FISH Sc RICHARDSON P.C.
`
`Frederick P. Fish
`1855—1930
`
`WK. Richardson
`18594951
`
`October 15 a 2012
`
`Attorney Docket No.: 26047-0003007/3000-US-0008CON5
`
`Commissioner for Patents
`
`PO. Box 1450
`
`Alexandria, VA 22313-1450
`
`Street Address
`One Marina Park Drive
`Boston, Massachusetts
`02210—1878
`
`Mail Address
`PO. BOX 1022
`MINNEAPOLIS, MINNESOTA
`55440—1022
`
`2516533570
`
`Facsimile
`
`877 769—7945
`
`\WEB SITE
`WWW.FR.COM
`
`This application iS a continuation of and claims priority to US. Patent Application
`® Serial No. 12/821,041, filed on June 22, 2010, which claims priority to US. Patent
`Application Serial No. 12/494,598, filed on June 30, 2009, and now abandoned. The
`contents of both prior applications are incorporated herein by reference.
`
`“LAN”
`AUSTIN
`
`BOSTON
`
`DALLAS
`
`lnyentor(s): JAMES S. BALDASSARRE AND RALF ROSSKAMP
`
`MW Title:
`Hovsrox
`
`METHODS OF REDUCING THE RISK OF OCCURRENCE OF
`PULMONARY EDEMA ASSOCIATED WITH INHALATION OF
`
`NEW VORK
`
`SILICON VALLEY
`
`SOUTHERN CALIFORNIA
`
`TWIN CITIES
`WASHINGTON, DC
`
`Assignee:
`
`1N0 Therapeutics LLC
`
`Enclosed are the following papers, including those required to receive a filing date
`under 37 C.F.R. § 1.53(b):
`
`Specification
`Claims
`Abstract
`
`Declarations (2)
`
`Enclosures:
`
`Pages
`22
`5
`1
`
`2
`
`Certification and Request for Prioritized Examination (Track I) (1 page)
`Application Data Sheet (6 pages)
`Power of Attorney to Prosecute Applications Before the USPTO (1 page)
`together with Statement Under 37 CFR 3.73 (c) (2 pages)
`
`001
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`PRAXAIR 1054
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`FISH a; RICHARDSON P.C.
`
`Commissioner for Patents
`
`October 15, 2012
`
`Page 2
`
`Basic Filing fee
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`The filing fee totaling $7050 is being paid concurrently herewith on the Electronic
`Filing System (EFS) by way of Deposit Account authorization. Apply all charges or
`credits to Deposit Account No. 06-1050, referencing Attorney Docket No. 26047-
`0003007.
`
`If this application is found to be incomplete, or if a telephone conference would
`otherwise be helpful, please call the undersigned at (617) 542-5070.
`
`Direct all correspondence to the following:
`
`94169
`PTO Customer Number
`
`Respectfully submitted,
`
`/Janis K. Fraser/
`
`Janis K. Fraser, Ph.D., J.D.
`
`Reg. No. 34,819
`Enclosures
`JKF/nab
`22918992.doc
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`Attorney Docket No. 26047—0003007/3000—US—0008CON5
`
`METHODS OF REDUCING THE RISK OF OCCURRENCE OF PULMONARY
`EDEMA ASSOCIATED WITH INHALATION OF NITRIC OXIDE GAS
`
`CROSS REFERENCE TO RELATED APPLICATIONS
`
`[0001]
`
`This application is a continuation of and claims priority to US. Patent
`
`Application Serial No. 12/821,041, filed on June 22, 2010, which claims priority to US. Patent
`
`Application Serial No. 12/494,598, filed on June 30, 2009 and now abandoned. The contents of
`
`both prior applications are incorporated herein by reference.
`
`BACKGROUND OF THE INVENTION
`
`[0002]
`
`INOmax®, (nitric oxide) for inhalation is an approved drug product for the
`
`treatment of term and near-term (>34 weeks gestation) neonates having hypoxic respiratory
`
`failure associated with clinical or echocardiographic evidence of pulmonary hypertension.
`
`[0003]
`
`The use of inhaled NO (iNO) has been studied and reported in the literature.
`
`(Kieler-Jensen M et al., 1994, Inhaled Nitric Oxide in the Evaluation of Heart Transplant
`
`Candidates with Elevated Pulmonary Vascular Resistance, J Heart Lung Transplantation
`
`13 2366—375; Pearl RG et al., 1983, Acute Hemodynamic Effects of Nitroglycerin in Pulmonary
`
`Hypertension, American College ofPhysicians 9929-13; Ajami GH et al., 2007, Comparison of
`
`the Effectiveness of Oral Sildenafll Versus Oxygen Administration as a Test for Feasibility of
`
`Operation for Patients with Secondary Pulmonary Arterial Hypertension, Pediatr Cardiol;
`
`Schulze—Neick I et al., 2003, Intravenous Sildenafil Is a Potent Pulmonary Vasodilator in
`
`Children With Congenital Heart Disease, Circulation 108(Suppl II):II-l67-II-l 73; Leporc JJ ct
`
`al., 2002, Effect of Sildenafil on the Acute Pulmonary Vasodilator Response to Inhaled Nitric
`
`Oxide in Adults with Primary Pulmonary Hypertension, The American Journal of Cardiology
`
`902677—680; and Ziegler JW et al., 1998, Effects of Dipyridamole and Inhaled Nitric Oxide in
`
`Pediatric Patients with Pulmonary Hypertension, American Journal ofRespiratory and Critical
`
`Care Medicine 158: 13 88-95).
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`SUMMARY OF THE INVENTION
`
`[0004]
`
`One aspect of the invention relates to a pre-screening methodology or protocol
`
`having exclusionary criteria to be evaluated by a medical provider prior to treatment of a patient
`
`with iNO. One objective of the invention is to evaluate and possibly exclude from treatment
`
`patients eligible for treatment with iNO, who have pre-existing left ventricular dysfunction
`
`(LVD). Patients who have pre-existing LVD may experience, and are at risk of, an increased
`
`rate of adverse events or serious adverse events (e.g., pulmonary edema) when treated with iNO.
`
`Such patients may be characterized as having a pulmonary capillary wedge pressure (PCWP)
`
`greater than 20 mm Hg, and should be evaluated on a case-by-case basis with respect to the
`
`benefit versus risk of using iNO as a treatment option.
`
`[0005]
`
`Accordingly, one aspect of the invention includes a method of reducing the risk
`
`or preventing the occurrence, in a human patient, of an adverse event (AE) or a serious adverse
`
`event (SAE) associated with a medical treatment comprising inhalation of nitric oxide, said
`
`method comprising the steps or acts of (a) providing pharmaceutically acceptable nitric oxide
`
`gas to a medical provider; and, (b) informing the medical provider that excluding human
`
`patients who have pre-existing left ventricular dysfunction from said treatment reduces the risk
`
`or prevents the occurrence of the adverse event or the serious adverse event associated with said
`
`medical treatment.
`
`[0006]
`
`Further provided herein is a method of reducing the risk or preventing the
`
`occurrence, in a human patient, of an adverse event or a serious adverse event associated with a
`
`medical treatment comprising inhalation of nitric oxide, said method comprising the steps or
`
`acts of (a) providing pharmaceutically acceptable nitric oxide gas to a medical provider; and,
`
`(b) informing the medical provider that human patients having pre-existing left ventricular
`
`dysfunction experience an increased risk of serious adverse events associated with said medical
`
`treatment.
`
`[0007]
`
`Another aspect of the invention is a method of reducing one or more of an AB or
`
`a SAE in an intended patient population in need of being treated with iNO comprising the steps
`
`or acts of (a) identifying a patient eligible for iNO treatment; (b) evaluating and screening the
`
`patient to identify if the patient has pre-existing LVD, and (c) excluding from iNO treatment a
`
`patient identified as having pre-existing LVD.
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`Attorney Docket No. 26047-0003007/3000-US-0008CON5
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`[0008]
`
`Another aspect of the invention is a method of reducing the risk or preventing the
`
`occurrence, in a patient, of one or more of an AB or a SAE associated with a medical treatment
`
`comprising iNO, the method comprising the steps or acts of (a) identifying a patient in need of
`
`receiving iNO treatment; (b) evaluating and screening the patient to identify if the patient has
`
`pre-existing LVD; and (c)administering iNO if the patient does not have pre-existing LVD,
`
`thereby reducing the risk or preventing the occurrence of the AE or the SAE associated with the
`
`iNO treatment. Alternatively, step (c) may comprise fitrther evaluating the risk versus benefit of
`
`utilizing iNO in a patient where the patients has clinically significant LVD before administering
`
`iNO to the patient.
`
`[0009]
`
`In an exemplary embodiment of the method, the method further comprises
`
`informing the medical provider that there is a risk associated with using inhaled nitric oxide in
`
`human patients who have preexisting or clinically significant left ventricular dysfunction and
`
`that such risk should be evaluated on a case by case basis.
`
`[0010]
`
`In another exemplary embodiment of the method, the method further comprises
`
`informing the medical provider that there is a risk associated with using inhaled nitric oxide in
`
`human patients who have left ventricular dysfunction.
`
`[0011]
`
`In an exemplary embodiment of the methods described herein, a patient having
`
`pre-existing LVD is characterized as having PCWP greater than 20 mm Hg.
`
`[0012]
`
`In an exemplary embodiment of the method, the patients having pre-existing
`
`LVD demonstrate a PCWP Z 20 mm Hg.
`
`[0013]
`
`In another exemplary embodiment of the method, the iNO treatment further
`
`comprises inhalation of oxygen (02) or concurrent ventilation.
`
`[0014]
`
`In another exemplary embodiment of the method, the patients having pre-
`
`existing LVD have one or more of diastolic dysfunction, hypertensive cardiomyopathy, systolic
`
`dysfunction, ischemic cardiomyopathy, viral cardiomyopathy, idiopathic cardiomyopathy,
`
`autoimmune disease related cardiomyopathy, drug-related cardiomyopathy, toxin-related
`
`cardiomyopathy, structural heart disease, valvular heart disease, congenital heart disease, or
`
`associations thereof.
`
`[0015]
`
`In another exemplary embodiment of the method, the patient population
`
`comprises children.
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`[0016]
`
`In another exemplary embodiment of the method, the patient population
`
`comprises adults.
`
`[0017]
`
`In another exemplary embodiment of the method, the patients who have pre-
`
`existing LVD are at risk of experiencing an increased rate of one or more AEs or SAEs selected
`
`from pulmonary edema, hypotension, cardiac arrest, electrocardiogram changes, hypoxemia,
`
`hypoxia, bradycardia, or associations thereof.
`
`[0018]
`
`In another exemplary embodiment of the method, the intended patient population
`
`in need of being treated with inhalation of nitric oxide has one or more of idiopathic pulmonary
`
`arterial hypertension characterized by a mean pulmonary artery pressure (PAPm) > 25 mm Hg
`
`at rest, PCWP S 15 mm Hg, and a pulmonary vascular resistance index (PVRI) > 3 u~m2;
`
`congenital heart disease with pulmonary hypertension repaired and unrepaired characterized by
`
`PAPm > 25 mm Hg at rest and PVRI > 3 u-mZ; cardiomyopathy characterized by PAPm >
`
`25 mm Hg at rest and PVRI > 3 u-mz; or the patient is scheduled to undergo right heart
`
`catheterization to assess pulmonary vasoreactivity by acute pulmonary vasodilatation testing.
`
`[0019]
`
`In another exemplary embodiment of any of the above methods, the method
`
`further comprises reducing left ventricular afterload to minimize or reduce the risk of the
`
`occurrence of an adverse event or serious adverse event being pulmonary edema in the patient.
`
`The left ventricular afterload may be minimized or reduced by administering a pharmaceutical
`
`dosage form comprising nitroglycerin or calcium channel blocker to the patient. The left
`
`ventricular afterload may also be minimized or reduced using an intra-aortic balloon pump.
`
`DETAILED DESCRIPTION OF THE EXEMPLARY EMBODIMENTS
`
`[0020]
`
`INOmax® (nitric oxide) for inhalation was approved for sale in the United States
`
`by the US. Food and Drug Administration (“FDA”) in 1999. Nitric oxide, the active substance
`
`in INOmax®, is a selective pulmonary vasodilator that increases the partial pressure of arterial
`
`oxygen (PaOz) by dilating pulmonary vessels in better ventilated areas of the lung, redistributing
`
`pulmonary blood flow away from the lung regions with low ventilation/perfusion (V/Q) ratios
`
`toward regions with normal ratios. INOmax® significantly improves oxygenation, reduces the
`
`need for extracorporeal oxygenation and is indicated to be used in conjunction with ventilatory
`
`support and other appropriate agents. The current FDA-approved prescribing information for
`
`INOmax® is incorporated herein by reference in its entirety. The CONTRAINDICATIONS
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`section of the prescribing information for INOmax® states that INOmax® should not be used in
`
`the treatment of neonates known to be dependent on right-to—left shunting of blood.
`
`[0021]
`
`INOmax® is a gaseous blend of NO and nitrogen (0.08% and 99.92%
`
`respectively for 800 ppm; and 0.01% and 99.99% respectively for 100 ppm) and is supplied in
`
`aluminium cylinders as a compressed gas under high pressure. In general, INOmax® is
`
`administered to a patient in conjunction with ventilatory support and 02. Delivery devices
`
`suitable for the safe and effective delivery of gaseous NO for inhalation include the INOvcnt®,
`
`1N Omax DS®, 1N Opulse®, 1N0blender®, or other suitable drug delivery and regulation
`
`devices or components incorporated therein, or other related processes, which are described in
`
`various patent documents including USPNs 5,558,083; 5,732,693; 5,752,504; 5,732,694;
`
`6,089,229; 6,109,260; 6,125,846; 6,164,276; 6,581,592; 5,918,596; 5,839,433; 7,114,510;
`
`5,417;950; 5,670,125; 5,670,127; 5,692,495; 5,514,204; 7,523,752; 5,699,790; 5,885,621; US
`
`Patent Application Serial Nos. 11/355,670 (US 2007/0190184); 10/520,270 (US
`
`2006/0093681); 11/401,722 (US 2007/0202083); 10/053,535 (US 2002/0155166); 10/367,277
`
`(US 2003/0219496); 10/439,632 (US 2004/0052866); 10/371,666 (US 2003/0219497);
`
`10/413,817 (US 2004/0005367); 12/050,826 (US 2008/0167609); and PCT/US2009/045266, all
`
`of which are incorporated herein by reference in their entirety.
`
`[0022]
`
`Such devices deliver INOmax® into the inspiratory limb of the patient breathing
`
`circuit in a way that provides a constant concentration of NO to the patient throughout the
`
`inspired breath. Importantly, suitable delivery devices provide continuous integrated
`
`monitoring of inspired 02, N02 and NO, a comprehensive alarm system, a suitable power
`
`source for uninterrupted NO delivery, and a backup NO delivery capability.
`
`[0023]
`
`As used herein, the term "children" (and variations thereof) includes those being
`
`around 4 weeks to 18 years of age.
`
`[0024]
`
`As used herein, the term "adult” (and variations thereof) includes those being
`
`over 18 years of age.
`
`[0025]
`
`As used herein, the terms "adverse even ” and "AE" (and variations thereof)
`
`mean any untoward occurrence in a subject or clinical investigation subject administered a
`
`pharmaceutical product (such as nitric oxide) and which does not necessarily have a causal
`
`relationship with such treatment. An adverse event can therefore be any unfavorable and
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`unintended sign (including an abnormal laboratory finding), symptom, or disease temporarily
`
`associated with the use of a medicinal/investigational product, whether or not related to the
`
`investigational product. A relationship to the investigational product is not necessarily proven
`
`or implied. However, abnormal values are not reported as adverse events unless considered
`
`clinically significant by the investigator.
`
`[0026]
`
`As used herein, the terms "adverse drug reaction" and ”ADR” (and variations
`
`thereof) mean any noxious and unintended response to a medicinal product related to any dose.
`
`[0027]
`
`As used herein, the terms "serious adverse even " and "SAE" (or "serious adverse
`
`drug reaction" and "serious ADR") (and variations thereof) mean a significant hazard or side
`
`effect, regardless of the investigator's opinion on the relationship to the investigational product.
`
`A serious adverse event or reaction is any untoward medical occurrence that at any dose: results
`
`in death; is life-threatening (which refers to an event/reaction where the patient was at risk of
`
`death at the time of the event/reaction, however this does not refer to an event/reaction that
`
`hypothetically may have caused death if it were more severe); requires inpatient hospitalization
`
`or results in prolongation of existing hospitalization; results in persistent or significant
`
`disability/incapacity; is a congenital anomaly/birth defect; or is a medically important event or
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`reaction. Medical and scientific judgment is exercised in deciding whether reporting is
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`appropriate in other situations, such as important medical events that may not be immediately
`
`life threatening or result in death or hospitalization but may jeopardize the subject or may
`
`require medical or surgical intervention to prevent one of the other outcomes listed above--these
`
`are also considered serious. Examples of such medical events include cancer, allergic
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`bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias
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`or convulsions that do not result in hospitalizations, or the development of drug dependency or
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`drug abuse. Serious clinical laboratory abnormalities directly associated with relevant clinical
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`signs or symptoms are also reported.
`
`[0028]
`
`Left Ventricular Dysfunction. Patients having pre-existing LVD may be
`
`described in general as those with elevated pulmonary capillary wedge pressure, including those
`
`with diastolic dysfunction (including hypertensive cardiomyopathy), those with systolic
`
`dysfunction, including those with cardiomyopathies (including ischemic or viral
`
`cardiomyopathy, or idiopathic cardiomyopathy, or autoimmune disease related cardiomyopathy,
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`and side effects due to drug related or toxic—related cardiomyopathy), or structural heart disease,
`
`valvular heart disease, congenital heart disease, idiopathic pulmonary arterial hypertension,
`
`pulmonary hypertension and cardiomyopathy, or associations thereof.
`
`Identifying patients with
`
`pre-existing LVD is known to those skilled in the medicinal arts, and such techniques for
`
`example may include assessment of clinical signs and symptoms of heart failure, or
`
`echocardiography diagnostic screening.
`
`[0029]
`
`Pulmonary Capillary chgc Prcssurc. Pulmonary capillary wedge pressure, or
`
`"PCWP", provides an estimate of left atrial pressure.
`
`Identifying patients with pre-existing
`
`PCWP is known to those skilled in the medicinal arts, and such techniques for example may
`
`include measuring by inserting a balloon-tipped, multi—lumen catheter (also known as a Swan-
`
`Ganz catheter). Measurement of PCWP may be used as a means to diagnose the severity of
`
`LVD (sometimes also referred to as left ventricular failure). PCWP is also a desired measure
`
`when evaluating pulmonary hypertension. Pulmonary hypertension is often caused by an
`
`increase in pulmonary vascular resistance (PVR), but may also arise from increases in
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`pulmonary venous pressure and pulmonary blood volume secondary to left ventricular failure or
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`mitral or aortic valve disease.
`
`[0030]
`
`In cardiac physiology, the term “afterload” is used to mean the tension produced
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`by a chamber of the heart in order to contract. If the chamber is not mentioned, it is usually
`
`assumed to be the left ventricle. However, the strict definition of the term relates to the
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`properties of a single cardiac myocyte. It is therefore of direct relevance only in the laboratory;
`
`in the clinic, the term “end-systolic pressure” is usually more appropriate, although not
`
`equivalent.
`
`[0031]
`
`The term "left ventricular afterload" (and variations thereof) refers to the pressure
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`that the chamber of the heart has to generate in order to eject blood out of the chamber. Thus, it
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`is a consequence of the aortic pressure, since the pressure in the ventricle must be greater than
`
`the systemic pressure in order to open the aortic valve. Everything else held equal, as afterload
`
`increases, cardiac output decreases. Disease processes that increase the left ventricular afterload
`
`include increased blood pressure and aortic valve disease. Hypertension (increased blood
`
`pressure) increases the left ventricular afterload because the left ventricle has to work harder to
`
`eject blood into the aorta. This is because the aortic valve won't open until the pressure
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`generated in the left ventricle is higher than the elevated blood pressure. Aortic stenosis
`
`increases the afterload because the left ventricle has to overcome the pressure gradient caused
`
`by the stenotic aortic valve in addition to the blood pressure in order to eject blood into the
`
`aorta. For instance, if the blood pressure is 120/80, and the aortic valve stenosis creates a trans-
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`valvular gradient of 30 mmHg, the left ventricle has to generate a pressure of l 10 mmHg in
`
`order to open the aortic valve and eject blood into the aorta. Aortic insufficiency increases
`
`afterload because a percentage of the blood that is ejected forward regurgitates back through the
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`diseased aortic valve. This leads to elevated systolic blood pressure. The diastolic blood
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`pressure would fall, due to regurgitation. This would result in an increased pulse pressure.
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`Mitral regurgitation decreases the afterload. During ventricular systole, the blood can
`
`regurgitate through the diseased mitral valve as well as be ejected through the aortic valve. This
`
`means that the left ventricle has to work less to eject blood, causing a decreased afterload.
`
`Afterload is largely dependent upon aortic pressure.
`
`[0032]
`
`An intra-aortic balloon pump (IABP) is a mechanical device that is used to
`
`decrease myocardial oxygen demand while at the same time increasing cardiac output. By
`
`increasing cardiac output it also increases coronary blood flow and therefore myocardial oxygen
`
`delivery. It consists of a cylindrical balloon that sits in the aorta and counterpulsates. That is, it
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`actively deflatcs in systole, increasing forward blood flow by reducing afterload, and actively
`
`inflates in diastole increasing blood flow to the coronary arteries. These actions have the
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`combined result of decreasing myocardial oxygen demand and increasing myocardial oxygen
`
`supply. The balloon is inflated during diastole by a computer controlled mechanism, usually
`
`linked to either an ECG or a pressure transducer at the distal tip of the catheter; some IABPs,
`
`such as the Datascope System 98XT, allow for asynchronous counterpulsation at a set rate,
`
`though this setting is rarely used. The computer controls the flow of helium from a cylinder into
`
`and out of the balloon. Helium is used because its low viscosity allows it to travel quickly
`
`through the long connecting tubes, and it has a lower risk of causing a harmful embolism should
`
`the balloon rupture while in use. Intraaortic balloon counterpulsation is used in situations when
`
`the heart's own cardiac output is insufficient to meet the oxygenation demands of the body.
`
`These situations could include cardiogenic shock, severe septic shock, post cardiac surgery and
`
`numerous other situations.
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`[0033]
`
`Patients eligible for treatment with iNO. In general, patients approved for
`
`treatment of iNO are term and near—term (>34 weeks gestation) neonates having hypoxic
`
`respiratory failure associated with clinical or echocardiographic evidence of pulmonary
`
`hypertension, a condition also known as persistent pulmonary hypertension in the newborn
`
`(PPHN). Due to the selective, non—systemic nature of iNO to reduce pulmonary hypertension,
`
`physicians skilled in the art further employ INOmax® to treat or prevent pulmonary
`
`hypertension and improve blood Oz levels in a variety of other clinical settings, including in
`
`both pediatric and adult patients suffering from acute respiratory distress syndrome (ARDS),
`
`pediatric and adult patients undergoing cardiac or transplant surgeries, pediatric and adult
`
`patients for testing to diagnose reversible pulmonary hypertension, and in pediatric patients with
`
`congenital diaphragmatic hernia.
`
`In most, if not all, of these applications, INOmax® acts by
`
`preventing or treating reversible pulmonary vasoconstriction, reducing pulmonary arterial
`
`pressure and improving pulmonary gas exchange.
`
`[0034]
`
`A small proportion of INOmax® sales stem from its use by clinicians in a
`
`premature infant population. In these patients, INOmax® is generally utilized by physicians as a
`
`rescue therapy primarily to vasodilate the lungs and improve pulmonary gas exchange. Some
`
`physicians speculate that INOmax® therapy may promote lung development and/or reduce or
`
`prevent the future development of lung disease in a subset of these patients. Although the
`
`precise mechanism(s) responsible for the benefits of INOmax® therapy in these patients is not
`
`completely understood, it appears that the benefits achieved in at least a majority of these
`
`patients are due to the ability of INOmax® to treat or prevent reversible pulmonary
`
`vasocon stri ction.
`
`[0035]
`
`In clinical practice, the use of INOmax® has reduced or eliminated the use of
`
`high risk systemic vasodilators for the treatment of PPHN. INOmax®, in contrast to systemic
`
`vasodilators, specifically dilates the pulmonary vasculature without dilating systemic blood
`
`vessels. Further, iNO preferentially vasodilates vessels of aveoli that are aerated, thus
`
`improving V/Q matching. In contrast, systemic vasodilators may increase blood flow to
`
`atelectatic (deflated or collapsed) alveoli, thereby increasing V/Q mismatch and worsening
`
`arterial oxygenation.
`
`(See Rubin LJ, Kerr KM, Pulmonary Hypertension, in Critical Care
`
`Medicine: Principles ofDiagnosis and Management in the Adult, 2d Ed., Parillo JE, Dellinger
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`RP (eds.), Mosby, Inc. 2001, pp. 900—09 at 906; Kinsella JP, Abman SH, The Role of Inhaled
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`Nitric Oxide in Persistent Pulmonary Hypertension of the Newborn, in Acute Respiratory Care
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`of the Neonates A Self-Study Course, 2d Ed, Askin DF (ed), NICU Ink Book Publishers, 1997,
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`pp. 369-378 at 372-73).
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`[0036]
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`INOmax® also possesses highly desirable pharmacokinetic properties as a lung—
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`specific vasodilator when compared to other ostensibly “pulmonary-specific vasodilators.” For
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`example, the short half-life of INOmax® allows INOmax® to exhibit rapid “on” and “off"
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`responses relative to INOmax® dosing, in contrast to non-gaseous alternatives. In this way,
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`INOmax® can provide physicians with a useful therapeutic tool to easily control the magnitude
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`and duration of the pulmonary vasodilatation desired. Also, the nearly instantaneous
`®
`inactivation of INOmax in the blood significantly reduces or prcvcnts vasodilatation ofnon-
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`pulmonary vessels.
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`[0037]
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`The pivotal trials leading to the approval of INOmax® were the CINRGI and
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`NINOS study.
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`[0038]
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`CINRGI study. (See Davidson et al., March 1998, Inhaled Nitric Oxide for the
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`Early Treatment of Persistent Pulmonary Hypertension of the term Newborn; A Randomized,
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`Double-Masked, Placebo-Controlled, Dose-Response, Multicenter Study; PEDIATRICS Vol.
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`101, No.3, p. 325).
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`[0039]
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`This study was a double—blind, randomized, placebo—controlled, multicenter trial
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`of 186 term and near-term neonates with pulmonary hypertension and hypoxic respiratory
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`failure. The primary objective of the study was to determine whether 1N Omax® would reduce
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`the receipt of extracorporeal membrane oxygenation (ECMO) in these patients. Hypoxic
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`respiratory failure was caused by meconium aspiration syndrome (MAS) (35%), idiopathic
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`persistent pulmonary hypertension of the newbom (PPHN) (30%), pneumonia/sepsis (24%), or
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`respiratory distress syndrome (RDS) (8%). Patients with a mean PaOz of 54 mm Hg and a
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`mean oxygenation index (OI) of 44 cm H20/mm Hg were randomly assigned to receive either
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`20 ppm INOmax® (n:97) or nitrogen gas (placebo; n:89) in addition to their ventilatory
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`support. Patients that exhibited a PaOZ > 60 mm Hg and a pH < 7.55 were weaned to 5 ppm
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`INOmax® or placebo. The primary results from the CINRGI study are presented in Table l.
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`ECMO was the primary endpoint of the study.
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`Table 1: Summary of Clinical Results from CINRGI Study
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`INOmax® P value
`Placebo
`
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`Death or ECMO 51/89 (57%)
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`30/97 (31%)
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`<0.001
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`[0040]
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`Significantly fcwcr neonates
`
`in the ECMO group required ECMO, and
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`1N Omax® significantly improved oxygenation, as measured by PaOz, 01, and alveolar-arterial
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`gradient.
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`[0041]
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`NINOS study. (See Inhaled Nitric Oxide in Full-Term and Nearly Full-Term
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`Infants with Hypoxic Respiratory Failure; NEJM, Vol. 336, No. 9, 597).
`
`[0042]
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`The Neonatal Inhaled Nitric Oxide Study (NINOS) group conducted a double-
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`blind, randomized, placebo-controlled, multicenter trial in 235 neonates with hypoxic
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`respiratory failure. The objective of the study was to determine whether iNO would reduce the
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`occurrence of death and/or initiation of ECMO in a prospectively defined cohort of term or
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`near-term neonates with hypoxic respiratory failure unresponsive to conventional therapy.
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`Hypoxic respiratory failure was caused by meconium aspiration syndrome (MAS; 49%),
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`pneumonia/sepsis (21%), idiopathic primary pulmonary hypertension of the newborn (PPI—lN;
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`17%), or respiratory distress syndrome (RDS; 11%). Infants 3 14 days of age (mean, 1.7 days)
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`with a mean PaOz of 46 mm Hg and a mean oxygenation index (OI) of 43 cm HgO/mmHg were
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`initially randomized to receive 100% O; with (n=114) or without (n=121) 20 ppm NO for up to
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`14 days. Response to study drug was defined as a change from baseline in PaOz 30 minutes after
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`starting treatment (full response = > 20 mmHg, partial = 10—20 mm Hg, no response = < 10 mm
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`Hg). Neonates with a less than full response were evaluated for a response to 80 ppm NO or
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`control gas. The primary results from the NINOS study are presented in Table 2.
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`Table 2: Summary of Clinical Results from NINOS Study
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`Death or ECMO*, T
`
`Control
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`(n=121)
`
`77 (64%)
`mm
`66 (55%)
`
`
`
`NO
`
`(n=114)
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`P value
`
`52 (46%)
`0.006
`141404 .E-
`44 (39%)
`0.014
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`* Extracorporeal membrane oxygenation
`T Death or need for ECMO was the study‘s primary end point
`
`[0043]
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`Adverse Events from CINRGI & NINOS. Controlled studies have included
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`325 patients on INOmax® doses of 5 to 80 ppm and 251 patients on placebo. Total mortality in
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`the pooled trials was 11% on placebo and 9% on lNOmaX®, a result adequate to exclude
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`INOmax® mortality being more than 40% worse than placebo.
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`[0044]
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`In both the NINOS and CINRGI studies, the duration of hospitalization was
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`similar in lNOmax® and placebo-treated groups.
`
`[0045]
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`From all controlled studies, at least 6 months of follow-up is available for
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`278 patients who received INOmax® and 212 patients who received placebo. Among these
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`patients, there was no evidence of an AB of treatment on the need for re-hospitalization, special
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`medical services, pulmonary disease, or neurological sequelae.
`
`[0046]
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`In the NINOS study, treatment groups were similar with respect to the incidence
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`and severity of intracranial hemorrhage, Grade IV hemorrhage, per ventricular leukomalacia,
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`cerebral infarction, seizures requiring anticonvulsant therapy, pulmonary hemorrhage, or
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`gastrointestinal hemorrhage.
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`[0047]
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`The table below shows adverse reactions that occurred in at least 5% of patients
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`receiving lNOmax® in the CINRGI study. None of the differences in these adverse reactions
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`were statistically significant when iNO patients were compared to patients receiving placebo.
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`Table 3: ADVERSE REACTIONS ON THE CINRGI TRIAL
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`Placebo (n=89)
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`Inhaled NO (n=97)
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`Hypokalemia
`
`5 (4.8%)
`
`9 (8.3%)
`
`16 (14.8%)
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`Thrombocytopenia 20 (19.2%)
`
`[0048]
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`Post-Marketing Experience. The following AEs have been reported as part of
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`the post-marketin g surveillance. These events have not been reported above. Given the nature of
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`spontaneously reported post-marketing surveillance data, it is impossible to determine the actual
`
`incidence of the events or definitively establish their causal relationship to the drug. The listing
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`is alphabetical: dose errors associated with the delivery system; headaches associated with
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`environmental exposure of INOmax® in hospital staff; hypotension associated with acute
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`withdrawal of the drug; hypoxemia associated with acute withdrawal of the drug; pulmonary
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`edema in patients with CREST syndrome.
`
`[0049]
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`An analysis of AEs and SAEs from both the CINRGI and NINOS studies, in
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`addition to post-marketing surveillance, did not suggest that patients wh