CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`214324Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross Discipline Team Leader Review NDA 214324
`
`Cross-Discipline Team Leader (CDTL) Review
`
`Subject
`
`Mohan Sapru, M.S., Ph.D.
`Branch Chief, New Drug Products Division II, Branch V
`Office ofNew Drug Products/OPQ
`CDTL Review
`
`Type of Application
`Applicant
`
`505(b)(1)
`United Therapeutics Corp.
`
`Date of Receipt
`
`16-April-2021
`
`PDUFAGoal Date
`
`16-October-2021
`
`Established/Proper Name_|Tyvaso DPI(treprostinil) inhalation powder
`
`Dosage forms; Strength
`Dry powderfor oral inhalation; 16 mcg, 32 mcg, 48 mcg, or 64 meg per
`cartridge
`
`Route of Administration
`
`Oralinhalation
`
`Proposed Indication(s)
`
`Treatment of pulmonary arterial hypertension (PAH; WHO Group 1)
`and pulmonary hypertension associated with interstitial lung disease
`(PH-ILD; WHOGroup 3) to improve exercise ability
`
`Regulatory Action
`
`Complete Response
`
`This CDTL review is based on the primary reviews, memos, and documented review input, as listed
`below:
`
`Material Reviewed/Consulted
`Review Team
`
`Integrated Quality Assessment
`(DARRTS,dated 30-September-2021)
`Device Inter-Center Consult Review ICC2100386
`(dated 01-October-2022)
`
`Daniel Jansen, Alexander Gontcharov,
`Akm Khairuzzaman, and Mohan Sapru
`Dongbo Wang (CDRH), and John
`Bender
`
`Non-Clinical Review (DARRTS,dated 22-June-2021)
`
`Baichun Yang, and Xuan Chi
`
`Clinical Review (DARRTS,dated 23-September-2021)
`
`Mitchell Psotka, and Fortunato Senatore
`
`
`
`
`Clinical Pharmacology Review (DARRTS,dated 23-
`September-2021)
`DMEPA Human Factors Validation Study Review, and
`Labeling Review (DARRTS,dated 03 September 2021,
`and 05-October-2021)
`DNDSIand OSIS Review (DARRTS,dated 24-June-2021)|Folaremi Adeyemo
`
`Xiaomeng Xu, and Manoj Khurana
`
`Ebony Whaley, and Colleen Little
`
`OPQ: Office of Pharmaceutical Quality; DMEPA: Division of Medication Error Prevention and
`Analysis; DNDSI: Division of New Drug Study Integrity; OSIS: Office of Study Integrity and
`Surveillance.
`
`Page 1 of 5
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`Reference ID: 4872227
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`1
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`

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`Cross Discipline Team Leader Review NDA 214324
`
`I. Background
`
`The Applicant has sought U.S. marketing approval for Tyvaso DPI(treprostinil) inhalation powder
`in accordance with Section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act. Treprostinil is
`a prostacyclin analogue, and its major pharmacologic actions are direct vasodilation of pulmonary
`and systemic arterial vascular beds and inhibition of platelet aggregation. The proposed
`combination product involves a change in dosage form for treprostinil from a solution for oral
`inhalation (Tyvaso® (treprostinil) inhalation solution (NDA 022387) to a dry powder for oral
`inhalation. Inhaled treprostinil therapy provides selectivity of the hemodynamic effects to the lung
`vasculature, thus reducing systemic side effects compared to other routes of administration. The
`safety and efficacy of treprostinil are supported by a comprehensive set of pharmacology,
`pharmacokinetic (PK), toxicology, and clinical studies conducted for UTC’s Tyvaso (treprostinil)
`inhalation solution (NDA 022387), Remodulin (treprostinil)
`Injection (NDA 021272), and
`Orenitram (treprostinil) extended-release tablets (NDA 203496).
`
`2. Quality Assessment Summary
`
`The proposed Tyvaso(treprostinil) inhalation powder (TYVASO DPI) contains the identical drug
`substance as the inhaled liquid formulation (TYVASO®). All CMC information regarding the
`proposedtreprostinil inhalation powder formulation (TYVASO DPI) is cross-referenced to DMF #
`™©® The DMF was reviewed by OPQ review teams and found to be adequate. Specifically,
`treprostinil drug substance has been well-characterized using state-of-the-art methods with regard
`to its structure and physicochemical characteristics. It is stable for
`o®and
`its manufacturing process is well-controlled. The critical quality attributes (CQAs) of the drug
`substance are adequately monitored per release specification.
`
`2.1 Drug Product: The proposed Tyvaso DPI (treprostinil) inhalation powder is a drug-device
`combination product, comprised of single-use cartridges containing a dry powder formulation of
`treprostinil inhalation powder at 16, 32, 48, or 64 mcg of treprostinil per cartridge, and a small,
`portable, reusable, breath-powered, dry powder inhaler. Pharmaceutical development studies
`adequately support the formulation design, including excipient selection and excipient levels. The
`proposed formulation involves the use of a non-compendial excipient fumaryl diketopiperazine
`(FDKP). Selection of FDKP for use in the proposed productis based on its utility as an excipient
`for pulmonary delivery by oral inhalation because it facilitates the particle matrix formation,
`crystallizes under acidic conditions and the crystals self-assemble to form particles with the
`appropriate properties. All CMC information concerning this excipient
`is provided in DMF-
`©®which was previously reviewed and found adequate as a part of the BLA-022472 approval
`process. The level of FDKP used in the proposed formulation is me compared to the level
`present in the previously approved product (Afrezza; BLA # 022472).
`
`The product manufacturing process is well-controlled and involves:
`
`ma)
`
`The in-process controls and testing are adequate, and
`manufacturing process and testing ensure uniformity of the drug substance in the Tyvaso DPI
`(treprostinil) inhalation powder. The productrelease specification involves testing ofall the product
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`Reference ID: 4872227
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`Cross Discipline Team Leader Review NDA 214324
`critical quality attributes (CQAs),_ including aerodynamic particle size distribution, uniformity of
`delivered dose,
`® and microbial
`limits. The Applicant has demonstrated: a)
`suitability ofthe proposed container closure system for the intended use, and b) product stability for
`a period of 18 months
`oe
`me
`oewhenstored at 5°C in the
`proposed commercial packaging.
`
`3. Device Evaluation
`
`under DMF
`
`oe
`consistently and effectively.
`
`ee)
`The inhaler used to deliver treprostinil inhalation powder (“TreT Inhaler”) contains
`(F
`PP
`(b)(4)
`DA approved: reviewed
`*“™ Briefly, the mhaler is a mechanical device consisting of
`|
`***). The TreT inhaler delivers the treprostinil inhalation powder
`(b)(4)
`(b)(4)
`© Extractables testing
`and toxicological risk assessment of the device component and biocompatibility evaluation ofall
`patient-contacting (via gas pathway) device components of the dry powder inhaler subject device
`demonstrate that the device is safe for the intended use.
`
`4. Human Factors (HF) Validation Study
`
`The Applicant performed human factors validation study of the proposed combination product,
`involving the use of dry powder inhaler device. Overall, the results of this study demonstrate that
`the user interface has been optimized to support the safe and effective use of the proposed
`combination product. The Applicant’s plan to consistently provide routine training to intended user
`of Tyvaso DPI seems reasonable, and the residualrisks are not significant.
`
`5. Non-Clinical
`
`Tyvaso DPI wasevaluated by (quantitative) structure-activity relationship (Osausing Derek
`Nexus and Leadscope Model Applier.All 7 impurities (
`® and
`oe) wewere identified
`as inactive (non-mutagenic) in DEREK Nexus and negative (non-mutagenic) in the Leadscope
`®©is identified as an impurity in Tyvaso DPIat a concentration
`Model Applier.
`above the qualification threshold of 1% for drug products with a maximum daily dose of the active
`pharmaceutical ingredient of<10 mg.
`™® Was qualified at a concentration ofup
`to §% in the final drug product.
`®@ was
`shown to have reduced
`phafnacodynamic effects compared to treprostinil, and it is expected to be
`era;
`® It is unlikely that the presence of
`* in Tyvaso DPI
`would be a safety concern for patients if present at up to “%. Furthermore, the safety of the
`excipient fumaryl diketopiperazine (FDKP) is supported by“a comprehensive battery of safety
`pharmacology and toxicology studies conducted for Afrezza (BLA 022472). Based on the results of
`the nonclinical pharmacology, PK, and toxicology studies conducted to support Tyvaso (NDA
`022387), Remodulin (NDA 021272), and Orenitram (NDA 203496), and the assessment of
`impurities present in Tyvaso DPI,it is considered that Tyvaso DPI has an acceptable safety profile
`and that there are no findings that preclude long-term inhalation administration in humans. In
`conclusion, this NDAis considered approvable from Pharmacology/Toxicology perspective.
`
`6. Clinical Pharmacology
`
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`Cross Discipline Team Leader Review NDA 214324
`The Applicant submitted three clinical studies. These include: i) a single dose-escalation Study
`MKC-475-001 in healthy subjects, ii) an open-label Study TIP-PH-101, assessing safety and
`tolerability of proposed treprostinil inhalation powder (TYVASO DPI) in subjects with PAH
`currently using inhaled liquid formulation (TYVASO®), and iii) a relative bioavailability and
`bioequivalence (BA/BE) study TIP-PH-102 between TYVASO DPI and TYVASO® in healthy
`subjects. The safety data (though limited) from the single and multiple dose studies did not indicate
`any notable difference in respiratory adverse events (AEs) between proposed treprostinil inhalation
`powder and TYVASO®. Given that the clinical use of proposed treprostinil inhalation powder
`involves titration to therapeutic goal, the higher Cmax level of treprostinil inhalation powder in the
`context of comparable overall AUC (except the modest deviation at the lowest tested dose) does not
`appear to be clinically relevant. In conclusion, the Clinical Pharmacology review team has made
`approval recommendation for this NDA.
`
`
`7. Clinical
`
`
` The proposed indication for treprostinil inhalation powder formulation (TYVASO DPI) is identical
`to inhaled liquid formulation (TYVASO®), specifically for the treatment of WHO group I PAH
`and WHO group III PH-ILD to improve exercise capacity. As concluded by the clinical review
`team, substantial evidence of effectiveness for the proposed treprostinil inhalation powder
`(TYVASO DPI) has been previously concluded based on the liquid formulation (TYVASO®) 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,
`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.
`
`
`
`Fumaryl diketopiperazine (FDKP), an excipient of TYVASO DPI™ also present in the approved
`human insulin powder (AFREZZA®) formulation, 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®. The exposure to the excipient FDKP via 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 proposed 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.
`
`8. Assessment of Manufacturing Facilities
`
`
` with an Official
`The drug substance testing facility,
`Action Indicated (OAI) classification is currently out of GMP compliance. The facility is
`responsible for analytical testing of the drug substance, which includes both physico-chemical and
`4
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`Reference ID: 4872227
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`(b) (4)
`
`(b) (4)
`
`(b) (4)
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`

`

`Cross Discipline Team Leader Review NDA 214324
`microbiological testing. The last inspection of the facility was a for-cause inspection to investigate
`
`failures of the MDI combination product andresulted in (OAI) classification.
`
`9. Safety; Statistical Evaluation, Pediatrics; Advisory Committee Meeting
`
`N/A
`
`10. Regulatory Action Recommendations
`
`Based on integrated quality review, OPQ has recommended a Complete Response (CR) action from
`
`tive because the drug substance testing facility,ee
`
`roduct
`
`quali
`
`with an Official Action Indicated (OAD) classification, is currently out of GMP
`compliance. Satisfactory resolution of GMP deficiencies concerning this facility is required before
`this application may be approved. In view of a) the current OAI classification for the listed facility,
`b) Agency’s policy of linking facility OAI classification to final actions on NDAs, and c) extensive
`consultation and inter-office discussions involving DCN, OPQ, OC, OND, OPQ policy and others
`about the facility OAI and regulatory and policy implications concerning action on this NDA,I
`agree with OPQ’s assessment and recommend a Complete Response (CR) regulatory action for this
`NDA.
`
`CR Deficiency to be Communicated the Applicant:
`
`During a recent inspection of the[iNNNNRS?Yor is
`
`application, our field investigator conveyed deficiencies to the representative of the facility. As a
`result of
`this inspection, FDA has classified this facility as Official Action Indicated (OAI) on
`Jor drug CGMP.Satisfactory resolution of these deficiencies is required before
`this application may be approved.
`
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`Reference ID: 4872227
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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/
`------------------------------------------------------------
`
`MOHAN K SAPRU
`10/14/2021 11:23:01 AM
`
`Reference ID: 4872227
`
`