Shire Reversal on Rare-Disease Drug Application Stumps Patients

Angus Russell, CEO of Shire Plc.
Angus Russell, chief executive officer of Shire Plc., stands for a portrait in front of the Nasdaq MarketSite in New York. Source: Shire

Cheryl Barcomb, a school-district clerk in Pittsford, New York, never wanted to start taking Shire Plc’s Replagal medicine for her rare genetic illness. Now, after more than two years, she doesn’t want to give it up.

Soon she won’t have a choice. Shire is ending a temporary program, begun at the U.S. Food and Drug Administration’s request, under which it provided Replagal for free to U.S. patients with Fabry disease. Last month the Dublin-based drugmaker dropped an application to gain the agency’s approval to sell the medicine, 13 days before an FDA advisory committee was to consider the proposal. The news shocked Barcomb, who relies on infusions of Replagal to help ease her strokes and crippling bouts of pain better than a rival drug.

Shire says the FDA wants additional clinical trials that will take years. The FDA said the agency had made no decision about whether further studies would be needed. Patients, confused by the conflicting statements, don’t know whom to blame: an overzealous regulator or a profit-minded company.

“If the FDA has a good reason for wanting more long-term studies, Shire should force them to make it in public,” said Ira Loss, an analyst at the investment research firm Washington Analysis who has been watching the agency for 35 years. “If they don’t, the committee would tell them they don’t have any reason to make this demand, and Shire looks like the victim.”

Either way, Loss said, patients deserve to know “what are the valid concerns when the FDA was happy to have the product here for two years.” The fact that Replagal is sold in 46 countries and has been on the market in the EU for more than a decade should have helped seal a quick FDA clearance, he said.

Dependent on Fabrazyme

The withdrawal will leave U.S. patients dependent on the only approved treatment, Fabrazyme, which has been in short supply since 2009, when a virus contaminated the Genzyme Corp. factory in Boston where it was produced. Yet some people do better on Replagal than Fabrazyme, so patients say they want access to both.

As of last month, Genzyme is able to take on demand globally, including the extra Replagal patients, said Lori Gorski, a spokeswoman for Genzyme in Cambridge, Massachusetts. The company was acquired by Sanofi last year.

Fabry is a so-called lysosomal storage disorder, caused by low levels of certain enzymes needed to break down fatty substances that can build up in the body’s organs. Only about 8,000 people worldwide are affected. Shire’s Replagal treats the majority of patients outside the U.S., while Genzyme’s Fabrazyme is used in the U.S.

Felt Better

Barcomb worried when the virus cut the supply of Fabrazyme. Faced with rationed doses, she was pleased to be able to take Replagal, and soon found it worked better for her than the Genzyme drug, she said.

Replagal brought an end to the mini-strokes Barcomb suffered from the disease, as well as her emergency room visits for pain. She also wasn’t groggy after the twice-monthly infusions, nor did she have bouts of fatigue as she had with Fabrazyme, she said. “I just felt better on Replagal,” Barcomb, 54, said by phone. “I don’t even think people realize anymore, ‘Oh, she’s sick.’”

Shire enrolled 140 U.S. patients into the free treatment program with the hope of winning a speedy FDA approval in return. Shire, which applied in 2009, withdrew and then resubmitted the application in 2010 after the FDA sought more data. The agency scheduled a March 27 meeting for a committee of outside experts to discuss Replagal.

Shire’s Withdrawal

On March 14, Shire said it was withdrawing the application. The FDA led the company to believe an approval was “highly unlikely” without lengthy and expensive clinical trials, said Jessica Cotrone, a Shire spokeswoman in Lexington, Massachusetts.

“There was no point in going through the exercise since our filing was motivated by the potential approval of Replagal for U.S. patients now,” Cotrone said. “It was clear that even if we were to get U.S. approval of the product, the approval would be in the distant future.” The company has no plans to re-apply.

Stephanie Yao, a spokesman for the agency in Silver Spring, Maryland, disputed Shire’s assertion.

“The FDA had not made any decision regarding the application, including the need for additional data,” she said. “We wanted advice on the efficacy and safety data that was contained in the application and we wanted to be able to discuss it in a public forum.” She declined to comment further and said the agency can’t release briefing documents prepared for the March 27 meeting of the Cardiovascular and Renal Drugs Advisory Committee without Shire’s permission.

Switching Back

Shire declined to release the documents, Cotrone said.

“Why didn’t Shire just give them the answers they were looking for?” said Barcomb, who is preparing for her switch back to Fabrazyme on May 30. “If they thought the FDA were going to reject it, why not just let them reject it?”

Shire might have wanted to keep the FDA briefing documents secret because they may have contained some information that would hurt sales outside the U.S., “though of course that’s speculative,” Loss said. Shire spokespeople didn’t respond to calls or e-mails seeking comment about that speculation. The Fabrazyme shortage helped double Replagal’s market share outside the U.S. to about 80 percent. Replagal sales surged 35 percent last year to $475.2 million.

Genzyme’s recovery from the virus contamination was delayed, so patients faced rationed dosing schedules or going without the drug completely.

‘Very Frustrating’

Genzyme Chief Executive Officer Henri Termeer said in 2009 the disruptions would be sorted out in weeks, which later changed to months. As patients worldwide struggled to cope with symptoms that were aggravated by limited doses, months turned to years.

“Hearing these assurances repeatedly over the years got very frustrating, and that’s why we got cautious with our thinking,” said Jack Johnson, head of the Fabry Support & Information Group, a Concordia, Missouri-based patient-support network representing about 1,200 members.

If the FDA is really to blame, said Loss, Shire could have removed any doubt as to the FDA’s demands by waiting for the advisory committee meeting.

“But honestly, what concerns could possibly be valid?” Loss said. “Why was this product good enough during the crisis and not good enough now?”

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