Shire Reports Positive Results From Signal Finding Study of Investigative Use of Vyvanse(R) (lisdexamfetamine dimesylate) Capsules (CII) as Adjunctive Treatment in Predominant Negative Symptom Schizophrenia

PHILADELPHIA, April 28, 2011 /PRNewswire-FirstCall/ -- 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.

About This Study

In this study, 92 adult subjects (mean age = 42.3) first entered a prospective stability assessment period for 3 weeks, wherein symptoms and environmental settings were judged to be appropriately stable; no Vyvanse was prescribed during this period. Subsequently in the 7-week open-label dose optimization period, subjects with clinically stable schizophrenia and predominant negative symptoms had Vyvanse added to their established atypical antipsychotic regimen, titrating Vyvanse to an individually-defined dose (range 20 to 70 mg per day). Subjects remained on this Vyvanse dose during the following 3-week dose maintenance period. Subjects with reductions in negative symptoms (measured by the modified SANS-18 total score) were eligible for subsequent randomization into a double-blind withdrawal phase (4-weeks), either continuing augmentation with Vyvanse or being switched to placebo, to assess symptom re-emergence or withdrawal symptoms. All commonly prescribed atypical antipsychotics were permitted as primary therapy. Subjects with clinically notable depressive or extrapyramidal symptoms/movement disorders (both of which may mimic negative symptoms) were excluded.

The primary efficacy measure was the modified SANS-18 score, which is the sum of all non-global SANS item ratings of affective flattening, inappropriate affect, alogia, avolition-apathy, and anhedonia-asociality. Safety measures included assessments of movement disorders, suicidal thinking, sleep quality, and amphetamine withdrawal and positive symptoms were examined.

In addition to the open-label findings detailed above, findings from the double-blind withdrawal period (n=69) indicated no emerging amphetamine withdrawal symptoms and no significant changes in negative symptoms during a 4-week, abrupt discontinuation (placebo) compared with continuation of Vyvanse (Week 14, p=0.21). The safety profile present in this 4-week period was similar to that seen in the prior 10-week period, and was similar across placebo (n=35) and Vyvanse (n=34) groups.

* The modified SANS-18 score is the sum of all non-global SANS item ratings of affective flattening, inappropriate affect, alogia, avolition-apathy, and anhedonia-asociality.

INDICATION

Vyvanse is a prescription medicine for the treatment of ADHD in children ages 6 to 17 and adults. Vyvanse should be used as part of a total treatment program that may include counseling or other therapies.

IMPORTANT SAFETY INFORMATION

Vyvanse is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep in safe place to prevent misuse and abuse. Selling or giving away Vyvanse may harm others, and is illegal. Vyvanse is a stimulant. Misuse of stimulants may cause sudden death and serious heart problems.

- Vyvanse should not be taken by patients who have:

Heart disease or hardening of the arteries, moderate to severe high blood pressure, overactive thyroid gland (hyperthyroidism), glaucoma, agitated states, a history of drug abuse, taken an anti-depression medicine called a monoamine oxidase inhibitor (MAOI) within the last 14 days, or sensitivity to, are allergic to, or had a reaction to other stimulant medicines.

- Vyvanse is a stimulant medicine. The following have been reported with use of stimulant medicines.

    Heart-related problems:
    - sudden death in patients who have heart problems or heart defects
    - stroke and heart attack in adults
    - increased blood pressure and heart rate

Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems. Call your doctor right away if you or your child have any signs of heart problems such as chest pain, shortness of breath, or fainting while taking Vyvanse.

    Mental (Psychiatric) problems:
    All Patients
    - new or worse behavior and thought problems
    - new or worse bipolar illness
    - new or worse aggressive behavior or hostility
    Children and Teenagers

- new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms

Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking Vyvanse, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious.

- Serious side effects have been reported with use of stimulant medicines such as Vyvanse, including:

- seizures, mainly in patients with a history of seizures

- eyesight changes or blurred vision

- motion and verbal tics. Patients with tics or Tourette's syndrome may experience a worsening of symptoms while taking Vyvanse.

- slowing of growth. Your child should have his or her height and weight checked often while taking Vyvanse. The doctor may stop treatment if a problem is found during these check-ups.

    - The most common side effects reported in studies of Vyvanse were:

    - upper belly pain - nausea             - dry mouth
    - dizziness        - weight loss        - trouble sleeping
    - irritability     - decreased appetite - vomiting

This is not a complete summary of safety information. For additional safety information, please click here for Full Prescribing Information (http://pi.shirecontent.com/PI/PDFs/Vyvanse_USA_ENG.pdf) and Medication Guide (http://medguide.shirecontent.com/MEDGUIDE/PDFs/MG_Vyvanse_USA_ENG.pdf), including Warning about Potential for Abuse, and discuss with your doctor.

Predominant Negative Symptoms of Schizophrenia

Despite five decades of pharmacological progress in the treatment of schizophrenia, effective treatment for predominant negative symptoms remains a substantial unmet medical need (Alphs 2006).

The negative symptom constellation in schizophrenia includes the following abnormalities (Andreasen 1993; Toomey et al 1998; Granholm et al 2007):

- Alogia ~ impoverished thinking and cognition, reflected in patients' reduced communication and emotional perception/expression abilities;

- Affect ~ flattening of the range and intensity of emotional expression, reflected in patients' reduced ability to perceive and use facial expressions, voice tone, eye contact, and appropriate body language to interact with others;

- Anhedonia and Asociality ~ difficulties experiencing pleasure, reflected in patients' loss of interest in pleasurable activities including a lack of involvement in social relationships and an inability to feel intimacy and closeness;

- Avolition and Apathy ~ lack of energy, drive and interest, reflected in patients' inability to mobilize themselves to initiate or persist in activities including basic grooming-hygiene, and work or school efforts.

Conventional antipsychotics have little effect on negative symptoms, while newer atypical antipsychotics have produced only limited reduction in negative symptoms. In 2002, the overall cost of schizophrenia in the US was estimated to be $62.7 billion, with $22.7 billion in direct costs and $32.4 billion in indirect costs (primarily from decreased productivity and unemployment) (Wu et al 2005). Health authorities recognize that negative symptoms of schizophrenia is a valid target for pharmacologic intervention and there are currently no approved medications for this indication in the United States.

References

1. Milev P et al. Predictive Values of Neurocognition and Negative Symptoms on Functional Outcome in Schizophrenia: A Longitudinal First-Episode Study With 7-Year Follow-Up. Am J Psychiatry (2005); 162: 495-506.

2. Wu E et al. The Economic Burden of Schizophrenia in the United States in 2002. J Clin Psychiatry (2005); 66(9): 1122-9.

3. Velligan D and Alphs L. Negative Symptoms in Schizophrenia: The Importance of Identification and Treatment. Psychiatric Times (2008); 25 (3).

4. Andreasen NC. Negative Symptoms in Schizophrenia: Definition and Reliability. Arch Gen Psychiatry (1982); 39(7): 784-8.

5. Granholm E et al. Effortful Cognitive Resource Allocation and Negative Symptom Severity in Chronic Schizophrenia. Schizophr Bull (2007); 33 (3): 831-42.

6. Toomey R et al. Negative, Positive, and Disorganized Symptom Dimensions in Schizophrenia, Major Depression, and Bipolar Disorder. J Nerv Ment Dis (1998); 186 (8): 470-6.

SHIRE PLC

Shire's strategic goal is to become the leading specialty biopharmaceutical company that focuses on meeting the needs of the specialist physician. Shire focuses its business on attention deficit hyperactivity disorder (ADHD), human genetic therapies (HGT) and gastrointestinal (GI) diseases as well as opportunities in other therapeutic areas to the extent they arise through acquisitions. Shire's in-licensing, merger and acquisition efforts are focused on products in specialist markets with strong intellectual property protection and global rights. Shire believes that a carefully selected and balanced portfolio of products with strategically aligned and relatively small-scale sales forces will deliver strong results.

For further information on Shire, please visit the Company's website: http://www.shire.com.

"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, the Company's results could be materially adversely affected. The risks and uncertainties include, but are not limited to, risks associated with: the inherent uncertainty of research, development, approval, reimbursement, manufacturing and commercialization of the Company's Specialty Pharmaceutical and Human Genetic Therapies products, as well as the ability to secure and integrate new products for commercialization and/or development; government regulation of the Company's products; the Company's ability to manufacture its products in sufficient quantities to meet demand; the impact of competitive therapies on the Company's products; the Company's ability to register, maintain and enforce patents and other intellectual property rights relating to its products; the Company's ability to obtain and maintain government and other third-party reimbursement for its products; and other risks and uncertainties detailed from time to time in the Company's filings with the Securities and Exchange Commission.

    For further information please contact:

    Investor Relations

    Eric Rojas ([email protected])
    +1-781-482-0999

    Sarah Elton-Farr ([email protected])
    +44-1256-894157


    Media

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    +44-1256-894-280

    Matthew Cabrey ([email protected])
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SOURCE Shire plc

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