Welcome to Orphan Diseases
The acquisition of TKT's platform was a shot across the bow of Genzyme, which had pioneered enzyme-replacement therapy as
far back as 1990 and proceeded to corner the orphan drug market. But for Shire to truly compete with Genzyme, it would have
to make inroads with patients, physicians, and payers. FDA's orphan drug designation provides seven years of market exclusivity
(in addition to the patent life), an incentive to R&D investment as well as a barrier to competition. "In the orphan space,
there's no prize for second place," says Barbara Deptula. "The first medicine to get approved wins orphan designation. The
rest get nothing."
Shire HGT's enzyme-replacement therapy (ERT) focuses on lysosomal storage diseases (LSD), which are caused by inherited
genetic defects. Each LSD has its own specific gene mutation, but they all produce a lifelong enzyme deficiency that leads
to serious metabolic malfunctions and other conditions. Often materializing in very young children, the symptoms can be serious,
even lethal, and include tissue damage, organ dysfunction, developmental delay, deafness, and blindness. Restoring the enzyme
via regular IV infusions of the missing protein can deal with symptoms, but it can't cure the disease.
Results came fast for Shire HGT. Since its inception in 2005, its platform has yielded two ERTs that have already won FDA
approval, a third whose PDUFA date is February 28, and a fourth likely to be reviewed in the fall. What makes Shire's ERT
technology unique is that it exclusively employs human cell lines to grow the recombinant DNA, producing proteins identical
to the naturally occurring prototype, says President of Shire HGT Sylvie Gregoire. In principle, this method produces ERTs
that are safer and more effective than those made in cell lines from other mammals. The HGT-branded proteins are also phosphorylated
for more efficient cell penetration. In 2006, Shire's launch of Elaprase marked a major breakthrough in Hunter syndrome, previously
treatable only by palliative means. 2008 sales came to $305 million.
Shire HGT has left the lab at times to do deals, not always to brilliant effect. In 2008, Shire snatched up Berlin-based biotech
Jerini for $521 million shortly before its lead compound, Firazyr (an orphan drug for angioedema), won EU approval. Annual
sales of the small-molecule drug were estimated as high as $400 million. But the NDA was rebuffed by FDA, and Shire has had
to bankroll an additional Phase III trial. Another setback was the $200 million milestone deal with New Jersey biotech Amicus
in 2007 to codevelop oral versions of drugs for Fabry, Gaucher, and Pompe diseases. If successful, that treatment advance
would have enabled Shire to leapfrog Genzyme's three top genetic disease products (pills always topping needles, especially
among children). But last November Amicus's lead compound bit the dust in Phase II, and Shire said goodbye.
Yet the Fates appears to favor Shire's bold ambitions, for Genzyme took a terrible tumble last summer when its main manufacturing
plant had to be shuttered following cell-line contamination by a rogue virus. The accident resulted in an abrupt halt in the
production of Cerezyme and Fabrazyme, the sole treatments for Gaucher and Fabry diseases, respectively. With shortages and
rationing in their future, patients and families worldwide suddenly faced dire straits.
FDA immediately asked Shire to fill the gap by establishing early-access programs for its two competing experimental ERTs:
Replagal, for Fabry; and velaglucerase alfa (v-alfa), for Gaucher. Replagal, long approved in the EU, quickly stepped in for
the Fabrazyme shortfall. In December, a longitudinal study proving the drug's efficacy ran in The Lancet, and Shire filed for FDA approval. With an expedited review, the company expects to launch Replagal in the US—after a 10-year
The request for v-alfa required Gregoire and her team to shift into highest gear. The ERT had just completed the first of
three Phase III trials. "We had to accelerate everything by 18 months—from analyzing the data to manufacturing the drug,"
This emergency delivery of v-alpha to treatment-deprived Gaucher patients was one of the rare occasions when FDA has permitted
the preapproval distribution of a drug. In return, the agency fast-tracked v-alfa's review for February 28. "It was immensely
satisfying for all of us to be able to do this, even though it was a lot of work," says Gregoire. "I mean, these are children
who need drugs or else they will die."
Analysts say that doctors and patients also report immense satisfaction with the two Shire ERTs, raising the company's hopes
that their drugs will prevail when Genzyme finally gets its act together. Biondo Group analyst Raymond Chung estimates that
Cerezyme will surrender 33 percent of its Gaucher market share by 2013, and Fabrazyme, 45 percent in Fabry. "Genzyme is not
used to having others encroach on its territory," he wrote in a recent analyst note. "Shire is a formidable rival with proven
worldwide successes and came to the rescue when physicians and patients were in dire need. This will not be forgotten. Expect
an intense battle here."
Shire HGT is certainly moving aggressively, investing 40 percent of its revenue in R&D and beginning to develop a new wave
of ERTs with harder-to-access targets like the central nervous system. "We're acting like a super-
biotech," says Gregoire.
The diversification into rare diseases has given Shire something more than a post-Adderall lease on life. Developing orphan
drugs for rare diseases has profoundly transformed Shire's culture, says Angus Russell. Saving children from a lifetime of
suffering and early death is about as good as it gets in the pharmaceutical business. In addition, because the diseases are
rare and complex, and the clinical trials small and personal, the ties between the drugmaker and the patient—and their family
and doctor—often become unusually close.
Exactly how this dynamic affects a company's culture hit home for Russell on an early visit to TKT in 2005. Walking down a
hallway with the then-CEO, Russell stopped to admire the many portraits of children on the wall. Recalls Russell: "I said,
'These photos are amazing. Who are these kids?' He said, 'These are our kids in the Elaprase trials for Hunter syndrome,
which has no cure.' He approached one photo and said, 'This is Jason. He's 10 years old, from Chicago. He's been in the study
for two years. He's got Stage II.' He went on like that until he got to number 6, and I said, 'Stop.' In my 20-odd years in
the industry, I never was in a business where you knew all your patients personally.' And he said, 'Welcome to our business.
This is what we do.'"
Russell's appreciation for this relationship inspired Shire's gritty new corporate branding campaign, which turns on the
word "brave" and the tagline "To be as brave as the people we help."