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

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`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
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`NDA or BLA Number
`Link to EDR
`Submission Date
`Submission Type
`Brand Name
`Generic Name
`Dosage Form and Strength
`
`Route of Administration
`Proposed Indication
`
`Applicant
`Associated IND
`OCP Review Team
`
`
`214324
`\\Cdsesub1\evsprod\NDA214324
`04/16/2021
`Priority review
`Tyvaso DPI®
`Treprostinil Inhalation Powder (TreT)
`Inhalation powder: Single-dose cartridges
`containing 16 µg, 32 µg, 48 µg, or 64 µg of
`treprostinil as a dry powder formulation for
`oral inhalation.
`Inhalation
`Pulmonary arterial hypertension to improve
`exercise ability. Pulmonary hypertension
`associated with interstitial lung disease to
`improve exercise ability.
`United Therapeutics Corporation
`IND134582
`Xiaomeng Xu, Manoj Khurana
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`Reference ID: 4862210
`
`NDA 214324
`Tyvaso DPI ® (Treprostinil Inhalation Powder)
`Page 1 of 14
`
`

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`TABLE OF CONTENTS
`
`
`
`1. EXECUTIVE SUMMARY ......................................................................................... 3
`1.1 RECOMMENDATIONS ..................................................................................................3
`1.2 SUMMARY OF IMPORTANT CLINICAL PHARMACOLOGY FINDINGS ..................................3
`2. QUESTION BASED REVIEW ..................................................................................... 4
`2.1 GENERAL ATTRIBUTES .......................................................................................................4
`2.2 GENERAL CLINICAL PHARMACOLOGY .................................................................................4
`2.3 ANALYTICAL SECTION .....................................................................................................10
`3. DETAILED LABELING RECOMMENDATIONS .................................................. 12
`
`4. APPENDIX .................................................................................................................... 14
`4.1 PROPOSED LABELING ..................................................................................................14
`
`
`
`Reference ID: 4862210
`
`NDA 214324
`Tyvaso DPI ® (Treprostinil Inhalation Powder)
`Page 2 of 14
`
`

`

`1. Executive Summary
`
`The Applicant, United Therapeutics Corporation, has submitted this 505(b)(1) NDA 214324
`seeking approval for TreT (Tyvaso DPI®), a treprostinil inhalation powder, intended to treat
`pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial
`lung disease to improve exercise ability. It is a new dosage form for treprostinil being a dry powder
`for oral inhalation (Tyvaso DPI®) compared to the solution for oral inhalation (Tyvaso®; NDA
`022387, US Approval 2002) currently marketed by the same sponsor.
`
`The NDA package for Tyvaso DPI® was received by the Agency on April 16, 2021 under a priority
`review with the PDUFA date of October 16, 2021.
`
`The applicant submitted three clinical studies, including a single dose-escalation Study MKC-475-
`001 in healthy subjects, an open-label Study TIP-PH-101 assessing safety and tolerability of TreT
`in subjects with PAH currently using Tyvaso, as well as a relative bioavailability and
`bioequivalence (BA/BE) study TIP-PH-102 between TreT and Tyvaso in healthy subjects.
`
`1.1 RECOMMENDATIONS
`
`The Office of Clinical Pharmacology/Division of Cardiometabolic and Endocrine Pharmacology
`(OCP/DCEP) has reviewed NDA 214324 submitted on 4/16/2021 and finds it acceptable to
`support approval.
`
`
`
`1.2 SUMMARY OF IMPORTANT CLINICAL PHARMACOLOGY FINDINGS
`
`The clinical pharmacological findings of this application rely on the results from the relative
`BA/BE study TIP-PH-102 and supported by the open-label study TIP-PH-101. Study MKC-475-
`001 dose not contribute to the systemic exposure comparison of TreT and Tyvaso, however, was
`reviewed only for supportive information for the dose proportionality assessment.
`
`• TIP-PH-102: a 6-period crossover study comparing systemic exposure of 3 doses (16, 48, 64
`µg) of TreT and 3 doses (18, 54, 72 µg) of Tyvaso in healthy volunteers. The TreT product
`doses of 16, 48, and 64 µg were claimed to provide similar systemic exposure to Tyvaso 18,
`54, and 72 µg, selected to accommodate the design and delivery differences between the two
`inhalation products.
`
`• TIP-PH-101: an open-label study to evaluate the safety and tolerability of TreT in subjects
`with PAH currently using Tyvaso. TreT was administered for three consecutive weeks, where
`the safety, clinical effect, as well as the exposure of TreT at the end of week 3 were evaluated.
`
`The key results from the relative BA/BE study TIP-PH-102 are as followings:
`
`• Cmax of TreT were consistently higher (24% to 39%) than Tyvaso (geometric mean ratios of
`TreT / Tyvaso and 90% CI were not within 80 - 125% bounds) across three tested does (low-,
`mid-, and high-dose levels of 16 µg TreT vs 18 µg Tyvaso, 48 µg TreT vs 54 µg Tyvaso, and
`64 µg TreT vs 72 µg Tyvaso, respectively).
`
`• AUC0-5hr of TreT and Tyvaso was comparable at mid- and high- dose levels. Whereas the
`AUC0-5hr ratio for low-dose level (i.e., 16 µg TreT versus 18 µg Tyvaso) was 15% higher.
`
`
`Reference ID: 4862210
`
`NDA 214324
`Tyvaso DPI ® (Treprostinil Inhalation Powder)
`Page 3 of 14
`
`

`

`• The safety data (though limited) from the single and multiple dose studies did not indicate any
`notable respiratory adverse events (AEs) difference between TreT and Tyvaso.
`
`Given that clinical use of TreT involves titration to therapeutic goal and the observations on
`respiratory AEs, which were comparable between TreT and Tyvaso across all doses, the higher
`Cmax level of TreT in the context of comparable overall AUC (except the modest deviation at the
`lowest tested dose) do not appear to be clinically relevant.
`
`
`
`2. QUESTION BASED REVIEW
`
`2.1 GENERAL ATTRIBUTES
`
`2.1.1 What pertinent regulatory background or history contributes to the current assessment
`of the clinical pharmacology of Tyvaso DPI®, treprostinil inhalation powder (TreT)?
`
`The Applicant, United Therapeutics Corporation, submitted this 505(b)(1) application for Tyvaso
`DPI®, intended for the treatment of PAH and pulmonary hypertension associated with interstitial
`lung disease to improve exercise ability. The proposed dose regimen: to initiate Tyvaso DPI® from
`16 µg per treatment, 4 separate treatment sessions each day, and to increase by additional 16 µg
`per treatment session at approximately 1- to 2- week intervals, if tolerated.
`
`The main objective of this 505(b)(1) NDA review is to provide evaluations of Study TIP-PH-102,
`which aimed to compare the systemic exposure of TreT and Tyvaso, as well as study TIP-PH-101,
`where the efficacy, safety, and tolerability of TreT were assessed. Tyvaso® was originally
`approved in 2002 under NDA 022387, intended for the treatment of PAH to improve exercise
`ability, as well as pulmonary hypertension associated interstitial lung disease to improve exercise
`ability. United Therapeutics Corporation is seeking approval of Tyvaso DPI® for the same
`indication as Tyvaso®.
`
`2.2 GENERAL CLINICAL PHARMACOLOGY
`
`2.2.1 What general clinical pharmacology features of treprostinil are relevant to the current
`submission?
`
`Three studies containing clinical pharmacology information were submitted in the current
`submission, including a single dose-escalation study MKC-475-001, an open-label study TIP-PH-
`101, and a relative BA/BE study TIP-PH-102. Food effect study, drug-drug interaction study, as
`well as special population study were not conducted in the current submission. For details on the
`general clinical pharmacology of treprostinil, readers are referred to the original NDA 022387
`review for Tyvaso®.
`
`
`
`2.2.2 Is the systemic exposure of Tyvaso DPI ® (treprostinil inhalation powder, TreT)
`comparable to that of Tyvaso® (treprostinil inhalation solution, Tyvaso) according to the
`data from the relative BA/BE study TIP-PH-102?
`
`
`
`
`Reference ID: 4862210
`
`NDA 214324
`Tyvaso DPI ® (Treprostinil Inhalation Powder)
`Page 4 of 14
`
`

`

`The data from the relative BA/BE study TIP-PH-102 showedthat a higher Cmax of TreT was
`observed from all the tested dose levels, where geometric mean ratios of TreT / Tyvaso and 90%
`CI were not within 80 - 125% bounds (Table 1). Though the AUCo-snr of TreT and Tyvaso at mid-
`and high-dose levels were comparable, the AUCo-snr for low-dose level was about 15% higher.
`
`The relative BA/BE study TIP-PH-102 was a 6-period crossover study comparing systemic
`exposure of 3 doses (16, 48, 64 ug) of TreT and 3 doses (18, 54, 72 1g) of Tyvaso in healthy
`volunteers. Such dose levels were chosen based on the PK results from study TIP-PH-101, where
`three dose ranges of Tyvaso were tested, including 36-42 t1g (6-7 breaths) Tyvaso vs 32 pg TreT,
`54-60 tg (8-10 breaths) Tyvaso vs 48 tg TreT, and 66-72 rg (11-12 breaths) Tyvaso vs 64 ng
`TreT. Total of 36 healthy male and female subjects aged from 21 to 55 were included. The primary
`objective was to evaluate the systemic exposure and pharmacokinetics (PK) of treprostinil
`admunistered as treprostinil inhalation powder (TreT)andtreprostinil inhalation solution (Tyvaso).
`Subject received a single dose of the study drug per treatment period followed by a washout period
`of either 24 or 48 hrs (approximately) prior to the next dose. PK samples were collected up to 5
`hrs post-dose.
`
`All 36 subjects were included in the PK population. The applicant conducted noncompartmental
`analysis and reported the corresponding PK parameters including AUCo-str, AUCo-int, Cmax Tmax,
`and ti for each tested dose level of TreT and Tyvaso. Bioequivalence procedures were used to
`compare the exposure of TreT and Tyvasofor each tested dose level by using AUCo-shr and Cmax
`as the primary PK parameters.
`
`The applicant reported that for AUCo-snr, the geometric least squares mean (GLSM) ratios for the
`low-, mid-, and high-dose comparisons were 115% (90% CI: 104.59, 127.42), 101% (90% CI:
`91.63, 111.65), and 91.5% (90% CI: 83.16, 100.78), respectively. Cmax values of treprostinil for
`TreT were higher than Tyvaso across matched-dose comparisons. The GLSM ratios of Cmax for
`the low-, mid-, and high-dose comparisons were 130% (90% CI: 115.55, 145.95), 139% (90% CI:
`124.13, 156.73), and 124% (90% CI: 110.56, 139.61), respectively.
`
`The study conduct per the review of study report (clinical and bioanalytical) was reasonable to
`teliably support the study findings. The study findings for treprostinil were reanalyzed and
`confirmed by the clinical pharmacology reviewer using SAS® (version 9.4), where AUCo-inr was
`also included for comparison (Table 1).
`
`Table 1. Summary of the Systemic Exposure Comparison of Treprostinil from TreT and
`Tyvaso from Study TIP-PH-102 (Geometric Least Squares Mean Ratio of TreT vs Tyvaso
`and 90% Confidence Intervals) (n=36)
`
`TreT 16 ptg vs Tyvaso 18 pg|AUCo-shr
`TreT 48 tg vs Tyvaso 54 pg|AUCo-shr
`TreT 64 tg vs Tyvaso 72 wg|AUCo-shr
`TreT 16 tg vs Tyvaso 18 pg
`TreT 48 tg vs Tyvaso 54 ug
`TreT 64
`ug vs Tyvaso 72 ug
`
`%Ratio TreT/Tyvaso |CI90 Lower|CI90 Upper
`
`TreT 64 tg vs Tyvaso 72 ig
`
`TreT 16 tg vs Tyvaso 18 pg
`TreT 48 pg vs Tyvaso 54 pg
`
`Reference ID: 4862210
`
`NDA214324
`
`Tyvaso DPI ® (Treprostinil Inhalation Powder)
`Page 5 of 14
`
`

`

`The Cmax of TreT is higher than Tyvaso across the studied dose levels (Figures 1 and 2). The peak
`concentrations of treprostinil for TreT and Tyvaso wereattained with a median Tmax of 0.17 — 0.25
`hr (ranged from 0.08 to 0.52 hr). The AUCo-int of TreT and Tyvaso were comparable at mid- and
`high- dose levels, whereas the AUCo-int ratio for the low-dose level was 17% higher.
`
`Figure 1. Plasma Treprostinil Concentration — Time Profiles (Mean and Standard Error) of
`TreT (Solid Blue Line) and Tyvaso (Dashed Red Line)
`
`© TreT 16ug
`Tyraso 18 ug
`
`(ngimL)
`Mean(+SE)PlasmeTrepostinil
`
`
`
`
`
`Mean(+SE)PlasmaTreposiinil(ngimL)
`
`
`
`
`
`( TreT #8 ug
`
`(ngimL)
`~ Tyeaso 54 ug Mean(+SE)
`
`PlasmaTrepostinil
`
`Time (hr)
`
`Time (hr)
`
`Figure 2. Box-Plot for the PK Parameters (Cmax and AUCo-snr) Comparison of TreT and
`Tyvaso by Dose Levels (16 pg TreT vs 18 ng Tyvaso, 48 ng TreT vs 54 Tyvaso ng, 64 ng TreT
`vs 72 ug Tyvaso)
`2.50 & TreT ug
`@ Tyvaso 15 ug
`@ TreT 46ug
`
`1 Tywaso 72 ug
`
`TreT 16 ug vs. Tyvase 18 ug
`
`TroT 48 ug vs. Tyvaso 54 ug
`Comparison Treatment Groups
`
`TroT 64 ug vs. Tyvaso72 ug
`
`—|
`
`L.
`
`TroT 48 ug vs. Tyvaso 54 ug
`Comparison Treatment Groups
`
`TreT 64 ug vs. Tyvaso72 ug
`
`NDA 214324
`Tyvaso DPI ® (Treprostinil Inhalation Powder)
`Page 6 of 14
`
`@ TreT 6 ug
`@ Tyvaso 15ug
`@ TreT 48 ug
`1 Tyvano 64 ug
`1B Tyas 724
`
`=
`
`TreT 16 ug vs. Tyvase 18 ug
`
`
`
`Cmax(ng/mL)
`
`
`
`AUCO-5(h'ng/mL)
`
`Reference ID: 4862210
`
`

`

`In conclusion, data from the relative BA/BE Study TIP-PH-102 indicated a higher Cmax of
`treprostinil from TreT than Tyvaso, and a comparable overall AUC (except the modest deviation
`at the low-dose level).
`
`The conclusions from Study TIP-PH-102 were generally consistent with the data collected from
`the open label study TIP-PH-101,
`in which PAH patients who were on stable Tyvaso
`administration transferred to TreT for three consecutive weeks. PK assessment were conducted at
`baseline with a dose of Tyvaso administration and at the end of week 3 with a dose of TreT
`admunistration. Three dose levels were tested in Study TIP-PH-101, including 32 pg TreT vs 36-
`42 wg (6-7 breaths) Tyvaso, 48 ug TreT vs 54-60 pg (8-10 breaths) Tyvaso, and 64 tg TreT vs
`66-72 wg (11-12 breaths) Tyvaso.
`
`Cmax was found to be consistently higher following TreT dosing than Tyvaso across the studied
`dose levels. Geometric mean Cmax was 38% and 36% higher, respectively, following 48 1g and 64
`ug TreT dosing, compared to 54-60 1g (8-10 breaths) and 66-72 yg (11-12 breaths) Tyvaso,
`respectively (Table 2). Since there were only 2 subjects enrolled into the 32 ug TreT group,
`exposure comparison oftreprostinil could not be made for this dose level.
`
`Table 2. Summary of the Systemic Exposure Comparison of Treprostinil from TreT and
`Tyvaso from Study TIP-PH-101 (Geometric Least Squares Mean Ratio of TreT vs Tyvaso)
`(n=51)
`
`136.05 TreT 32 tg vs Tyvaso 36 - 42 pg
`
`%eRatio TreT/Tyvase
`
`NA
`138.32
`
`NA
`104.44
`128.08
`
`TreT 32 tg vs Tyvaso 36 - 42 ug
`TreT 48 tg vs Tyvaso 54 - 60 pg
`TreT 64 tg vs Tyvaso 66 - 72 ig
`
`Cmax
`Cmax
`Cmax
`
`TreT 48 tg vs Tyvaso 54 - 60 pg
`TreT 64
`tg vs Tyvaso 66 - 72 hg
`
`Geometric mean value of AUCo-shr was 4% higher following 48 pg TreT dosing, compared to 54-
`60 tg (8-10 breaths) Tyvaso, whichis consistent with the findings in Study TIP-PH-102. For the
`64 ug TreT treatment group, geometric mean AUCo-shr was found to be 28% higher than 66-72 pg
`(11-12 breaths) Tyvaso dosing. However, in Study TIP-PH-102, the AUCo-shr of treprostinil from
`64 ug TreT was 8% lower than 72 tg Tyvaso. This could be due to the difference of the study
`designs. In study TIP-PH-102, 64 tpg TreT was compared with 72 tg Tyvaso, where in Study TIP-
`PH-101 a dose range of 66 to 72 1g Tyvaso were used.
`
`Dose proportionality:
`
`The applicant assessed the dose-proportionality of TreT single doses of 30 mcg to 180 mcg in
`Study MCK-574-001, and single doses of 16 mcg, 48 mcg, and 64 mcg in Study TIP-PH-102. A
`power modelwas used: In(PK) = In(Bo) + Bi*ln(Dose) + ¢, where B1 represents slope and a value
`of B1 ~ 1 indicates dose proportional relationship. Treprostinil was foundto be slightly less than
`proportional increase in both studies (Table 3). These findings for treprostinil were reanalyzed and
`confirmed bythe clinical pharmacology reviewer.
`NDA214324
`
`Tyvaso DPI ® (Treprostinil Inhalation Powder)
`Page 7 of 14
`
`Reference ID: 4862210
`
`

`

`Study Number|Dependent Variable|Estimate (61)|CI 90 Lower|CI 90 Upper
`In(Cmax)
`0.822
`0.698
`0.946
`In(AUCo-shr
`0.865
`0.764
`0.900
`0.824
`0.917
`0.853
`
`TIP-PH-102
`
`In(AUCo-shr
`
`0.976
`0.982
`
`Table 3. Dose Proportionality Assessment of Treprostinil in TreT
`
`MCK-475-001
`
`0.965 In(Cmax)
`
`In addition, the applicant also reported a smaller inter-subject variability of treprostinil exposure
`from TreT than Tyvasotreatment arms, characterized by geometric coefficient of variance (CV%)
`of Cmax and AUCo-shr. For Cmax, the inter-subject variability for the TreT arm wasranging from
`26.6% to 28.9% compared to the Tyvaso arm ranging from 53.4% to 59.8%. The same trend was
`found for the inter-subject variability of AUCo-snr, where the inter-subject variability for the TreT
`arm AUCo-shr was foundto be ranging from 21.8% to 24.1%, compared to the Tyvaso arm ranging
`from 41.9% to 44.1%. This could be due to the difference of the administration devices. TreT is
`administrated using a single dose cartridge, whereas Tyvaso is administrated using a nebulizer.
`Regardless, the data indicates relatively more predictable PK behavior for TreT in comparison to
`Tyvaso.
`
`2.2.3 Are the PK differences noted with TreT compared to Tyvasoclinically relevant?
`
`The higher Cmax level of TreT in the context of comparable overall AUC (except the modest
`deviation at the lowest tested dose) do not appear to be clinically relevant, given that clinical use
`of TreT involvestitration to therapeutic goal and the observations on clinical effect. Adverse
`events of interest (respiratory AEs) further support this notion, where no notable respiratory AEs
`difference were observed between TreT and Tyvaso from Study TIP-PH-102 and TIP-PH-101.
`Detailed assessment of the respiratory AEsis discussed below.
`
`According to the prescribing information, Tyvaso is recommendedto be initiated from 3 breaths
`(18 ug) per treatment session, and to be increased an additional 3 breaths per treatment session at
`approximately 1- to 2-week intervals,iftolerated. The target maintenance dosesare 9 to 12 breaths
`(54 to 72 ug) per treatment session, 4 times daily. Similarly, TreT was proposedto be initiated
`from 16 pg per treatment, 4 separate treatment sessions each day, andto be increased by additional
`16 ug per treatment session at approximately 1- to 2- week intervals, if tolerated. Such titration
`allows patients adjust to proper maintenance dose levels from both clinical efficacy and safety
`aspects.
`
`The observed respiratory AEs(respiratory, thoracic, and mediastinal disorders) from Study TIP-
`PH-102 when compared between TreT and Tyvaso, the incidences were comparable between the
`two treatments at each dose level after single dose administration (Figure 3). Data on respiratory
`AEsof TreT after three weeks multiple dose treatment from the switching Study TIP-PH-101 was
`also evaluated (Figure 3). For both studies, no obvious dose-dependentincrease ofrespiratory AEs
`was observed at the mid- and high-dose levels (Figure 3). In Study TIP-PH-102, there was an
`approximately 15% increase of respiratory AEs from the low-dose level to mid-dose level. In
`Study TIP-PH-101, though no respiratory AEs were observedat the dose level of 32 1g TreT, the
`NDA 214324
`
`Tyvaso DPI ® (Treprostinil Inhalation Powder)
`Page 8 of 14
`
`Reference ID: 4862210
`
`

`

`limited sample size (N=2) was not enough to support a statistic conclusion. Regardless, the overall
`respiratory safety profiles were comparable between TreT and Tyvaso treatments from Study TIP-
`PH-102 and TIP-PH-101.
`
`
`
`Figure 3. Respiratory AEs (Respiratory, Thoracic, and Mediastinal Disorders) of TreT and
`Tyvaso from Study TIP-PH-102 and TIP-PH-101
`
`
`
`Compared to the baseline treatment with Tyvaso, there was a numeric increase from baseline of 6-
`minute walk distance (6MWD) mean values at the end of week 3 treatment with TreT and during
`the optional extension phase with TreT (Figure 4). However, in absence of a parallel Tyvaso
`control group, after accounting for the large variability of 6MWD values, and small number of
`tested subjects (N=51), the numeric improvement of 6MWD does not support any conclusion of a
`clinically significant therapeutic effect difference between TreT and Tyvaso.
`
`
`
`Figure 4. Mean Change of 6-Minute Walk Distance (6MWD) from Baseline
`
`
`In summary, in the context of the higher Cmax of TreT in reference to Tyvaso, the safety data did
`not show any notable trend in the respiratory AEs. For overall adquacy of the submitted safety
`databases, as well as the detailed safety assessements, please also refer to the clincial review of
`this submission.
`
`
`
`
`Reference ID: 4862210
`
`NDA 214324
`Tyvaso DPI ® (Treprostinil Inhalation Powder)
`Page 9 of 14
`
`

`

`2.3 ANALYTICAL SECTION
`
`1. Summary of overall performance:
`
`A solid phase extraction followed by HPLC-MS/MS method was used to determine the
`concentrations of treprostinil in human plasma. Treprostinil-d4 (Mass 393.2, 335.1) was used as
`internal standard (IS) for treprostinil (Mass 389.2, 331.3). The analytical method was fully
`validated, where the validation results met the criteria based on the FDA guidance of bioanalytical
`method validation (Table 4).
`
`
`
`Table 4. Analytical Method Validation Results and Assessment
`Parameters Results
`Validation Assessment
`Calibration
`LLOQ-ULOQ 0.0100 – 5.00 ng/mL
`8 non-zero calibrators,
`Curve
`(%Bias = -1.6 to 2.2).
`% Bias±15%
`0.0100 ng/mL (%RSD = 17.7, %Bias = 8.0),
`0.0300 ng/mL (%RSD = 14.0, %Bias = -3.0),
`0.130 ng/mL (%RSD = 1.5, %Bias = 8.5),
`0.600 ng/mL (%RSD = 1.2, %Bias = -5.5),
`3.75 ng/mL (%RSD = 2.2, %Bias = -6.4%).
`Six individual normal matrix lots plus one
`lipemic lot (≥ 300 mg/dL of triglycerides)
`and one hemolytic blank (2% hemolysis)
`were analyzed for their potential
`interferences with the analyte and the internal
`standard. No significant interference was
`detected for the analyte and its internal
`standard.
`LLOQ 0.0100 ng/mL, %RSD = 17.7,
`%Bias = 8.0%.
`Two blank matrix samples were analyzed
`immediately following the highest calibration
`standard. No evidence of carryover.
`Auto-sampler, bench-top, freeze-thaw, stock
`solution and long-term stability, performed
`three replicates at L and HQC concentrations. %RSD ± 15%, % Bias±15%
`
`Quality
`Controls
`(QCs)
`
`Selectivity
`
`Sensitivity
`
`Carryover
`
`Stability
`
`%RSD ± 15%, % Bias ±15%,
`and LLOQ %RSD ± 20%,
`% Bias ±20%
`
`Blank and zero calibrators is
`free of interference, spiked
`samples ± 20% LLOQ, IS
`response in the blank ≤5% of
`average IS responses of
`calibrators and QCs
`
`%RSD ± 20%, % Bias±20%
`
`≤ 20% LLOQ
`
`
`
`2. Method performance information for treprostinil during the analysis of clinical study samples
`from Study TIP-PH-102 is included below:
`
` Calibration standard curve performance in the study was assessed. The precision and mean
`accuracy values (% Nom.) ranged from 3.5 to 8.0 and from 98.0 to 103.0, respectively.
`
` The precision, accuracy, and nominal concentration of low, lower middle, middle, and high
`QC samples during the study were 7.3% and 98.0% (LQC: 0.0300 ng/mL), 6.9% and
`102.3% (LMQC: 0.130 ng/mL), 4.5% and 96.3% (MQC: 0.600 ng/mL), and 5.1% and
`97.9% (HQC: 3.75 ng/mL), respectively.
`
`
`Reference ID: 4862210
`
`NDA 214324
`Tyvaso DPI ® (Treprostinil Inhalation Powder)
`Page 10 of 14
`
`

`

` A total of 2445 samples were analyzed for treprositinil. 2412 samples met the acceptance
`criteria (98.7%). There were 173 samples reanalyzed to test the reproducibility of the
`method. It was observed that 98.3% of the ISR results had a relative % difference within
`±20%, which is within the acceptance criteria.
`
` The study sample storage period from first sample collection until the completion of
`analysis was 250 days at -10 to -30°C. Stability of QC samples after storage in a freezer
`set to maintain -10 to -30°C for 882 days was established.
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`• OSIS decided an inspection was not needed for clinical study TIP-PH-102 per their protocol.
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`In summary, the bioanalytical method was validated and robust in supporting the results and
`conclusions from the relative BA/BE clinical study TIP-PH-102.
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`Reference ID: 4862210
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`NDA 214324
`Tyvaso DPI ® (Treprostinil Inhalation Powder)
`Page 11 of 14
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`

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`Recommendations:
`The Office of Clinical Pharmacology/Division of Cardiometabolic and Endocrine Pharmacology
`has the following labeling recommendations for revisions to the Applicant’s proposed language
`based on the information reviewed under the current submission.
`[Note: The underlined blue text is the recommendedrevision and strikethrough text is the
`deletion]
`
`Reference ID: 4862210
`
`3. Detailed Labeling Recommendations
`
`Tyvaso DPI ® (Treprostinil Inhalation Powder)
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`

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`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/
`------------------------------------------------------------
`
`XIAOMENG XU
`09/23/2021 07:52:32 PM
`
`MANOJ KHURANA
`09/23/2021 08:00:13 PM
`
`Reference ID: 4862210
`
`