Shire Turns Attention To Vyvanse Two Years Before Adderall XL Generics

Shire will seek to transition patients from Adderall XR to its next-generation attention deficit/hyperactivity disorder drug Vyvanse prior to 2009, when Adderall XR generics are expected to launch.

U.K.-based Shire received approval from FDA Feb. 23 for use of Vyvanse (lisdexamfetamine) in treatment of ADHD in children ages six to 12.

Shire is anticipating the loss of exclusivity for Adderall XR (amphetamine extended-release) in April 2009 following a patent litigation settlement with Barr in August.

The transition will likely be a smooth one, Shire said, citing its experience moving patients from Adderall immediate-release to the extended-release version when the latter drug was approved in 2001 (¹ , p. 7).

The company said it will augment its 470-rep ADHD sales force to promote Vyvanse, and is considering introducing a direct-to-consumer advertising campaign.

Shire will hold off on launching Vyvanse until the second quarter while it ramps up manufacturing capacity and awaits final scheduling approval from the Drug Enforcement Administration, the firm said.

DEA has published a proposed rule to classify Vyvanse as a Schedule II controlled substance, which would place it in the same class as Adderall XR, Johnson & Johnson's Concerta and Novartis' Ritalin . Because the public comment period for the proposed rule ends March 26, Vyvanse will not launch until after that date.

Shire has attempted to differentiate Vyvanse from other ADHD products on the market by emphasizing the drug's decreased likelihood of abuse. The firm has previously maintained that Vyvanse could receive more favorable scheduling than Adderall XR due to its possible lower abuse potential.

Explaining the lower potential for abuse, Shire noted that lisdexamfetamine's d-amphetamine "is covalently linked to l-lysine, a naturally occurring amino acid. The combination is rapidly absorbed from the gastrointestinal tract and converted to d-amphetamine, which is responsible for Vyvanse's activity."

The drug will be available in three, once-daily dosage strengths: 30 mg, 50 mg and 70 mg.

Vyvanse was evaluated in all three doses in children ages six to 12 in a 290-patient, Phase III, randomized, double-blind, placebo-controlled study.

After four weeks of once-daily treatment, "significant improvements in patient behavior" were observed based on the ADHD Rating Scale (ADHD-RS-IV) compared with placebo, according to the ² labeling.

"Mean effects at all doses were fairly similar, although the highest dose (70 mg/day) was numerically superior to both lower doses."

The effects were maintained from the morning, approximately 10 a.m., until early evening, approximately 6 p.m., based on the Connor's Parent Rating scale.

Shire also conducted a double-blind, placebo-controlled, randomized, cross-over design analog classroom study in 52 children ages six to 12.

After a three-week open-label dose titration with Adderall XR, patients were randomly assigned to receive Adderall XR (10 mg, 20 mg or 30 mg), Vyvanse (30 mg, 50 mg or 70 mg) or placebo once-daily for one week.

"A significant difference in patient behavior, based upon the average of investigator ratings on the Swanson, Kotkin, Agler, M.Flynn and Pelham(SKAMP)-Deportment scores across the eight sessions of a 12-hour treatment day, was observed between patients who received Vyvanse compared to patients who received placebo," labeling states. The effect was similar for all eight sessions.

Adverse events occurring in at least 5 percent of patients in the four-week study included upper abdominal pain, decreased appetite, dizziness, dry mouth, irritability, insomnia, nausea, vomiting and decreased weight.

Vyvanse is the first product to be approved following FDA's Feb. 21 announcement that manufacturers of 15 ADHD drugs would need to include patient medication guides to warn of possible cardiovascular and psychiatric risks.

The agency also requires that those risks be included in the "Warnings" section in labeling of ADHD drugs (³ (Also see "ADHD Class Warnings Could Be Strengthened Pending FDA Research" - Pink Sheet, 28 Aug, 2006.), p. 11).

The Vyvanse medication guide cautions that heart-related problems have been reported with stimulant medications like lisdexamfetamine including sudden death in patients with cardiovascular problems or defects, stroke and heart attacks in adults and increased blood pressure and heart rate.

In line with FDA's recommendations, the medication guide also notes that psychiatric problems have been reported with stimulant medicines, such as "new or worse behavior and thought problems, new or worse bipolar illness, and new or worse aggressive behavior or hostility" in all patients, as well as new psychotic or manic symptoms in children and teenagers.

The label for Vyvanse also includes a boxed warning on amphetamines' potential for abuse and risk of cardiovascular events or sudden death.

Unlike a number of recently approved products, Shire chose the older labeling format for Vyvanse, rather than the format outlined in FDA's 2006 physician labeling rule.

Shire has previously said it would seek to add an indication in adults to the Vyvanse label, but that data on that population would not be available until 2008.

Shire has several other ADHD drugs awaiting approval from FDA. The company submitted an NDA in August for SPD503 (guanfacine) with the proposed trade name Connexyn .

In July, the firm submitted SPD465, which is designed to provide sustained release of medication for 16 hours. SPD465 has a May 21, 2007 standard review user fee date for treatment of adult ADHD; the agent has the same active ingredient as the Adderall franchise.

Other products in Shire's ADHD franchise include Daytrana (methylphenidate transdermal system).

The firm is set to acquire full rights to Vyvanse through its proposed acquisition of New River Pharmaceuticals. In February, Shire announced plans to acquire the Philadelphia-based firm in a $2.6 billion all cash transaction.

The approval follows two "approvable" letters for Vyvanse (NDA 021977), issued in October and December.

- Brooke McManus ([email protected])