SILVER SPRING, Md. and
RESEARCH TRIANGLE PARK, N.C.,
June 16, 2021 /PRNewswire/ -- United
Therapeutics Corporation (Nasdaq: UTHR) today announced that the
U.S. Food and Drug Administration (FDA) accepted for
priority review the New Drug Application (NDA) for Tyvaso
DPI™ (inhaled treprostinil) for the treatment of pulmonary arterial
hypertension (PAH) and pulmonary hypertension associated
with interstitial lung disease (PH-ILD). United Therapeutics
expects the agency's review to be complete in October 2021. FDA also indicated that they have
not identified any potential review issues at this time.
Tyvaso DPI is a next-generation dry powder formulation of
Tyvaso. If approved, Tyvaso DPI is expected to provide a more
convenient method of administration as compared with traditional
nebulized Tyvaso therapy.
"The acceptance of the Tyvaso DPI NDA for review represents an
important regulatory step toward offering this meaningful new
product to both PAH and PH-ILD patients," said Martine Rothblatt, Ph.D., Chairperson and Chief
Executive Officer of United Therapeutics. "If approved, Tyvaso DPI
will represent yet another path to help us achieve our goal of
serving 25,000 patients by the end of 2025."
The NDA includes data from the BREEZE study that
demonstrated safety and tolerability of Tyvaso DPI in patients with
PAH transitioning from Tyvaso® (treprostinil) Inhalation
Solution. A separate study in healthy volunteers demonstrated
comparable treprostinil exposure between Tyvaso DPI and Tyvaso
Inhalation Solution.
In its communications with United Therapeutics, the FDA
indicated that approval of the NDA will be subject to an inspection
of the Tyvaso DPI manufacturing facility operated by MannKind
Corporation; FDA and MannKind have jointly targeted the third
quarter of 2021 to complete the inspection.
About Tyvaso DPI™
Tyvaso DPI™ is an investigational drug-device combination
therapy comprised of a dry powder formulation of treprostinil and a
small, portable, dry powder inhaler. If approved, Tyvaso DPI is
expected to provide a more convenient method of administration
compared with traditional nebulized Tyvaso® therapy.
United Therapeutics is developing Tyvaso DPI under a collaboration
and license agreement with MannKind Corporation (Nasdaq: MNKD).
Tyvaso DPI incorporates the dry powder formulation technology and
Dreamboat® inhalation device technology used in
MannKind's Afrezza® (insulin human) Inhalation Powder
product, which was approved by the FDA in 2014.
United Therapeutics and MannKind are also developing
BluHale®, a Bluetooth-connected accessory for the Tyvaso
DPI inhaler with a companion mobile application intended to help
the patient track information about inhaler use.
About the BREEZE and healthy volunteer
PK studies
The BREEZE study was a single-sequence study in which 51
subjects on a stable regimen of Tyvaso Inhalation Solution were
transitioned to Tyvaso DPI at a corresponding treprostinil dose.
The primary objective of the study was to evaluate the safety and
tolerability of Tyvaso DPI during a three-week treatment phase in
PAH patients previously treated with Tyvaso Inhalation
Solution.
Secondary objectives of the study were to evaluate: (1) the
systemic exposure and pharmacokinetics of treprostinil when
delivered as Tyvaso Inhalation Solution and Tyvaso DPI; (2)
six-minute walk distance (6MWD) at study entry and after
three weeks of treatment with Tyvaso DPI; (3) the long-term safety
and tolerability of Tyvaso DPI during an optional extension phase
(OEP) in patients previously treated with Tyvaso Inhalation
Solution; (4) patient satisfaction with and preference for inhaled
treprostinil devices assessed at study entry when patients were
using Tyvaso Inhalation Solution and after three weeks using Tyvaso
DPI; and (5) patient-reported PAH symptoms and impact
(PAH-SYMPACT®) assessed at study entry when
patients were using Tyvaso Inhalation Solution and after three
weeks using Tyvaso DPI.
Primary safety and tolerability objective. Transition
from Tyvaso Inhalation Solution to Tyvaso DPI was safe and well
tolerated. Forty-nine out of 51 patients (96%) completed the
treatment phase and there were no study drug related adverse
events. Most adverse events experienced during the study were mild
to moderate in severity and occurred at severities and frequencies
consistent with those seen in other inhaled treprostinil studies in
patients with PAH.
Secondary objectives. Three weeks after switching from
Tyvaso Inhalation Solution to Tyvaso DPI, patients in the
BREEZE study demonstrated:
- Improvements in 6MWD compared to baseline. These improvements
in 6MWD compared to baseline were sustained in the OEP through the
data cut-off date.
- Improvements in overall satisfaction with the Tyvaso DPI
inhaler compared to the Tyvaso Inhalation Solution nebulizer at
baseline using an internally developed satisfaction and preference
questionnaire.
- Improvement in patient-reported outcomes using the validated
PAH-SYMPACT questionnaire.
Optional extension phase. Subjects in BREEZE were
given the opportunity to continue in an OEP. All subjects who
completed the treatment phase (49/51) elected to continue in the
OEP.
BREEZE PK observations. The
BREEZE study demonstrated comparable PK between Tyvaso
Inhalation Solution and Tyvaso DPI in PAH patients.
Detailed data from the BREEZE study will be presented in
upcoming publications and scientific conferences.
Healthy volunteer PK study. The healthy volunteer
pharmacokinetic (PK) study was a randomized six-period,
six-sequence crossover study of three dose levels of Tyvaso DPI and
three dose levels of Tyvaso Inhalation Solution in 36 healthy
volunteers. The primary objective of the study was to evaluate the
systemic exposure and PK of treprostinil administered as Tyvaso DPI
and Tyvaso Inhalation Solution. Secondary objectives of the study
evaluated the safety and tolerability of Tyvaso DPI.
Study results. Subjects demonstrated comparable systemic
treprostinil exposure for each corresponding Tyvaso DPI and Tyvaso
Inhalation Solution dose level. Between-subject variability for
both AUC0-5h and Cmax was approximately 50%
less for Tyvaso DPI compared to Tyvaso Inhalation Solution,
suggesting a more precise dosing profile for Tyvaso DPI relative to
nebulized Tyvaso.
Safety. The adverse event profile for Tyvaso DPI in
healthy volunteers was consistent with known prostacyclin effects
and previous studies of Tyvaso Inhalation Solution.
Detailed data from the healthy volunteer PK study will be
presented in upcoming publications and scientific conferences.
About PH-ILD
Interstitial lung disease (ILD) is a group of lung
diseases that are characterized by significant scarring or fibrosis
of the bronchioles and alveolar sacs within the lungs. Increased
fibrotic tissue in ILD prevents oxygenation and free gas exchange
between the pulmonary capillaries and alveolar sacs, and the
condition can present with a wide range of symptoms, including
shortness of breath with activity, labored breathing and fatigue.
Pulmonary hypertension (PH) frequently complicates the
course of patients with interstitial lung disease and is associated
with worse functional status measured by exercise capacity, greater
supplemental oxygen needs, decreased quality of life, and worse
outcomes.
An estimated 30,000 patients in the
United States may suffer from PH-ILD, which is included
within Group 3 of the World Health Organization (WHO)
classification of PH. Only Tyvaso Inhalation Solution is approved
to treat patients with this disease.
About PAH
Also known as World Health Organization (WHO) Group 1
Pulmonary Hypertension, Pulmonary arterial hypertension
(PAH) is life-threatening high blood pressure in the
arteries of the lungs, affecting the ability of the heart and lungs
to work properly in afflicted patients. PAH is a serious,
progressive disease for which there is no cure.
About TYVASO® (treprostinil) Inhalation
Solution
INDICATION
TYVASO (treprostinil) is a prostacyclin mimetic indicated for
the treatment of:
- Pulmonary arterial hypertension (PAH; WHO Group 1) to improve
exercise ability. Studies 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 controlled clinical experience
with inhaled treprostinil has been on a background of bosentan (an
endothelin receptor antagonist) or sildenafil (a phosphodiesterase
type 5 inhibitor). The controlled clinical experience 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 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 is a pulmonary and systemic vasodilator. In patients
with low systemic arterial pressure, TYVASO may produce symptomatic
hypotension.
- TYVASO inhibits platelet aggregation and increases 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.
DRUG INTERACTIONS/SPECIFIC POPULATIONS
- The concomitant use of TYVASO 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 in the
placebo-controlled study 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.
- 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 were similar to the
experience in studies of PAH.
Please see Full Prescribing Information, the TD-100 and
TD-300 TYVASO® Inhalation System Instructions for
Use manuals, and other additional information
at www.tyvaso.com or call 1–877–UNITHER
(1-877-864-8437).
United Therapeutics: Enabling Inspiration
United Therapeutics Corporation focuses on the strength of a
balanced, value-creating biotechnology model. We are confident in
our future thanks to our fundamental attributes, namely our
obsession with quality and innovation, the power of our brands, our
entrepreneurial culture, and our bioinformatics leadership. We also
believe that our determination to be responsible citizens – having
a positive impact on patients, the environment, and society – will
sustain our success in the long term.
Through our wholly owned subsidiary, Lung Biotechnology PBC, we
are focused on addressing the acute national shortage of
transplantable lungs and other organs with a variety of
technologies that either delay the need for such organs or expand
the supply. Lung Biotechnology is the first public benefit
corporation subsidiary of a public biotechnology or pharmaceutical
company.
Please visit unither.com to learn more.
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
relating to the timing and outcome of FDA review of our NDA for
Tyvaso DPI, our goal of serving 25,000 patients by 2025, the
potential benefits of Tyvaso DPI for patients, our ability to
create value and sustain our success in the long-term, and our
efforts to develop technologies that either delay the need for
transplantable organs or expand the supply 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 June 16, 2021 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 is a registered trademark of United Therapeutics
Corporation.
TYVASO DPI is a trademark of United Therapeutics
Corporation.
AFREZZA, BLUHALE, and DREAMBOAT are registered trademarks of
MannKind Corporation.
PAH-SYMPACT is a registered trademark of Actelion
Pharmaceuticals Ltd société anonyme.
For Further Information Contact:
Dewey Steadman at (202) 919-4097
Email: ir@unither.com
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SOURCE United Therapeutics Corporation