Facility Inspection Issue Stalls FDA Approval of Tyvaso DPI for PH-ILD

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by Steve Bryson PhD |

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FDA approval of Tyvaso DPI on hold/Pulmonary Fibrosis News/news illustration

An open inspection issue at a third-party testing facility has put on hold United Therapeutics’ application seeking the approval of Tyvaso DPI, an investigational dry powder inhaled formulation of treprostinil for pulmonary hypertension associated with interstitial lung disease (PH-ILD), a group of disorders that also includes idiopathic pulmonary fibrosis (IPF).

Efforts are underway to resolve the issue — as identified by the U.S. Food and Drug Administration (FDA) — at the facility, which was conducting analytical testing on the PH-ILD therapy, according to United.

“We are confident that the single deficiency identified in the [FDA’s] complete response will be resolved quickly and that Tyvaso DPI can receive approval by the summer of 2022, if not earlier,” Martine Rothblatt, PhD, chairperson and CEO of United, said in a press release.

In a recent letter from the FDA in response to United’s approval request, the agency did not cite any deficiencies or problems related to the manufacturing, testing, and packaging of Tyvaso DPI by MannKind Corporation, nor did it note any issues with the inhaler device, the company said.

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According to United, all additional requests from the FDA have been addressed and the therapy’s approval and launch are expected to take place by mid-2022.

Additionally, the labeling for Tyvaso DPI, which was revised by the FDA, includes the same indications as are given for Tyvaso, a liquid-based inhaled formulation of treprostinil, the company said. United said the label does not contain any boxed warnings or contraindications — a tally of specific situations in which the therapy should not be used because it may be harmful.

“We are very pleased with the FDA’s feedback on the label, which will ultimately enable us to bring Tyvaso DPI to thousands of patients in need,” Rothblatt said.

Treprostinil is a vasodilator medicine, which helps lower blood pressure by expanding blood vessels in the lungs. PH-ILD comprises a group of conditions caused by significant scarring (fibrosis) of lung tissue, including IPF, which can lead to high blood pressure in lung blood vessels, or pulmonary hypertension.

Tyvaso is approved in the U.S. to improve exercise ability in people with PH-ILD, as well as in those with pulmonary arterial hypertension (PAH), a disease characterized by high pulmonary blood pressure caused by the narrowing of the arteries connecting the heart to the lungs. United also is marketing an oral form of treprostinil, called Orenitram, as well as an injectable form named Remodulin.

The new formulation here, Tyvaso DPI, is a dry powder form of Tyvaso delivered by Dreamboat, a small portable inhalation device developed by MannKind, which was previously approved by the FDA. The companies also are developing an accessory for Tyvaso DPI called BluHale, which can connect to a mobile application via Bluetooth to help patients track inhaler use.

Earlier this year, United asked the FDA to approve Tyvaso DPI, which then received priority review. At that time, the agency indicated that the therapy’s approval would be subject to an inspection of the MannKind facility.

The facility issue has proved a setback for United, as the FDA declined to approve its application “at this time,” the company said.

Although not cited as a deficiency, the FDA’s letter also indicated that the agency had not yet completed its review of a recently submitted Citizen’s Petition regarding the safety of a substance in Tyvaso DPI that helps deliver treprostinil.

The 19-page Citizen’s Petition — used by individuals and community organizations that wish to make requests to the FDA — asks that Tyvaso DPI not be approved until further safety testing is conducted in PH-ILD and PAH patients.

“Both PAH and PHILD are chronic, progressive pulmonary diseases that leave patients with limited capacity to withstand further lung injury or compromise in lung function,” the petition states.

At issue is that Tyvaso DPI contains the same dry powder particle formulation as Afrezza, an approved inhaled treatment for diabetes. Afrezza use is associated with an increased risk of acute bronchospasm — spasming and contraction of the airways — in people with chronic lung diseases such as asthma and chronic obstructive pulmonary disease (COPD).

As a result, Afrezza carries a boxed warning that these patients should not use the medicine. This is thought to be caused, at least partly, by the presence of the same substance that is also found in Tyvaso DPI.

Given that, the petition said United’s application “potentially raises significant safety issues.”

For its part, United said it expects Tyvaso DPI to be “a groundbreaking advancement for PAH and PH-ILD patients.”

“We reaffirm the achievability of our near-term goal of doubling the number of patients on Tyvaso by the end of 2022, and our longer-term goal of having 25,000 patients on our products by the end of 2025,” said Michael Benkowitz, president and chief operating officer of United.

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