Data released for once-daily guanfacine extended release trial in children with ADHD

Shire – November 16, 2006 — Shire plc (Nasdaq: SHPGY, LSE: SHP, TSX: SHQ) announced today that once-daily doses of the investigational medication guanfacine extended release (GXR, also referred to as SPD503), a selective alpha-2A-adrenoceptor agonist, significantly improved symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD) in children aged 6 to 17 years when used as a monotherapy. The phase III trial results were presented today at the 2006 U.S. Psychiatric & Mental Health Congress (USPMHC) annual meeting. Two additional studies also released at the meeting report the pharmacokinetic profile of guanfacine extended release.

Shire submitted a New Drug Application (NDA) for guanfacine extended release on August 24, 2006. If approved, guanfacine extended release, which is not a central nervous system stimulant, will be the first once-daily selective alpha-2A-adrenoceptor agonist compound indicated for the treatment of ADHD.

“Guanfacine extended release was developed to allow once-daily dosing through a controlled release formulation,” said Eliseo Salinas, MD, Shire EVP and Chief Scientific Officer. “Research studies have shown that the extended-release formulation of guanfacine effectively provided day-long ADHD symptom control with a single daily dose based on several standard symptom measures.”

Monotherapy with Once-Daily Guanfacine Extended Release Significantly Improved ADHD Symptoms

In this study, investigators randomized 345 subjects to receive placebo or 2 mg, 3 mg or 4 mg guanfacine extended release once daily. The study consisted of three periods: screening (maximum of 14 days), washout (about one week for discontinuation of current ADHD medication) and double-blind treatment (eight weeks). Titration was done in a forced-dose manner by increasing guanfacine extended release in 1 mg increments per week, from 1 mg per day during the first week to a maximum of 4 mg daily in weeks four and five according to randomization. The guanfacine extended release dose was then decreased at the same weekly rate starting in weeks six and seven.

Compared to placebo, children aged 6 to 17 years treated with guanfacine extended release showed significant improvements in the core symptoms of ADHD (hyperactivity, impulsivity and inattention), as reflected by total scores on the primary efficacy measurement, the ADHD Rating Scale (ADHD-RS-IV). The ADHD-RS-IV is a standard test for diagnosing ADHD in children and adolescents and for assessing their response to treatment. The scale, which contains 18 items, is based on the ADHD diagnosis criteria as defined in the DSM-IV TR, a publication of the American Psychiatric Association. A reduction in the ADHD-RS-IV score reflects improvement.

Overall, average reductions in ADHD-RS-IV total scores were 16.7 points for guanfacine extended release and 8.9 for placebo (P <.0001). Investigators observed improvement in ADHD-RS-IV scores as early as two weeks after dosing began, with significant improvement in all guanfacine extended release dose groups occurring at the third week and continuing through the last evaluation at week five. Also, an analysis by weight-adjusted actual dose (mg/kg) showed reductions in ADHD-RS-IV total scores from baseline of 34 percent to 65 percent for guanfacine extended release doses compared with 23 percent for placebo.

Significance was also seen in all secondary efficacy measures, which included scores on the Clinical Global Impression of Improvement (CGI-I), Clinical Global Impression of Severity (CGI-S), Conners' Parent Rating Scale- Revised: Short Form (CPRSR) and Conners' Teacher Rating Scale-Revised: Short Form (CTRS-R).

"As the first selective alpha-2A-adrenoceptor agonist being developed as an ADHD treatment, guanfacine extended release will be a welcomed addition to our armamentarium of ADHD medications. In this clinical trial, guanfacine extended release significantly improved ADHD symptoms based on several standard measures of response," noted Raun Melmed, MD, Medical Director of the Melmed Center in Scottsdale, AZ. "As a practicing physician I can say our community is always interested in expanding the range of ADHD treatment options which need to be used in the context of an overall treatment program, so patients can receive individualized and optimal care."

Guanfacine extended release was generally well-tolerated in this study. The most commonly reported treatment-emergent adverse events were somnolence, headache, fatigue, upper abdominal pain, and sedation. Incidence of sedative events (somnolence, sedation and fatigue) were usually mild or moderate in severity. Modest decreases in mean systolic and diastolic blood pressure and pulse were reported.

Guanfacine Extended Release Formulation

Guanfacine extended release, a novel formulation of guanfacine, was developed by incorporating ionic polymers, enteric polymers, and organic acids within the tablet matrix. This formulation was designed to control and prolong the release of guanfacine, in contrast to the immediate, burst-like release provided by the commercially available Immediate Release (IR) formulation of guanfacine, which is indicated as a treatment for hypertension.

About Guanfacine Extended Release

Shire is seeking approval of 1 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg and 4 mg once-daily guanfacine extended release doses for the control of ADHD symptoms throughout the day in children aged 6 to 17 years. The guanfacine extended release NDA includes data from two placebo-controlled trials in children and adolescents ages 6 to 17 evaluating the compound’s safety and efficacy in controlling ADHD symptoms evaluated on a once-weekly basis using the ADHD Rating Scale, which included both hyperactive/impulsive and inattentive subscales.

Guanfacine extended release is a once-daily formulation of the selective alpha-2A-adrenoceptor agonist. Unlike some other ADHD treatments, guanfacine extended release is not a central nervous system stimulant or a controlled substance.

Adrenergic receptors are present on almost all kinds of cells in the body and act as receptors for two neurotransmitters, epinephrine (adrenaline) and norepinephrine, used by nerve cells to communicate. An agonist is a molecule that acts similar to these neurotransmitters by also binding to receptors. It is hypothesized that guanfacine HCl binds to the alpha-2A-adrenergic cell receptor to act directly in the part of the brain called the prefrontal cortex, an area that is associated with working memory, behavioral inhibition, attention and cognitive control, as well as the ability to orchestrate thought and action.  Full press release about extended release guanfacine can be found here:

Extended-release guanfacine for children with ADHD

Editorial note:  Guanfacine, which used to be known by the now defunct brand name of Tenex, is well-known to child and adolescent psychiatrists as an effective “second-line,” non-stimulant medication for ADHD, but is lesser known to the general public.  Shire’s studies completed in hopes of FDA approval (a likely outcome) will provide better controlled clinical data in children than we have had on this ADHD medication before.  A word of caution, however, is needed.  An older study of guanfacine’s use for ADHD in children who had a parent with bipolar disorder showed a worrisome occurrence of manic-like symptoms in some of these children when placed on guanfacine.  It is likely that children at risk for bipolar disorder were not placed in Shire’s ADHD clinical trial; therefore, our knowledge regarding the use of guanfacine for ADHD where there is a family history of bipolar disorder is limited — Dr. Z.