By Kim Coghill
BETHESDA, Md. ¿ A government committee Wednesday gave United Therapeutics Corp. (UTC) the thumbs up on Remodulin, a subcutaneous treatment for pulmonary arterial hypertension (PAH).
In a 6-to-3 vote, the Cardiovascular and Renal Drugs Advisory Committee recommended approval of the orphan drug formerly known as UT-15 and Uniprost (treprostinol sodium). The FDA will make the final decision, and typically follows the advice of the committee.
Martine Rothblatt, UTC¿s CEO, told BioWorld Today that she was elated by the decision, ¿and particularly happy for the patients we can help.¿
Before the meeting broke, Jeffrey Borer, the committee¿s acting chairman, said the 6-to-3 vote in favor ¿is teetering toward approval. What you have heard is a committee that wants more data on labeling and postmarketing studies.¿
In the motion to recommend approval, three committee members requested additional information to ease their minds about some questions surrounding the drug.
UT-15 is an analogue of prostacyclin, a molecule produced naturally within the body to keep blood vessels healthy. People suffering with PAH, a life-threatening condition, have reduced levels of prostacyclin within the blood vessels in their lungs, resulting in dizziness, fainting, diminished exercise ability and potentially right-heart failure.
GlaxoSmithKline plc¿s Flolan (epoprostenol) is the only available treatment for PAH patients and has been used for PAH in conjunction with other conditions.
According to the FDA, Remodulin was developed for a larger population than Flolan and has other advantages in that it is administered via injection. Flolan is administered intravenously through a surgically implanted catheter by a portable, battery-operated pump. The drug lasts only 3 to 5 minutes, so it must be continuously pumped into the body. Remodulin is an injection that will last several hours.
Silver Spring, Md.-based UTC conducted two identical Phase III studies aimed at evaluating the change in exercise capacity as measured by distance walked in six minutes. Both studies were international, multicenter, double blinded and placebo controlled.
At issue among committee members was UTC¿s failure to meet its primary endpoint, which required participants to be able to walk 55 meters after 12 weeks of dosing. At the close of the trials, patients were able to walk 10 meters.
Steve Nissen, a committee member and vice chairman of the department of cardiology and a professor of medicine at Ohio State University, the Cleveland Clinic Foundation, Cleveland, said the committee should be more liberal in its decision on Remodulin. ¿This is an orphan disease and these people are desperate. I¿m willing to change my standards because the treatments are limited. I think they were close on the primary endpoint and there¿s value in the totality of the data.¿
The U.S. market is about 30,000 to 50,000 patients.
Other committee members said the choice of endpoints and design of trials could have masked the true effectiveness of Remodulin.
¿I¿m not sure 55 meters should have even been selected as the endpoint and I¿m not sure I should approve something that only helps you walk three-quarters of a block in New York City,¿ said Borer, director of the division of pathophysiology at Weill Medical Center at Cornell University in New York.
Thomas Fleming, the committee investigator and professor and chair of the department of biostatistics at the University of Washington in Seattle, argued that the endpoints did not achieve statistical significance, and ¿I¿m wondering if we should have looked at this over a longer period of time. There are no data to assess the effects after 12 weeks, so we are left with nonsignificant exercise, pain and possible long-term effects.¿
UTC submitted its new drug application (NDA) for Remodulin on Oct. 16, 2000, and received six-month priority review status requiring FDA action no later than July 16. Initially an advisory committee meeting to hear the application was scheduled Feb. 9, but in mid-December the FDA informed the company that a hearing would not be necessary. (See BioWorld Today, Dec. 18, 2000.)
The meeting was later rescheduled.
UTC¿s stock (NASDAQ:UTHR) closed Wednesday at $8.97, down $3.38, or 27.37 percent, when an FDA briefing document appeared to indicate the drug would not be recommended for approval. There was no trading on the stock Thursday.
The advisory committee today will hear an application from Actelion Ltd., of Switzerland and South San Francisco, for Tracleer (bosentan), the first oral medication for the same indication. It is partnered with Genentech Inc. A briefing document released by the FDA Thursday indicated that Tracleer would receive recommended approval.