Shire Release: Phase 3 Guanfacine Hydrochloride Extended Release (GXR) Study Shows Improvement In Core Symptoms Of Attention-Deficit/Hyperactivity Disorder (ADHD) In Children And Adolescents
Zug, Switzerland – December 8, 2014 – Results published in European
Neuropsychopharmacology demonstrate the efficacy of the Attention-Deficit/Hyperactivity
Disorder (ADHD) medication, guanfacine hydrochloride extended release (GXR). The Phase III
study (SPD503-316) shows a significant reduction in ADHD core symptoms and global
functioning in children and adolescents living with the disorder when treated with GXR.1
The placebo controlled Phase III study assessed the efficacy and safety of once-daily doseoptimised GXR in the treatment of children and adolescents aged 6-17 years with moderate-tosevere symptoms of ADHD. Subjects were randomised to receive GXR 1-4 mg/day (children)/ 4- 7 mg/day (adolescents), placebo or atomoxetine (ATX) 10-100 mg/day as a reference arm to validate the study design.1 As ATX was included as a reference arm, no comparisons can be made between ATX and GXR.
GXR is a long-acting, once-daily, non-stimulant medicine which contains the active substance guanfacine hydrochloride – a selective alpha2A-adrenergic receptor agonist.2 It is currently approved for use in the US (as INTUNIV®) as a monotherapy and adjunctively with a stimulant medication for ADHD in children/adolescents aged 6-17.3 In Canada (as INTUNIV XR™) it is approved for the same indications in children/adolescents aged 6-12.4 In March 2014, Shire submitted the Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) for the monotherapy treatment of ADHD in children/adolescents aged 6-17 years.
In this study, GXR (3.6 mg mean dose) was shown to significantly improve ADHD core symptoms compared with placebo [change in ADHD-RS-IV total score was -23.9 vs -15, respectively; p<0.001-. Similarly, ATX (42.1 mg mean dose) significantly improved ADHD-RS-IV total score compared with placebo [-18.8 vs -15; p=0.017], further validating the study design.1 ATX was included as a reference arm and therefore no comparison can be made between itself and GXR.
A key secondary endpoint was the change from baseline to endpoint on the Global Clinical Impression-Improvement (CGI-I) scale. The proportion of subjects achieving a CGI-I scale score of “much improved” or “very much improved” was 67.9% and 56.3% in the GXR and ATX groups, respectively, compared with 44.1% in the placebo group [p<0.001 and p=0.024 in the GXR and ATX groups, respectively].*1
The proportion of subjects experiencing treatment-emergent adverse events (TEAEs) were 77.2%, 67.9% and 65.8% in the GXR, ATX and placebo groups, respectively.* The majority of reported TEAEs were of mild or moderate intensity, and the most commonly reported TEAEs in the GXR group were headache, fatigue and somnolence.1
“We are pleased to report that GXR has shown improved outcomes compared with placebo for children and adolescents living with ADHD. These data increase the body of evidence on the safety and efficacy of GXR,” said Tamara Kiechle, Shire Global Medical Lead Neuroscience.
“Each individual’s experience of ADHD is different, and Shire believes the individual needs of those living with ADHD must be considered, allowing for tailored therapy and appropriate management.”
- END -
About Attention-Deficit/Hyperactivity Disorder
Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder in children and adolescents,5-7 and is recognised by the World Health Organization (WHO).8 The core symptoms are inattention, hyperactivity and impulsivity.5,6 Worldwide prevalence of ADHD is estimated to be between 5.29% and 7.1%, and just under 5% in Europe for children and adolescents (<18 years).9,10 While the exact origin of ADHD is unknown, it is recognised that the disorder may be caused by the interplay between genetic and environmental factors.11-13
About the SPD503-316 study1
• A Phase III, double-blind, randomised, multicentre, parallel-group, placebo- and activereference, dose-optimisation study
• Male and female children/adolescents (6--17 years old [n=272]) with a diagnosis of ADHD of at least moderate severity, as defined by a baseline ADHD-RS-IV with a total score of 32 or higher and a minimum Clinical Global Impression-Severity (CGI-S) score of 4, were enrolled into the study
• Subjects who took between 80% and 120% of their total medication were considered to be compliant with the study protocol
•Children participated in the study for 10 weeks and adolescents for 13 weeks
• Conducted in 58 centres across 11 European countries (Austria, France, Germany, Ireland, Italy, Poland, Romania, Spain, Sweden, the UK and Ukraine), the USA and Canada between January 2011 and May 2013
• For more information on the SPD503-316 study, please refer to the online manuscript or ClinicalTrials.gov (http://1.usa.gov/1DUr1Zz)
Further SPD503-316 secondary endpoints1
•Once-daily GXR significantly improved functioning compared with placebo
º The placebo-adjusted difference in least squares (LS) mean change from baseline in the Weiss Functional Impairment Rating Scale-Parent (WFIRS-P) learning and school domain for GXR was -0.22 [p=0.003] and for WFIRS-P family domain was -0.21 [p=0.006]. The corresponding values for ATX were -0.16 [p=0.026] and -0.09 [p=0.242] respectively*
º The placebo-adjusted difference in LS mean change from baseline in WFIRS-P global score for GXR was -0.17 [ p<0.001] and for ATX was -0.10 [ p=0.048]*
• Once-daily GXR significantly improved individual ADHD equally well compared with placebo
º The placebo-adjusted difference in LS mean change from baseline in ADHDRS- IV hyperactivity/impulsivity subscale score for GXR was -4.8 [p<0.001] and a similar change was seen for the inattention subscale score -4.1 [p<0.001]. The corresponding values for ATX were -2.0 [p=0.014] and -1.6 [ p=0.053]*
• Compared with placebo, the difference in the percentage of patients with normal/borderline CGI-S for GXR was 12.3% [p=0.004] and 0.7% [p=0.69] for ATX*
For further information please contact:
Media
Audrey Abernathy aabernathy@shire.com +1 484 595 2389
NOTES TO EDITORS
Shire enables people with life-altering conditions to lead better lives.
Our strategy is to focus on developing and marketing innovative specialty medicines to meet significant unmet patient needs.
We provide treatments in Neuroscience, Rare Diseases, Gastrointestinal, and Internal Medicine and we are developing treatments for symptomatic conditions treated by specialist physicians in other targeted therapeutic areas, such as Ophthalmology.
www.shire.com
THE “SAFE HARBOR” STATEMENT UNDER THE PRIVATE SECURITIES LITIGATION REFORM ACT OF 1995 Statements included herein that are not historical facts are forward-looking statements. Such forward-looking statements involve a number of risks and uncertainties and are subject to change at any time. In the event such risks or uncertainties materialize, Shire’s results could be materially adversely affected. The risks and uncertainties include, but are not limited to, that: • Shire’s products may not be a commercial success;
• revenues from ADDERALL XR are subject to generic erosion and revenues from INTUNIV will become subject to generic competition starting in December 2014;
• the failure to obtain and maintain reimbursement, or an adequate level of reimbursement, by third-party payors in a timely manner for Shire's products may impact future revenues, financial condition and results of operations;
• Shire conducts its own manufacturing operations for certain of its Rare Diseases products and is reliant on third party contract manufacturers to manufacture other products and to provide goods and services. Some of Shire’s products or ingredients are only available from a single approved source for manufacture. Any disruption to the supply chain for any of Shire’s products may result in Shire being unable to continue marketing or developing a product or may result in Shire being unable to do so on a commercially viable basis for some period of time;
• the development, approval and manufacturing of Shire’s products is subject to extensive oversight by various regulatory agencies. Submission of an application for regulatory approval of any of our product candidates, such as our planned submission of a New Drug Application to the FDA for Lifitegrast, may be delayed for any number of reasons and, once submitted, may be subjected to lengthy review and ultimately rejected. Moreover, regulatory approvals or interventions associated with changes to manufacturing sites, ingredients or manufacturing processes could lead to significant delays, increase in operating costs, lost product sales, an interruption of research activities or the delay of new product launches;
• the actions of certain customers could affect Shire's ability to sell or market products profitably. Fluctuations in buying or distribution patterns by such customers can adversely impact Shire’s revenues, financial condition or results of operations;
•investigations or enforcement action by regulatory authorities or law enforcement agencies relating to Shire’s activities in the highly regulated markets in which it operates may result in significant legal costs and the payment of substantial compensation or fines;
• adverse outcomes in legal matters and other disputes, including Shire’s ability to enforce and defend patents and other intellectual property rights required for its business, could have a material adverse effect on Shire’s revenues, financial condition or results of operations;
• Shire faces intense competition for highly qualified personnel from other companies, academic institutions, government entities and other organizations. Shire is undergoing a corporate reorganization and the consequent uncertainty could adversely impact Shire’s ability to attract and/or retain the highly skilled personnel needed for Shire to meet its strategic objectives;
• failure to achieve Shire’s strategic objectives with respect to the acquisition of ViroPharma Incorporated may adversely affect Shire’s financial condition and results of operations; and other risks and uncertainties detailed from time to time in Shire’s filings with the Securities and Exchange Commission, including those risks outlined in “Item 1A: Risk Factors” in Shire’s Annual Report on Form 10-K for the year ended December 31, 2013.
References
1. Hervas A, et al. Efficacy and safety of extended-release guanfacine hydrochloride in children and adolescents with attention-deficit/hyperactivity disorder: a randomized, controlled, phase III trial. Primary Manuscript. Eur Neuropsychopharm 2014; 24:1861-1872
2. Uhlén S & Wikberg JES. Delineation of rat kidney a-2A and a-2B-adrenoceptors with [3H]RX821002 radiology and binding: Computer modelling reveals that guanfacine is an a-2Aselective compound. Eur J Pharmacol 1991; 202:235-243.
3. Intuniv US Prescribing Information 2013.
4. Intuniv XR Product Monograph 2013.
5. Pliszka S and the AACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment Of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2007; 46(7):894-921.
6. Bloom B, et al. Summary health statistics for U.S. children: National health interview survey, 2010. Vital Health Stat 10 2011; (250):1-80.
7. McCarthy S, et al. The epidemiology of pharmacologically treated attention deficit hyperactivity disorder (ADHD) in children, adolescents and adults in UK primary care. BMC Pediatr 2012; 12:78.
8. International Classification of Diseases, 10th ed., (ICD-10). World Health Organization 2007. Chapter 5,F90. http://apps.who.int/classifications/icd10/browse/2010/en#/F90-F98. Last accessed October 2014.
9. Polanczyk G, et al. The worldwide prevalence of ADHD: A systematic review and metaregression analysis. Am J Psych 2007; 164:942-948.
10. Willcutt EG. The prevalence of DSM-IV attention-deficit/hyperactivity disorder: A meta-analytic review. Neurotherapeutics 2012; 9:490-499.
11. Langley K, et al. Effects of low birth weight, maternal smoking in pregnancy and social class on the phenotypic manifestation of attention deficit hyperactivity disorder and associated antisocial behaviour: Investigation in a clinical sample. BMC Psychiatry 2007; 7:26.
12. Dickstein SG, et al. The neural correlates of attention deficit hyperactivity disorder: an ALE metaanalysis. J Child Psychol Psychiatry 2006; 47:1051-1062.
13. Nigg J, et al. Measured gene-by-environment interaction in relation to attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2010; 49:863-873.
Help employers find you! Check out all the jobs and post your resume.
The placebo controlled Phase III study assessed the efficacy and safety of once-daily doseoptimised GXR in the treatment of children and adolescents aged 6-17 years with moderate-tosevere symptoms of ADHD. Subjects were randomised to receive GXR 1-4 mg/day (children)/ 4- 7 mg/day (adolescents), placebo or atomoxetine (ATX) 10-100 mg/day as a reference arm to validate the study design.1 As ATX was included as a reference arm, no comparisons can be made between ATX and GXR.
GXR is a long-acting, once-daily, non-stimulant medicine which contains the active substance guanfacine hydrochloride – a selective alpha2A-adrenergic receptor agonist.2 It is currently approved for use in the US (as INTUNIV®) as a monotherapy and adjunctively with a stimulant medication for ADHD in children/adolescents aged 6-17.3 In Canada (as INTUNIV XR™) it is approved for the same indications in children/adolescents aged 6-12.4 In March 2014, Shire submitted the Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) for the monotherapy treatment of ADHD in children/adolescents aged 6-17 years.
In this study, GXR (3.6 mg mean dose) was shown to significantly improve ADHD core symptoms compared with placebo [change in ADHD-RS-IV total score was -23.9 vs -15, respectively; p<0.001-. Similarly, ATX (42.1 mg mean dose) significantly improved ADHD-RS-IV total score compared with placebo [-18.8 vs -15; p=0.017], further validating the study design.1 ATX was included as a reference arm and therefore no comparison can be made between itself and GXR.
A key secondary endpoint was the change from baseline to endpoint on the Global Clinical Impression-Improvement (CGI-I) scale. The proportion of subjects achieving a CGI-I scale score of “much improved” or “very much improved” was 67.9% and 56.3% in the GXR and ATX groups, respectively, compared with 44.1% in the placebo group [p<0.001 and p=0.024 in the GXR and ATX groups, respectively].*1
The proportion of subjects experiencing treatment-emergent adverse events (TEAEs) were 77.2%, 67.9% and 65.8% in the GXR, ATX and placebo groups, respectively.* The majority of reported TEAEs were of mild or moderate intensity, and the most commonly reported TEAEs in the GXR group were headache, fatigue and somnolence.1
“We are pleased to report that GXR has shown improved outcomes compared with placebo for children and adolescents living with ADHD. These data increase the body of evidence on the safety and efficacy of GXR,” said Tamara Kiechle, Shire Global Medical Lead Neuroscience.
“Each individual’s experience of ADHD is different, and Shire believes the individual needs of those living with ADHD must be considered, allowing for tailored therapy and appropriate management.”
- END -
About Attention-Deficit/Hyperactivity Disorder
Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder in children and adolescents,5-7 and is recognised by the World Health Organization (WHO).8 The core symptoms are inattention, hyperactivity and impulsivity.5,6 Worldwide prevalence of ADHD is estimated to be between 5.29% and 7.1%, and just under 5% in Europe for children and adolescents (<18 years).9,10 While the exact origin of ADHD is unknown, it is recognised that the disorder may be caused by the interplay between genetic and environmental factors.11-13
About the SPD503-316 study1
• A Phase III, double-blind, randomised, multicentre, parallel-group, placebo- and activereference, dose-optimisation study
• Male and female children/adolescents (6--17 years old [n=272]) with a diagnosis of ADHD of at least moderate severity, as defined by a baseline ADHD-RS-IV with a total score of 32 or higher and a minimum Clinical Global Impression-Severity (CGI-S) score of 4, were enrolled into the study
• Subjects who took between 80% and 120% of their total medication were considered to be compliant with the study protocol
•Children participated in the study for 10 weeks and adolescents for 13 weeks
• Conducted in 58 centres across 11 European countries (Austria, France, Germany, Ireland, Italy, Poland, Romania, Spain, Sweden, the UK and Ukraine), the USA and Canada between January 2011 and May 2013
• For more information on the SPD503-316 study, please refer to the online manuscript or ClinicalTrials.gov (http://1.usa.gov/1DUr1Zz)
Further SPD503-316 secondary endpoints1
•Once-daily GXR significantly improved functioning compared with placebo
º The placebo-adjusted difference in least squares (LS) mean change from baseline in the Weiss Functional Impairment Rating Scale-Parent (WFIRS-P) learning and school domain for GXR was -0.22 [p=0.003] and for WFIRS-P family domain was -0.21 [p=0.006]. The corresponding values for ATX were -0.16 [p=0.026] and -0.09 [p=0.242] respectively*
º The placebo-adjusted difference in LS mean change from baseline in WFIRS-P global score for GXR was -0.17 [ p<0.001] and for ATX was -0.10 [ p=0.048]*
• Once-daily GXR significantly improved individual ADHD equally well compared with placebo
º The placebo-adjusted difference in LS mean change from baseline in ADHDRS- IV hyperactivity/impulsivity subscale score for GXR was -4.8 [p<0.001] and a similar change was seen for the inattention subscale score -4.1 [p<0.001]. The corresponding values for ATX were -2.0 [p=0.014] and -1.6 [ p=0.053]*
• Compared with placebo, the difference in the percentage of patients with normal/borderline CGI-S for GXR was 12.3% [p=0.004] and 0.7% [p=0.69] for ATX*
For further information please contact:
Media
Audrey Abernathy aabernathy@shire.com +1 484 595 2389
NOTES TO EDITORS
Shire enables people with life-altering conditions to lead better lives.
Our strategy is to focus on developing and marketing innovative specialty medicines to meet significant unmet patient needs.
We provide treatments in Neuroscience, Rare Diseases, Gastrointestinal, and Internal Medicine and we are developing treatments for symptomatic conditions treated by specialist physicians in other targeted therapeutic areas, such as Ophthalmology.
www.shire.com
THE “SAFE HARBOR” STATEMENT UNDER THE PRIVATE SECURITIES LITIGATION REFORM ACT OF 1995 Statements included herein that are not historical facts are forward-looking statements. Such forward-looking statements involve a number of risks and uncertainties and are subject to change at any time. In the event such risks or uncertainties materialize, Shire’s results could be materially adversely affected. The risks and uncertainties include, but are not limited to, that: • Shire’s products may not be a commercial success;
• revenues from ADDERALL XR are subject to generic erosion and revenues from INTUNIV will become subject to generic competition starting in December 2014;
• the failure to obtain and maintain reimbursement, or an adequate level of reimbursement, by third-party payors in a timely manner for Shire's products may impact future revenues, financial condition and results of operations;
• Shire conducts its own manufacturing operations for certain of its Rare Diseases products and is reliant on third party contract manufacturers to manufacture other products and to provide goods and services. Some of Shire’s products or ingredients are only available from a single approved source for manufacture. Any disruption to the supply chain for any of Shire’s products may result in Shire being unable to continue marketing or developing a product or may result in Shire being unable to do so on a commercially viable basis for some period of time;
• the development, approval and manufacturing of Shire’s products is subject to extensive oversight by various regulatory agencies. Submission of an application for regulatory approval of any of our product candidates, such as our planned submission of a New Drug Application to the FDA for Lifitegrast, may be delayed for any number of reasons and, once submitted, may be subjected to lengthy review and ultimately rejected. Moreover, regulatory approvals or interventions associated with changes to manufacturing sites, ingredients or manufacturing processes could lead to significant delays, increase in operating costs, lost product sales, an interruption of research activities or the delay of new product launches;
• the actions of certain customers could affect Shire's ability to sell or market products profitably. Fluctuations in buying or distribution patterns by such customers can adversely impact Shire’s revenues, financial condition or results of operations;
•investigations or enforcement action by regulatory authorities or law enforcement agencies relating to Shire’s activities in the highly regulated markets in which it operates may result in significant legal costs and the payment of substantial compensation or fines;
• adverse outcomes in legal matters and other disputes, including Shire’s ability to enforce and defend patents and other intellectual property rights required for its business, could have a material adverse effect on Shire’s revenues, financial condition or results of operations;
• Shire faces intense competition for highly qualified personnel from other companies, academic institutions, government entities and other organizations. Shire is undergoing a corporate reorganization and the consequent uncertainty could adversely impact Shire’s ability to attract and/or retain the highly skilled personnel needed for Shire to meet its strategic objectives;
• failure to achieve Shire’s strategic objectives with respect to the acquisition of ViroPharma Incorporated may adversely affect Shire’s financial condition and results of operations; and other risks and uncertainties detailed from time to time in Shire’s filings with the Securities and Exchange Commission, including those risks outlined in “Item 1A: Risk Factors” in Shire’s Annual Report on Form 10-K for the year ended December 31, 2013.
References
1. Hervas A, et al. Efficacy and safety of extended-release guanfacine hydrochloride in children and adolescents with attention-deficit/hyperactivity disorder: a randomized, controlled, phase III trial. Primary Manuscript. Eur Neuropsychopharm 2014; 24:1861-1872
2. Uhlén S & Wikberg JES. Delineation of rat kidney a-2A and a-2B-adrenoceptors with [3H]RX821002 radiology and binding: Computer modelling reveals that guanfacine is an a-2Aselective compound. Eur J Pharmacol 1991; 202:235-243.
3. Intuniv US Prescribing Information 2013.
4. Intuniv XR Product Monograph 2013.
5. Pliszka S and the AACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment Of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2007; 46(7):894-921.
6. Bloom B, et al. Summary health statistics for U.S. children: National health interview survey, 2010. Vital Health Stat 10 2011; (250):1-80.
7. McCarthy S, et al. The epidemiology of pharmacologically treated attention deficit hyperactivity disorder (ADHD) in children, adolescents and adults in UK primary care. BMC Pediatr 2012; 12:78.
8. International Classification of Diseases, 10th ed., (ICD-10). World Health Organization 2007. Chapter 5,F90. http://apps.who.int/classifications/icd10/browse/2010/en#/F90-F98. Last accessed October 2014.
9. Polanczyk G, et al. The worldwide prevalence of ADHD: A systematic review and metaregression analysis. Am J Psych 2007; 164:942-948.
10. Willcutt EG. The prevalence of DSM-IV attention-deficit/hyperactivity disorder: A meta-analytic review. Neurotherapeutics 2012; 9:490-499.
11. Langley K, et al. Effects of low birth weight, maternal smoking in pregnancy and social class on the phenotypic manifestation of attention deficit hyperactivity disorder and associated antisocial behaviour: Investigation in a clinical sample. BMC Psychiatry 2007; 7:26.
12. Dickstein SG, et al. The neural correlates of attention deficit hyperactivity disorder: an ALE metaanalysis. J Child Psychol Psychiatry 2006; 47:1051-1062.
13. Nigg J, et al. Measured gene-by-environment interaction in relation to attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2010; 49:863-873.
Help employers find you! Check out all the jobs and post your resume.