrolled and randomized to either ecopipam or placebo for 30 days, followed by a 2-week washout and then crossed to the alternative treatment for 30 days
• Primary outcome measure was the total tic score.
• Results: Relative to placebo, reduction in total tic score was greater for ecopipamat 16 days (mean difference, -3.7; 95% CI, -6.5 to -0.9; P = 0.011) and 30 days mean difference, -3.2; 95% CI, -6.1 to -0.3; P = 0.033).
• Adverse events: predominantly mild to moderate, with only 5 rated severe (2 for ecopipam and 3 for placebo).
• Conclusions: Ecopipam reduced tics and was well tolerated. This placebo-controlled study of ecopipam supports further clinical trials in children and adolescents with Tourette syndrome.
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Gilbert, L. D. Ecopipam, a D1 Receptor Antagonist, for Treatment of Tourette Syndrome in Children: A Randomized, Placebo-controlled Crossover Study. 2018.
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Gilbert, L. D.. Ecopipam, a D1 Receptor Antagonist, for Treatment of Tourette Syndrome in Children: A Randomized, Placebo-controlled Crossover Study. 2018.
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Gilbert, L. D. Ecopipam, a D1 Receptor Antagonist, for Treatment of Tourette Syndrome
in Children: A Randomized, Placebo-controlled Crossover Study. 2018.
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Endocannabinoids and Tourette Syndrome?
Endocannabinoid system plays a role in motor inhibition.
Highest density of central cannabinoid (CB1) receptors: frontal cortex, basal ganglia, cerebellum, hypothalamus, hippocampus, and nucleus accumbens……all areas implicated in pathophysiology of TS.
Endocannabinoids bind to CB1 receptors and impact: monoamines (DA), and excitatory (glutamate) and inhibitory (GABA) neurotransmitters.
Evidence suggests that delta THC increases intra-cortical inhibition; thus THC may reduce central TS disinhibition through modulation of neurotransmitter release, including DA.
Two early RCTs (2002; 2003) by Dr. Kirsten Muller-Vahl in 36 adults with TS reported that dronabinol was more effective than PBO in tic reduction.
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Under Investigation: Safety and Efficacy of Cannabis in
Tourette Syndrome (Phase 2)
Sponsor: University Health Network, Toronto
No controlled trials of inhaled cannabis to date. Various medical cannabis products are authorized in Canada with different THC and CBD contents. No data regarding dosing, efficacy and safety of these products in treatment of TS.
Design: double blind, randomized, crossover pilot to compare efficacy and safety of 3 vaporized cannabis products with different THC and CBD contents, and placebo, in adults with TS. Subjects randomized to one of 4 treatment arms; each will receive a single dose of one of 3 cannabis products + placebo with order determined by treatment assignment.
PK/pD profiles of THC and CBD products will be correlated with tic symptoms.
3 cannabis drug product formulations: different CBD/THC and placebo compositions in different order:
A: THC 10%; CBD <0.5%. B: THC 8.6%, CBD 8.6%
C: THC 0.6%; CBD 14% D: Placebo: THC <0.3%; CBD 0.3%
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In the Pipeline: Study To Examine Efficacy of a Therapeutic
THX-110 for Tourette Syndrome
Sponsor: Therapix Biosciences
► Proof of concept study evaluates efficacy and safety of dronabinol + PEA for management of tics and other symptoms (rage attacks, anxiety, depression, sleep difficulties) in TS
► First part: randomized, controlled study (1:1); second part: open label.
► THX contains dronabinol (THC) and PEA.
► Hypothesis: PEA + dronabinol should be more effective than dronabinolalone.
► Key Inclusion: 60 adults, ages 18-65; TTS greater than or = 18; CGI Severity greater than or = 4
► Key Exclusion: Cannabis dependence or use in 30 days prior to enrollment or positive drug screen
► Primary outcome measure: Change in TTS at endpoint at 12 weeks compared to baseline
► What is New? Defined compound; evaluation of non-tic psychiatric symptoms
► Strengths: Experienced investigator; combination treatment
► Location: Hanover, Germany; PI: Kirsten Muller-Vahl, M.D.
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MonoacylglycerolLipase (MGLL)
In the Pipeline: Serine Hydrolase: Abide Therapeutics
Diverse Substrates Proteins, peptides,
phospholipids, neutral lipids, protein PTMs, etc.
A Large Enzyme Family~1% of human genome
>250 Serine Hydrolases in humans
Diverse Functions CNS signaling, digestion, inflammation,
metabolism, life cycles of viruses and bacteria
Common MechanismEmploys a nucleophilic,
active-siteserine residue for catalysis
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• Excessive neurotransmission is a hallmark of several CNS disorders
• Endocannabinoid signaling through CB1 is a general feedback mechanism to inhibit excessive neurotransmission
• MGLL inhibition amplifies endocannabinoid tone and rectifies overactive synapses, maintaining spatial and temporal specificity of CNS circuits
MGLL Inhibition Rectifies Excessive Synaptic Activity (Abide Therapeutics)
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In the Pipeline: Abide Therapeutics: ABX-1431: Phase 1b Tourette Syndrome Trial Results
ABX-1431 40 mgFasted
ABX-1431 40 mgFasted
Placebo
Placebo
Period 1 Period 2
N = 20
Single dose (40 mg fasted), double
blind, placebo crossover study in 20
adult TS patients; Extension (20mg
with food) in 7 patients
Positive impact on key endpoints of Tourette Syndrome
ABX-1431: well tolerated safety profile: No SAEs; most commonly observed AEs: headache, somnolence, fatigue
Strong target engagement of MGLL with 40 mg dose
Extension with lower drug exposure yielded inconclusive data in 7 patients
Design:
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In the Pipeline: A Randomized, Placebo Controlled Study of ABX-1431 in Adult Patients with Tourette Syndrome or Chronic Motor Tic Disorder
Study Sponsor: Abide Therapeutics
• N=48 adult participants; age 18-64
• Two part study: Part 1: double blind, placebo controlled study at two target dose levels. Up to 30 day screening period, 56 day treatment period, and 14 day follow up (10-14 weeks).Part 2: optional, non-controlled open label study. 4 weeks after last Part 1 study visit, subject can receive open label ABX-1431for an additional 6 weeks (28 day treatment; 14 day follow up period). Dosing: 10 mg capsule, up to 40 mg.
• Primary Outcome Measure: Change in YGTSS TTS from Baseline
• Key Inclusion: TTS must be greater than or equal to 22 at baseline
• Key Exclusion: Alcohol or drug abuse/dependence
• What is New? New compound
• Strengths: Promising early Phase 1 results
• Location: 7 European sites
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Summary: Tics and Tourette’s Disorder: What’s New?
► 3 FDA approved medications in US for treatment of tics and Tourette’s Disorder. Off label agents are usually recommended as first line pharmacotherapy for better safety and tolerability.
► Novel agents under investigation or in pipeline may hold promise as pharmacotherapeutics for tics and Tourette Syndrome
► VMAT2 inhibitors: Phase 1 evidence suggests may be better tolerated than tetrabenazine. Two new compounds have different trial designs (parallel group vs. open label randomized withdrawal) and different samples (US vs. global). Little risk for dyskinesia,
► Ecopipam: Phase 2 study shows preliminary efficacy and tolerability; larger trial getting underway soon. D1 receptor antagonist is first in class with specific development program for TS.
► Cannabis related compounds are numerous; impact of THC and CBD need to be dissected. Positive results may point to an endocannabinoid system dysfunction in TS. Despite current public clamor for use, more scientific data is needed. Controlled studies of different compounds with adults are the first step.
► MGLL inhibition enhances endocannabinoid tone; early phase 1 trial is promising…. Larger trials are needed.
► Tune in next year!!!
