Shire plc announced today the positive results of studies of the investigational medication guanfacine extended release (GXR, previously referred to as SPD503), a selective alpha-2A-adrenoceptor agonist. These data from two short-term phase III placebo-controlled studies and two long-term phase III open-label studies, presented at the 2007 American Psychiatric Association (APA) annual meeting, demonstrated that GXR significantly improved all core symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD) in children aged 6 to 17 years.

"Guanfacine extended release, the first selective alpha-2A-adrenoceptor agonist to be tested in well-controlled studies as a treatment for ADHD, holds potential based on the significant improvements in ADHD symptoms documented in four studies of this investigational drug," stated co-author Joseph Biederman, M.D., lead investigator, chief of clinical and research program in pediatric psychopharmacology at Massachusetts General Hospital and professor of psychiatry at Harvard Medical School. "Moreover, these data presented at this medical conference add evidence that GXR when dosed once daily may continue to control children's ADHD symptoms for up to 24 months."

GXR, a nonstimulant, is not a controlled substance and does not appear to have a mechanism for potential abuse or dependence. Shire submitted a New Drug Application (NDA) for GXR on August 24, 2006, which is currently under FDA review. The NDA provided data on GXR 1 mg to 4 mg taken once daily for the treatment of children and adolescents with ADHD.

GXR Yielded Significant Reductions in ADHD-RS-IV Scores in Two Short-Term Trials

Results from two short-term, double-blind, randomized phase III clinical trials presented at this medical conference, demonstrated that GXR significantly controlled all core symptoms of ADHD, including inattention, hyperactivity and impulsivity in children aged 6 to 17 years previously diagnosed with ADHD, as measured by several standardized tests when compared to placebo treatment.

In the two short-term trials, the primary endpoint was a reduction in ADHD symptoms as measured by the ADHD Rating Scale (ADHD-RS-IV). ADHD-RS-IV is a standardized, validated test for assessing symptoms of ADHD in children and for assessing their response to treatment. This scale, which contains 18 items, is based on the ADHD diagnostic criteria as defined in the APA's Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision®.

In the first trial, 301, investigators compared 2 mg, 3 mg or 4 mg GXR doses to placebo during an eight-week treatment period. The participants randomized to GXR all began at the 1 mg dose. At weekly visits, doses were titrated in 1 mg increments over the first four weeks to achieve the randomized dose. Then, doses were tapered down weekly so that all participants randomized to GXR received the 1 mg dose at week eight.

Participants achieved overall significant mean reductions from baseline in ADHD-RS-IV total scores by study end, -16.7 points vs. -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 GXR dose groups occurring at the third week.

Effect sizes, caculated using results from the ADHD-RS-IV scores and evaluated using weight-adjusted actual doses, were 0.44 (0.01 to 0.04 mg/kg), 0.58 (0.05 to 0.08 mg/kg), 1.19 (0.09 to 0.12 mg/kg), and 1.34 (0.13 to 0.17 mg/kg). In general, effect sizes are categorized as small (0.2), medium (0.5) and large (0.8).

In the second short-term trial, 304, investigators examined 1 mg, 2 mg, 3 mg and 4 mg doses and placebo during nine weeks of treatment. During the first three weeks, patients started at 1 mg with doses escalating in once-weekly 1 mg increments to achieve their randomized dose at week three. Then, participants maintained their assigned dose for three weeks, followed by three weeks of decreased dosing, so that all participants were taking 1 mg doses during week nine. Participants achieved overall significant mean reductions in ADHD-RS-IV total scores by study end, -19.6 points vs. -12.2 for placebo (P <.0001).

Safety data collected in trials 301 and 304 shows that participants using GXR had adverse events which were generally mild to moderate in severity, with most common side effects being sedative in nature. In trial 301, sedation-related treatment-emergent adverse events were among the most common but were usually transient and mild or moderate in severity. Treatment related adverse events greater than 10 percent included somnolence (32 percent), fatigue (18 percent), upper abdominal pain (14 percent) and sedation (13 percent). Mean decreases observed in heart rate, and systolic and diastolic blood pressure were modest. In trial 304, common treatment related adverse events greater than 5 percent included somnolence (27 percent), fatigue (9.4 percent) and nausea (5.1 percent). Small to modest changes in blood pressure, pulse rate, and ECG were observed with GXR but were not clinically meaningful.

Long-Term ADHD Symptom Improvement with GXR

Trial 303 was a long-term, open-label, safety follow-up study of 240 participants enrolled in trial 301. The objective was to assess the long-term safety of GXR 2 mg, 3 mg, and 4 mg doses in the treatment of ADHD for up to two years. In this study, investigators documented the ability of GXR to maintain clinically meaningful efficacy of ADHD symptoms for up to 24 months of treatment. Patients were optimized to a dose ranging between 2 mg to 4 mg. Doses could be adjusted by 1 mg per monthly visit.

In this trial, the most common treatment-emergent adverse events were somnolence (30.4 percent), headache (26.3 percent), fatigue (14.2 percent) and sedation (13.3 percent). However, somnolence, sedation and fatigue typically occurred early in the study and most resolved as treatment continued. The incidence of syncopal events was less than 1 percent. In some of the patients who did experience syncope, potential contributing factors were noted (such as dehydration, sudden change in body position, and hot environment). While small changes in average blood pressure and pulse rate occurred, cardiovascular events were uncommon.

For all doses, the mean ADHD-RS-IV total scores and subscale scores showed significant improvement from baseline to endpoint: -18.1 points on the ADHD-RS-IV total; -8.5 points on the ADHD-RS-IV hyperactive/impulsive subscale and -9.5 points on the ADHD-RS-IV inattentive subscale (P <.001).

Similar to the 303 study, the objective of the 305 open-label trial was to assess the long-term safety and efficacy of GXR for the treatment of ADHD in children and adolescents aged 6 to 17 years. During the first month of this study, investigators made weekly adjustments as needed to each participants' once-daily GXR doses from 1 mg to 4 mg for optimal dosing, as defined by 30 percent or more improvement in ADHD-RS-IV total scores.

In this trial, the most commonly reported treatment emergent adverse events greater than 10 percent were somnolence (29.9 percent), headache (19.7 percent), upper respiratory tract infection (15.1 percent), fatigue (12.4 percent) and sedation (11.2 percent). The incidence of syncopal events was less than 2 percent. As in the 303 open-label study, potential contributing factors were noted in some of the patients who did experience syncope. No clinically relevant trends in ECGs, hematologic or laboratory parameters, vital signs, urinalyses, or physical examination were seen.

Interim results from trial 305 showed that for all doses, the mean ADHD-RS-IV total scores showed significant improvement of -21.6 points from baseline to endpoint (P <.001).

About Guanfacine Extended Release

Shire is seeking approval of GXR as monotherapy for the treatment of ADHD symptoms throughout the day in children aged 6 to 17 years, with dosage strengths of 1mg - 4 mg daily. The GXR 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 a selective alpha-2A-adrenoceptor agonist. Unlike some other ADHD treatments, guanfacine extended release is not a central nervous system stimulant or a controlled substance and does not appear to have a mechanism for potential abuse or dependence.

It has been shown that guanfacine HCI binds selectively to the alpha 2A adrenergic cell receptors that are found throughout the part of the brain called the prefrontal cortex. The prefrontal cortex is an area of the brain associated with executive functioning, i.e., working memory, behavioral inhibition, regulation of attention, distractibility, impulsivity, and frustration tolerance.

Approximately 7.8 percent of all school-age children, or about 4.4 million U.S. children aged 4 to 17 years, have been diagnosed with ADHD at some point in their lives, according to the CDC. ADHD is one of the most common psychiatric disorders in children and adolescents. The disorder is also estimated to affect approximately 9.8 million adults across the U.S. based on a retrospective survey of adults aged 18 to 34, projected to the full U.S. adult population. ADHD is a neurological brain disorder that manifests as a persistent pattern of inattention and/or hyperactivity-impulsivity that is more frequent and severe than is typically observed in individuals at a comparable level of development. To be properly diagnosed with ADHD, a child needs to demonstrate at least six of nine symptoms of inattention; and/or at least six of nine symptoms of hyperactivity/impulsivity; the onset of which appears before age 7 years; that some impairment from the symptoms is present in two or more settings (e.g., at school and home); that the symptoms continue for at least six months; and that there is clinically significant impairment in social, academic or occupational functioning and the symptoms cannot be better explained by another psychiatric disorder.

Although there is no "cure" for ADHD, there are accepted treatments that specifically target its symptoms. The most common standard treatments include educational approaches, psychological or behavioral modification, and medication.

Source: Porter Novelli