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`1521-0031;]216403-533- 620525.00
`PHARMACOLUGICAL REVIEWS
`Copyright 0 2012 by The American Society for Pharmacology and Experimental Therapeutics
`Pharmami Rev 64:583-620. 2012
`
`Vol. 64. No. 3
`558733771667
`
`ASSOCIATE EDITOR: CLIVE PAGE
`
`The Pharmacological Treatment of Pulmonary
`Arterial Hypertension
`
`Lyn R. Frumki n
`
`DepartmentofChemicalandSystemsBiology.StanfordUniversitySchcoiofMcdicimuStanford, California
`
`Abstract ................................................................................ 584
`I. Introduction ............................................................................ 584
`11. Current treatment options ............................................................... 586
`A. History of product approvals .......................................................... 586
`1. Epoprostenol ...................................................................... 586
`2. Treprostinil ....................................................................... 586
`3. Iloprost ........................................................................... 587
`4. Bosentan ......................................................................... 587
`5. Ambrisentan ...................................................................... 588
`6. Nitric oxide ....................................................................... 588
`7. Sildenafil ......................................................................... 589
`8. Tadalafil ......................................................................... 589
`B. Additional therapies and approaches ................................................... 589
`C. Approved drugs ...................................................................... 589
`1. Epoprostenol ...................................................................... 589
`a. Mechanism of action ............................................................ 589
`13. Clinical studies ................................................................. 590
`c. Special considerations........................................................... 591
`d. Commercial considerations ...................................................... 591
`2. Treprostinil ....................................................................... 592
`a. Mechanism of action ............................................................ 592
`b. Clinical studies (subcutaneous infusion) .......................................... 592
`c. Clinical studies {intravenous infusion) ............................................ 593
`d. Clinical studies (inhalation) ..................................................... 594
`e. Oral treprostinil ................................................................ 594
`f Commercial considerations ...................................................... 595
`
`3. Iloprost ........................................................................... 596
`a Mechanism of action ............................................................ 596
`13. Clinical studies ................................................................. 596
`c. Commercial considerations ...................................................... 596
`4. Bosentan ......................................................................... 597
`a. Mechanism of action ............................................................ 597
`b. Clinical studies ................................................................. 597
`
`c. Expansion of product label ....................................................... 598
`d. Commercial considerations ...................................................... 599
`e. Additional pulmonary arterial hypertension and pulmonary hypertension
`populations .................................................................... 600
`f. Additional study populations .................................................... 601
`5. Ambrisentan ...................................................................... 601
`a. Clinical studies ................................................................. 601
`b. Commercial considerations ...................................................... 603
`
`Address correspondence to: Dr, Lyn Frurnkin, 2543 1!? 56th Ave. SW, Seattle, WA 98116. E—mail: lfrumkin©stanfordedu
`This article is available online at httpflpharmrev.aspetjoumals.org.
`http:#dx.doi.org/10.1124lpr.111.005587.
`
`583
`
`
`
`“oz'62qmewuo1ean6liqLuci;pepeclumca
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`

`584
`
`FRUMKIN
`
`6. Sitaxentan ........................................................................ 603
`a. Withdrawn from market ........................................................ 603
`7. Nitric oxide ....................................................................... 603
`a. Mechanism of action ............................................................ 603
`b. Clinical studies ................................................................. 603
`8. Sildenafil ......................................................................... 604
`a. Mechanism of action ............................................................ 604
`b. Clinical studies ................................................................. 604
`
`c. Long-term follow-up ............................................................ 605
`d. Label expansion. ............................................................... 605
`e. Commercial considerations ...................................................... 606
`9. Tadalafil ......................................................................... 607
`a. Clinical studies ................................................................. 607
`
`b. Long-term follow-up ............................................................ 608
`c. Commercial considerations ...................................................... 608
`
`III. Drugs in late—stage development .......................................................... 608
`A. Tyrosine kinase inhibitor (imatinib) .................................................... 608
`B. Soluble guanylate cyclase stimulator (riociguatl ......................................... 609
`C. Nonprostanoid prostacyclin receptor
`agonist (selexipag) ................................................................... 610
`D. Tissue—targeting endothelin receptor
`antagonist (macitentan) ............................................................... 610
`E. Serotonin transport inhibitor (escitalopram) ............................................ 611
`F. Serotonin receptor antagonist {terguride) ............................................... 611
`G. Prostacyclin analog (beraprostnmodified release} ......................................... 611
`H. Endothelial nitric oxide synthase {cicletanine} ........................................... 614
`I Gene therapy with progenitor endothelial cells .......................................... 614
`IV. Comparison of approved therapies ........................................................ 614
`V. Conclusion .............................................................................. 615
`
`Acknowledgments ....................................................................... 615
`References .............................................................................. 615
`
`
`
`Pulnlonary arterial hypertension (PAH)
`Abstract
`is a life-threatening and progressive disease of various
`origins characterized by pulmonary vascular remodel-
`ing that leads to increased pulmonary vascular resis-
`tance and pulmonary arterial pressure, most often re-
`sulting in right-sided heart failure. The most common
`symptom at presentation is breathlessness, with im-
`paired exercise capacity as a hallmark of the disease.
`Advances in understanding the pathobiology over the
`last 2 decades have led to therapies (endothelin receptor
`antagonists, phosphodiesterase type 5 inhibitors, and
`prostacyclins or analogs) initially directed at reversing
`
`the pulmonary vasoconstriction and more recently di-
`rected toward reversing endothelial cell dysfunction
`and smooth muscle cell proliferation. Despite these ad-
`vances, disease progression is common even with use of
`combination regimens targeting multiple mechanistic
`pathways. Overall 5-year survival for PAH has increased
`significantly from approximately 30% in the 19303 to
`approximately 60% at present, yet remains abysmal.
`This review summarizes the mechanisms of action, clin-
`ical data, and regulatory histories of approved PAH
`therapies and describes the latest agents in late-stage
`clinical development.
`
`I. Introduction
`
`Pulmonary arterial hypertension (PAH‘) is a progres-
`sive disease characterized by increased pulmonary vas—
`
`lAbbreviations: 5—HT, 5-hydroxytryptamine (serotonin); AWP, av—
`erage wholesale price; CI, confidence interval; CML, chronic myelog-
`enous leukemia; COPD, chronic obstructive pulmonary disease;
`CTEPH, chronic thromboembolic pulmonary hypertension; EMA,
`European Medicines Agency; EPC, endothelial progenitor cell; ERA,
`endotheliu receptor antagonist; ET, endothelin; EU, European
`Union; FDA, U.S. Food and Drug Administration; mPAP, mean
`pulmonary artery pressure; NAION, nonarteritic anterior ischemic
`
`cular resistance, leading to chronic elevation in pulmo-
`nary arterial pressure resulting from restricted flow
`through the pulmonary arterial circulation. These
`pathobiological features typically lead to right—sided
`
`optic neuropathy; NYHA, New York Heart Association; P450, cyto~
`chrome P450; PAH, pulmonary arterial hypertension; PDE, phos—
`phodiesterase; PDGF, platelet-derived growth factor; PDGF-R,
`platelet—derived growth factor receptor; PH, pulmonary hyperten—
`sion; PPHN, persistent pulmonary hypertension oi' the newborn;
`prostacyclin, prostaglandin 1.2; PVR, pulmonary vascular resistance;
`WHO, World Health Organization.
`
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`TREATMENT OF PULMONARY ARTERIAL HYPERTENSION
`
`585
`
`heart failure and premature death (Barst et al., 2004b;
`Galié et al., 200%) No large-scale epidemiological stud—
`ies evaluating the prevalence of PAH have been pub—
`lished, but several registries in the United States and
`Europe suggest that the prevalence of PAH in adults is
`approximately 12 to 50 per million people (Humbert et
`al., 2006; Peacock et al., 2007; Frost et al., 2011). This
`
`figure may be an underestimation given continued ads
`vances in the diagnosis of the disease. The Registry to
`EValuate Early And Long-term pulmonary arterial hy-
`pertension (REVEAL) is the largest registry of PAH
`reported to date, with 2525 US. adults meeting tradi-
`tional hemodynamic criteria; mean age at diagnosis was
`50 years with a four-to—one female predominance (Ba»
`desch et al., 2010).
`The current classification of pulmonary hyperten-
`sion (PH) has group 1 synonymous with PAH and its
`subcategories (Table 1) (Simonneau et al., 2009). Id-
`iopathic PAH occurs in the absence of known risk
`factors and is the most common form of the disease
`
`(Galié et al., 2009b; Badesch et al., 2010). Figure 1
`shows the distribution of additional subcategories of
`PAH reported from REVEAL, which includes a familial
`form (now termed heritable), a form attributable to
`drugs and t0xins, and forms in association with connec—
`tive tissue diseases, congenital heart diseases, HIV in-
`fection, portal hypertension, and other systemic condi-
`tions (Badesch et al., 2010).
`PAH is a lethal disease. The median period of survival
`after diagnosis, based on an early US. National Insti-
`tutes of Health Registry with prospective follow-up, was
`less than 3 years for 194 untreated patients with idio-
`pathic or heritable PAH (formerly called primary pul-
`monary hypertension) with a mean age of 36 years (Rich
`et al., 1987; D’Alonzo et al., 1991). At present, average
`survival after diagnosis in adults is estimated at 5 to 7
`years (Gomberg-Maitland et al., 2011; Kane et al., 2011;
`Benza et al., 2012), with a similarly poor overall prog-
`nosis in children {Barst et al., 2011a).
`The pathobiology of PAH is poorly understood but
`includes pathologic changes in the intima, media, and
`adventitial layers of the vascular wall. Both vascular
`endothelial and smooth muscle cells have characteristics
`
`of abnormal growth, with excess cellular proliferation
`and apoptosis resistance (Fig. 2). These abnormalities in
`resident vascular cells, in combination with inflamma-
`tion, excess vasoconstriction, and in situ thrombosis,
`contribute to physical narrowing of the distal pulmonary
`arterioles. This narrowing causes a dramatic increase in
`pulmonary vascular resistance, which leads to the
`chronic and progressive elevation of pulmonary arterial
`pressure. Odd clusters of immature blood vessels with
`endothelial cell proliferation (called plexiform lesions)
`are also characteristic pathologic abnormalities in PAH
`and are not found in diseases of the systemic circulation
`(Rabinovitch 2007).
`
`TABLE 1
`Current clinical classification of’pnimonory hypertension from the 4th
`Wort'd Symposium on Piiffilflflfifj' Hypertension {Dana Point, CA. 2008}
`[Reprinted from Simonneau G. Robbins iM, Bcghetti M. Channick RN, [Jelcmix M,
`Danton CF, Elliott CG, Gaine SP, Gladwin MT. ding 2C, Krowka MJ. Langleben D,
`Nakanislu N, and Sousa R [2009) Updated clinical classification of pulmonary
`hypertension. J Am Cot! Cordiof 54:343—354. Copyrigth 2009 Elscvicr. Used with
`permission]
`
`1. Group 1 pulmonary arterial hypertension (PAH)
`1.1. Idiopathic PAH
`1.2. Heritable
`1.2.1. BMPR2
`1.2.2. ALKI, endoglin [with or without hereditary
`hemorrhagic telangiectasia)
`1.2.3. Unknown
`1.3. Drug— and toxin—induced
`1.4. Associated with
`1.4.1. Connective tissue diseases
`1.4.2. HIV infection
`1.4.3. Portal hypertension
`1.4.4. Congenital heart diseases
`1.4.5. Schistosomiasis
`1.4.6. Chronic hemolytic anemia
`1.5 Persistent pulmonary hypertension of the newborn
`1'. Pulmonary vane-occlusive disease (PVOD) andfor pulmonary
`capillary hemangiomatosis (PCHJ
`2. Group 2 pulmonary hypertension owing to left heart disease
`2.1. Systolic dysfunction
`2.2. Diastolic dysfunction
`23. Valvular disease
`3. Group 3 pulmonary hypertension owing to lung diseases andfor
`hypoxia
`3.1. Chronic obstructive pulmonary disease
`3.2. Interstitial lung disease
`3.3. Other pulmonary diseases with mixed restrictive and
`obstructive pattern
`3.4. Sleep—disordered breathing
`3.5. Alveolar hypoventilation disorders
`3.6. Chronic exposure to high altitude
`3.7. Developmental abnormalities
`4. Group 4 chronic thromboerubolic pulmonary hypertension
`(CTEPH)
`5. Group 5 pulmonary hypertension with unclear multifactorial
`mechanisms
`5.1. Hematologic disorders: myeloproliferative disorders,
`splenectomy
`5.2. Systemic disorders: sarcoidosis, pulmonary Langerhans cell
`histiocy'tosis: lymphangioleiomyomatosis,
`neurofibromatosis, vasculitis
`5.3. Metabolic disorders: glycogen storage disease, Gaucher
`disease, thyroid disorders
`5.4. Others: tumora] obstruction, fibrosing mediastinitis,
`chronic renal failure on dialysis
`ALKI, activin receptor-like kinasc type 1: EM PR2, bone morphogenetic protein
`receptor type ‘2.
`
`Therapies for PAH target the prostacyclin, endothe-
`lin, or nitric oxide (NO) pathways and are believed to be
`efficacious by reversing or diminishing vasoconstriction,
`vascular endothelial cell proliferation, smooth muscle
`cell proliferation, and endothelial dysfunction (Boutet et
`al., 2008; McGoon and Kane, 2009). For example, pros-
`tacyclins are potent vasodilators that can also inhibit
`vascular smooth muscle growth. PAH is associated with
`reduced pulmonary levels of prostacyclin as a result of
`underexpression of endothelial prostacyclin synthase.
`Endothelin receptor antagonists (ERAS) block the elfect
`of endothelin, a potent endogenous vasoconstrictor and
`mitogen, at smooth muscle cell receptors. Phosphodies-
`
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`

`586
`
`A
`
`PCH
`PPHN
`<o.1%
`o.
`FPAH
`W09w 2.1%
`0.4%
`_
`
`
`
`FRUMKJN
`
`B
`
`
`Other
`5.5%
`
`
`HIV_,_
`
`4%
`
`
`
` Drugs!
`
`Toxins
`10.5%
`
`
`FIG. 1. World Health Organization (WHO) group 1 PAH classification of REVEAL (U.S. Registry) patients at enrollment. A, WHO group 1
`classification. B, breakdown of associated PAH (APAH) subgroup. The most current classification revised the category of familial PAH (FPAH) used
`at the time of the REVEAL registry to heritable PAH to reflect advances in identifying familial cases with and without germline mutations (Simonneau
`et al_, 2009) (Table 1]. CHD, congenital heart disease; CVDICTD, collagen vascular diseasefconnective tissue disease; HT, hypertension; IPAH,
`idiopathic PAH; PCH, pulmonary capillary hemangiomatosis; PVOD. pulmonary venoocclusive disease. [Reprinted from Bade-sch DH, Raskob GE.
`Elliott CG, Krichman AM, Farber HW, Frost AE. Barst RJ, Benza RI... Liou TG, Turner M, et al. (2010} Pulmonary arterial hypertension: baseline
`characteristics from the REVEAL Registry, Chest 137:376 —387. Copyright © 2010 American College of Chest Physicians. Used with permission]
`
`terase type 5 (PDE-5) inhibitors facilitate vasodilation
`by promoting the activity of the nitric oxide pathway by
`inhibiting degradation of cGMP, a second messenger
`that prompts relaxation of vascular smooth muscle. New
`therapies under development target these and addi-
`tional pathways.
`
`11. Current 'h'eatment Options
`
`A. History of Product Approvals
`
`Approved drugs currently used in the treatment of
`PAH in North America or the European Union (EU)
`include the orally administered PDE-5 inhibitors silde—
`nafil (Revatio) and tadalafil (Adcirca), the dual ERA
`bosentan (Tracleer), and the selective endothelin-1A re—
`ceptor antagonist ambrisentan [Letairis (United States);r
`Volibris (internationalfl. Patients with more advanced
`disease are often treated with prostacyclins or prostacy-
`clin analogs such as iloprost (Ventavis) or treprostinil
`(Tyvaso) given as multiple daily inhalations, epopros-
`tenol (Flolam’Veletri) or treprostinil (Remodulin) given
`as continuous intravenous infusions, or treprostinil also
`used as a continuous subcutaneous infusion. Intrave-
`
`nous injection of sildenafil is approved for patients who
`are currently prescribed but are temporarily unable to
`take oral sildenafil. Inhaled nitric oxide (INOmax) is
`approved for the neonatal form of PAH—persistent pul—
`monary hypertension of the newborn (PPHN).
`This section briefly reviews the route of administra—
`tion, mechanism of action, and approval histories of 8
`drugs (including their different formulations) that tar-
`get the prostacyclin (epoprostenol, iloprost, treprostinil),
`endothelin (bosentan, ambrisentan), and nitric oxide
`(tadalafil, sildenafil, NO) pathways and are currently
`used in the treatment of PAH in North America or the
`
`and Drug Administration (FDA) approved epoprostenol
`in 1995 for use as a continuous intravenous treatment
`
`for patients with World Health Organization (WHO)
`functional classes III (moderate) and IV (severe) symp—
`toms and for primary pulmonary hypertension that does
`not respond adequately to conventional therapy. Subse-
`quent label revisions have included the addition of pa-
`tients with PAH related to scleroderma (2000) and all
`
`patients with PAH (PH group 1) regardless of etiology to
`improve exercise capacity (2011).
`Epoprostenol reduces morbidity and improves surviv-
`al; the latter has been demonstrated mainly in those
`with idiopathic PAH in a pivotal controlled trial (com-
`paring conventional therapy) and in open-label, obser-
`vational studies that have also included other subgroups
`of PAH. Adverse events are primarily related to its con-
`tinuous intravenous delivery system and include jaw
`pain, nausea, and diarrhea, with potentially serious,
`life-threatening complications such as bloodstream in-
`fections, sepsis, thromboembolic events, and inadvertent
`drug interruption. With the availability of other thera-
`pies, epoprostenol is most often reserved for patients
`with advanced symptoms who do not adequately im—
`prove on oral or inhaled drugs. It is unusual for a patient
`to be awaiting transplantation without receiving epopro-
`stenol. Epoprostenol is available in over 20 countries,
`including the United States, Canada, Japan, Australia,
`and select regions in Europe. The patent for epopros-
`tenol expired in 2007. In 2008, the FDA approved both
`the first generic version of epoprostenol and a new in-
`travenous formulation (i.e., Veletri) that is more stable
`at room temperature.
`2. Treprostinil.
`’I‘reprostinil is a prostacyclin analog
`administered as a continuous subcutaneous or intrave—
`
`EU (Fig. 3). The drugs are reviewed in more detail in
`subsequent sections.
`1. Epoprostenol. Epoprostenol, which requires con-
`tinuous infusion through a central venous catheter and
`infusion pump, is synthetic prostacyclin. The US. Food
`
`nous infusion (Remodulin) or by inhalation (Tyvaso).
`The FDA (and Health Canada) approved treprostinil
`given subcutaneously in 2002 for the relief of symptoms
`associated with exercise in patients with PAH in New
`York Heart Association (NYHA) functional classes 11 to
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`

`TREATMENT OF PULMONARY ARTERIAL HYPERTENSION
`
`58'?
`
`® RISK Fnc'rons AND
`ASSOCIATED C O H DITIONS
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`
`FIG. 2. Characteristic pathological features of PAH. Top, diagram showing progression to vasoconstriction (and related smooth muscle hypertro-
`phy}, vascular cell proliferation, and thrombosis in situ. [Reprinted from Gaine S [2000} Pulmonary hypertension. JAMA 284:3160 —3168. Copyright
`© 2000 American Medical Association. Used with pennission.l Bottom, representative optical coherence tomography images of distal pulmonary
`arteries with comparable luminal areas for patient with normal pulmonary artery pressure EA] and patient with idiopathic PAH diagnosed 5 years
`earlier {B3, showing vascular intima and media nearly twice the thickness (0.28 versus 0.16 mm). Scale her, 1.0 mm. Courtesy of Dr. Yoshihiro
`Fukumotn (Tohoku University, Sendai, J spam.
`
`IV (mild to severe symptoms}. Treprostinil was subse-
`quently launched in most of Europe, Canada, and other
`regions. Infusion site pain and reactions are the most
`common adverse events with subcutaneous treprostinil;
`these events are reported in more than 80% of patients
`but wane over time in many (Galié et al., 2009b]. In
`2004, on the basis of data establishing bioequivalence,
`the FDA approved an intravenous formulation of trepro-
`stinil for patients with PAH in functional classes II to IV
`who do not tolerate the subcutaneous form or in whom
`
`intravenous administration may be preferable to subcu-
`taneous infusion. In early 2006, the FDA expanded the
`intravenous Remodulin label
`to include patients in
`whom transition from epoprostenol may provide a better
`Overall quality of life because of its temperature stability
`and longer half-life. In 2009, an inhaled form of trepro-
`stinil was approved in the United States to improve
`
`exercise capacity in patients with PAH in functional
`class III (moderate), with recommended four times daily
`dosing.
`Iloprost is a prostacyclin analog initially
`3. Iloprost.
`approved as an aerosolized form in the EU and Australia
`(in 2003) for patients with idiopathic PAH and func—
`tional class III status, and in the United States (in 2004)
`for patients with PAH and functional class III (moderate)
`or IV (severe) symptoms. Iloprost was later launched in
`additional regions. Iloprost is generally well tolerated, al-
`though a significant limitation is its short elimination half-
`life (20 —25 min), with recommended dosing of six to nine
`times daily. The most frequent adverse events are cough,
`headache, and flushing.
`4. Bosentan. Bosentan is a dual—endothelin [ET-1MB)
`receptor antagonist that was initially approved by the
`FDA in 2001 to improve exercise ability and decrease the
`
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`588
`
`FRUMKI'N
`
`bosentan Idual EM] approved as oral
`agent by FDA for PAH with moderate
`or severe functional class symptoms
`2001
`
`epaprostenol isynthenc prostacyclln]
`approved by FDA as continuous
`IU infusion for primaryI pulmonary
`hypertension wlth moderate or severe
`functional class symptoms
`
`epoprostencl approved by FDA as new form ulatlon
`for continuous N infusion that is more stable at room
`temperature and can be relrigerated longer in advance of
`use BDDFCNEd for urirnar)r pulmonary hypertension or
`PAH associated with the scle roderma spectrum of disease in
`those with moderate or severe functional clasa syrn prams
`
`Iloprost [nrosracyciln analogue]
`
`approved in EU for inhalation In
`
`those with rdlupathlc sin and
`moderate fu nctlonai class symptoms
`2008
`
`2003
` slldenafi iPDE-S inhlhltori
`
`
`approved by FDR as oral agent Inr
`1995
`
`PAH {PH Group 1}
`2005
`
`
`
`I 990
`
`2010
`
`2009
`MA V
`Iadalafi {PDE—S Inhlbltorl approved by FDA
`as oral agent for BtH (PI-I Group 1 I
`JUL Y
`treprostinll (Inhaled) approved by FDA for
`those wlrh PAH IPH Group 1] and moderate
`functional class syrn ptorns
`NOV
`slldenafl approved by FDA as Ill" bolus
`Injection tar those with PAH iPH Group I 1
`renunorarrl:t unable [0 rates oral form
`
`1999
`urtl'l: oxide approvep by FDA as
`inhaled agent for term and marten-r1
`I: 34 weeks} neonates wlth hypmilr.
`resplratnry fallure associated wlth PH
`
`
`
`
`
`
`2004
`
`tneprostinil approved by FDA as contlnuous
`IV infusion for those with PAH and mild to
`severe functional dais symptoms mm: are
`unable to [derate 5.: Inl'uslon!
`
`
`
`
`
`2002
`
`treprostinil Iprostacydln analogue] approved
`
`by FDA as contlnuous ac. rntusron for PAH
`wlth Mild to severe fu nctlonal class symptoms
`
`200?
`ambrisentan {selective EM] approved by
`FDA as oral agent. for PAH {PH Group I] with
`mild or moderate functional class symptoms
`
`Fm. 3.
`
`'I‘imcline of first approval of drugs (and their difi’ercnt formulationsi currently used for PAH in North America or the EU,
`
`rate of clinical worsening in patients with PAH in WHO
`functional classes III and IV. Because of risk of toxicity,
`bosentan is available in the United States only through
`a restricted distribution program that monitors liver
`function enzyme values and pregnancy status on a
`monthly basis. Subsequent approvals have occurred in
`more than 50 regions. In Canada and the EU, the initial
`indication was more restrictive than in the United
`
`States, reflecting the predominant study population en-
`rolled in the pivotal bosentan trial: PAH that is idio-
`pathic or associated with scleroderma and WHO func-
`tional class III symptoms.
`In 2006,
`the label was
`extended in Canada to include patients with either PAH
`related to HIV infection or congenital heart disease
`(functional class III or IV status) and in the EU to
`
`include patients with PAH related to congenital systemic-
`tu-pulmonary shunts or Eisenmenger syndrome (class III
`status). In the EU (in 2008) and the United States and
`Canada (in 2009), the label was further revised to include
`patients with mild (class II) symptoms. In 2009, the EU
`label was expanded to include a pediatric dispersible for-
`mulation.
`5. Ambrisentan. Ambrisentan is an oral selective
`
`ETA—receptor antagonist approved in the United States
`in 2007. The drug was indicated as a once-daily treat—
`ment for patients with PAH and WHO functional class II
`(mild) or III (moderate) symptoms to improve exercise
`
`capacity and delay clinical worsening. Ambrisentan was
`later approved for use in Canada (in 2008), EU (2008),
`New Zealand (in 2009), Australia {in 2009), and Japan
`(in 2010). A subsequent U.S.
`label revision specified
`treatment of patients with PAH regardless of functional
`status. Ambrisentan was initially dispensed in the
`United States only to patients through a restricted dis-
`tribution program that monitored liver function enzyme
`values and pregnancy status on a monthly basis (as is
`the case with bosentan). In 2011, the FDA removed the
`requirement for monthly monitoring of liver function
`values with ambrisentan as a result of additional data
`
`reporting no significant increase in hepatic toxicity com-
`pared with patients with PAH not receiving an ERA. As
`a result, ambrisentan requires restricted distribution
`solely for pregnancy monitoring in women of childbearing
`potential because of risk of drug-related teratogenicity.
`6. Nitric Oxide. NO is a potent pulmonary vasodila-
`tor that can be rapidly delivered to the lung by inhala-
`tion. Nitric oxide (lNOmax) for inhalation was approved
`by the FDA in 1999 for term and near-term (older than
`34 weeks’ gestation) neonates with hypoxic respiratory
`failure and PPHN. In 2001, approval in the EU was
`obtained and subsequently expanded to include patients
`with peri- and postoperative PH in conjunction to car-
`diac surgery.
`
`UNITED THERAPEUTICS, EX. 2069
`
`WATSON LABORATORIES V. UNITED THERAPEUTICS, |PR2017-01621
`
`Page 6 of 38
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`

`

`TREATMENT OF PULMONARY ARTERIAL HYPERTENSION
`
`589
`
`7. Siidencfii. Sildenafil is an oral PDE-5 inhibitor
`initially developed and marketed for erectile dysfunction
`(trade name Viagra). Sildenafil (trade name Revatio)
`was approved in 2005 as a thrice-daily therapy for PAH
`by the FDA and European Medicines Agency (EMA).
`Subsequent approvals have occurred in over 50 coun—
`tries. In the United States, sildenafil is indicated for
`patients with PAH regardless of functional class. In the
`EU, sildenafil use is restricted to the predominant pop-
`ulation studied in the pivotal phase 3 trial: patients with
`PAH that is either idiopathic or associated with connec—
`tive tissue disease in functional class II (mild) or III
`
`(moderate). Sildenafil is also approved as an intrave~
`nous injection for patients who are temporarily unable
`to take oral sildenafil and in the EU as an oral suspen-
`sion for the treatment of patients with PAH aged 1 to 17
`years.
`
`8. Todaiofil. Tadalafil is also an oral PDE~5 inhibi-
`tor, approved in 2009 in the United States and EU (and
`in 2010 in Canada and Japan) as a once-daily therapy to
`improve exercise capacity in patients with PAH. The EU
`label specifies use in those with mild to moderate func-
`tional class, reflecting the predominant phase 3 pivotal
`study population.
`
`B. Additional Therapies and Approaches
`
`Conventional therapy for PAH has included oral
`anticoagulation, supplemental oxygen, diuretics, and
`digoxin, although their use has not been evaluated in
`randomized controlled clinical studies. Microscopic
`thrombi have been observed in postmortem lung tis-
`sue of patients with idiopathic PAH (Fuster et al.,
`1984), and idiopathic PAH has been associated with a
`hypercoagulable state (Tournier et al., 2010). Al-
`though benefits of anticoagulaticn use have been re-
`ported mainly in those with idiopathic PAH and PAH
`associated with anorexigen use, and observational stud-
`ies have led to conflicting conclusions (Johnson et al.,
`2012), long-term anticoagulation is believed to improve
`survival (Frank et al., 1997; Johnson et al., 2006). Hyp~
`oxia is a potent vasoconstrictor of the pulmonary vascu-
`lature, and supplemental oxygen is recommended to
`maintain oxygen saturation greater than 92% during
`sleep; ambulatory oxygen may benefit those with cor—
`rectable desaturation on exercise (Galié et al., 2009b).
`Calcium—channel blockade is very effective in some
`patients with PAH who respond favorably with acute
`vasodilator testing using epoprostenol or inhaled NO
`[e.g., decrease in mean pulmonary artery pressure
`(mPAP) of at least 10 mm Hg to a nadir 540 mm Hg
`with no clinically significant decrease in cardiac output]
`(Barst et al., 2009). Most acute responders have been
`observed among those with idiopathic or heritable PAH;
`Overall, approximately 8% of adults with idiopathic or
`heritable PAH respond favorably to acute vasodilator
`testing. Recommended calcium channel blockers for
`PAH are limited to nifedipine, amlodipine, and dilti-
`
`azem; verapamil is not used because of its potential for
`negative inotropy (Young et al., 1983; Packer at al.,
`1984)