CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`214324Orig1s000
`
`CLINICAL REVIEW(S)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`NDA 214324
`Tyvaso DPI (inhaled treprostinil)
`
`Clinical/Decisional Memo
`Application Type NDA
`Application Number(s) 214324
`Priority or Standard Class 1 resubmission
`Submit Date(s) 12/23/22
`Received Date(s) 12/23/22
`PDUFA Goal Date 5/23/22
`Division/Office Division of Cardiology and Nephrology
`Author Name(s) Mary Ross Southworth through Norman Stockbridge
`Review Completion Date 5/23/22
`Established/Proper Name Treprostinil powder
`(Proposed) Trade Name Tyvaso DPI
`Applicant United Therapeutics
`Dosage Form(s) Single-use cartridges containing 16, 32, 48, or 64 mcg
`Applicant Proposed Dosing
`Oral inhalation in 4 separate, equally spaced treatment sessions
`Regimen(s)
`per day
`Applicant Proposed
`Pulmonary arterial hypertension (PAH; WHO Group 1) to
`Indication(s)/Population(s)
`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%).
`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%)
`Recommended Action Approval
`Recommended
`Same as proposed.
`Indication(s)/Population(s)
`(if applicable)
`
`CDER Clinical Review Template
`Version date: March 8, 2019 for all NDAs and BLAs
`
`1
`
`Reference ID: 4987747
`
`

`

`NDA 214324
`Tyvaso DPI (inhaled treprostinil)
`
`The original application for Tyvaso DPI received a complete response on 10/15/2021 because of
`deficiencies at a facility involved in producing the drug product. In that review cycle, the clinical
`review by Mitch Psotka (finalized 9/23/2021) recommended approval based on the submitted
`data. The sponsor has now resubmitted the application with updated facility information and
`OPQ advises that the facility deficiencies have been addressed and recommends approval.
`
`No new clinical data were included in the resubmission; however, during the original review
`cycle DCN became aware of a Citizens Petition (regulations.gov; FDA-2021-P-0714) submitted to
`the FDA that raised concerns about the pulmonary safety of fumaryl diketopiperazine (FDKP),
`an excipient included in Tyvaso DPI. An assessment of the Tyvaso DPI drug product in the
`original clinical review, did not indicate a safety concern.
`
`The excipient FDKP is also found in Afrezza, an FDA-approved form of inhaled insulin powder.
`The labeling for Afrezza includes warnings1,2 about the risk of acute bronchospasm in patients
`with chronic lung disease, a contraindication in patients with asthma or COPD, and instructions
`to screen patients for these conditions prior to initiation. The Petitioner argued there was a
`need for additional clinical data and specific statements in product labeling for Tyvaso DPI
`based on the assertion that FDKP is responsible for the acute bronchospasm observed in
`Afrezza’s clinical trials. In responding to the Citizens Petition, the Division assessed the need for
`further study and changes to the proposed labeling for the Tyvaso DPI product.
`
`Regarding the concern related to the excipient, the association between FDKP and Afrezza’s
`bronchospasm risk is speculative, and a causal role has not been established. In the view of
`
`1
`2
`
`CDER Clinical Review Template
`Version date: March 8, 2019 for all NDAs and BLAs
`
`2
`
`Reference ID: 4987747
`
`

`

`NDA 214324
`Tyvaso DPI (inhaled treprostinil)
`
`DCN, there is no need for further study or assessment of the risk given the lack of a clinical
`safety signal and the labeling for Tyvaso DPI, both described below.
`
`The small clinical trial (BREEZE)3 of Tyvaso DPI in patients with PAH which included patients
`with underlying respiratory co-morbidities reported no cases of bronchospasm. These data
`allow for adequate characterization of the safety profile and supports a positive benefit risk
`profile consistent with approval. This determination is unchanged from the previous clinical
`review.
`
`To understand more fully the pulmonary safety of Tyvaso DPI and implications for labeling,
`FDA’s Adverse Event Reporting system (FAERS) was searched for cases of acute bronchospasm
`associated with marketed Tyvaso inhalation solution (IS-treprostinil solution), which contains
`the same drug substance as Tyvaso DPI. Several cases of acute bronchospasm shortly after
`Tyvaso IS use were identified (see postmarketing review of 5/3/2022). Another prostaglandin
`(Ventavis, NDA 21779) is associated with bronchospasm. Despite the absence of bronchospasm
`cases with Tyvaso DPI at this time, bronchospasm has been identified as a potential risk for the
`class of inhaled prostaglandins. Tyvaso DPI will include the following in the Warnings and
`Precautions section of labeling:
`
` Bronchospasm
`5.4
`Like other inhaled prostaglandins, Tyvaso DPI may cause acute bronchospasm. Patients
`with asthma or 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 DPI.
`
`Including this warning in section 5 of labeling adequately informs prescribers about the risk and
`its mitigation. The indicated population for Tyvaso DPI would be expected to have undergone
`pulmonary diagnostics. The prescribers of Tyvaso DPI have expertise in managing pulmonary
`health and are expected to be knowledgeable about co-morbidities.
`
`Completed Reviews
`
`
`
`
`Integrated Quality Review (1/31/2022)-recommendation approval.
`Proprietary Name Review (2/17/2022)- support approval
`
`3 BREEZE included 51 patients with PAH (WHO Group 1) who were switched from Tyvaso
`inhalation solution to Tyvaso DPI and continued use of Tyvaso DPI for 3 weeks. In the study, no
`cases of bronchospasm were observed. Fourteen patients who participated in BREEZE had a
`baseline history of chronic lung disease, including asthma, ILD, and COPD. None of these
`patients, however, experienced bronchospasm or other SAEs. Further, 12 of these 14 patients
`remained in the open-label extension of BREEZE.
`
`CDER Clinical Review Template
`Version date: March 8, 2019 for all NDAs and BLAs
`
`3
`
`Reference ID: 4987747
`
`(b) (4)
`
`

`

`NDA 214324
`Tyvaso DPI (inhaled treprostinil)
`
` DMEPA labeling memos (2/18/2022)- support approval
`
`CDER Clinical Review Template
`Version date: March 8, 2019 for all NDAs and BLAs
`
`4
`
`Reference ID: 4987747
`
`Appears this way in original
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`MARY R SOUTHWORTH
`05/23/2022 07:17:38 AM
`
`NORMAN L STOCKBRIDGE
`05/23/2022 07:23:08 AM
`
`Reference ID: 4987747
`
`

`

`Clinical Review
`Mitchell Psotka, MD PhD
`NDA 214324
`Tyvaso DPI (treprostinil powder for inhalation)
`
`CLINICAL REVIEW
`Application Type 505(b)(1) NDA
`Application Number(s) 214324 / S0002
`Priority or Standard Priority
`Submit Date(s) 16 April 2021
`Received Date(s) 16 April 2021
`PDUFA Goal Date 16 October 2021
`Division/Office Division of Cardiology and Nephrology (DCN) / Office of
`Cardiology, Hematology, Endocrinology, and Nephrology
`(OCHEN) / Office of New Drugs (OND)
`Reviewer Name(s) Mitchell Psotka, MD PhD
`Review Completion Date 23 September 2021
`Established/Proper Name Treprostinil (powder)
`(Proposed) Trade Name Tyvaso DPI
`Applicant United Therapeutics
`Dosage Form(s) Single-use cartridges containing 16, 32, 48, or 64 mcg
`Applicant Proposed Dosing
`Oral inhalation in 4 separate, equally spaced treatment sessions
`Regimen(s)
`per day, during waking hours
`Applicant Proposed
`Indicated for the treatment of:
`Indication(s)/Population(s)
`•
`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%).
`•
`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%).
`Approval
`
`Recommendation on
`Regulatory Action
`Recommended
`Indication(s)/Population(s)
`(if applicable)
`
`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
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`1
`
`Reference ID: 4861620
`
`

`

`Clinical Review
`Mitchell Psotka, MD PhD
`NDA 214324
`Tyvaso DPI (treprostinil powder for inhalation)
`
`heritable PAH (56%) or PAH associated with connective tissue
`diseases (33%).
`•
`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%).
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`2
`
`Reference ID: 4861620
`
`

`

`Clinical Review
`Mitchell Psotka, MD PhD
`NDA 214324
`Tyvaso DPI (treprostinil powder for inhalation)
`
`Table of Contents
`
`Glossary ..........................................................................................................................................6
`
`1.
`
`Executive Summary.................................................................................................................8
`1.1.
`Product Introduction........................................................................................................8
`1.2.
`Conclusions on the Substantial Evidence of Effectiveness...............................................8
`1.3.
`Benefit-Risk Assessment ..................................................................................................9
`1.4.
`Patient Experience Data.................................................................................................16
`
`2. Regulatory Background .........................................................................................................17
`2.1. U.S. Regulatory Actions and Marketing History.............................................................17
`
`3.
`
`Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on
`Efficacy and Safety ................................................................................................................17
`3.1. Nonclinical Pharmacology/Toxicology ...........................................................................17
`
`4. Review of Relevant Individual Trials Used to Support Efficacy .............................................17
`4.1.
`BREEZE (TIPPH101).........................................................................................................17
`4.1.1. Study Design ...........................................................................................................17
`4.1.2. Study Results ..........................................................................................................20
`
`5. Review of Safety....................................................................................................................31
`5.1.
`Safety Results.................................................................................................................32
`5.2. Analysis of Submission-Specific Safety Issues ................................................................32
`
`6.
`
`Labeling Recommendations ..................................................................................................34
`6.1.
`Prescription Drug Labeling.............................................................................................34
`
`7. Appendices............................................................................................................................35
`7.1.
`Financial Disclosure........................................................................................................35
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`3
`
`Reference ID: 4861620
`
`

`

`Clinical Review
`Mitchell Psotka, MD PhD
`NDA 214324
`Tyvaso DPI (treprostinil powder for inhalation)
`
`Table of Tables
`
`Table 1. Benefit-Risk Integrated Assessment ...............................................................................10
`Table 2. Patient Experience Data Relevant to this Application ....................................................16
`Table 3. Treprostinil Dose Conversion Assignments.....................................................................18
`Table 4. Patient Disposition.........................................................................................................23
`Table 5. Demographic and Baseline Characteristics for Patients in the BREEZE Study ................24
`Table 6. Treatment Adherence in the Treatment Phase .............................................................26
`Table 7. 6-Minute Walk Test Distance at Baseline and Week 3 in BREEZE...................................26
`Table 8. 6-Minute Walk Test Distance Difference at Week 3 in BREEZE ......................................27
`Table 9. 6-Minute Walk Test Distance by Treprostinil Dose in BREEZE........................................28
`Table 10. PAH-SYMPACT Scores at Baseline and Week 3 in BREEZE ............................................31
`Table 11. Summary of Adverse Events in BREEZE.........................................................................33
`Table 12. Adverse Events >5% by System Organ Class and Treatment Dose ...............................33
`Table 13. Adverse Event Profile for Treprostinil Inhaled Liquid Formulation in TRIUMPH I (from
`the Tyvaso Label)..........................................................................................................................34
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`4
`
`Reference ID: 4861620
`
`

`

`Clinical Review
`Mitchell Psotka, MD PhD
`NDA 214324
`Tyvaso DPI (treprostinil powder for inhalation)
`
`Table of Figures
`
`Figure 1. Study Design Schematic.................................................................................................19
`Figure 2. Study Schedule of Events...............................................................................................19
`Figure 3. Study Patient Disposition Flow Diagram........................................................................22
`Figure 4. Mean Treprostinil Concentration versus Time (Linear) .................................................29
`Figure 5. Mean Treprostinil Concentration versus Time (semi-log) .............................................30
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`5
`
`Reference ID: 4861620
`
`

`

`Clinical Review
`Mitchell Psotka, MD PhD
`NDA 214324
`Tyvaso DPI (treprostinil powder for inhalation)
`
`Glossary
`
`6MWD
`AC
`AE
`AR
`BLA
`BPCA
`BRF
`CBER
`CDER
`CDRH
`CDTL
`CFR
`CMC
`COSTART
`CRF
`CRO
`CRT
`CSR
`CSS
`DMC
`ECG
`eCTD
`ETASU
`FDA
`FDAAA
`FDASIA
`GCP
`GRMP
`ICH
`IND
`ISE
`ISS
`ITT
`IQR
`MedDRA
`mITT
`
`6-minute walk test distance
`advisory committee
`adverse event
`adverse reaction
`biologics license application
`Best Pharmaceuticals for Children Act
`Benefit Risk Framework
`Center for Biologics Evaluation and Research
`Center for Drug Evaluation and Research
`Center for Devices and Radiological Health
`Cross-Discipline Team Leader
`Code of Federal Regulations
`chemistry, manufacturing, and controls
`Coding Symbols for Thesaurus of Adverse Reaction Terms
`case report form
`contract research organization
`clinical review template
`clinical study report
`Controlled Substance Staff
`data monitoring committee
`electrocardiogram
`electronic common technical document
`elements to assure safe use
`Food and Drug Administration
`Food and Drug Administration Amendments Act of 2007
`Food and Drug Administration Safety and Innovation Act
`good clinical practice
`good review management practice
`International Council for Harmonization
`Investigational New Drug Application
`integrated summary of effectiveness
`integrated summary of safety
`intent to treat
`interquartile range
`Medical Dictionary for Regulatory Activities
`modified intent to treat
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`6
`
`Reference ID: 4861620
`
`

`

`Clinical Review
`Mitchell Psotka, MD PhD
`NDA 214324
`Tyvaso DPI (treprostinil powder for inhalation)
`
`NCI-CTCAE
`NDA
`NME
`OCS
`OPQ
`OSE
`OSI
`PAH
`PBRER
`PD
`PH-ILD
`PI
`PK
`PMC
`PMR
`PP
`PPI
`PREA
`PRO
`PSUR
`REMS
`SAE
`SAP
`SGE
`SOC
`TEAE
`WHO
`
`National Cancer Institute-Common Terminology Criteria for Adverse Event
`new drug application
`new molecular entity
`Office of Computational Science
`Office of Pharmaceutical Quality
`Office of Surveillance and Epidemiology
`Office of Scientific Investigation
`pulmonary arterial hypertension
`Periodic Benefit-Risk Evaluation Report
`pharmacodynamics
`pulmonary hypertension associated with interstitial lung disease
`prescribing information or package insert
`pharmacokinetics
`postmarketing commitment
`postmarketing requirement
`per protocol
`patient package insert
`Pediatric Research Equity Act
`patient reported outcome
`Periodic Safety Update report
`risk evaluation and mitigation strategy
`serious adverse event
`statistical analysis plan
`special government employee
`standard of care
`treatment emergent adverse event
`World Health Organization
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`7
`
`Reference ID: 4861620
`
`

`

`Clinical Review
`Mitchell Psotka, MD PhD
`NDA 214324
`Tyvaso DPI (treprostinil powder for inhalation)
`
`1. Executive Summary
`
`Product Introduction
`
`1.1.
`
`Treprostinil is a prostacyclin mimetic currently indicated for the treatment of WHO group I
`pulmonary arterial hypertension (PAH) as an intravenous (REMODULIN®), subcutaneous
`(REMODULIN®), oral (ORENITRAM™), and inhaled liquid formulation (TYVASO®), as well as WHO
`group III pulmonary hypertension associated with interstitial lung disease (PH-ILD) as an inhaled
`liquid formulation (TYVASO®), to improve exercise ability. Pharmacologically, treprostinil causes
`direct vasodilation of pulmonary and systemic arterial vascular beds and inhibits platelet
`aggregation, decreasing pulmonary artery pressure.
`
`The current dosing regimen of the Treprostinil inhaled liquid formulation (TYVASO®) is to
`initiate at 3 breaths of approximately 6 mcg of treprostinil each, or 18 mcg per session, in 4
`separate treatment sessions each day approximately 4 hours apart, during waking hours. If 3
`breaths are not tolerated the dose can be reduced to 1 or 2 breaths. The dosage should be
`increased every 1-2 weeks by 3 additional breaths to a target maintenance dose of 9-12 breaths
`(54-72 mcg) per treatment session, if tolerated. The current liquid formulation is available in 2.9
`mL ampules containing 1.74 mg of treprostinil.
`
`Treprostinil inhaled powder formulation (TYVASO DPI™) contains the identical drug substance
`as the inhaled liquid formulation (TYVASO®) and is submitted with a proposed indication
`identical to the approved indication for (TYVASO®), specifically for the treatment of WHO group
`I PAH and WHO group III PH-ILD to improve exercise capacity. TYVASO DPI™ is submitted as a
`drug-device combination product with the Tyvaso DPI Inhaler, which is comprised of single-use
`cartridges containing a powder formulation of treprostinil and a hand-held reusable breath-
`powered inhaler. The single use cartridges contain 16, 32, 48, or 64 mcg of treprostinil powder
`for inhalation.
`
`The proposed dosing regimen of treprostinil inhaled powder (TYVASO DPI™) is to initiate at one
`16 mcg cartridge per treatment session, in 4 separate treatment sessions each day
`approximately 4 hours apart, during waking hours. The dosage should be increased every 1-2
`weeks by an additional 16 mcg cartridge per treatment session. The sponsor did not propose a
`.
`
`Conclusions on the Substantial Evidence of Effectiveness
`
`1.2.
`
`Substantial evidence of effectiveness for the drug product treprostinil administered by
`inhalation has been previously concluded based on the liquid formulation in the 12-week,
`placebo-controlled TRIUMPH I study of 235 patients with WHO group I PAH, and in the 16-
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`8
`
`Reference ID: 4861620
`
`(b) (4)
`
`

`

`Clinical Review
`Mitchell Psotka, MD PhD
`NDA 214324
`Tyvaso DPI (treprostinil powder for inhalation)
`
`week, placebo-controlled INCREASE study of 326 patients with WHO group III PH-ILD, where
`treated patients had increased exercise capacity as measured by 6-minute walk test distance
`compared to placebo.
`In the BREEZE study included in this submission, patients on a stable regimen of inhaled
`liquid treprostinil were transitioned to an approximate corresponding dose of open-label
`inhaled treprostinil powder (TYVASO-DPI) and followed initially for 3 weeks. The switch from
`inhaled Treprostinil liquid to the inhaled powder formulation was not associated with a
`decrement in exercise capacity as measured by the 6-minute walk test distance.
`
`1.3.
`
`Benefit-Risk Assessment
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`9
`
`Reference ID: 4861620
`
`Appears this way in original
`
`

`

`Clinical Review
`Mitchell Psotka, MD PhD
`NDA 214324
`Tyvaso DPI (treprostinil powder for inhalation)
`
`Table 1. Benefit-Risk Integrated Assessment
`
`Benefit-Risk Integrated Assessment
`
`Evidence for the safety and effectiveness of the drug product treprostinil when administered by inhalation comes from the liquid formulation
`(TYVASO®) used in the 12-week, placebo-controlled TRIUMPH I study of 235 patients with WHO group I PAH, and in the 16-week, placebo-
`controlled INCREASE study of 326 patients with WHO group III PH-ILD. In these studies, treatment with treprostinil inhaled liquid demonstrated
`a placebo-corrected median change in peak 6-minute walk test distance (6MWD) of 20 meters after 12 weeks for patients with WHO group I
`PAH and a placebo-corrected median change in peak 6MWD of 21 meters after 16 weeks for patients with WHO group III PH-ILD. No additional
`studies evaluating the effectiveness of the treprostinil inhaled powder formulation were submitted for the current review.
`
`The safety and tolerability of the treprostinil inhaled powder formulation (TYVASO DPI™) was studied in the 3-week open-label BREEZE study
`wherein 51 patients with WHO group I PAH treated with stable doses of treprostinil inhaled liquid were transitioned to a similar dose of
`treprostinil inhaled powder. Pharmacokinetic testing demonstrated similar AUCs for all doses between the treprostinil inhaled liquid
`formulation and powder formulation, although the Cmax for the inhaled powder formulation was greater than 120% of the liquid formulation
`for all doses. However, in the BREEZE study there was no clinically significant change in 6-minute walk test distance, patient-reported outcome
`assessment, or increase in adverse events associated with the transition from treprostinil inhaled liquid to treprostinil inhaled powder. Two
`patients (3.9%) withdrew from the 3-week study due to treatment-related adverse events of dyspnea and globus pharyngus, and 3 additional
`patients (4.1%) withdrew in the open-label optional extension phase due to treatment-related adverse events of dyspnea and chest pain.
`Otherwise, the prevalence of adverse events was similar to those reported in the TRIUMPH I study of the treprostinil inhaled liquid formulation,
`with the most common being cough and headache.
`
`Fumaryl diketopiperazine (FDKP), an excipient of TYVASO DPI™ also contained in the approved human insulin powder (AFREZZA®), was
`comprehensively evaluated as a potential etiology of acute bronchospasm listed as a black-box warning for patients with chronic lung disease in
`the AFREZZA® label. However, the labelled black box warning does not specify whether the excipient or drug product may be responsible for
`concern for increased risk of bronchospasm. Pulmonary function testing did not implicate the excipient as a major cause of pulmonary
`dysfunction during the evaluation of that product. In addition, no reports of serious bronchospasm were identified during the 3-year
`assessment for the Risk Evaluation and Mitigation Strategy (REMS) for AFREZZA®.
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`10
`
`Reference ID: 4861620
`
`

`

`Clinical Review
`Mitchell Psotka, MD PhD
`NDA 214324
`Tyvaso DPI (treprostinil powder for inhalation)
`
`The exposure to the excipient FDKP by the treprostinil inhaled powder formulation appears acceptable, as the AFREZZA® maximal dose of co-
`administered FDKP is
` mg and the co-administered dose of FDKP in the 64 mcg cartridge of treprostinil inhaled powder is
` mg. The
`BREEZE clinical trial of treprostinil inhaled powder with the excipient FDKP included patients with asthma, chronic obstructive pulmonary
`disease, and interstitial lung disease, and there were no bronchospastic adverse events reported during the 3-week randomized follow-up
`period, nor during the optional extension phase.
`
`Dimension
`
`Analysis of
`Condition
`
`Benefit-Risk Dimensions
`Evidence and Uncertainties
` Pulmonary hypertension manifest as WHO group I (Pulmonary arterial
`hypertension [PAH]) and WHO group III (pulmonary hypertension
`associated with interstitial lung disease [PH-ILD]), is a pathologic
`elevation in pulmonary vascular resistance and pulmonary artery
`pressures which impair right ventricular function and may cause
`heart failure and death despite currently available therapies.
` Pulmonary vasodilators used in combination are standard of care,
`including PDE5 inhibitors, Endothelin receptor antagonists,
`Prostacyclin analogs and mimetics, and a Soluble guanylate cyclase
`stimulator. These agents reduce pulmonary artery pressure with
`associated improvements in exercise capacity, and some improve
`time to clinical worsening, but there is not robust evidence that
`they improve survival for patients with PAH or PH-ILD.
` Treprostinil is a prostacyclin mimetic that causes direct pulmonary
`vascular and systemic arterial vasodilation as well as inhibits
`platelet aggregation. Following inhalation of treprostinil in a liquid
`formulation, pulmonary artery pressure decreases, however
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`Current
`Treatment
`Options
`
`Reference ID: 4861620
`
`Conclusions and Reasons
`WHO group I PAH and WHO group III PH-ILD
`are serious chronic medical conditions that
`cause substantial morbidity and mortality.
`
`Currently available therapies for WHO group I
`PAH and WHO group III PH-ILD incompletely
`reduce risk for serious morbidity and mortality.
`
`11
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`Mitchell Psotka, MD PhD
`NDA 214324
`Tyvaso DPI (treprostinil powder for inhalation)
`
`Dimension
`
`Evidence and Uncertainties
`patients may find this formulation difficult to regularly administer.
`
`Conclusions and Reasons
`
`The applicant seeks approval for a novel
`formulation of liquid treprostinil based on a
`demonstration of pharmacokinetic
`bioequivalence. Relative bioavailability
`requirements set forth in §21 CFR 320.24
`appear to be met by the treprostinil inhaled
`powder formulation, and no additional
`evidence of effectiveness was submitted with
`this application.
`
`Benefit
`
` No additional evidence for effectiveness was submitted as part of the
`application for treprostinil inhaled powder (TYVASO DPI™). The
`application relies on the evidence from the approved formulations of
`treprostinil, including those currently indicated for the treatment of
`WHO group I pulmonary arterial hypertension (PAH) as an
`intravenous (REMODULIN®), subcutaneous (REMODULIN®), and
`inhaled liquid formulation (TYVASO®), as well as WHO group III
`pulmonary hypertension associated with interstitial lung disease (PH-
`ILD) as an inhaled liquid formulation (TYVASO®), to improve exercise
`ability.
` Evidence for the safety and effectiveness of the drug product
`treprostinil administered by inhalation comes from the liquid
`formulation (TYVASO®) used in the 12-week, placebo-controlled
`TRIUMPH I study of 235 patients with WHO group I PAH, and in the
`16-week, placebo-controlled INCREASE study of 326 patients with
`WHO group III PH-ILD. In these studies, treatment with treprostinil
`inhaled liquid demonstrated a placebo-corrected median change in
`peak 6-minute walk test distance (6MWD) of 20 meters after 12
`weeks for patients with WHO group I PAH and a placebo-corrected
`median change in peak 6MWD of 21 meters after 16 weeks for
`patients with WHO group III PH-ILD.
` Evidence for relative bioavailability comes from a 6-treatment, 6-
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`12
`
`Reference ID: 4861620
`
`

`

`Clinical Review
`Mitchell Psotka, MD PhD
`NDA 214324
`Tyvaso DPI (treprostinil powder for inhalation)
`
`Dimension
`
`Risk and Risk
`Management
`
`Evidence and Uncertainties
`period, 6-sequence, crossover study of TYVASO® and TYVASO DPI™ in
`36 healthy volunteers. Treprostinil systemic exposure following
`inhalation of TYVASO DPI™ demonstrated similar AUCs for all doses
`compared to the treprostinil inhaled liquid (TYVASO®) formulation,
`although the Cmax for the inhaled powder formulation was greater
`than 120% of the liquid formulation for all tested doses.
` The current label for treprostinil inhaled liquid (TYVASO®) describes
`the following adverse reactions:
`o Warnings and Precautions: Tyvaso may cause symptomatic
`hypotension. Tyvaso inhibits platelet aggregation and
`increases the risk of bleeding. Tyvaso dosage adjustments
`may be necessary if inhibitors or inducers of CYP2C8 are
`added or withdrawn.
`o Adverse Reactions: Most common adverse reactions (≥4%)
`are cough, headache, nausea, dizziness, flushing, throat
`irritation, pharyngolaryngeal pain, diarrhea, and syncope
` The safety of the excipient fumaryl diketopiperazine (FDKP) in TYVASO
`DPI™ was comprehensively evaluated as part of the approved
`(AFREZZA®) inhaled human insulin powder application. The
`AFREZZA® label carries a black-box warning for risk of acute
`bronchospasm in patients with chronic lung disease. Nevertheless:
`o Pulmonary function testing did not implicate the excipient as
`a major cause of pulmonary dysfunction during the
`evaluation of AFREZZA®
`o No reports of serious bronchospasm were identified during
`the 3-year assessment for the Risk Evaluation and Mitigation
`
`Conclusions and Reasons
`
`No new risks associated with treprostinil
`formulated as an inhaled powder (TYVASO
`DPI™) were identified in the BREEZE study.
`
`There was no evidence implicating the
`excipient FDKP as an etiology of adverse
`events.
`
`Despite the limitations of short follow-up and
`small size of the BREEZE study, labelling is
`considered sufficient to ensure that the
`benefits outweigh the risks for treprostinil
`inhaled powder (TYVASO DPI™) in the target
`populations.
`
`CDER Clinical Review Template
`Version date: September 6, 2017 for all NDAs and BLAs
`
`13
`
`Reference ID: 4861620
`
`

`

`Conclusions and Reasons
`
`Clinical Review
`Mitchell Psotka, MD PhD
`NDA 214324
`Tyvaso DPI (treprostinil powder for inhalation)
`
`Dimension
`
`Evidence and Uncertainties
`Strategy (REMS) for AFREZZA®
`o The exposure to the excipient FDKP by the treprostinil
`inhaled powder formulation (
` mg in the highest TYVASO
`DPI™