Much attention around Shire PLC, the fast-growing specialist pharmaceutical company, focuses these days on its rare diseases and newly formed regenerative medicines business, but 61% of its revenues are generated by its core traditional specialty pharma subsidiary. The company’s portfolio mix is striking, because though Shire top executives talk of their customer-centric niche markets, the specialist R&D pipeline looks a lot like primary care territory.

Shire, however, says it’s staying true to its roots by focusing on tough-to-treat sub-segments of some common diseases, such as major depressive disorder, and persistent heartburn.

Shire’s historical specialty pharma unit, built on the company’s attention deficit hyperactivity disorder franchise, includes Vyvanse (lisdexamfetamine) and Intuniv (guanfacine), as well as gastrointestinal therapies like Lialda (mesalamine) and the constipation drug Resolor (prucalopride). Shire picked up the latter through its 2010 acquisition of Movetis Also see "Shire Offers €428 Million for Movetis To Expand Its GI Drug Portfolio" - Pink Sheet, 3 August, 2010..

The company’s two other units are attracting a lot of attention nowadays. Human Genetic Therapies, born of the $1.6 billion cash acquisition of Transkaryotic Therapies in 2005, is the home of therapies for tough-to-treat, rare genetic diseases using intrathecal delivery of enzymes Also see "Shire/TKT: The Price of Diversification" - In Vivo, 1 May, 2005..Shire will be analyzing and reporting results for Phase I/II programs in two lead programs targeting Hunter syndrome and Sanfilippo syndrome later this year and results will inform the design of pivotal studies,

Shire’s new third division centers around regenerative medicine assets gained in its May 2011 $750 million acquisition of Advanced BioHealing that brought over Dermagraft, a skin substitute made of living cells that is used to treat diabetic foot ulcers Also see "Advanced BioHealing To Bring Regeneration To Shire" - Pink Sheet, 23 May, 2011.. There’s legroom left in that product, despite its already strong growth – the product generated sales of $105 million for Shire from the time of acquisition in June 2011 until the end of the year. Commercial activities have centered primarily around hospitals, but Dermagraft could be targeted at dialysis centers, where people with end-stage renal disease are treated and wound management is secondary and somewhat neglected, said CEO Angus Russell in a recent interview. End-stage renal disease patients often develop secondary diabetes and foot ulcers, which can then lead to foot amputation and reduced life expectancy.

Shire also sees a lot of room to develop popular products in its core specialty pharma unit. In 2011, total company revenue rose by $792 million, or 23% to $4.2 billion ([A#14120209002]). Sales of three specialist drugs - Vyvanse, Lialda and Intuniv – contributed almost $39% or $307 million, of 2011 revenue growth.

The company is aiming to expand Vyvanse’s international reach in ADHD with approval in Europe; an application in the region is pending review, and a decision expected by the end of 2012 Also see "Shire Looks To Europe to Expand ADHD Franchise, But U.S.-Style Success Will Be Tough" - Pink Sheet, 25 April, 2011.. It also signed a deal with Shionogi & Co. Ltd. in November to co-develop and co-promote Vyvanse and Intuniv in the fledgling Japanese ADHD market ([A#14111122005]). Those are wide open markets, where ADHD is under-diagnosed, and, many argue, under-treated.

Depending on the outcomes of ongoing trials, Vyvanse could also find a home in one or more of four new indications: major depressive disorder (MDD); excessive daytime sleepiness (EDS); negative symptom schizophrenia (NSS); and binge eating disorder (BED). Of the new indications for Vyvanse, the most advanced is major depressive disorder, with a Phase III trial enrolling in 2012.

Specialist Face Of Primary Care

These are potentially big patient populations, traditionally the province of general practitioners, but Russell, who has emphatically steered Shire into a specialist focus, takes issue with those who suggest that the pipeline is treading into primary care territory Also see "As Pharma Falters, Shire Specialist Model Hits Sweet Spot" - Pink Sheet, 2 August, 2011.. Though selective serotonin reuptake inhibitors are widely available, for example, up to two-thirds of patients with depression do not get adequate symptom relief and are candidates for add-on therapies. Those patients typically are treated by specialists.

Pleasing payers? Full registration program for Vyvanse in major depressive disorder will include a number of scales to help assess improvement in disability.

“What happens when the physician has used all the SSRIs and the primary care physician has nothing else? Refers you back to the specialist. You’re going back to the psychiatrist. That’s who we talk to,” Russell said.

Shire’s specialist sales strategy has been influenced by its experience with rare diseases, where close relations with physicians, patients, and advocacy groups, as well as well-honed support services, play prominent roles in commercialization. The company advocates a “holistic approach” to diseases, even widespread ones, such as ADHD, where, among other activities, it is now sponsoring research into the balance between therapies, diet, exercise, and different patients, says Russell. In specialty pharma, although it has not abandoned the traditional detail model, the company has shifted some resources from sales to more scientifically grounded medical science liaisons. It now has a higher MSL to sales ratio than ever before, with MSLs communicating broad information about disease management, not just about particular Shire drugs.

This approach will be put to the test, as the company appears to become increasingly confident in results of its life cycle management programs for Vyvanse and its other drugs Also see "Shire CEO Angus Russell On The Value Proposition For Drugs" - Pink Sheet, 18 April, 2011.. A few years ago, the company explored areas where a dopamine modulator such as Vyvanse might have benefit and came up with four possibilities: EDS, MDD, BED and NSS. Execs felt they would be lucky if one of these four programs would bear fruit, but the drug has achieved positive Phase Il results in three out of four – MDD, EDS and schizophrenia– with Phase II results in the fourth area of BED due in the first quarter of 2013 (See table).

“We may have a decision in the first quarter between a number of very good options for Vyvanse,” said Jeffrey Jonas, senior vice president of R&D for Shire’s specialty pharma and Advanced BioHealing/regenerative medicine units.

Shire Pipeline, As of Feb. 9, 2012

Shire's development programs include late-stage trials of established drugs in new indications, as well as novel candidates for rare diseases acquired through deals.

Shire

In a Phase II trial of 246 patients, a population enriched with non-responders to anti-depressants, the drug was shown to significantly improve patients’ condition, on top of an SSRI. Based on the results to date, the company is confident that it can demonstrate the drug’s positive effects as an adjuvant/augmentation therapy in a targeted pivotal trial of 2,000 people – which is a modestly-sized study considering that depression trials typically enroll 10,000 patients – as part of a full registration program.

The primary efficacy measure in the study assesses overall depressive symptomology. Shire says the development program in depression also includes a number of scales to assess and describe improvement in measures of disability, resource utilization and other patient-reported outcomes and quality of life measures that will be of interest to clinicians, patients and payers.

In EDS, based on market research, the company designed a trial to show superiority toCephalon Inc.’s Nuvigil (armodafinil), and subsequently ran a study showing better results for the highest dose of Vyvanse compared to Nuvigil in EDS, according to results released in January 2011.

Schizophrenia seems like a particularly high-risk gamble as a new indication for Vyvanse, seeing as conventional wisdom is firmly fixed against using drugs with Vyvanse’s mechanism of action as a treatment, due to fears about exacerbating positive symptoms. But the company has been exploring the benefits for patients with disease characterized mainly by negative symptoms such as apathy and asociality, and with mild positive symptoms, such as delusions and hallucinations, where unmet need remains high. Vyvanse performed well in this population. The company is now finalizing the design of a double-blind, placebo-controlled, dose-ranging study as a follow-up. Secondary endpoints will include effect on social functioning, health economic outcomes and other functional measures.

“We are optimistic that we will be able to change the way people think about dopamine and schizophrenia based on these data,” Jonas said.

As for binge eating disorder, no drugs are currently FDA-approved. The Diagnostic and Statistical Manual of Mental Disorders is being revised and in draft versions of an update, this condition was listed as an independent disorder for the first time Also see "DSM-V Revisions Could Open - Or Close - Opportunities For Drug Industry" - Pink Sheet, 1 March, 2010.. Writing in a Jan. 13 note, UBS analyst Guillaume van Renterghem concluded that in light of the regulatory hurdle for getting an amphetamine approved for an eating disorder and the risk of off-label use in obese patients, “we assume the product will be discontinued in that indication.” However, should the drug win approval, it could add $500 million in Vyvanse peak sales, the analyst concluded.

Resolor Heads For U.S. Shore

Other specialty catalysts with primary care legs coming up include the 2012 release of results from two Phase III trials of Lialda in diverticulitis – PREVENT 1 and PREVENT 2. Good treatments are lacking for this disease, notes Russell, and while there is a component of primary care in diverticulitis, the vast majority of cases that are acute or chronic are managed by specialists.

Gastroesophageal reflux disorder (GERD) has typically been considered the province of primary care, but Shire believes it has specialist segments worth targeting. The company has the 5-HT4 inhibitor Resolor in Phase II for refractory GERD. Even though proton pump inhibitors are widely available, many people still have recurrent problems with GERD, Russell comments.

In 2012, Shire will also be embarking on a Phase III trial of Resolor in chronic constipation. Uncertainty over regulatory requirements in constipation has put a damper on development in the space, particularly for 5-HT4 agonists like Resolor. But in November 2011, an advisory committee recommended that companies should not be required to conduct dedicated cardiovascular studies, despite safety concerns raised by two previously approved products in the class, Johnson & Johnson’s Propulsid (cisapride) and Novartis AG’s Zelnorm (tegaserod) ([A#00111205001]).The improved regulatory outlook led Shire in January to acquire U.S. rights to the drug from [Janssen Pharmaceutical Ltd.], complementing the rest-of-world rights it already held through the Movetis acquisition (Also see "Deals Of The Week: Shire/Janssen, Pfizer/SFJ Pharma, AstraZeneca/IMS Health" - Pink Sheet, 16 January, 2012.

Ironwood Pharmaceuticals Inc., which has the eagerly awaited linaclotide pending FDA review, estimates that in the U.S., some 13 million have chronic constipation and 18 million have constipation-predominant irritable bowel syndrome (IBS-CC).

In Europe, Resolor is indicated only for a subpopulation of CC: women in whom laxatives fail to provide adequate relief. Within the subgroup of patients who don’t respond to laxatives, Shire sees a number of possible niche populations that could be studied, including those with underlying neurological disorders, such as diabetic neuropathy.

“We at Shire consider it entirely within our focus to work with health authorities on providing treatment to those difficult-to-treat patients who have inadequate relief from their current laxative therapy – with or without other underlying diseases,” the company said.

--Wendy Diller contributed reporting to this story

On A Revenue Roll, Shire Takes Specialist Tactics To “Primary Care” Markets

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