Michael Huss

Child and Adolescent Psychiatry, Johannes Gutenberg University Mainz, Mainz, Germany

Separating efficacy and sedative effects of guanfacine extended release in children and adolescents with ADHD from four randomized, controlled, phase 3 clinical trials

Research was funded by Shire Development LLC

DRAFT SLIDES

Co-authors

Keith McBurnett,1 Andrew J Cutler,2 Amaia Hervas,3 Joan Gu,4 Bryan Dirks,4 Jeffrey H Newcorn5

1Department of Psychiatry, University of California, San Francisco, CA, USA 2Florida Clinical Research Center, Bradenton, FL, USA 3Child and Adolescent Mental Health Unit, University Hospital Mútua de Terrassa, Barcelona, Spain 4Shire, Lexington, MA, USA 5Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Disclosures

The following authors have received compensation for serving as consultants or speakers for, or they or the institutions they have worked for have received research support or royalties from, the companies or organizations indicated below

– M Huss: Actelion, Eli Lilly, Engelhard Arzneimittel, Janssen-Cilag, Medice, Novartis, Shire and Steiner Arzneimittel

– K McBurnett: Abbott Laboratories, Cephalon Inc., Eli Lilly and Company, Johnson & Johnson, Lexicon Pharmaceuticals Inc., McNeil Consumer Healthcare, National Institute of Mental Health, New River Pharmaceuticals Inc., Otsuka America Pharmaceutical Inc., Shire and Sigma-Tau Pharmaceuticals Inc.

– A J Cutler: AbbVie [Abbott], Akili Interactive, Arbor Pharmaceuticals, AstraZeneca, Eli Lilly, Euthymics, Janssen, Johnson & Johnson PRD, Lundbeck, Neos Therapeutics, Neurovance, Novartis, Noven, Otsuka, Pfizer [NextWave], Purdue, Rhodes Pharmaceuticals, Shire, Sunovion, Supernus and Teva

– A Hervas: Eli Lilly, Janssen and Shire

– J H Newcorn: Alcobra, Biobehavioral Diagnostics, Cerecor, Enzymotec, Ironshore, Neos, National Football League, Rhodes, Shire and Sunovion

J Gu and B Dirks are employees of Shire and own stocks or stock options

Guanfacine extended release (GXR)

Non-stimulant treatment approved for children and adolescents with ADHD

– USA and Canada: as monotherapy or an adjunct to stimulant therapy

– Europe: when stimulants are not suitable, not tolerated or have been shown to be ineffective

In pivotal GXR trials, common TEAEs were somnolence, fatigue and sedation

To investigate whether sedation may have confounded the efficacy outcomes (i.e. may have accounted for improvement in hyperactivity) in four RCTs in children and adolescents with ADHD, post hoc analyses were conducted to compare:

– time courses of sedative TEAEs and GXR response

– change in symptoms in individuals with and without sedative TEAEs

RCT, randomized controlled trial; TEAE, treatment-emergent adverse event

SPD503-301: randomization to GXR 2, 3 or 4 mg or placebo (1:1:1:1)

SPD503-304: randomization to GXR 1, 2, 3 or 4 mg or placebo (1:1:1:1:1)

Study designs: two fixed-dose studies

aGXR was initiated at 1 mg/day on day 1 and increased weekly by 1 mg until randomized dose was reached (2 mg at week 1, 3 mg at week 2 and 4 mg at week 3). GXR, guanfacine extended release; PBO, placebo

Study week

SPD503-301 (N = 345)

Children and adolescents (6–17 years)

SPD503-304 (N = 324)

Children and adolescents (6–17 years)

0 1 2 3 4 5 6 7 8 9 13 12

Escalationa

1–4 mg

Maintenance 2–4 mg

Taper

Escalationa 1–4 mg

Maintenance 1–4 mg

Taper

Follow-up

Follow-up

GX

R

PB

O

GX

R

PB

O

Study designs: two dose-optimization studies

SPD503-312: randomization to GXR or placebo (1:1) SPD503-316: randomization to GXR, placebo or ATX (reference) (1:1:1)

aGXR was initiated at 1 mg/day on day 1 and increased weekly by 1 mg until an ‘acceptable’ response (30% reduction from baseline in ADHD Rating Scale IV total score and a Clinical Global Impression-Improvement score of 1 or 2, with tolerable side effects) was achieved. bATX dose range was based on participants’ weight at baseline. ATX, atomoxetine; GXR, guanfacine extended release; PBO, placebo

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 0 G

XR

P

BO

Children and adolescents (6–17 years)

Optimizationa 1–7 mg

Maintenance 1–7 mg

Optimizationb 0.5–1.2 mg/kg (< 70 kg)

40–100 mg (≥ 70 kg)

Maintenance 0.5–1.2 mg/kg (< 70 kg)

40–100 mg (≥ 70 kg)

ATX

Follow-up Taper

Follow-up Taper

GX

R

PB

O

SPD503-312 (N = 314)

SPD503-316 (N = 338)

Optimizationa 1–7 mg

Maintenance 1–7 mg

Taper Follow-up

GX

R

PB

O

Optimizationa 1–4 mg

Maintenance 1–4 mg

Study week

Adolescents (13–17 years)

Adolescents (13–17 years)

Children (6–12 years)

Time courses of sedative TEAEs and response: pooled SPD503-301 and 304 data

Data are presented by randomized dose. aDefined as somnolence, sedation and hypersomnia. bDefined as having ≥ 30% reduction from baseline in ADHD Rating Scale IV total score; analysis based on last observation carried forward. GXR, guanfacine extended release; PBO, placebo; TEAE, treatment-emergent adverse event

0

5

10

15

20

Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8

Inci

den

ce o

f se

dat

ive

TEA

Es (

%)

PBO (n=149)

GXR 1 mg (n=61)

GXR 2 mg (n=150)

GXR 3 mg (n=151)

GXR 4 mg (n=151)

0

25

50

75

100

Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Endpoint

Pro

po

rtio

n o

f re

spo

nd

ers

(%) PBO (n=141)

GXR 1 mg (n=57)

GXR 2 mg (n=147)

GXR 3 mg (n=142)

GXR 4 mg (n=144)

GXR (all doses) PBO

Mean onset (days) 12.0 6.4

Mean duration (days) 17.8 27.0

Incidence of sedative TEAEsa

Cumulative treatment responseb

PBO (n = 149)

GXR 1 mg (n = 61)

GXR 2 mg (n = 150)

GXR 3 mg (n = 151)

GXR 4 mg (n = 151)

PBO (n = 141)

GXR 1 mg (n = 57)

GXR 2 mg (n = 147)

GXR 3 mg (n = 142)

GXR 4 mg (n = 144)

ADHD-RS-IV total score in patients with and without reported sedative TEAEs

GXR significantly reduced ADHD-RS-IV total score compared with placebo in the absence of sedative TEAEs

*p < 0.001. Data based on last observation carried forward. LS means, effect sizes and p values are based on type III sum of squares from an ANVOVA model for the change from baseline, including treatment group, age group, study, and pooled country (SPD503-312 and 316 only) as fixed effects, and baseline value as a covariate. Sedative events: somnolence, sedation and hypersomnia. aAll GXR doses combined. ADHD-RS-IV, ADHD Rating Scale IV; GXR, guanfacine extended release; LS, least-squares; NS, not significant; TEAE, treatment-emergent adverse event

−15

−10

−5

0

5

Pla

ceb

o-a

dju

sted

LS

mea

n

chan

ge f

rom

bas

elin

e to

en

dp

oin

t in

AD

HD

-RS-

IV t

ota

l sc

ore

(9

5%

CI)

Effect size 0.49 0.17 0.67 0.31

NS

*

NS

*

n = 297a n = 124

n = 132 n = 215

n = 193a n = 17

n = 134 n = 51

SPD503-301 and 304 SPD503-312 and 316

Without sedative

TEAEs

Without sedative

TEAEs

With sedative

TEAEs

With sedative

TEAEs

GXR Placebo

Summary and conclusions

The results presented suggest that:

– the time-courses of sedative TEAEs and treatment response with GXR were independent in these studies (i.e. sedation occurred early and typically preceded response)

– GXR significantly reduces ADHD symptoms in patients without sedative TEAEs

These findings from group analytic approaches are relevant for the majority of patients, but may not fully explain trajectories of response and tolerability in individual patients

Overall, these findings suggest that sedation does not account for the symptomatic improvement associated with GXR

GXR, guanfacine extended release; TEAE, treatment-emergent adverse event

Acknowledgements

Under the direction of the authors, David Gothard and Isabelle Kaufmann, employees of Oxford PharmaGenesis, provided writing assistance for this presentation. Editorial assistance in fact checking, copy editing, formatting and proofreading was also provided by Oxford PharmaGenesis

Caleb Bliss from Shire Development LLC reviewed and edited the presentation for scientific accuracy

Shire International GmbH provided funding to Oxford PharmaGenesis for support in writing and editing this presentation

ADHD-RS-IV subscale scores

ADHD-RS-IV total score by ADHD subtype

Back-up

-15

-10

-5

0

ADHD-RS-IV subscale scores

GXR improved ADHD symptoms of both inattention and hyperactivity-impulsivity

*p < 0.001. Data based on last observation carried forward. LS means, effect sizes and p values are based on type III sum of squares from an ANCOVA model for the change from baseline, including treatment group, age group, study, and pooled country (SPD503-312 and 316 only) as fixed effects, and baseline value as a covariate. aAll GXR doses combined. ADHD-RS-IV, ADHD Rating Scale IV; GXR, guanfacine extended release; LS, least-squares

Effect size 0.63 0.50 0.67

n = 266 n = 266

n = 490a n = 141

Pla

ceb

o-a

dju

sted

LS

mea

n c

han

ge

fro

m b

asel

ine

to e

nd

po

int

in

AD

HD

-RS-

IV s

core

(9

5%

CI)

Total Inattention subscale

Hyperactivity- Impulsivity

subscale

Total

*

* *

Hyperactivity- Impulsivity

subscale

Inattention subscale

SPD503-301 and 304 SPD503-312 and 316

GXR Placebo

0.61 0.54 0.61

*

* * –5

–10

–15

-15

-10

-5

0

ADHD-RS-IV total score by ADHD subtype

GXR significantly improved core ADHD symptoms across the inattentive and combined/hyperactive-impulsive subtypes

***p < 0.001; **p < 0.01; *p < 0.05. Data based on last observation carried forward. LS means, effect sizes and p values are based on type III sum of squares from an ANCOVA model for the change from baseline, including treatment group, age group, study, and pooled country (SPD503-312 and 316 only) as fixed effects, and baseline value as a covariate. aAll GXR doses combined. ADHD-RS-IV, ADHD Rating Scale IV; GXR, guanfacine extended release; LS, least-squares

Inattentive subtype

Effect size 0.50 0.64 0.64 0.52

Combined/ hyperactive-

impulsive subtype

Inattentive subtype

Combined/ hyperactive-

impulsive subtype

Pla

ceb

o-a

dju

sted

LS

mea

n c

han

ge

fro

m b

asel

ine

to e

nd

po

int

in

AD

HD

-RS-

IV t

ota

l sco

re (

95

% C

I)

n = 61 n = 56

n = 205 n = 210

GXR Placebo

n = 127a n = 363a

n = 38 n = 103

–5

–10

–15

**

*** *** *

SPD503-301 and 304 SPD503-312 and 316