Atty. Dkt. No. 080618~0463
`
`U.S. PROVISIONAL PATENT APPLICATION
`
`for
`
`METE RED DOSE INHALER TREPROSTINIL TREATMENT FOR
`
`PULMONARY HYPERTENSION
`
`Inventors:
`
`Horst Olschewski
`
`Robert Roscigno
`
`Lewis J. Rubin
`
`Thomas Schmehl
`
`Werner Seegcr
`
`Carl Steritt
`
`Robert Vnswinckel
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`UNITED THERAPEUTICS, EX. 2100
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`Atty. Dkt. No. 080618-0463
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`METERED DOSE INHALER TREPROSTINIL TREATMENT FOR
`
`PULMONARY HYPE-RTENSION
`
`[0001] The present application relates to treatment of pulmonary hypertension and,
`in particular, to treatment ot‘pulmonary hypertension by administering treprostinil
`using a metered dose inhaler.
`
`BACKGROUND OF THE INVENTION
`
`[0002] All blood is driven through the lungs via the pulmonary circulation in order,
`among other things, to replenish the oxygen which it dispenses in its passage around
`the rest of the body via the systemic circulation. The flow through both circulations is
`
`in normal circumstances equal, but the resistance offered to it in the pulmonary
`circulation is generally much less than that of the systemic circulation. When the
`
`resistance to pulmonary blood flow increases, the pressure in the circulation is greater
`for any particular flow. This is referred to as pulmonary hypertension (PH).
`
`Generally, pulmonary hypertension is defined through observations of pressures
`above the normal range pertaining in the majority of people residing at the same
`
`altitude and engaged in similar activities.
`
`[0003] Most often pulmonary hypertension is a manifestation of an obvious or
`
`explicable increase in resistance, such as obstruction to blood flow by pulmonary
`emboli, malfunction of the heart‘s valves or muscle in handling blood after its passage
`through the lungs, diminution in pulmonary vessel caliber as a reflex response to
`hypoventilation and low oxygenation, or a mismatch of vascular capacity and
`
`essential blood flow, such as shunting of blood in congenital abnormalities or surgical
`removal of lung tissue. Such pulmonary hypertension is referred to as secondary
`hypertens i on.
`
`[0004] There remain some cases of pulmonary hypertension where the cause of the
`
`increased resistance is as yet inexplicable. They are described as idiopathic (primary)
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`Atty. Dkt. No. 080618-0463
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`pulmonary hypertension (PPH) and are diagnosed by and after exclusion of the causes
`
`of secondary pulmonary hypertension. Despite the possibility of a varied etiology,
`cases of idiopathic pulmonary hypertension tend to comprise a recognizable entity.
`
`Approximately 65% of the most commonly afflicted are female and young adults,
`though it has occurred in children and patients over 50. Life expectancy from the
`
`time of diagnosis is short, about 3 to 5 years, though occasional reports of
`
`spontaneous remission and longer survival are to be expected given the nature of the
`
`diagnostic process. Generally, however, progress is inexorable via syncope and right
`heart failure and death is quite often sudden.
`
`[0005]
`
`Pulmonary hypertension refers to a condition associated with an elevation of
`
`pulmonary arterial pressure (PAP) over normal levels.
`
`In humans, a typical mean
`
`PAP is approximately 12-15 mm Hg. Pulmonary hypertension, on the other hand, is
`
`sometimes marked by PAP increases by at least 5 to 10 mm Hg over normal levels.
`
`PAP readings as high as 50 to 100 mm Hg over normal levels have been reported.
`
`When the PAP markedly increases, plasma can escape from the capillaries into the
`lung interstitiurn and alveoli. Fluid buildup in the lung (pulmonary edema) can result,
`with an associated decrease in lung function that can in some cases be fatal.
`
`Pulmonary hypertension may either be acute or chronic. Acute pulmonary
`[0006]
`hypertension is often a potentially reversible phenomenon generally attributable to
`
`constriction of the smooth muscle ofthe pulmonary blood vessels, which may be
`
`triggered by such conditions as hypoxia (as in high-altitude sickness), acidosis,
`inflammation, or pulmonary embolism. Chronic pulmonary hypertension is
`
`characterized by major structural changes in the pulmonary vasculature, which result
`
`in a decreased cross-sectional area ofthe pulmonary blood vessels. This may be
`
`caused by, for example, chronic hypoxia, thromboembolism, or unknown causes
`
`(idiopathic or primary pulmonary hypertension).
`
`Pulmonary hypertension has been implicatcd in several life-threatening
`[0007]
`clinical conditions, such as adult respiratory distress syndrome ("ARDS") and
`
`persistent pulmonary hypertension of the newborn (“PPHN”), Zapol et al., Acute
`
`Respiratory Failure, p. 241-273, Marcel Dekker, New York (1985); Peckham, J. Pcd.
`
`WASHJSAIYoii
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`2
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`Atty. Dkt, No. 080618-0463
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`93:1005 (1978). PPHN, a disorder that primarily affects full-term infants, is
`
`characterized by elevated pulmonary vascular resistance, pulmonary arterial
`
`hypertension, and right-to-left shunting ofblood through the patent ductus arteriosus
`
`and foramen ovale of the newbom's heart. Mortality rates range from 12-50%. Fox,
`
`Pediatrics 59:205 (1977); Dw0retz, Pediatrics 84:1 (1989). Pulmonary hypertension
`
`may also result in a potentially fatal heart condition knoWn as "cor pultnonale,“ or
`
`pulmonary heart disease. Fishman, "Pulmonary Diseases and Disorders" 2“"1 Ed,
`
`McGraw~HilL New York (1988).
`
`[0008] Currently, there is no treatment for pulmonary hypertension that can be
`
`administered using compact inhaling devices such as a metered dose inhaler.
`
`SUMMARY OF THE INVENTION
`
`[0009] One embodiment is a method for treating pulmonary hypertension in a
`
`subject, comprising administering to the subject treprostinil or its derivative, or a
`
`phannaceutically acceptable salt thereof by a metered dose inhaler.
`
`[0010] Another embodiment is a kit for treating pulmonary hypertension in a
`
`subject, comprising (i) an effective amount of treprostinil or its derivative, or a
`
`pharmaceutically acceptable salt thereof; (ii) a metered dose inhaler; (iii) instructions
`for use in treating pulmonary hypertension.
`
`[0011] Administration of treprostinil by a metered dose inhaler provides pulmonary
`hypertension patients with a high degree of autonomy.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIGURE 1 pulmonary and systemic changes in hemodynamics following the
`[0012]
`inhalation ofplacebo (open circles), 30pg treprostinil (triangles), 45 ug treprostinil
`
`(squares) or 60ug treprostinil (black circles) applied by a metered dose inhaler. A
`
`single short inhalation of treprostinil induced sustained reduction of PAP and PVR
`
`that outlasted the observation period of 120 minutes at doses of45 and 60pg MDI-
`TRE. Systemic arterial pressure and resistance were not significantly affected, PAP
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`Atty. Dkt. No. 080618-0463
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`= pulmonary artery pressure; I’VR = pulmonary vascular resistance; SAP = systemic
`
`arterial pressure; SVR = systemic vascular resistance. Data are given as mean +
`SEM.
`
`FIG. 2 presents hemodynamic changes induced by the inhalation of placebo
`[0013]
`(cpen circles)= 30];g treprostinil (triangles), 4Sug treprostinil (squares) or (Song
`
`treprostinil (black circles) applied by a metered dose inhaler. Treprostinil induced
`
`sustained elevation of cardiac output. Heart rate was rather unchanged as a sign for
`low Spillover of MDI—TRE to the systemic circulation. Gas exchange was not
`
`negatively affected. CO = cardiac output; HR = heart rate; SaO2 = arterial oxygen
`saturation; Sv02 2 central venous oxygen saturation. Data are given as mean 1 SEM.
`
`[0014]
`
`FIG. 3 shows areas under the curve for changes in pulmonary vascular
`
`resistance (PVR) calculated for an observation period of 120 minutes after inhalation
`
`from a metered dose inhaler.
`
`I’VR was markedly lowered by treprostinil inhalation.
`
`The increased pulmonary vasodilation over time with the two highest doses mainly
`relies on the more sustained effect over time. Data are shown as mean i 95%
`
`confidence intervals.
`
`[0015]
`
`FIG. 4 demonstrates Ventilation—perfusion matching measured with the
`
`multiple inert gas elimination technique. Five patients (3 [lug TRE, 11:2; 45 pg TRE,
`
`n2] ; 60pg TRE, n=2) with pre-cxisting gas exchange problems were investigated for
`
`changes in ventilation-perfusion ratios. All patients had significant shunt flow at
`
`baseline. Shunt-flow and low VIQ areas were not significantly changed by nitric
`oxide (NO) inhalation or treprostinil inhalation from a metered dose inhaler (MDI-
`
`TRE). MDI—TRE applied at high treprostinil concentrations did thus not negatively
`affect ventilation-perfusion matching and gas-exchange. Data are given as mean a:
`95% confidence intervals.
`
`[0016]
`
`FIG. 5 presents response ot‘pulmonary vascular resistance (PVR) to inhaled
`
`treprostinil vs. iloprost — period effects. a) First inhalation with treprostinil (n=22) vs.
`first inhalation with il0prost (n=22); b) second inhalation with treprostinil (n=22) vs.
`second inhalation with iloprost (r1322). The PVR decrease with treprostinil was
`
`WASILT 541 set .3
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`Atty. Dkt. No. 080618-0463
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`delayed and prolonged, compared to iloprost. Due to carryover effects from the first
`
`period, in the second period, the effects of both drugs appeared shortened. Data are
`
`shown as percent of baseline values (mean i 95% confidence interval).
`
`[001?]
`
`FIG. 6 presents response of PVR and systemic arterial pressure (SAP) to
`
`inhalation of treprostinil vs. iloprost A dose effects. a) Inhalation of 7.5 pg iloprost (in
`6 min) vs. 7.5 pg treprostinil (6 min) (n=l4, in randomized order). b) Inhalation of
`
`7.5 pg iloprost (6 min) vs. 15 pg treprostinil (6 min) (11:14, in randomized order). c)
`
`Inhalation of7.5 pg iloprost (6 min) vs. 15 pg trcprostinil (3 min) (n46, in
`
`randomized order). Data are shown as percent of baseline values (mean + 95%
`
`confidence interval). Iloprost, filled circles; Treprostinil, open triangles.
`
`[0018]
`
`FIG. 7 presents hemodynamic response to inhalation of treprostinil vs.
`
`iloprost. Data from n=44 patients, who inhaled both drugs in randomized order,
`
`shoWn as percent of baseline values (mean i 95% confidence interval). PVR,
`
`pulmonary vascular resistance; PAP, mean pulmonary arterial pressure; SAP, mean
`
`systemic arterial pressure; CO, cardiac output.
`
`[0019]
`
`FIG. 8 presents phannacodynamics after treprostinil inhalation vs. placebo.
`
`Placebo or treprostinil in doses of 30pg, 60pg or 90pg were inhaled (means i 95 %
`
`confidence intervals). Maximal decrease of PVR was comparable for all doses. The
`
`duration of pulmonary vasodilation (PVR—decreasc) appeared to be dose dependent.
`
`PVR, pulmonary vascular resistance; PAP, mean pulmonary arterial pressure; SAP,
`
`mean systemic arterial pressure; CO, cardiac output; SaOz, arterial oxygen saturation;
`
`SvOZ, mixed venous oxygen saturation.
`
`FIG. 9 presents areas between the placebo and the treprostinil curves (ABC).
`[0020]
`ABC was calculated for a 3-hour period after inhalation of TRE or placebo from the
`
`relative changes ofhemodynamic parameters (means i: 95 % confidence intervals).
`
`PVR, puimonary vascular resistance; PAP, mean pulmonary arterial pressure; SAP,
`
`mean systemic arterial pressure; SVR, systemic vascular resistance.
`
`|00211
`
`FIG. 10 presents hemodynamic responses to the inhalation of I Spg
`
`treprostinil. Minimizing inhalation time by increasing TRE concentration, A pulse of
`5
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`Atty. Dkt. No. 080618-0463
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`aerosol was generated every 6 seconds. TRE aerosol was inhaled in concentrations of
`
`100ug/ml (18 pulses; n=6), 200ugfml (9 pulses; n=6), 600ugr’ml (3 pulses; n=2 1),
`
`1000ugfml (2 pulses; n=7) and 2000ug/ml (1 pulse; n=8). Data are shown as means I
`
`95 % confidence intervals. PVR, pulmonary vascular resistance; PAP, mean
`
`pulmonary arterial pressure; SAP, mean systemic arterial pressure; CO, cardiac
`
`output.
`
`[0022]
`
`FIG. 1 1 presents areas between the placebo curve and the responses to lSug
`
`treprostinil applied at increasing concentrations to minimize inhalation time. For
`
`details of aerosol generation see FIG. 9. Mean 2L. SEM of relative changes of
`
`hemodynamie parameters [observation time 120 min). PAP, pulmonary arterial
`
`pressure, SAP, systemic arterial pressure, PVR, pulmonary vascular resistance, CO,
`
`cardiac output, SaO2, systemic arterial oxygen saturation, SvOZ, pulmonary arterial
`
`oxygen saturation.
`
`[0023]
`
`FIG. 12 presents pharmacokinetics of treprostinil after single inhalation.
`
`Treprostinil plasma levels after inhalation of 30ug, 60ug, 90ug or 120ug treprostinil
`
`(6 min inhalation period; experiments correspond to those shOWn in figure 4 and 5).
`
`Data with error bars represent means a. SEM.
`
`DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
`
`1)
`E6
`[0024] Unless otherwise specified, the term a or “an” used herein shall mean “one
`or more.”
`
`[0025] The inventors discovered that treprostinil can be administered using compact
`inhaling device such as a metered dose inhaler. Furthermore, the inventors discovered
`
`that such administering does not cause systemic side effects and gas exchange
`
`deteriorations or disruptions.
`
`[0026] Accordingly, one embodiment of invention is a method for treating
`
`pulmonary hypertension in a subject, comprising administering to the subject, such as
`
`human being, treprostinil or its derivative, or a pharmaceutically acceptable salt using
`a metered dose inhaler.
`
`WASIl__Ij-1l?b|.3
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`[0027] Treprostinil, or 9-deoxy-2’,9«alpha-methano-3-oxa~4,5,6-trinor-3,7—(1’3’-
`interphenylene}-13,l4—dihvdro-prostaglandin F1, is a prostaeyclin analogue, first
`described in US patent 4,306,075. US Patent No. 5,153,222 describes use of
`
`treprostinil for treatment of pulmonary hypertension. Treprostinil is approved for the
`intravenous as Well as subcutaneous route, the latter avoiding septic events associated
`
`with continuous intravenous catheters. US patents Nos. 6,521,212 and 6,5 76,033
`describe administration of treprostinil by inhalation for treatment of pulmonary
`hypertension.
`
`[0028] The term “acid derivative" is used herein to describe (31-4 alkyl esters and
`
`amides, including amides wherein the nitrogen is optionally substituted by one or two
`C l -4 alkyl groups.
`
`[0029] The present invention also encompasses methods of using Treprostinil or its
`derivatives. or pharmaceutically acceptable salts thereof.
`In one embodiment, a
`
`method uses Treprostinil sodium, currently marketed under the trade name of
`REMODULING-c The FDA has approved 'I‘repro stinil sodium for the treatment of
`
`pulmonary arterial hypertension by injection of dose concentrations of 1.0 mgme, 2.5
`mg/mL, 5.0 mg;'mL and 10.0 mg/mL. The chemical structure formula for Treprostinil
`sodium is:
`
`0H
`
` IIIIIIfIIOH
`
`
`(a)
`'l‘reprostinil sodium is sometimes designated bythc chemical names:
`[0030]
`[(1R,2R,3a5,9a.5')-2,3,3a,4,9,9a-hexahydro~2-hydroxy-l—[(3S}-3 -hydroxyoetyl]-1H-
`benzD‘]inden-S-yl]oxy]aeetie acid; or (b) 9-deoxy-2’,9n0L-methano-3-oxa-4,5,6-trinor-
`
`3,?«(1’,3’~interphcnylene)-l3.l4~dihydro-prostaglandin F1. Treprostinil sodium is
`
`WASH _1 541701.}
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`Atty. Dkt. No. 080618~U463
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`also knOWn as: UT-lS; LRX-IS; ISAUSI; UNIPROSTTM; BW AISAU; and U-
`
`62,840. The molecular weight of Treprostinil sodium is 390.52, and its empirical
`
`formula IS CHI-134.05.
`
`[0031] The present invention extends to methods of using physiologically
`
`acceptable salts of Treprostinil, as well as non-physiologically acceptable salts of
`
`Treprostinil that may be used in the preparation of the pharmacologically active
`
`compounds of the invention.
`
`[0032]
`
`Physiologically acceptable salts of 'l‘rcprostinil include salts derived from
`
`bases. Base salts include ammonium salts (such as quaternary ammonium salts),
`alkali metal salts such as those of sodium and potassium, alkaline earth metal salts
`
`such as those of calcium and magnesium, salts with organic bases such as
`
`dicyelohexylamine and N-methyl-D~glucamine, and salts with amino acids such as
`
`arginine and lysine.
`
`[0033] Quaternary ammonium salts can be formed, for example, by reaction with
`
`lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and
`
`iodides, with dialkyl sulphates, with long chain halides, such as decyl, lauryl,
`
`myristyl, and stearyl chlorides, bromides, and iodides, and with aralkyl halides, such
`
`as benzyl and phenethyl bromides.
`
`[0034] Treprostinil is administered by inhalation, which in the present context refers
`
`to the delivery of the active ingredient or a combination of active ingredients through
`
`a respiratory passage, wherein the subject in need of the active in gredi ent(s) through
`the subjects airways, such as the nose or mouth.
`
`[0035] A metered dose inhaler in the present context means a device capable of
`
`delivering a metered or bolus dose ofrespiratory drug, such as treprostinil, to the
`
`lungs. One example ofthe inhalation device can be a pressurized metered dose
`
`inhaler, a device which produces the aerosol clouds for inhalation from solutions of
`
`respiratory drugs in chlorofluorocarbon (CFC) andfor hydrotluoroalkanc (HFA)
`solutions.
`
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`[0036] The inhalation device can be also a dry powder inhaler.
`
`In such case, the
`
`reSpiratory drug is inhaled in solid formulation, usually in the form ofa powder with
`
`particle size less than 10 micrometers in diameter or less than S micrometers in
`
`diameter.
`
`[0037] The metered dose inhaler can be a soft mist inhaler (SMI), in which the
`
`aerosol cloud can be generated by passing a solution containing a respiratory drug
`through a nozzle or series of nozzles. The aerosol generation can be achieved in SMI,
`
`for example, by mechanical, electromechanical or thermomechanical process.
`
`Examples of soft mist inhalers include the Respimat® Inhaler (Boeringer Ingelheim
`GmbH), the AERx® Inhaler (Aradigm Corp), the MysticTM Inhaler (Ventaira
`
`Pharmaceuticals, Inc) and the AiraTM Inhaler (Chrysalis Technologies Incorporated).
`
`For a review of soft mist inhaler technology, see eg. M. Hindle, The Drug Delivery
`Companies Report, Autumaninter 2004, pp. 31-34. The aerosols for SMI can be
`
`generated from a solution of a respiratory drug eontaining pharmaceuti cally
`
`acceptable excipients. The solution can be, for example, a solution of treprostinil in
`
`water, ethanol or a mixture of the two.
`
`[0038] The amount of treprostinil that can be administered in a single event can be
`
`from about IS ug to about 100 pg or from about lSug to about 90 ug or from about
`
`30 ug to about 90 pg or from about 30 ug to about 60ug.
`
`[0039] Administering oftreprostinil in a single event can be carried out in a limited
`
`number of breaths by a patient. For example, treprostinil can be administered in 20
`
`breaths or less, or in ID breaths or less, or than 5 breaths or less. Preferably,
`
`treprostinil is administered in 3, 2 or 1 breaths.
`
`[0040| The total time of a single administering event can be less than 5 minutes, or
`
`less than 1 minute, or less than 30 seconds.
`
`[004]] Treprostinil can be administered a single time per day or several times per
`day.
`
`\N'ASII__IS4I?EJI.3
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`[0042] Administration of treprostinil using a metered dose inhaler can be carried out
`
`by administering a formulation with treprostinil concentration from about 500 ugj’ml
`
`to about 2500 pgfml, or from about 800 tight] to about 2200 ug’ml, or from about
`
`1000 ug/ml to about 2000 ugfml.
`
`[0043]
`
`In some embodiments, the method of treatment of pulmonary hypertension
`
`can fimher comprise administering at least one supplementary agent selected from the
`
`group consisting of sildenatil, tadalafil, calcium channel blockers (diltiazem,
`
`amlodipine, nifedipine), bosentan, sitaxsentan, ambrisentan, and pharmaceutically
`
`acceptable salts thereof. In some embodiments, the supplementary agents can be
`
`included in the treprostinil formulation and, thus, can be administered simultaneously
`with treprostinil using a metered dose inhaler.
`In some embodiments, the
`
`supplementary agents can be administered separately from treprostinil.
`
`In some
`
`embodiments, the application of intravenous prostaeyclin (flolan), intravenous
`
`iloprost or intravenous or subcutaneous treprostinil can be administered in addition to
`
`metered dose inhaler treprostinil.
`
`[0044] The present invention also provides a kit for treating pulmonary
`
`hypertension, that includes (i) a metered dose inhaler containing a pharmaceutical
`formulation comprising treprostinil or its derivative, or a pharmaceutically acceptable
`salt thereof; and (ii) instructions for use of in treating pulmonary hypertension.
`
`[0045] As used herein, the phrase “instructions for use” shall mean any FDA-
`
`mandated labeling, instructions, or package inserts that relate to the administration of
`
`Treprostinil or its derivatives, or pharmaceutically acceptable salts thereof, for
`
`treatment of pulmonary hypertension by inhalation. For example, instructions for use
`
`may include, but are not limited to, indications for pulmonary hypertension,
`
`identification of specific symptoms associated with pulmonary hypertension, that can
`
`be ameliorated by Trcprostinil, and recommended dosage amounts for subjects
`
`suffering from pulmonary hypertension.
`
`WAS|{__]54|?61.3
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`10
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`[0046] The present invention can be illustrated in more detail by the following
`
`example, however, it should be understood that the present invention is not limited
`thereto.
`
`EXAMPLE 1
`
`OPEN LABEL STUDY UPON ACUTE SAFETY, TOLERABILITY
`
`AND HEMODYNAMIC EFFECTS OF INHALED TREPROSTINIL
`
`DELIVERED IN SECONDS.
`
`[0047] A study was conducted of acute vasodilator challenge during right heart
`
`catheter investigation to determine the safety, tolerability and pulmonary vasodilatory
`
`potency of inhaled treprostinil applied in seconds by a sofi mist inhaler (SMI-TRE).
`
`The study produced evidence for a long lasting favourable effect of SMI—TRE on
`
`pulmonary hemodynamics in absence of systemic side effects and gas exchange
`
`disruptions.
`
`[0048]
`
`Summary:
`
`Inhaled nitric oxide (20 ppm; n=45) and inhaled treprostinil
`
`sodium (TRE; n=41) or placebo (n24) were applied once during right heart catheter
`
`investigation. TRE was delivered in 2 breaths (lUUUttgfml aerosol concentration;
`
`30ug dose; n=12), 3 breaths (lOOOugfml; 4Sug; n=9) or 2 breaths (ZOOOpg/ml; 60ug;
`ntZU) from a Respimat® SMI. Pulmonary hemodynamics and blood gases were
`
`measured at defined time points, observation time following TRE application was 120
`
`minutes. TRE doses of 30pg, 45ug and 60pg reduced pulmonary vascular resistance
`
`(PVR) to 84.4 i 8.7 %, 71.4 i 17.5 % and 77.5 J; 7.2 % ofbaseline values,
`
`reSpectively (mean i- 95% confidence interval). The 120 minute area under the curve
`
`for PVR for placebo. 30ug, 45ug and 60ug TRE was 1230 i 1310, -870 i 940, -2450
`
`t 2070 and -2000 i 900 min %, respectively. Reduction ofPVR by a single
`
`inhalation ofthe two higher doses outlasted the observation period of 120 minutes.
`
`Reduction ot‘systemic vascular resistance and pressure was negligible, showing a
`
`high pulmonary selectivity for SMl-TRE.
`
`Intrapulmonary selectivity was also
`
`provided by SMI-TRE as ventilation/perfusion matching, assessed by the multiple
`
`inert gas elimination technique in 5 patients with gas exchange problems, was not
`
`wasngsmsts
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`Atty. Dkt. No. 0806180463
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`significantly different after SMLTRE compared to inhaled nitric oxide. No
`
`significant side effects were observed.
`
`[0049] Conclusions: The acute application of inhaled trepro stinil with a metered
`
`dose inhaler in 2—3 breaths was safe, well tolerated and induced a strong and sustained
`
`pulmonary selective vasodilation.
`
`Methods and Patients
`
`[0050] A total number of 45 patients with moderate to severe precapillary
`
`pulmonary hypertension were enrolled. Patient characteristics were: female to male
`
`ratio (firn) = 29/16, age 59 i 2.3 years, pulmonary artery pressure (PAP) 45 :t 1.8
`
`mmHg, pulmonary vascular resistance (PVR) 743 d: 52 dynesscm's, pulmonary
`
`artery wedge pressure (PAWP) 8.6 i 0.5 mmHg, central venous pressure (CVP) 6.4 i
`
`0.7 mran, cardiac output (CO) 4.5 i 0.2 l/min, central venous oxygen saturation
`
`(Sv02) 62.3 t 1.2 mmHg (mean 1 Standard Error of the Mean). Disease etiologies
`
`were idiopathic PAH (iPAH) (n=l3), PAH other (n=1 1), chronic thromboembolic
`
`pulmonary hypertension (CTEPH) (n=17) and pulmonary fibrosis (n=4). Table 1
`
`presents the patient characteristics of the different groups.
`
`Table l.
`
`[005]]
`
`Patient characteristics of the different treatment groups. Data are given as
`
`mean :l: Standard Error ofthe Mean (SEM). PAP == pulmonary artery pressure; PVR =
`
`pulmonary vascular resistance; C0 = cardiac output; SAP = systemic arterial
`
`pressure; SaO2 = arterial oxygen saturation; Sv02 = central venous oxygen
`saturation.
`
`W.v\SH_]54|'.-’bl.3
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`
`Placebo
`30ug TRE
`-
`45ug Tali—T 60pg TRE
`
`_
`(F4)
`1_ (n=12)
`(9:?)
`(F20) _1
`
`
`Age [years]
`5
`61:: 8
`53.9 i 3.9
`1
`54.2 i 5.7
`65.5 i 3.1
`54.3 a: 2.8
`39.?e20
`PAP [mml-Ig]
`49.5:t 10.1
`45s 3.1
`I
`
`.
`
`
`
`
`
`
`
`
`
`PVR [Dynes]
`896 a 163
`597 53.9
`1049 a 107‘L
`663 i 81
`
`(:0 [l/min] _'— 4.46 :t 0.9 E572 i 0.4
`l
`3.9 i 0.4
`"""'21'.'4 i 0.3
`
`ISAP[rang]
`98i8.l
`90.1 $3.2
`82.8i3.9
`86.1 $2.0
`l
`_ Sa02 [%]
`85.3 i4.5
`900$ 1.1
`89.6i1.1
`306i 0.5
`51.92198]
`57.5 $3.9
`66.0i 1.6
`59.1 a 3.4
`62.5 i 1Q
`
`
`|
`
`I
`
`[0052] Baseline values were determined 20-30 minutes after placement of the
`
`catheter. Heart rate, pulmonary and systemic blood pressure and cardiac output were
`
`measured and blood gases were taken during each pharmacological intervention at
`
`defined time points. Pharmacological interventions included the inhalation of 20 ppm
`
`nitric oxide (NO) after evaluation of baseline parameters (11:45) and the consecutive
`
`inhalation of‘placebo (n=4), 30pg SMI-TRE (n=12), 45ug SMI—TRE (n=9) or 60ug
`
`(n=20) SMI—TRE. Placebo and treprostinil was applied with the Respimatg' SMI. For
`
`filling of this device with treprostinil sodium, the placebo solution was withdrawn
`
`from the device with a syringe and treprostinil solution was injected into the device
`
`under sterile conditions. Aerosol quality was controlled before and after refilling of
`
`the SMI devices by laser diffraetometry, see e. g. Gessler T, Sehmehl T, Hoeper MM,
`
`Rose F, Ghofrani HA, Olschewski H et al. Ultrasonic versusjet nebulization of
`
`iloprost in severe pulmonary hypertension. Eur Respir J. 2001 ;1 7:14-19 incorporated
`
`herein in its entirety. The aerosol sizes before (placebo) and after filling (treprostinil)
`
`Were unchanged, the aerosol volume delivered by one cycle from the SMI was 15111.
`
`The solution used for aerosol generation was prepared from treprostinil sodium salt
`
`using a standard protocol. The SMI was either filled with a concentration of
`
`1000ug/ml treprostinil sodium (one aerosol puff: lSug TRE) or with 2000ugv’rnl
`
`(one puff= 30ug TRE). The different doses were applied as 2 puffs IOOOugt'ml
`
`(30ug). 3 puffs 1000ugr’ml (45pg) and 2 puffs 2000ugjml {60ug). The placebo was
`
`inhaled as 2 puffs from a placebo-SM]. Hemodynamics and gas—exchange parameters
`
`were recorded for 120 minutes after TRE inhalation. This study used the Respimat'li'
`
`device, because the implemented “sofi mist” technology was well suited for the
`
`deposition ofsueh highly active drugs like prostanoids.
`
`13
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`Atty. Dkt. No. 080618-0463
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`[0053] The impact of SMl-TRE on ventilation-perfusion matching was assessed in
`
`five patients (30ttg TRE, n=2; 4Sug TRE, n=l; éflug TRE, n=2) with pre-existing gas
`
`exchange problems by use ofthe multiple inert gas elimination technique (MIGET),
`
`see e. g. Wagner PD, Saltzman HA, West J B. Measurement of continuous distributions
`
`of ventilation-perfusion ratios:
`
`theory. J Appl Physiol. 1974; 36:588-99; Ghofrani
`
`HA, Wiedemann R, Rose F, Schennuly RT, Olschewski H, Weissmann N et a1.
`
`Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised
`
`controlled trial. Lancet. 2002;360:895-900, both incorporated herein in their entirety.
`
`[0054]
`
`Statistics. Mean values, standard deviation, standard error of the mean and
`
`95% confidence intervals were calculated. Statistical analysis was done by use of a
`
`paired t-test.
`
`[0055] Results. The inhalation of treprostinil sodium from the metered dose inhaler
`
`(SMI-TRE) was well tolerated, only mild and transient cough for a maximum of one
`
`minute was reported. No systemic side effects like headache, flush, nausea or
`
`dizziness were observed.
`
`'- [0056] Two to three breaths of SMI-TRB induced a strong pulmonary vasodilation
`
`that outlasted the observation time of 120 minutes (45 and 60ug). The lower dose of
`
`30 ug TRE induced a somewhat shorter effect on pulmonary vascular resistance;
`
`however, the maximal pulmonary vasodilation was comparable.
`
`In contrast, placebo
`
`inhalation did not induce pulmonary vasodilation.
`
`ln fact a slight increase in PVR
`
`over the time of the right heart catheter investigation could he recorded following
`
`placebo inhalation (Figure l). The effect of SMl-TRE on systemic vascular resistance
`
`and pressure was very small and not clinically significant. Cardiac output was
`
`significantly increased over the whole observation period, whereas heart rate was
`
`rather unchanged. Gas exchange was not influenced by SMI-TRB (Figure 2). The
`
`maximal changes in hemodynamie and gas-exchange parameters compared to
`
`baseline values are depicted in Table 2.
`
`u-nsrusmsis
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`Table 2.
`
`Atty. Dkt. No. 080618-0463
`
`[0057] Extremes of the relative changes ofhemodynamic and gas exchange
`
`parameters compared to baseline after inhalation of Placebo (n=4), 30ug treprostinil
`
`(n=12), 45pg treprostinil (n=9) and 60pg treprostinil (n=20). Highest (max) and
`
`lowest (min) values during the observation period are shovm. Data are given as
`
`percent of baseline values (mean i SEM). PAP = pulmonary artery pressure; PVR =
`
`pulmonary vascular resistance; SVR a systemic vascular resistance; CO = cardiac
`
`output; SAP = systemic arterial pressure; HR 2 heart rate; Sa02 = arterial oxygen
`
`saturation; SvOZ = central venous oxygen saturation.
`
`[
`Placebo
`jsoagras
`I45ugTRE __!__60ugTRE
`
`99.4i3.0
`‘83.4i3.2
`77.6i6.8
`79.5i2.4
`PAP(min)
`
`PVR (rm 101.4i 1.9
`84.4:t4.4
`71.4: 8.9
`77.5: 3.7
`
`
`
`co (max)
`99.74 1.1
`108.8i3.8
`108.6i 5.6
`103.8 $2.0
`
`
`"‘
`SVR (min)
`#143 i 4.3
`97.7 i 4.2
`92 a 3.9
`91.3 i 2.1
`
`
`
`SAP (min)
`102.?i1.7
`92.3 i1.9 "T961 i 1.5
`wi_9‘3f.6i2.9
`
`'J—lR(max)
`105i2.1
`106.1 i2.9_-':— 9914:24
`101.1 i0.9 l
`
`
`95.8 :t 0.9
`94.4 i 1.8
`101 :t 0.3
`98.2 i 0.4
`SaO2 (min)
`
`| SvOZ (max)
`104.5 i 1.4
`102.4 i 1.3 _J_104.5 i 4.4
`102 a 1.0
`
`
`
`
`
`
`'
`
`[0058] The areas under the curve for PVR were calculated for placebo and the
`
`different SMl-TRE doses over the 120 minute observation period (figure 3). A dose
`
`effect of SMI-TRE with a trend to a more sustained effect with the two highest doses
`could be observed.
`
`[0059] The inhalation ofa highly concentrated aerosol is in theory prone to
`
`disturbances of gas exchange because the deposition of even small amounts of aerosol
`
`may deliver high doses locally and thereby antagonize the hypoxic pulmonary
`
`vasoconstriction in poorly ventilated areas. This would then lead to increased shunt
`
`flow or increase of low ventilation/perfusion (WQ) areas. We addressed this questiOn
`
`in five patients with the multiple inert