Shire plc (LSE: SHP, NASDAQ: SHPGY), the global specialty biopharmaceutical company, today announced positive results from a signal-finding study of Vyvanse(R) (lisdexamfetamine dimesylate) Capsules (CII) assessing its effect in a prospective examination of adults with negative symptom predominant schizophrenia. This study met its pre-defined primary end points. Vyvanse is a prescription medicine currently approved in the US, Canada, and Brazil for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). Vyvanse should only be used to treat ADHD.
This investigational, phase 2, 14-week, flexible dose, multi-center study consisted of a 10 week open-label (n = 92) and a 4 week double-blind component (n = 69). Vyvanse was administered orally as adjunctive therapy (20 to 70 mg per day, titrated over 7 weeks) to 92 clinically stable patients with predominant negative symptom schizophrenia (ages of 18 to 55), taking established maintenance doses of atypical antipsychotic medications. In the open-label, primary efficacy analysis, Vyvanse demonstrated significant improvement (p<0.0001) in negative symptoms after 10 weeks, compared to baseline, as measured by blinded-raters using the Scale for the Assessment of Negative Symptoms modified total score or SANS-18* [LOCF; mean change of -12.9 plus or minus 10.0 (95% CI -15.0 to -10.8)].
In order to assess the potential impact on positive symptom exacerbation, the Positive and Negative Syndrome Scale (PANSS) was administered as a secondary end point. This assessment documented the lack of positive symptom exacerbation, as Vyvanse demonstrated significant improvement from baseline to 10-week end point on both positive and overall psychiatric symptoms as measured by the PANSS positive subscale (LOCF; mean change -1.0 plus or minus 2.2; 95% CI -1.4 to -0.5; p<0.0001) and PANSS Total score (LOCF; mean change -9.8 plus or minus 9.0; 95% CI -11.7 to -8.0; p<0.0001). The PANSS is a commonly used measurement scale for the assessment of schizophrenia symptoms worldwide.
In the 10-week open-label phase, 23 subjects (out of 92) discontinued from the study. Five subjects discontinued due to an adverse event. Of these 5 subjects, 3 subjects discontinued due to serious adverse events. Two of the serious adverse event reports were of exacerbation of schizophrenia. The other 3 subjects discontinued due to involuntary jaw movements, elevated blood pressure or sleepiness.
Forced discontinuation criteria were also used to further ensure patient safety. These criteria included changes in positive symptoms, compliance, urine drug screen, caregiver relationship, and thoughts of self-harm or harm to others. By these criteria, 5 additional subjects were discontinued in the open-label phase (2 subjects with positive symptom change, 1 subject with non-compliance, 1 subject with self-harm thoughts, and 1 subject who terminated their caregiver relationship). The remaining subjects (n = 13) withdrew for various other reasons including: protocol violation, withdrawal by subject, or failure to meet randomization requirement.
In the double-blind phase, 13 subjects (out of 69) discontinued from the study. Two subjects withdrew due to a serious adverse event, reported as the exacerbation of schizophrenia (1 subject taking placebo and 1 subject taking Vyvanse). A third subject (taking placebo) experienced a serious adverse event of dyspepsia and was discontinued due to failure to take investigational product. Additionally, 2 subjects were discontinued because they met forced discontinuation criteria due to positive urine drug screens (1 taking placebo, 1 taking Vyvanse).
The adverse events (greater than or equal to 5%) reported in this study included headache (14.1%), insomnia and decreased appetite (10.9% each), dizziness (8.7%), dry mouth (6.5%) and diarrhea (5.4%). Mean changes in blood pressure and pulse were all consistent with the current product labeling in ADHD. There were no notable effects on ECG or clinical laboratory assessments.
"If these results are confirmed in controlled clinical trials, they would represent a significant step forward to address the unmet need of treating the negative symptoms of schizophrenia, including a fundamental re-examination of dopaminergic and noradrenergic transmission across brain regions in treating the negative symptoms of schizophrenia," commented Dr. Henry Nasrallah, Professor of Psychiatry and Neuroscience and Director of the Schizophrenia Research Program at the University of Cincinnati College of Medicine.
"These findings suggest that the benefit-risk profile of Vyvanse in this population may be different from current thinking and require further study," added Dr. Jeffrey Jonas, Senior Vice President of Research and Development for Shire's Specialty Pharmaceuticals business. "Shire is well-positioned to provide scientific leadership to review and develop pathways for this understanding with global clinical communities and regulatory authorities."
Schizophrenia is estimated to cost $62.7 billion annually in the US alone. For over 50 years, amphetamine use in schizophrenia has been characterized by its risk for exacerbation of 'positive' symptoms such as delusions and hallucinations. This risk of positive symptom exacerbation effectively eliminated the exploration of the potential benefit of amphetamine for 'negative' symptoms, such alogia, anhedonia, avolition, asociality, and apathy. Patients with 'predominant negative symptom schizophrenia' present clinically with mild positive symptoms and moderate to severe negative symptoms. Atypical antipsychotic agents have minimal effects on negative symptoms. As the negative symptoms of schizophrenia are associated with poor social and occupational function, the lack of available treatment makes negative symptoms a substantial unmet medical need (Milev 2005; Wu et al 2005).
Vyvanse is a stimulant medication and federally controlled substance (CII) because it can be abused or lead to dependence. Keep Vyvanse in a safe place to prevent misuse and abuse. Selling or giving away Vyvanse may harm others, and is against the law. Misuse of stimulants may cause sudden death and serious cardiovascular adverse events.
Vyvanse is a prescription medicine currently approved for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). Efficacy for Vyvanse in ADHD was based on two controlled trials in children aged 6 to 12, one controlled trial in adolescents aged 13 to 17, and two controlled trials in adults. Vyvanse should be used as part of a total treatment program that may include counseling or other therapies.