Up to 60,000 patients in the United States may
have PPF, with only one approved therapy available
United Therapeutics Corporation (Nasdaq: UTHR), a public
benefit corporation, announced today that the first patient has
enrolled in the registration-phase TETON PPF study, which will
evaluate nebulized Tyvaso® (treprostinil) Inhalation Solution in
698 adult patients with progressive pulmonary fibrosis
(PPF). This is in addition to two separate ongoing
registration-phase studies, TETON 1 and TETON 2, of nebulized
Tyvaso in patients with another type of pulmonary fibrosis
(PF) known as idiopathic pulmonary fibrosis
(IPF).
The 52-week study will evaluate the impact of nebulized Tyvaso
on a key prognostic indicator for PPF known as forced vital
capacity (FVC). PPF is a progressive form of interstitial
lung disease (ILD) characterized by the loss of the ability
of the lungs to transfer oxygen into the blood, ultimately
resulting in respiratory failure and death.
Nebulized Tyvaso is currently approved by the U.S. Food and Drug
Administration (FDA) to treat both pulmonary arterial
hypertension and pulmonary hypertension (PH) associated with
interstitial lung disease (PH-ILD). The PH-ILD indication,
which includes patients with PH associated with IPF and PPF, was
added to the nebulized Tyvaso label in March 2021 based on the
successful results of the INCREASE study. Nebulized Tyvaso is only
approved for use for PPF patients who may also have documented PH,
to improve exercise capacity. The TETON PPF study seeks to evaluate
the use of nebulized Tyvaso in PPF patients irrespective of whether
or not they have PH.
“The progressive pulmonary fibrosis phenotype represents a group
of ILD patients who only have limited treatment options currently
available to them,” said Steven Nathan, M.D., Medical
Director of the Advanced Lung Disease and Lung Transplant Program
at Inova Fairfax Hospital in Falls Church, Virginia, who is also
chair of the TETON program steering committee. “The broader ILD
data set from the INCREASE study showed improvements in FVC beyond
just IPF patients, and the data provide the foundation for further
study of inhaled treprostinil’s anti-fibrotic and disease modifying
mechanism of action in patients with other forms of fibrotic lung
disease like PPF.”
“The initiation of the global TETON PPF study illustrates
confidence in nebulized Tyvaso as a potential treatment option for
patients with fibrotic lung disease,” said Natalie Breytenbach,
Pharm.D., Associate Director, Global Product Development at
United Therapeutics and the company’s lead for the TETON PPF study.
“The expansion of TETON into the PPF patient population allows us
to continue to evaluate inhaled treprostinil’s potential for
treating this vulnerable group of patients in a robust global
pivotal study.”
The TETON program in IPF and PPF was prompted by data from the
INCREASE study of nebulized Tyvaso for the treatment of PH-ILD,
which demonstrated improvements in certain key parameters of lung
function in pulmonary hypertension patients with fibrotic lung
disease (improved absolute FVC and reduced exacerbations of
underlying lung disease). Specifically, in the INCREASE study,
treatment with nebulized Tyvaso resulted in significant
improvements in percent predicted FVC at weeks 8 and 16, with
subjects having an underlying etiology of IPF showing the greatest
improvement (week 8: 2.5%; p=0.0380 and week 16: 3.5%; p=0.0147).
In May 2022, data from the INCREASE open-label, long-term extension
trial were presented at a medical conference, indicating that
improvements in FVC were sustained for at least 64 weeks for PH-ILD
patients with underlying IPF. For those patients who received
placebo during the INCREASE study, marked improvements in FVC were
observed following transition to nebulized Tyvaso during the
open-label extension study. These data points, combined with
substantial preclinical evidence of antifibrotic activity of
treprostinil, suggest that nebulized Tyvaso may offer a treatment
option for patients with IPF and PPF.
Tyvaso DPI® (treprostinil) Inhalation Powder is not being
evaluated in the TETON program, but United Therapeutics intends to
seek FDA approval to expand the Tyvaso DPI label to include IPF and
PPF, following completion of the TETON studies and any FDA-required
bridging studies.
About TETON PPF
The TETON PPF study is a 698-patient, multicenter, randomized,
double-blind, placebo-controlled phase 3 registration study to
evaluate the safety and efficacy of nebulized Tyvaso in subjects
with progressive pulmonary fibrosis (PPF) over a 52-week
period. This third registration study is part of the global TETON
program evaluating nebulized Tyvaso for the treatment of idiopathic
pulmonary fibrosis (IPF) and PPF and will be conducted at
sites globally.
Subjects will be randomly allocated 1:1 to receive nebulized
Tyvaso or placebo. All subjects will initiate nebulized Tyvaso or
placebo at a dose of three breaths administered four times daily
(QID) and will titrate to a target dosing regimen of 12
breaths QID. Study drug doses may be titrated up as tolerated,
until the target dose or maximum clinically tolerated dose is
achieved.
The primary endpoint of the study is the change in FVC from
baseline to week 52. Secondary endpoints include: (1) time to
clinical worsening; (2) time to first acute exacerbation of
interstitial lung disease (ILD); (3) overall survival at
week 52; (4) change in percent predicted FVC from baseline to week
52; (5) change in the King’s Brief Interstitial Lung Disease
questionnaire; and (6) change in the diffusing capacity of the
lungs for carbon monoxide.
Other data collected in the study will include the plasma
N-terminal pro-brain natriuretic peptide (NT-proBNP)
concentration and supplemental oxygen use. Safety assessments
include adverse event and serious adverse event monitoring, vital
signs, clinical laboratory parameters, and electrocardiogram
parameters.
About PPF
Progressive pulmonary fibrosis (PPF) is a group of
interstitial lung disease (ILD) conditions that exhibit
progressive, self-sustaining fibrosis, and display a similar
disease course to idiopathic pulmonary fibrosis (IPF). PPF
includes idiopathic interstitial pneumonias (other than IPF),
autoimmune ILDs, chronic fibrosing hypersensitivity pneumonitis,
and fibrotic ILDs related to environmental or occupational
exposure. It is estimated that 13% to 40% of patients with these
various ILDs will go on to develop PPF1. Patients with PPF exhibit
decreased lung function, poor quality of life, and increased
mortality despite usual treatments for the underlying ILD.
Estimates for median transplant free survival and overall survival
are approximately 2.9 years and 3.7 years, respectively.2,3
Further, United Therapeutics estimates there are up to 60,000 PPF
patients in the United States.
About Tyvaso® Inhalation Solution and Tyvaso DPI® Inhalation
Powder
INDICATION
TYVASO (treprostinil) Inhalation Solution and TYVASO DPI
(treprostinil) Inhalation Powder are prostacyclin mimetics
indicated for the treatment of:
- Pulmonary arterial hypertension (PAH; WHO Group 1) to improve
exercise ability. Studies with TYVASO establishing effectiveness
predominately included patients with NYHA Functional Class III
symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH
associated with connective tissue diseases (33%).
The effects diminish over the minimum
recommended dosing interval of 4 hours; treatment timing can be
adjusted for planned activities.
While there are long-term data on use of
treprostinil by other routes of administration, nearly all clinical
experience with inhaled treprostinil has been on a background of an
endothelin receptor antagonist (ERA) and/or a phosphodiesterase
type 5 (PDE-5) inhibitor. The controlled clinical experience with
TYVASO was limited to 12 weeks in duration.
- Pulmonary hypertension associated with interstitial lung
disease (PH-ILD; WHO Group 3) to improve exercise ability. The
study with TYVASO establishing effectiveness predominately included
patients with etiologies of idiopathic interstitial pneumonia (IIP)
(45%) inclusive of idiopathic pulmonary fibrosis (IPF), combined
pulmonary fibrosis and emphysema (CPFE) (25%), and WHO Group 3
connective tissue disease (22%).
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
- TYVASO and TYVASO DPI are pulmonary and systemic vasodilators.
In patients with low systemic arterial pressure, either product may
produce symptomatic hypotension.
- Both products inhibit platelet aggregation and increase the
risk of bleeding.
- Co-administration of a cytochrome P450 (CYP) 2C8 enzyme
inhibitor (e.g., gemfibrozil) may increase exposure (both Cmax and
AUC) to treprostinil. Co-administration of a CYP2C8 enzyme inducer
(e.g., rifampin) may decrease exposure to treprostinil. Increased
exposure is likely to increase adverse events associated with
treprostinil administration, whereas decreased exposure is likely
to reduce clinical effectiveness.
- Like other inhaled prostaglandins, TYVASO and TYVASO DPI may
cause acute bronchospasm. Patients with asthma or chronic
obstructive pulmonary disease (COPD), or other bronchial
hyperreactivity, are at increased risk for bronchospasm. Ensure
that such patients are treated optimally for reactive airway
disease prior to and during treatment with TYVASO and TYVASO
DPI.
DRUG INTERACTIONS/SPECIFIC POPULATIONS
- The concomitant use of either product with diuretics,
antihypertensives, or other vasodilators may increase the risk of
symptomatic hypotension.
- Human pharmacokinetic studies with an oral formulation of
treprostinil (treprostinil diolamine) indicated that
co-administration of the cytochrome P450 (CYP) 2C8 enzyme
inhibitor, gemfibrozil, increases exposure (both Cmax and AUC) to
treprostinil. Co-administration of the CYP2C8 enzyme inducer,
rifampin, decreases exposure to treprostinil. It is unclear if the
safety and efficacy of treprostinil by the inhalation route are
altered by inhibitors or inducers of CYP2C8.
- Limited case reports of treprostinil use in pregnant women are
insufficient to inform a drug-associated risk of adverse
developmental outcomes. However, pulmonary arterial hypertension is
associated with an increased risk of maternal and fetal mortality.
There are no data on the presence of treprostinil in human milk,
the effects on the breastfed infant, or the effects on milk
production.
- Safety and effectiveness in pediatric patients have not been
established.
- Across clinical studies used to establish the effectiveness of
TYVASO in patients with PAH and PH‑ILD, 268 (47.8%) patients aged
65 years and over were enrolled. The treatment effects and safety
profile observed in geriatric patients were similar to younger
patients. In general, dose selection for an elderly patient should
be cautious, reflecting the greater frequency of hepatic, renal, or
cardiac dysfunction, and of concomitant diseases or other drug
therapy.
ADVERSE REACTIONS
- Pulmonary Arterial Hypertension (WHO
Group 1)
In a 12-week, placebo-controlled study
(TRIUMPH I) of 235 patients with PAH (WHO Group 1 and nearly all
NYHA Functional Class III), the most common adverse reactions seen
with TYVASO in ≥4% of PAH patients and more than 3% greater than
placebo were cough (54% vs 29%), headache (41% vs 23%), throat
irritation/pharyngolaryngeal pain (25% vs 14%), nausea (19% vs
11%), flushing (15% vs <1%), and syncope (6% vs <1%). In
addition, adverse reactions occurring in ≥4% of patients were
dizziness and diarrhea.
In a 3-week, open-label, single-sequence,
safety and tolerability study (BREEZE) conducted in 51 patients on
stable doses of TYVASO who switched to a corresponding dose of
TYVASO DPI, the most commonly reported adverse events seen with
TYVASO DPI in ≥4% of PAH patients during the 3-week treatment phase
included cough (35.3%), headache (15.7%), dyspnea (7.8%), and
nausea (5.9%).
- Pulmonary Hypertension Associated with
ILD (WHO Group 3)
In a 16-week, placebo-controlled study (INCREASE) of 326
patients with PH-ILD (WHO Group 3), adverse reactions with TYVASO
were similar to the experience in studies of PAH.
Please see Full Prescribing Information for TYVASO or TYVASO
DPI, Instructions for Use manuals for TD-100 and TD-300 TYVASO®
Inhalation System and TYVASO DPI™ Inhalation Powder, and additional
information at www.TYVASOHCP.com or call 1‑877‑UNITHER
(1-877-864-8437).
TYVISIhcpMAY2022
United Therapeutics: Enabling Inspiration
At United Therapeutics, our vision and mission are one. We use
our enthusiasm, creativity, and persistence to innovate for the
unmet medical needs of our patients and to benefit our other
stakeholders. We are bold and unconventional. We have fun; we do
good. We are the first publicly traded biotech or pharmaceutical
company to take the form of a public benefit corporation. Our
public benefit purpose is to provide a brighter future for patients
through the development of novel pharmaceutical therapies; and
technologies that expand the availability of transplantable
organs.
You can learn more about what it means to be a PBC here:
unither.com/pbc.
Forward-looking Statements
Statements included in this press release that are not
historical in nature are “forward-looking statements” within the
meaning of the Private Securities Litigation Reform Act of 1995.
Forward-looking statements include, among others, statements
regarding the planned enrollment, conduct, and design of the TETON
1, TETON 2, and TETON PPF clinical studies, the potential for
Tyvaso to become a treatment option for patients with fibrotic lung
disease, our plans to seek IPF and PPF indications for the Tyvaso
DPI label, and our goals of innovating for the unmet medical needs
of our patients and to benefit our other stakeholders and
furthering our public benefit purpose of developing novel
pharmaceutical therapies and technologies that expand the
availability of transplantable organs. These forward-looking
statements are subject to certain risks and uncertainties, such as
those described in our periodic reports filed with the Securities
and Exchange Commission, that could cause actual results to differ
materially from anticipated results. Consequently, such
forward-looking statements are qualified by the cautionary
statements, cautionary language and risk factors set forth in our
periodic reports and documents filed with the Securities and
Exchange Commission, including our most recent Annual Report on
Form 10-K, Quarterly Reports on Form 10-Q, and Current Reports on
Form 8-K. We claim the protection of the safe harbor contained in
the Private Securities Litigation Reform Act of 1995 for
forward-looking statements. We are providing this information as of
October 31, 2023, and assume no obligation to update or revise the
information contained in this press release whether as a result of
new information, future events, or any other reason.
TYVASO and TYVASO DPI are registered trademarks of United
Therapeutics Corporation.
1 Olson AL, Patnaik P, Hartmann N, et al. Prevalence and
incidence of chronic fibrosing interstitial lung diseases with a
progressive phenotype in the United States estimated in a large
claims database analysis. Adv Ther. 2021;38:4100-4114.
2 Platenburg MGJP, van der Vis JJ, Grutters JC, van Moorsel CHM.
Decreased survival and lung function in progressive pulmonary
fibrosis. Medicina. 2023;59:296.
3 Cottin V, Teague R, Nicholson L, et al. The burden of
progressive-fibrosing interstitial lung disease. Front Med.
2022;9:799912.
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version on businesswire.com: https://www.businesswire.com/news/home/20231031999258/en/
Dewey Steadman at (202) 919-4097
https://ir.unither.com/contact-uthr/
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