CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`214324Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`
`
`

`

`Division of Risk Management (DRM)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`NDA
`214324
`October 16, 2021
`2021-794
`
`Brian Caruth, Pharm.D., BCPS
`Laura Zendel, Pharm.D., BCPS
`Cynthia LaCivita, Pharm.D.
`October 4, 2021
`Evaluation of Need for a REMS
`
`Treprostinil
`Tyvaso DPI
`United Therapeutics Corporation
`Prostacyclin Mimetic
`Inhalation Powder
`16 mcg to 64 mcg inhaled orally four times daily during waking hours
`
`
`Application Type
`Application Number
`PDUFA Goal Date
`OSE RCM #
`
`Reviewer Name(s)
`Team Leader
`Division Director
`Review Completion Date
`Subject
`
`Established Name
`Trade Name
`Name of Applicant
`Therapeutic Class
`Formulation(s)
`Dosing Regimen
`
`
`
`Reference ID: 4867408
`
`1
`
`

`

`Table of Contents
`
`EXECUTIVE SUMMARY ......................................................................................................................................................... 3
`1
`Introduction ..................................................................................................................................................................... 3
`2 Background ...................................................................................................................................................................... 3
`2.1
`Product Information ........................................................................................................................................... 3
`2.2
`Regulatory History ............................................................................................................................................... 4
`3
`Therapeutic Context and Treatment Options .................................................................................................... 4
`3.1
`Description of the Medical Condition .......................................................................................................... 4
`3.2
`Description of Current Treatment Options ............................................................................................... 5
`4 Benefit Assessment ....................................................................................................................................................... 6
`5 Risk Assessment & Safe-Use Conditions .............................................................................................................. 8
`Expected Postmarket Use ........................................................................................................................................... 8
`6
`7 Risk Management Activities Proposed by the Applicant ............................................................................... 9
`8 Discussion of Need for a REMS ................................................................................................................................. 9
`9
`Conclusion & Recommendations ........................................................................................................................... 10
`10
`Appendices ................................................................................................................................................................ 10
`10.1 References ............................................................................................................................................................. 10
`
`
`
`Reference ID: 4867408
`
`2
`
`

`

`EXECUTIVE SUMMARY
`This review by the Division of Risk Management (DRM) evaluates whether a risk evaluation and
`mitigation strategy (REMS) for Tyvaso DPI (treprostinil) is necessary to ensure the benefits outweigh its
`risks. United Therapeutics Corporation submitted a New Drug Application (NDA) 214324 for treprostinil
`with the proposed indication for the treatment of pulmonary arterial hypertension ([PAH]; World Health
`Organization [WHO] Group 1) or pulmonary hypertension associated with interstitial lung disease (PH-
`ILD; WHO Group 3) to improve exercise ability in adult patients. Treprostinil is associated with an
`increased risk for cough and throat irritation, headache, nausea, flushing, and syncope. The Applicant
`did not submit a proposed REMS or risk management plan with this application.
`The Division of Risk Management (DRM) has determined that a REMS is not needed to ensure the
`benefits of treprostinil outweigh its risks. The increased risk for cough and throat irritation, headache,
`nausea, flushing, and syncope are similar to the currently approved referenced formulations (NDA
`022387 [treprostinil inhalation solution], NDA 021272 [treprostinil injection], NDA 203496 [treprostinil
`diolamine]). The excipient, fumaryl diketopiperazine (FDKP), is referenced in the approved BLA 022472
`([insulin human] inhalation powder). The most commonly reported adverse events for treprostinil
`inhalation powder observed in the single-sequence safety and tolerability study (TIP-PH-101
`[NCT03950739]) were similar to the adverse events in the placebo-controlled study (TRIUMPH I
`[NCT00147199]) conducted for the referenced formulation of treprostinil inhalation solution.
`Treprostinil is likely to be prescribed in a specialized setting by cardiologists and pulmonologists familiar
`with pulmonary hypertension (PH) therapy. Prescribers are expected to closely monitor patients for
`disease progression and response to therapy with frequent follow-up visits. The risks of treprostinil will
`be communicated in the Adverse Reactions section in labeling.
`1 Introduction
`This review by the Division of Risk Management (DRM) evaluates whether a risk evaluation and
`mitigation strategy (REMS) for Tyvaso DPI (treprostinil) is necessary to ensure the benefits outweigh its
`risks. United Therapeutics Corporation submitted a New Drug Application (NDA) 214324 for treprostinil
`with the proposed indication for the treatment of pulmonary arterial hypertension (PAH; World Health
`Organization [WHO] Group 1) or pulmonary hypertension associated with interstitial lung disease (PH-
`ILD; WHO Group 3) to improve exercise ability in adult patients. This application is under review in the
`Division of Cardiology and Nephrology (DCN). The Applicant did not submit a proposed REMS or risk
`management plan with this application.
`2 Background
`2.1 PRODUCT INFORMATION
`Treprostinil is a prostacyclin mimetic proposed for the treatment of pulmonary arterial hypertension
`(PAH; WHO Group 1) or pulmonary hypertension associated with interstitial lung disease (PH-ILD; WHO
`Group 3) to improve exercise ability in adult patients. Prostacyclins are potent dilators of pulmonary and
`systemic blood vessels and also mediate a variety of cellular processes including inhibiting inflammation,
`smooth muscle cell proliferation, and platelet aggregation.1 Inhalation of prostacyclin analogs provide
`selectivity of the hemodynamic effects to the lung vasculature reducing pulmonary arterial pressure and
`stabilizing systemic arterial pressure.
`
`3
`
`
`Reference ID: 4867408
`
`

`

`Tyvaso DPI is proposed to be available as an inhalation powder in a 16 mcg, 32 mcg, 48 mcg, or 64 mcg
`single dose cartridge. The content of the cartridge is administered using the corresponding inhaler.
`Duration of treatment is expected to be long term and likely administered in an outpatient setting.a
`Tyvaso DPI, while not a new molecular entity, utilized the 505(b)2 pathway relying on the Agency’s
`previous findings of safety and effectiveness for the referenced approved formulations and excipients.b
`Tyvaso DPI uses the same active pharmaceutical ingredient (API) approved in Remodulin (treprostinil
`injection, NDA 021272) and Tyvaso (treprostinil inhalation solution, NDA 022387). It is also the same
`active moiety as the drug substance approved in Orenitram (treprostinil diolamine, NDA 203496).
`Tyvaso DPI contains 1% treprostinil adsorbed onto carrier particles consisting of fumaryl
`diketopiperazine (FDKP). Afrezza (insulin human inhalation powder, BLA 022472) uses FDKP and was
`approved on June 27, 2014 with a Communication Plan REMS to ensure the benefits of the drug
`outweighed the risk of acute bronchospasm in patients with chronic lung disease. The REMS was
`eliminated on April 13, 2018 according to available safety data, the status of the communication plan
`activities, and the results of the 3-Year Assessment Review findings that the goals of the REMS were
`being met.2
`2.2 REGULATORY HISTORY
`The following is a summary of the regulatory history for NDA 214324 relevant to this review:
`• 01/29/2018: IND 134582 received for treprostinil
`• 04/16/2021: NDA 214324 received for treprostinil
`• 06/15/2021: FDA granted Priority Review designation citing the use of a Rare Pediatric Disease
`Priority Review Voucher (PRV BLA 761171)
`3 Therapeutic Context and Treatment Options
`3.1 DESCRIPTION OF THE MEDICAL CONDITION
`Pulmonary Arterial Hypertension (PAH) is a progressive and fatal lung disease of multifactorial etiology.3
`Clinical presentation typically involves exertional dyspnea and fatigue that progresses over time until
`severe pulmonary hypertension (PH) with right ventricular (RV) failure develops. Increased pulmonary
`pressures leading to RV failure is the major cause of death in this rare disease.c According to
`international registry data, the incidence and prevalence ranges from 2.5 to 7.1 cases per million and 5
`to 52 per million adults, respectively.4,d Surveillance data in the United States suggests increased
`mortality associated with PH in men, women, and all race and ethnic groups.5 The 7-year survival rate is
`about 49%.6
`
`
`
`a Section 505-1 (a) of the FD&C Act: FDAAA factor (D): The expected or actual duration of treatment with the drug.
`b Section 505-1 (a) of the FD&C Act: FDAAA factor (F): Whether the drug is a new molecular entity.
`c Section 505-1 (a) of the FD&C Act: FDAAA factor (B): The seriousness of the disease or condition that is to be
`treated with the drug.
`d Section 505-1 (a) of the FD&C Act: FDAAA factor (A): The estimated size of the population likely to use the drug
`involved.
`
`
`Reference ID: 4867408
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`4
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`

`

`3.2 DESCRIPTION OF CURRENT TREATMENT OPTIONS
`Non pharmacologic interventions for managementof PH include exercise as tolerated, counselling
`against smoking, and maintaining a normal body massindex (BMI). Current FDA-approved treatment
`optionsfor PH include prostacyclin derivatives, endothelin receptor antagonists (ERA),
`phosphodiesterase-5 (PDE-5) inhibitor, and a soluble guanylate cyclase (sGC) stimulator (Table 1).
`
`Table 1: FDA-Approved Treatment Options for Pulmonary Hypertension
`Product Trade Name
`Year of
`EYhcas
`4th
`
`(Generic)
`
`Approval
`
`Uetore AET ay 4]
`ation
`Prostacyclin Derivatives
`
`Tralee late Melee lary
`
`.
`
`Fluid Retention, Hemoglobin
`and Hematocrit Decrease,
`PVOD, Decreased Sperm Counts
`Fluid Retention, Hemoglobin
`and Hematocrit Decrease,
`PVOD, Decreased Sperm Counts
`Hepatotoxicity, Fluid Retention,
`Hemoglobin and Hematocrit
`Decrease, PVOD, Decreased
`Sperm Counts
`
`ReboundPHfollowing Abrupt
`Withdrawal, Hypotension,
`Bleeding, PVOD
`Syncope, PVOD, Bronchospasm,
`Avoid Contact with Skin and
`Eyes, and Ingestion
`Hypotension, Bleeding,
`.
`Rebound PAHfollowing Abrupt
`Withdrawal
`
`Oral, IV,
`SubQ, INH
`
`Endothelin Receptor Antagonists
`
`Yes
`
`(Embryo-Fetal Toxicity)
`
`Yes
`(Embryo-Fetal Toxicity
`and Hepatotoxicity)
`
`Yes
`(Embryo-Fetal Toxicity)
`
`Phosphodiesterase-5 (PDE-5) Inhibitors
`
`Oral, IV
`ra
`
`2005
`
`2009
`
`Mortality with Pediatric Use,
`Epistaxis, Vaso-OcclusiveCrisis
`.
`,
`Hypotension, PVOD,VisualLoss,
`Hearing Impairment, Priapism
`Hypotension, PVOD,VisualLoss,
`.
`.
`.
`Hearing Impairment, Priapism
`
`Soluble Guanylate Cyclase (sGC) Stimulator
`Yes
`
`.
`
`Flolan, Veletri
`(epoprostenol)
`
`Ventavis
`(iloprost)
`
`Orenitram, Remodulin,
`Tyvaso
`(treprostinil)
`Uptravi
`
`Letairis
`
`(ambrisentan)
`
`Tracleer
`(bosentan)
`
`Opsumit
`(macitentan)
`
`Revatio
`(sildenafil)
`
`Adcirca
`.
`(tadalafil)
`
`Adempas
`
`Reference ID: 4867408
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`

`

`No safety issues warranting a REMS have been identified for current FDA-approved prostacyclin
`derivatives or PDE-5 inhibitors. All ERAs and the sGC stimulator require a REMS with elements to assure
`safe use (ETASU) to ensure the benefits outweigh the risk of embryo-fetal toxicity. The bosentan REMS
`also addresses the risk of hepatotoxicity. In general, the warnings and precautions for prostacyclin
`derivatives are similar, as are the warnings and precautions for PDE-5 inhibitors. Pulmonary Veno-
`Occlusive Disease (PVOD) has been identified in all classes of currently FDA-approved treatment options
`for PH despite similar signs and symptoms of PVOD and progressive PH. Modest changes in mortality
`rates and progressive clinical manifestations of PH represent an unmet medical need.
`4 Benefit Assessment
`The efficacy of treprostinil inhalation powder for the treatment of pulmonary arterial hypertension
`(PAH; WHO Group 1) or pulmonary hypertension associated with interstitial lung disease (PH-ILD; WHO
`Group 3) to improve exercise ability in adult patients relies on the Agency’s previous findings of safety
`and effectiveness for the referenced approved formulations and excipients. Additional efficacy data was
`evaluated as a secondary outcome measure in one single-sequence, open-label, multicenter phase 1b
`study (TIP-PH-101 [NCT03950739]). The study enrolled 51 patients (8 males and 43 females), 23 to 82
`years of age (median age at baseline 57 years) with PAH on a stable regimen of treprostinil inhalation
`solution for at least 3 months with a baseline 6-Minute Walk Distance (6MWD) of at least 150 meters
`and evidence of forced expiratory volume in one second (FEV1) of at least 60% and FEV1/forced vital
`capacity ratio of at least 60% during the six months prior to enrollment. Patients were excluded if they
`were pregnant or lactating, taking any other prostacyclin derivatives, had a history of uncontrolled sleep
`apnea, parenchymal lung disease, or hemodynamically significant left-sided heart disease, or had
`experienced an acute exacerbation of disease or hospitalization for any reason within 30 days of the
`screening visit or between screening and baseline. The study evaluated a 32 mcg, 48 mcg, and 64 mcg
`dose of treprostinil inhalation powder administered four times daily for three weeks. At the end of the
`treatment phase, patients were offered the opportunity to continue treprostinil inhalation powder in
`the Optional Extension Phase (OEP) of the study with clinic visits every eight weeks. The main evaluation
`of efficacy included a 6-Minute Walk Test (6MWT), Preference Questionnaire for Inhaled Treprostinil
`Devices (PQ-ITD) and the PAH-Symptoms and Impact (PAH-SYMPACT) Questionnaire (Table 2).
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4867408
`
`6
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`

`

`Bielwe Pes
`Baseline (n)
`WeekThree(n)
`
`Mean(SD
`Median
`
`interquartile
`
`Table 2: Summary of Efficacy Results From TIP-PH-101 Study
`Pale
`Ele
`v2
`yay
`2
`24
`6MWDChangefrom baseline (m)
`
`yp
`20
`
`7
`
`PQ-ITD statement“I am satisfied with the inhaler” (n)
`Strongly Disagree
`Disagree
`
`!.
`
`Agree
`Strongly Agree
`
`Mean(SD)
`Median
`Interquartile
`
`Mean(SD)
`Median
`Interquartile
`
`Mean(SD)
`Median
`interquartile
`
`PAH-SYMPACT Questionnaire Change from baseline
`Cardiopulmonary Symptoms Domain Score
`
`OTs rsd
`0.16, 0.17
`
`Cardiovascular Symptoms DomainScore
`
`zo Po
`-0.40, 0.60
`
`Physical Impacts Domain Score
`-0.01 (1.01)
`-0.09 (0.40)
`
`-0.21 (0.48)
`
`Overall
`51
`>0
`
`p=0.0217
`11.5 (32.9
`
`-14, 33
`-46, 110
`p=0.0001
`
`Ww©
`
`p=0.2451
`-0.05 (0.27)
`
`-0.17, 0.17
`-0.7, 0.5
`p=0.2492
`-0.06 (0.33)
`
`-0.20, 0
`-1, 0.6
`p=0.0438
`-0.14 (0.46)
`
`-0.43, 0
`-1.1, 1
`p=0.0048
`-0.17 (0.40)
`
`utee S
`©Pant
`
`Cognitive and Emotional Impacts Domain Score
`
`PoC
`
`Mean(SD)
`Median
`interquartile
`
`-0.25, 0
`1.3, 0.5
`Source: Adapted from Applicant’s original submission April 16, 2021; Table 4-3, 4-5, 4-6, and 4-7, Appendix 2.7.3
`
`An 11.5 meter mean increase from baseline was observed in the 6MWDat weekthreefor treprostinil
`inhalation powder. According to a response of agree or strongly agree to the PQ-ITD statement “I am
`satisfied with the inhaler,” patient-reported satisfaction with the inhaled treprostinil device was
`improved at week three (95.7% [44/46]) comparedto baseline (31.4% [16/51]). Mean changes at week
`three compared to baseline improved forall domain scores. According to results from the PAH-
`SYMPACT Questionnaire, the mean scores(-0.05 to -0.17) for all domains improved at week three
`comparedto baseline. Improved domain scoresfor the physical impacts (-1.1 to 1 [p=0.0438]) and
`cognitive and emotional impacts (-1.3 to 0.5 [p=0.0048]) werestatistically significant. The Applicant
`concluded the supplementalefficacy data from the TIP-PH-101 study demonstrated significant
`improvementsin the 6MWD, PQ-ITD, and PAH-SYMPACT Questionnaire for patients with PAH.
`
`Reference ID: 4867408
`
`

`

`The clinical reviewer concluded the short-term efficacy results of the TIP-PH-101 study did not show
`clinical worsening for patients transitioning from treprostinil inhalation solution to treprostinil inhalation
`powder.e This determination relied on the eight meter median increase from baseline in 6MWD and
`unchanged median results for the cardiopulmonary symptoms, cardiovascular symptoms, and cognitive
`and emotional impacts domain scores from the PAH-SYMPACT Questionnaire.
`5 Risk Assessment & Safe-Use Conditions
`The safety of treprostinil inhalation powder for the treatment of pulmonary arterial hypertension (PAH;
`WHO Group 1) or pulmonary hypertension associated with interstitial lung disease (PH-ILD; WHO Group
`3) to improve exercise ability in adult patients relied on the Agency’s previous findings of safety and
`effectiveness for the referenced approved formulations and excipients. Additional safety analysis relies
`on data from the treatment phase and OEP in the TIP-PH-101 study. A total of 51 patients enrolled in the
`study and 49 patients enrolled in the OEP after completing the treatment phase. The three most
`common adverse events (AE) during the treatment phase (incidence ≥ 4%) include cough, headache, and
`dyspnea.
`There were no deaths or treprostinil related serious adverse events during the TIP-PH-101 study. During
`the treatment phase, two patients experienced AEs of dyspnea and globus pharyngeus leading to
`treprostinil discontinuation. During the OEP, two additional patients experienced AEs leading to
`treprostinil discontinuation due to dyspnea and chest pain with dyspnea.
`The review team also evaluated the use of the FDKP excipient in treprostinil inhalation powder. The TIP-
`PH-101 study included 12 patients with respiratory disease (COPD [5], asthma [4], and ILD [3]). No
`patients with a history of COPD, asthma, or non-PAH respiratory disease withdrew from treprostinil
`inhalation powder therapy and there was no evidence of bronchospasm in this small cohort of patients.
`Additional review of the TIP-PH-101 study demonstrated little to no dose-dependent increase of AEs
`(respiratory, thoracic, and mediastinal disorders) for treprostinil inhalation powder and a substantial
`increase in AEs associated with the transition from treprostinil inhalation solution to treprostinil
`inhalation powder was not observed.
`Overall, the most commonly reported adverse events for treprostinil inhalation powder observed in the
`TIP-PH-101 study were similar to the adverse events in the placebo-controlled study (TRIUMPH I
`[NCT00147199]) conducted for the referenced approved formulation of treprostinil inhalation solution.7
`The clinical reviewer concluded the safety profile of treprostinil is consistent with predicted risks of
`prostacyclin mimetic therapy and the overall benefit-risk profile appears acceptable.
`6 Expected Postmarket Use
`Treprostinil is likely to be prescribed in an outpatient setting by cardiologists and pulmonologists
`familiar with PAH therapy. The likely prescribers are expected to be familiar with predicted risks of
`inhaled prostacyclin therapy and closely monitor patients for disease progression and response to
`therapy with frequent follow-up visits for this rare disease.
`
`e Section 505-1 (a) of the FD&C Act: FDAAA factor (C): The expected benefit of the drug with respect to such disease
`or condition.
`
`
`Reference ID: 4867408
`
`8
`
`

`

`7 Risk Management Activities Proposed by the Applicant
`The Applicant did not propose any risk management activities for treprostinil beyond routine
`pharmacovigilance and labeling.
`8 Discussion of Need for a REMS
`The clinical reviewer recommends approval of treprostinil citing the Agency’s previous findings of safety
`and efficacy for the referenced approved formulations and excipients (NDA 022387, NDA 021272, NDA
`203496, and BLA 022472), safety and efficacy data from the phase 1b TIP-PH-101 study, the seriousness
`of PH, and an adequately favorable benefit-risk profile.
`A REMS for Afrezza (BLA 022472), referenced in this application for the excipient FDKP, was approved on
`June 27, 2014 with a REMS that comprised of a communication plan to ensure the benefits of the drug
`outweighed the risk of acute bronchospasm in patients with chronic lung disease. The REMS was
`eliminated on April 13, 2018.2 DRM documented, in detail, the Agency decision regarding the need for a
`REMS.8 The rationale for the REMS included that additional measures were needed to disseminate
`information about the risk of acute bronchospasm in patients with chronic lung disease, citing concern
`for the estimated size of the population likely to use the drug outside a clinical study and that
`prescribers of insulin do not routinely need to consider lung function when prescribing insulin. In
`addition, no reports of serious bronchospasm were identified during the 3-year REMS assessment
`review.
`Although acute bronchospasm in patients with asthma and patients with chronic obstructive pulmonary
`disease (COPD) was observed in material reviewed for BLA 022472, no patients with a history of COPD,
`asthma, or non-PAH respiratory disease withdrew from treprostinil inhalation powder therapy in the
`TIP-PH-101 study and there was no evidence of bronchospasm in these 12 patients with respiratory
`disease.
`Previous findings for the referenced approved formulations and excipients (NDA 022387, NDA 021272,
`NDA 203496, and BLA 022472) and data from the phase 1b TIP-PH-101 study evaluated efficacy and
`safety of treprostinil inhalation powder in adults with PH. The short-term efficacy and safety results of
`the TIP-PH-101 study did not show clinical worsening for patients transitioning from treprostinil
`inhalation solution to treprostinil inhalation powder and did not produce any new safety findings for
`treprostinil inhalation powder compared to treprostinil inhalation solution, which is not currently
`approved with a REMS. In general, healthcare providers who treat PH should be familiar with predicted
`risks of inhaled prostacyclin therapy and closely monitor patients for disease progression and response
`to therapy with frequent follow-up visits for this rare disease. Relying on a smaller estimated patient
`population size, likely prescribers to include cardiologists and pulmonologists, and limited therapeutic
`options for patients with PH compared to those identified in BLA 022472, a REMS is not necessary to
`ensure that the benefits outweigh the risks for treprostinil inhalation powder for the intended
`population. Therefore, this reviewer is not recommending a REMS for the management of the risks of
`treprostinil inhalation powder.
`
`
`
`Reference ID: 4867408
`
`9
`
`

`

`9 Conclusion & Recommendations
`Relying on the data available, a REMS is not necessary to ensure the benefits of treprostinil inhalation
`powder outweigh the risks for cough and throat irritation, headache, nausea, flushing, and syncope. The
`safety concerns associated with treprostinil inhalation powder use are similar to the referenced
`approved formulations of treprostinil and they are not currently approved with a REMS. Healthcare
`providers who treat PAH should be familiar with monitoring and treating predicted risks of inhaled
`prostacyclin therapy. The risks of cough and throat irritation, headache, nausea, flushing, and syncope
`will be communicated in labeling in Adverse Reactions. At the time of this review, labeling is still under
`negotiation and the clinical review is ongoing. Should DCN have any concerns or questions or if new
`safety information becomes available, please send a consult to DRM.
`10 Appendices
`10.1 REFERENCES
`
`
`1 Lang IM, Gaine SP. Recent advances in targeting the prostacyclin pathway in pulmonary arterial
`hypertension. European Respiratory Review. 2015;24:630-641.
`2 Pippins, J. Afrezza REMS Elimination Memo. DARRTS Reference ID: 4249716. April 13, 2018.
`3 Bisserier M, Pradhan N, Hadri L. Current and emerging therapeutic approaches to pulmonary
`hypertension. Reviews in Cardiovascular Medicine. 2020;21(2):163-179.
`4 Prins KW, Thenappan T. World Health Organization Group I Pulmonary Hypertension: Epidemiology
`and Pathophysiology. Cardiology Clinics. 2016;34(3):363-374.
`5 George MG, Schieb LJ, Ayala C, Talwalkar A, Levant S. Pulmonary hypertension surveillance: United
`States, 2001 to 2010. Chest. 2014;146(2):476-495.
`6 Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation of long-term survival
`from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest.
`2012;142(2):448-456.
`7 See Tyvaso at https://www.accessdata.fda.gov/drugsatfda docs/label/2021/022387s017lbl.pdf
`8 See FDA REMS Review for Afrezza (BLA 22472), dated June 24, 2014, available at
`https://www.accessdata.fda.gov/drugsatfda docs/nda/2014/022472Orig1s000RiskR.pdf
`
`
`Reference ID: 4867408
`
`10
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`Signature Page 1 of 1
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`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/
`------------------------------------------------------------
`
`BRIAN J CARUTH
`10/04/2021 05:10:19 PM
`
`LAURA A ZENDEL
`10/04/2021 05:54:31 PM
`
`CYNTHIA L LACIVITA
`10/04/2021 09:23:17 PM
`
`Reference ID: 4867408
`
`(
`
`
`
`