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FDA Inhaler Instructions Doubts Cause Delay in UT's PAH Drug
(BioWorld Today Via Acquire Media NewsEdge) Regulatory Roundup
Shares of United Therapeutics Corp. fell 10 percent Monday after the Silver Spring, Md.-based firm said it expected a delay in the approval of Tyvaso (treprostinil), an inhaled version of the company's approved pulmonary arterial hypertension (PAH) drug Remodulin, an injectable drug.
The firm's shares (NASDAQ:UTHR) lost $6.58 Monday, to close at $59.70.
United Therapeutics and its subsidiary, Lung Rx Inc., had submitted the new drug application (NDA) for Tyvaso in June 2008 based principally on the results of the 235-patient randomized, double-blind, placebo-controlled Phase III TRIUMPH-1 trial, which met its primary efficacy endpoint of improvement of 20 meters in the median change of distance in the six-minute walk.
The FDA set April 30 as the Prescription Drug User Fee Act (PDUFA) action date.
However, regulators had raised concerns about the use instructions for the nebulizer that delivers Tyvaso. The FDA wanted to ensure that patients who had never used the inhalers could do so properly based on their understanding of the instructions.
United Therapeutics had submitted revised instructions for use of the OptiNeb nebulizer to the FDA. But based on comments the company received last Friday from the agency, the firm said it was anticipating that regulators may require an additional small human factors testing (HFT) study in healthy patients to determine whether the revised instructions for using Tyvaso's inhaler were sufficient.
CEO Martine Rothblatt said Monday that his company was "not entirely certain" that the study would need to be done. But, he told investors and analysts during a conference call that, based on United Therapeutics' interaction with the FDA, "it will very probably be done."
Even though the firm had no clear order from the FDA for the HFT study, United Therapeutics decided that it was the "right thing to do" to inform shareholders as soon as possible about the potential for a delay in Tyvaso's approval, Rothblatt explained.
Given that the OptiNeb portable nebulizer device has been approved and used successfully for years in Europe, Rothblatt said his company was "surprised" by the FDA's comments.
Nonetheless, he insisted that the potential need for the HFT study would be a "minor blip in the introduction of what is otherwise going to be a really great product in the pulmonary hypertension space.
"It is disappointing that we will not able to remain confident about meeting the PDUFA date," Rothblatt said.
But, he maintained, such delays are "common" and are "ordinarily rather brief." In every significant achievement, Rothblatt said, "there are always minor blips and bumps along the way."
He assured investors that a "small delay" in the PDUFA date is "not a big thing. In fact, it is a common thing in the drug development business," he insisted.
If the study indeed needs to be conducted, Rothblatt said, "We will put all of our best resources into doing it and doing whatever the FDA asks us to do." And, he added, United Therapeutics would "work assiduously to complete the study as quickly as possible."
Rothblatt said he expected that any delay would be "limited to just a few months."
Since Tyvaso, a prostacyclin - one of the most ubiquitous hormones in the human body - was not scheduled to be launched until this summer there was never any expectation of there being any material 2009 revenues associated with the drug, Rothblatt said. But, he added, "we are keen on making it available as rapidly as possible."
Leerink Swann Analyst Joseph Schwartz said it was important to note that the FDA has not yet requested additional data around Tyvaso's active ingredient.
HFT studies, which look at the ability of the instructions for use to guide patients when taking the device apart, putting it back together and cleaning the device, are among the "most minor studies in terms of severity for device amendments," Schwartz noted.
Given that Tyvaso met its primary endpoint with a high degree of statistical significance and it has been shown to be safe and well tolerated in patients with PAH, along with the medication's orphan drug status, the drug is likely to have a "clear win at the FDA," he predicted.
If the FDA does require an HFT study, said analyst Jonathan Aschoff, of Brean Murray Carret & Co., such a requirement would be a "relatively low-level barrier" to Tyvaso's approval.
He predicted the FDA would grant Tyvaso's NDA a three-month extension rather than issue a complete response letter.
In addition to the injectable and inhaled versions of treprostinil, United Therapeutics is testing an oral version of the drug. However, results released last fall showed that the oral drug failed to meet the primary endpoint of improving the six-minute walk distance at 16 weeks with statistical significance. Nevertheless, the results indicated a positive trend with an 11-meter improvement. (See BioWorld Today, Nov. 18, 2008.)
In other regulatory actions:
? Melior Discovery Inc., of Exton, Pa., said the FDA approved its investigational new drug application for clinical studies of MLR-1023, a first-in-class kinase activator, as a treatment of Type II diabetes.
? Noven Pharmaceuticals Inc., of Miami, said its partner, Shire plc, of Basingstoke, UK, has withdrawn its European marketing authorization application for Daytrana (methylphenidate transdermal system) as a treatment for attention-deficit/hyperactivity disorder because regulatory authorities requested an additional clinical study. Daytrana is approved in the U.S. to treat pediatric patients for ADHD.
? Orexo AB, of Uppsula, Sweden, said the FDA approved Edluar (formerly Sublinox, OX22) for the short-term treatment of insomnia characterized by difficulties with sleep initiation. The approval triggered a $5 million milestone to Orexo from its partner Stockholm, Sweden-based Meda AB, which acquired the exclusive worldwide commercialization license for Edluar last year. The firms expect to launch the product in the U.S. during the second half of this year. Orexo is expected to receive royalties on sales of Edluar under the partnership.
? Sirion Therapeutics Inc., of Tampa, Fla., said the FDA has accepted for review its supplemental NDA for Durezol (difluprednate ophthalmic emulsion) 0.05 percent to treat endogenous anterior uveitis, an inflammation of the eye's iris, choroid and ciliary body. The drug was approved by the FDA in June 2008 for the treatment of postoperative inflammation and pain associated with ocular surgery.
? XenoPort Inc., of Santa Clara, Calif., said the FDA accepted for review the NDA for Solzira (gabapentin enacarbil) as a potential treatment for moderate-to-severe primary restless legs syndrome. The NDA was submitted by XenoPort's U.S. partner, GlaxoSmithKline plc, of London. The FDA's acceptance of the NDA triggered a $23 million milestone payment to XenoPort from GSK, which the U.S. firm initially expected to receive last fall. However, GSK had withdrawn the NDA because of a formatting issue and later resubmitted the application. (See BioWorld Today, Dec. 31, 2008.) n
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