Shire Reports Positive Phase II Results for Investigative Use of Vyvanse® (lisdexamfetamine dimesylate) Capsules, (CII)

PHILADELPHIA, December 8, 2011 /PRNewswire/ --

Shire plc (LSE: SHP, NASDAQ: SHPGY), the global specialty biopharmaceutical company, today announced positive Phase II results in a prospective clinical study of Vyvanse® (lisdexamfetamine dimesylate) Capsules, (CII) as adjunctive therapy to primary antidepressant treatment in adults with partial or full remission of recurrent major depressive disorder (MDD) and significant, persistent cognitive impairments.  Lisdexamfetamine dimesylate 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.  

Vyvanse is a stimulant medication and federally controlled substance (CII) because it can be abused or lead to dependence.  Misuse of stimulants may cause sudden death and serious cardiovascular adverse events.

Shire is investigating the use of Vyvanse as adjunctive therapy for patients with MDD.  Some patients with MDD may continue to have cognitive impairment despite resolution of depressive symptoms following antidepressant therapy, although the time course and prevalence of cognitive symptoms in patients with MDD has not been fully characterized.  This study, which examined MDD patients with partially or fully remitted symptoms of depression, met its primary end point, which was, change from baseline to end point in the Global Executive Composite (GEC) T-score of the Behavioral Rating Inventory of Executive Function - Adult Version (BRIEF-A) self-report. The BRIEF-A (self-report) is a 75-item instrument that assesses behaviors associated with specific domains of executive functions in adults. This scale is used in a variety of conditions in addition to depression.

This exploratory, double-blind, placebo-controlled, parallel-group, multi-center study consisted of a two-week screening period, a nine-week double-blind period and a two-week single-blind period. During the entire study, subjects continued taking established maintenance doses of antidepressant monotherapy. Subjects in this study had mild or less than mild depressive symptoms (total score of ≤ 18 on the Montgomery-Åsberg Depression Rating Scale [MADRS] at screening and baseline). The screening was followed by 1:1 randomization to Vyvanse (n = 71) or placebo (n = 72) augmentation for 9 weeks.  Double-blind Vyvanse (or placebo) was administered orally as adjunctive therapy (20 to 70 mg per day, titrated over the initial 6 weeks), with the optimal individual dose being continued during a 3-week dose maintenance period. A 2-week single-blind phase followed the double-blind phase wherein all subjects were administered placebo.

On the primary efficacy measure, GEC T-score of the BRIEF-A self-report, Vyvanse was superior to placebo. "These data are intriguing in that they remind us of the impairment in executive functioning that patients may continue to manifest with mild depressive symptoms," stated Dr. Jeffrey Jonas, Senior Vice President of Research and Development for Shire's Specialty Pharmaceuticals business.  "We will explore with regulatory agencies how these new findings might support our development program for Vyvanse as an adjunctive therapy in patients with MDD."

On a secondary end point, mean change in MADRS total score from baseline to end point, Vyvanse was superior to placebo. The MADRS is a validated scale which is commonly used by investigators to assess the severity of depressive illness. "The results of this secondary end point (MADRS) reinforce Shire's decision to investigate Vyvanse as adjunctive therapy in MDD. This trial reflects Shire's approach to patient-centric targeting to potentially optimize outcomes in otherwise heterogeneous disorders," added Dr. Jonas.

Over all periods of the study, 24 subjects (out of 143) discontinued (11 on Vyvanse and 13 on placebo) treatment. During the double-blind phase, 5 subjects withdrew due to an adverse event (4 on Vyvanse and 1 on placebo).  The 4 events which led to discontinuation from Vyvanse were loss of consciousness, suicidal ideation, rash, and worsening of depression.  In the placebo group, 1 subject discontinued due to headaches.  During the double-blind phase, 5 serious adverse events (SAEs) were reported: 2 on Vyvanse (aforementioned loss of consciousness [related], suicidal ideation [not related]), and 3 on placebo (viral gastroenteritis, rhabdomyolysis, and salmonellosis). Treatment-emergent adverse events (TEAEs) (≥ 5% and at least two times placebo rate) occurring in the Vyvanse treatment arm were decreased appetite (22.5%), insomnia (14.1%), urinary tract infection (9.9%), hyperhidrosis (5.6%), and somnolence (5.6%). 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.

About This Study

A total of 143 subjects (aged 18 to 55) entered the study with at least 8 weeks of maintenance on their antidepressant monotherapy. Permitted antidepressants included the generic or branded forms of selective serotonin reuptake inhibitors (SSRIs).  The subjects had no greater than mild depressive symptoms (MADRS total score ≤ 18) and continued to exhibit significant executive function impairments (EFI; ≥1 standard deviation from normal; GEC T-score of ≥60 on the BRIEF-A self-report) during the screening period and at baseline. The subsequent 9-week double-blind phase consisted of a 6-week dose-optimization period titrating Vyvanse from the initial 20-mg dose to an optimal dose of up to 70 mg of Vyvanse or matching placebo, and followed by a 3-week dose maintenance period to evaluate clinical response.  Subjects who completed the double-blind phase of the study entered a single-blind phase with placebo over a 2-week period to evaluate the maintenance of treatment response and safety of the withdrawal of amphetamine.  Subjects with either a prior diagnosis of ADHD or who fulfilled DSM-IV-TR^® criteria for ADHD were excluded.  Subjects who had symptomatic manifestations that contraindicated treatment with Vyvanse or may have confounded efficacy or safety assessments were also excluded.  In addition, subjects treated with medications such as serotonin-norepinephrine reuptake inhibitors (SNRIs), typical or atypical antipsychotics, mood stabilizers, tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) were excluded from the study.

The primary efficacy was the mean change in GEC T-scores of the BRIEF-A (self-report) from baseline to the end of the 9-week double-blind phase.  Additionally, the study included a number of secondary end points. Safety assessments included TEAEs, vital signs, 12-lead ECG, clinical laboratory assessments, and Suicidality Tracking Scale (STS).  

About Vyvanse^®

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 a 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 the use of Vyvanse in the treatment of ADHD. 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.

About Major Depressive Disorder (MDD) and Inadequate Response in MDD

Major Depressive Disorder (MDD), also known as major depression, is a mental disorder that causes depressed mood, loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, low energy, and poor concentration.  MDD affects approximately fourteen million patients in the United States alone, and costs for treating this condition exceeded $83.1 billion in 2000.  It is estimated that MDD will become the second leading cause of morbidity worldwide across all ages by 2020.

While an extensive number of antidepressants have been approved for monotherapy in MDD, many patients remain symptomatic by incomplete resolution of MDD symptoms despite treatment with antidepressant monotherapy at appropriate doses and trial duration.  These patients with an inadequate therapeutic response represent up to two-thirds of patients treated with antidepressant monotherapy.  Commonly, these inadequate responders remain symptomatic with respect to mood, concentration, motivation, and interest, often reflected by impairment in multiple domains (eg, work/school, social life, and home/family life).  Major health authorities recognize inadequate response in MDD as a valid target for pharmacologic intervention, with two medications being currently approved in the US and/or the EU.

Notes to editors

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, human genetic therapies, gastrointestinal diseases and regenerative medicine 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 Pharmaceuticals, Human Genetic Therapies and Regenerative Medicine products, as well as the ability to secure 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.

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