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

By Shire Plc, PRNE
Wednesday, April 27, 2011

PHILADELPHIA, April 28, 2011 - 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

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

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

"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

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.


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.


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

- 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

- 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
( and Medication Guide
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

- 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

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


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:

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

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'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


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
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reimbursement for its products; and other risks and uncertainties detailed
from time to time in the Company's filings with the Securities and Exchange

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