( 19 ) United States
`( 12 ) Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0134162 A1
`( 43 ) Pub . Date :
`May 9 , 2019
`Hansen
`
`US 20190134162A1
`
`( 54 ) SEMAGLUTIDE IN CARDIOVASCULAR
`CONDITIONS
`( 71 ) Applicant : Novo Nordisk A / S , Bagsvaerd ( DK )
`( 72 ) Inventor : Oluf Kristian Hoejbjerg Hansen ,
`Vaerloese ( DK )
`( 73 ) Assignee : Novo Nordisk A / S , Bagsvaerd ( DK )
`( 21 ) Appl . No . :
`16 / 097 , 032
`( 22 ) PCT Filed :
`Apr . 28 , 2017
`PCT / EP2017 / 060160
`( 86 ) PCT No . :
`$ 371 ( c ) ( 1 ) ,
`( 2 ) Date :
`
`Oct . 26 , 2018
`
`Foreign Application Priority Data
`( 30 )
`Apr . 28 , 2016
`( EP ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16167458 . 5
`Sep . 12 , 2016
`( EP ) . . . . . . . . . . . .
`. . . 16188262 . 6
`Publication Classification
`
`( 51 ) Int . CI .
`A61K 38 / 26
`A61P 3 / 10
`A61P 9 / 10
`U . S . CI .
`CPC . . . . . . . . . . . . . . . .
`
`( 52 )
`
`( 2006 . 01 )
`( 2006 . 01 )
`( 2006 . 01 )
`A61K 38 / 26 ( 2013 . 01 ) ; A61P 9 / 10
`( 2018 . 01 ) ; A61P 3 / 10 ( 2018 . 01 )
`( 57 )
`ABSTRACT
`The present invention relates to the GLP - 1 receptor agonist
`semaglutide for use in medicine .
`
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`MPI EXHIBIT 1295 PAGE 1
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`MPI EXHIBIT 1295 PAGE 2
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`Patent Application Publication
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`1500 1118
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`MPI EXHIBIT 1295 PAGE 3
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`

`

`US 2019 / 0134162 A1
`
`May 9 , 2019
`
`SEMAGLUTIDE IN CARDIOVASCULAR
`CONDITIONS
`[ 0001 ] The present invention relates to the GLP - 1 receptor
`agonist semaglutide for use in treating a subject having
`diabetes and high cardiovascular risk .
`BACKGROUND
`[ 0002 ] Diabetes is a metabolic disorder characterized by
`hyperglycaemia that is associated with a high risk of car
`diovascular and other serious health - related consequences .
`A person with diabetes is two to three times more likely to
`die from cardiovascular causes than people with no history
`of diabetes , even after controlling for other cardiovascular
`risk factors . They are also at very high risk of developing
`serious microvascular complications ultimately leading to
`premature death : nephropathy and renal failure , retinal dis
`ease and blindness , autonomic and peripheral neuropathy , as
`well as other conditions related to the cardiovascular system :
`hypertension , lower limb amputation , cognitive decline , and
`erectile dysfunction .
`[ 0003 ] The majority of people with diabetes have type 2
`diabetes , which is characterised by insulin resistance and
`eventually impaired insulin secretion . Optimal glycaemic
`control is the treatment goal in subjects with type 2 diabetes ,
`since the risk of long - term complications is increased with
`poor glycaemic control . Despite the availability of several
`oral anti - diabetic drugs and insulin , a significant proportion
`of subjects with type 2 diabetes do not achieve the recom
`mended target levels for glycaemic control and are at high
`risk of developing cardiovascular disease or microvascular
`complications . Thus , there is an unmet medical need for
`treatment alternatives that not only provide glycaemic con
`trol but also reduce the risk of cardiovascular disease in
`subjects with type 2 diabetes .
`SUMMARY
`In some embodiments the present invention relates
`[ 0004 ]
`to a method of treating type 2 diabetes , comprising admin
`istering semaglutide in a therapeutically effective amount to
`a subject in need thereof , wherein said subject has clinical
`evidence of cardiovascular disease and / or subclinical evi
`dence of cardiovascular disease ; wherein said method delays
`or reduces development of a major adverse cardiovascular
`event ( MACE ) .
`BRIEF DESCRIPTION OF DRAWINGS
`FIG . 1 shows time from randomisation to first
`[ 0005 ]
`non - fatal MI following administration of semaglutide
`( Sema ) or its placebo .
`[ 0006 ]
`FIG . 2 shows time from randomisation to first
`revascularisation following administration of semaglutide
`( Sema ) or its placebo .
`[ 0007 ] FIG . 1 - 2 show the number of subjects at risk for the
`relevant event ( s ) at different time points after randomisation
`and are Kaplan - Meier plots of time to event .
`DESCRIPTION
`[ 0008 ] The present invention relates to methods of admin
`istering the GLP - 1 receptor agonist semaglutide to a subject
`having diabetes and high cardiovascular risk . The term “ high
`cardiovascular risk ” as used herein refers to clinical evi
`dence of at least one cardiovascular disease and / or subclini -
`
`cal evidence of at least one cardiovascular disease . In some
`embodiments high cardiovascular risk is present if the
`subject has clinical or subclinical evidence of at least one
`cardiovascular disease .
`[ 0009 ]
`In some embodiments the present invention relates
`to a method of treating type 2 diabetes , comprising admin
`istering semaglutide in a therapeutically effective amount to
`a subject in need thereof , wherein said subject has clinical
`evidence of cardiovascular disease and / or subclinical evi
`dence of cardiovascular disease ; wherein said method
`reduces the risk of cardiovascular events compared to pla
`cebo . In some embodiments the clinical evidence of cardio
`vascular disease and / or subclinical evidence of cardiovas
`cular disease were present before initiation of semaglutide
`administration .
`100101 In some embodiments the present invention relates
`to a method of reducing the risk of MACE in subjects with
`type 2 diabetes mellitus and high cardiovascular risk . In
`some embodiments the present invention relates to a method
`of reducing the risk of MACE in subjects with type 2
`diabetes mellitus and high cardiovascular risk , wherein said
`MACE is selected from the group consisting of non - fatal
`MI , non - fatal stroke , CV death caused by MI , and CV death
`caused by stroke . In some embodiments said MACE is
`selected from the group consisting of non - fatal MI and CV
`death caused by MI . In some embodiments said MACE is
`selected from the group consisting of non - fatal stroke and
`CV death caused by stroke .
`[ 0011 ]
`In some embodiments the present invention relates
`to a method of delaying myocardial infarction or stroke in
`subjects with type 2 diabetes mellitus and high cardiovas
`cular risk . In some embodiments the terms " delaying ” as
`used herein refers to " preventing ” . In some embodiments the
`present invention relates to a method of preventing cardio
`vascular events in subjects with type 2 diabetes , wherein
`said “ cardiovascular events ” is one or more major adverse
`cardiovascular events , and wherein " major adverse cardio
`vascular event " is as defined herein .
`[ 0012 ]
`In some embodiments the present invention relates
`to a method of treating type 2 diabetes , comprising admin
`istering semaglutide in a therapeutically effective amount to
`a subject in need thereof , wherein said subject has clinical
`evidence of cardiovascular disease and / or subclinical evi
`dence of cardiovascular disease ; wherein said method
`reduces or delays a major adverse cardiovascular event
`( MACE ) .
`[ 0013 ]
`In some embodiments MACE is events selected
`from the group consisting of cardiovascular ( CV ) death ,
`non - fatal MI , non - fatal stroke , revascularisation , hospital
`isation for unstable angina pectoris , and hospitalisation for
`heart failure . The term " non - fatal MI ” as used herein refers
`to non - fatal myocardial infarction . In some embodiments
`MACE is events selected from the group consisting of CV
`death , non - fatal MI , and non - fatal stroke .
`[ 0014 ]
`In some embodiments the method reduces or
`delays a major adverse cardiovascular event ( MACE ) . In
`some embodiments the method reduces the risk of said
`subject developing a major adverse cardiovascular event
`( MACE ) . In some embodiments the method reduces the risk
`of said subject developing its first MACE . Thus , in some
`embodiments the MACE referred to herein is first MACE ,
`e . g . after initiating administration of semaglutide . The term
`“ first MACE ” as used herein refers to the first MACE event
`of a subject after initiation of semaglutide administration .
`
`MPI EXHIBIT 1295 PAGE 4
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`

`

`US 2019 / 0134162 A1
`
`May 9 , 2019
`
`In some embodiments MACE is selected from the
`[ 0015 ]
`group consisting of CV death , non - fatal MI , non - fatal stroke ,
`revascularisation , hospitalisation for heart failure , and hos
`pitalisation for unstable angina pectoris . In some embodi
`ments MACE ( e . g . selected from the group consisting of CV
`death , non - fatal MI , non - fatal stroke , revascularisation , hos
`pitalisation for heart failure , and hospitalisation for unstable
`angina pectoris ) is reduced or delayed by at least 1 %
`compared to placebo . In some embodiments MACE ( e . g .
`selected from the group consisting of CV death , non - fatal
`MI , non - fatal stroke , revascularisation , hospitalisation for
`heart failure , and hospitalisation for unstable angina pecto
`ris ) is reduced or delayed by from about 20 % to about 35 %
`compared to placebo . In some embodiments MACE ( e . g .
`selected from the group consisting of CV death , non - fatal
`MI , non - fatal stroke , revascularisation , hospitalisation for
`heart failure , and hospitalisation for unstable angina pecto
`ris ) is reduced about 27 % compared to placebo . In some
`embodiments the first MACE ( e . g . selected from the group
`consisting of CV death , non - fatal MI , non - fatal stroke ,
`revascularisation , hospitalisation for heart failure , and hos
`pitalisation for unstable angina pectoris ) is reduced or
`delayed by at least 1 % compared to placebo . In some
`embodiments the first MACE ( e . g . selected from the group
`consisting of CV death , non - fatal MI , non - fatal stroke ,
`revascularisation , hospitalisation for heart failure , and hos
`pitalisation for unstable angina pectoris ) is reduced or
`delayed by from about 20 %
`to about 27 % compared to
`placebo . In some embodiments the first MACE ( e . g . selected
`from the group consisting of CV death , non - fatal MI ,
`non - fatal stroke , revascularisation , hospitalisation for heart
`failure , and hospitalisation for unstable angina pectoris ) is
`reduced about 27 % compared to placebo .
`[ 0016 ]
`In some embodiments MACE is selected from the
`group consisting of CV death , non - fatal MI , and non - fatal
`stroke . In some embodiments MACE ( e . g . selected from the
`group consisting of CV death , non - fatal MI , and non - fatal
`stroke ) is reduced or delayed by at least 10 % compared to
`placebo . In some embodiments MACE ( e . g . selected from
`the group consisting of CV death , non - fatal MI , and non
`fatal stroke ) is reduced or delayed by from about 20 % to
`about 30 % compared to placebo . In some embodiments
`MACE ( e . g . selected from the group consisting of CV death ,
`non - fatal MI , and non - fatal stroke ) is reduced or delayed
`about 26 % compared to placebo . In some embodiments
`MACE ( e . g . selected from the group consisting of CV death ,
`non - fatal MI , and non - fatal stroke ) has a hazard ratio of
`about 0 . 74 compared to placebo . In some embodiments
`MACE ( e . g . selected from the group consisting of CV death ,
`non - fatal MI , and non - fatal stroke ) has a hazard ratio of 0 . 74
`with a 95 % CI of ( 0 . 58 ; 0 . 95 ) compared to placebo . In some
`embodiments the risk of said subject developing a MACE
`( e . g . selected from the group consisting of CV death , non
`fatal MI , and non - fatal stroke ) is reduced by at least 10 %
`compared to placebo . In some embodiments the subject
`developing its first MACE ( e . g . selected from the group
`consisting of CV death , non - fatal MI , and non - fatal stroke )
`is reduced or delayed by at least 10 % compared to placebo .
`In some embodiments the first MACE ( e . g . selected from the
`group consisting of CV death , non - fatal MI , and non - fatal
`stroke ) is reduced or delayed by from about 20 % to about
`30 % compared to placebo . In some embodiments the first
`MACE ( e . g . selected from the group consisting of CV death ,
`non - fatal MI , and non - fatal stroke ) is reduced or delayed
`
`about 26 % compared to placebo . In some embodiments the
`subject developing its first MACE ( e . g . selected from the
`group consisting of CV death , non - fatal MI , and non - fatal
`stroke ) has a hazard ratio of about 0 . 74 compared to placebo .
`In some embodiments the subject developing its first MACE
`( e . g . selected from the group consisting of CV death , non
`fatal MI , and non - fatal stroke ) has a hazard ratio of 0 . 74 with
`a 95 % CI of ( 0 . 58 ; 0 . 95 ) compared to placebo .
`[ 0017 ]
`In some embodiments the MACE is non - fatal MI .
`In some embodiments the non - fatal MI is reduced or delayed
`by at least 10 % compared to placebo . In some embodiments
`the non - fatal MI is reduced or delayed by from about 15 %
`to about 35 % compared to placebo . In some embodiments
`the non - fatal MI is reduced or delayed by about 26 %
`compared to placebo .
`[ 0018 ]
`In some embodiments the MACE is non - fatal
`stroke . In some embodiments the non - fatal stroke is reduced
`or delayed by at least 10 % compared to placebo . In some
`embodiments the non - fatal stroke is reduced or delayed by
`from about 20 % to about 60 % compared to placebo . In some
`embodiments the non - fatal stroke is reduced or delayed by
`from about 30 % to about 50 % compared to placebo . In some
`embodiments the non - fatal stroke is reduced or delayed by
`about 39 % compared to placebo .
`[ 0019 ]
`In some embodiments the MACE is revascularisa
`tion . In some embodiments the revascularisation is reduced
`or delayed by at least 10 % compared to placebo . In some
`embodiments the revascularisation is reduced or delayed by
`from about 20 % to about 60 % compared to placebo . In some
`embodiments the revascularisation is reduced or delayed by
`from about 30 % to about 50 % compared to placebo . In some
`embodiments the revascularisation is reduced or delayed by
`about 38 % compared to placebo . Revascularisation may be
`coronary revascularisation or peripheral revascularisation .
`[ 0020 ]
`In some embodiments the MACE is hospitalisation
`for unstable angina pectoris . In some embodiments the
`hospitalisation for unstable angina pectoris is reduced or
`delayed by at least 10 % compared to placebo . In some
`embodiments the hospitalisation for unstable angina pectoris
`is reduced or delayed by from about 10 % to about 30 %
`compared to placebo . In some embodiments the hospital
`isation for unstable angina pectoris is reduced or delayed by
`about 18 % compared to placebo .
`[ 0021 ]
`In some embodiments the administration of sema
`glutide is
`a chronic treatment in which semaglutide is
`administered for at least 16 months ( such as at least 30
`months , and optionally up to 54 months ) , and wherein said
`method reduces or delays non - fatal myocardial infarction
`( MI ) .
`In some embodiments the administration of sema
`[ 0022
`glutide is a chronic treatment in which semaglutide is
`administered for at least 18 months ( such as at least 30
`months , and optionally up to 54 months ) , and wherein said
`method reduces the need or risk of requiring revascularisa
`tion .
`[ 0023 ]
`In some embodiments the MACE is CV death . In
`some embodiments the CV death is reduced by at least 1 %
`compared to placebo . In some embodiments the CV death is
`reduced or delayed by from about 1 % to about 3 % compared
`to placebo . In some embodiments the CV death is reduced
`or delayed by about 2 % compared to placebo .
`[ 0024 ]
`The term “ placebo " as used herein refers to a
`formulation identical to the semaglutide formulation except
`not comprising semaglutide and the placebo was adminis
`
`MPI EXHIBIT 1295 PAGE 5
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`US 2019 / 0134162 A1
`
`May 9 , 2019
`
`tered in the volume used in the equivalent semaglutide
`dosage . A subject receiving placebo may also include con
`comitant medication , such as one or more oral anti - diabetic
`drugs ( OADs ) , or human NPH insulin or long - acting insulin
`analogue or premixed insulin , alone or in combination with
`one or two OAD ( S ) .
`[ 0025 ]
`“ CV death ” may be defined as death , wherein the
`cause of death is selected from the group consisting of
`cardiovascular disease or is unknown . In some embodiments
`CV death may be defined as death where no clearly docu
`mented non - cardiovascular cause exists . CV death may
`include death resulting from an acute myocardial infarction ,
`sudden cardiac death , death due to heart failure , death due to
`stroke , death due to cardiovascular procedures , death due to
`CV haemorrhage , and death due to other CV causes with a
`specific , known CV cause ( e . g . , pulmonary embolism or
`peripheral arterial disease ) .
`[ 0026 ] “ Non - fatal MI ” may be defined as myocardial
`necrosis consistent with myocardial ischemia without death
`of the subject . In some embodiments MI is diagnosed based
`on the redefinitions suggested by the ESC ( European Society
`of Cardiology ) / ACCF ( American College of Cardiology
`Foundation ) / AHA ( American Heart Association ) / WHF
`( World Heart Federation ) task force , as described in Thy
`gesen K , et al . “ Universal Definition of Myocardial Infarc
`tion . ” J Am Coll Cardiol 2007 Nov . 27 ; 50 ( 22 ) : 2173 - 95 .
`[ 0027 ] “ Revascularisation " may be defined as restoration
`of perfusion to a body part or organ that has suffered
`ischemia , e . g . by unblocking obstructed or disrupted blood
`vessels or by surgically implanting replacements such as a
`stent . More specifically , " coronary revascularisation ” may
`be defined as improvement of myocardial blood flow , and
`" peripheral revascularisation " may be defined as improve
`ment of peripheral arterial blood flow .
`[ 0028 ] “ Hospitalisation for unstable angina pectoris ” may
`be defined as unscheduled hospitalisation characterised by
`1 ) ischemic discomfort 10 minutes in duration occurring at
`rest , or in an accelerating pattern with frequent episodes
`associated with progressively decreased exercise capacity ;
`2 ) no elevation in cardiac biomarkers and no evidence of
`acute MI ; and 3 ) at least one selected from the group
`consisting of : a . New or worsening ST or T wave changes on
`resting ECG ( in the absence of confounders , such as LBBB
`or LVH ) Transient ST elevation ( duration < 20 minutes ) ,
`and / or new ST elevation at the 3 point in two contiguous
`leads with the cut - points : 20 . 1 mV in all leads other than
`leads V2 - V3 where the following cut - points apply : 20 . 2 mV
`in men 40 years ( 20 . 25 mV in men < 40 years ) or 0 . 15 mV
`in women , and / or ST depression and T - wave changes , and / or
`New horizontal or down - sloping ST depression 20 . 05 mV in
`two contiguous leads and / or new T inversion 0 . 3 mV in
`two contiguous leads with prominent R wave or R / S ratio
`> 1 ; b . Definite evidence of inducible myocardial ischemia as
`demonstrated by : an early positive exercise stress test ,
`defined as ST elevation or 2 mm ST depression prior to 5
`mets , or stress echocardiography ( reversible wall motion
`abnormality ) , or myocardial scintigraphy ( reversible perfu
`sion defect ) , or MRI ( myocardial perfusion deficit under
`pharmacologic stress ) , and believed to be responsible for the
`myocardial ischemic symptoms / signs ; c . Angiographic evi
`dence of new or worse 70 % lesion and / or thrombus in an
`epicardial coronary artery that is believed to be responsible
`for the myocardial ischemic symptoms / signs ; and d . Need
`for coronary revascularization procedure ( PCI or CABG ) for
`
`the presumed culprit lesion ( s ) ( this criterion would be ful
`filled
`if revascularization was undertaken during the
`unscheduled hospitalization , or subsequent to transfer to
`another institution without interceding home discharge ) . The
`term
`" cardiac biomarkers ”
`in connection with unstable
`angina pectoris may include troponin and CK - MB .
`[ 0029 ] “ Non - fatal stroke ” may be defined as an acute
`episode of focal or global neurological dysfunction caused
`by brain , spinal cord , or retinal vascular injury as a result of
`haemorrhage or infarction , e . g . , ischemic stroke , or haem
`orrhagic stroke , without death of the subject . In some
`embodiments ischemic stroke is defined as an acute episode
`of focal cerebral , spinal , or retinal dysfunction caused by
`infarction of central nervous system tissue ( for example ,
`haemorrhage may be a consequence of ischemic stroke , and
`in this situation , the stroke is an ischemic stroke with
`haemorrhagic transformation and not a haemorrhagic
`stroke ) . In some embodiments haemorrhagic stroke is
`defined as an acute episode of focal or global cerebral or
`spinal dysfunction caused by intraparenchymal , intraven
`tricular , or subarachnoid haemorrhage .
`[ 0030 ] “ Hospitalisation for heart failure ” may be defined
`as hospitalisation for at least 24 hours with a primary
`diagnosis of heart failure ; wherein at least one of the
`following clinical manifestations of heart failure is present :
`Dyspnoea ( dyspnoea with exertion , dyspnoea at rest , ortho
`pnea , paroxysmal nocturnal dyspnoea ) , decreased exercise
`tolerance , fatigue , and other symptoms of worsened end
`organ perfusion or volume overload ; and wherein initiation
`or intensification of treatment specifically for heart failure
`including at least one of : a . augmentation in oral diuretic
`therapy , b . intravenous diuretic , inotrope , or vasodilator
`therapy , c . mechanical or surgical intervention ( including : i .
`Mechanical circulatory support ( e . g . , intra - aortic balloon
`pump , ventricular assist device ) or ii . Mechanical fluid
`removal ( e . g . , ultrafiltration , hemofiltration , dialysis ) ) . Other
`symptoms of worsened end - organ perfusion or volume
`overload may include ( i ) at least TWO physical examination
`findings OR ( 11 ) one physical examination finding and at
`least ONE laboratory criterion ) , including : a . Physical
`examination findings considered to be due to heart failure ,
`including new or worsened : i . Peripheral oedema , ii . Increas
`ing abdominal distention or ascites ( in the absence of
`primary hepatic , disease ) , iii . Pulmonary rales / crackles /
`crepitations , iv . Increased jugular venous pressure and / or
`hepatojugular reflux , v . S3 gallop , vi . Clinically significant
`or rapid weight gain thought to be related to fluid retention ;
`b . Laboratory evidence of new or worsening HF , if obtained
`within 24 hours of presentation , including : i . Increased
`B - type natriuretic peptide ( BNP ) / N - terminal pro - BNP ( NT
`proBNP ) concentrations consistent with decompensation of
`heart failure ( such as BNP > 500 pg / mL or NT - proBNP
`> 2 , 000 pg / mL ) , in patients with chronically elevated natri
`uretic peptides , a significant increase should be noted above
`baseline ; ii . Radiological evidence of pulmonary congestion ;
`iii . Non - invasive diagnostic evidence of clinically signifi
`cant elevated left - or right - sided ventricular filling pressure
`or low cardiac output ( for example , echocardiographic cri
`teria could include : Ele ' > 15 or D - dominant pulmonary
`venous inflow pattern , plethoric inferior vena cava with
`minimal collapse on inspiration , or decreased left ventricular
`outflow tract ( LVOT ) minute stroke distance ( time velocity
`integral ( TVI ) ) ) ; OR iv . Invasive diagnostic evidence with
`right heart catheterization showing a pulmonary capillary
`
`MPI EXHIBIT 1295 PAGE 6
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`US 2019 / 0134162 A1
`
`May 9 , 2019
`
`wedge pressure ( pulmonary artery occlusion pressure ) 18
`mmHg , central venous pressure 12 mmHg , or a cardiac
`index < 2 . 2 L / min / m² .
`[ 0031 ]
`In some embodiments the methods of the present
`invention reduce the occurrence of an event . In some
`embodiments the methods of the present invention reduce
`the occurrence of an event compared to placebo .
`Subject and Subpopulations
`[ 0032 ]
`The subject to be administered semaglutide accord
`ing to the present invention may be human , such as an adult
`human . In some embodiments said subjects are adults .
`[ 0033 ]
`In some embodiments the subject to receive sema
`glutide administration according to the methods of the
`present invention has type 2 diabetes as well as ( i ) clinical
`evidence of cardiovascular disease , and / or ( ii ) subclinical
`evidence of cardiovascular disease . These cardiovascular
`diseases may be referred to as concomitant , i . e . one or more
`cardiovascular diseases are present in the subject at the same
`time as type 2 diabetes .
`[ 0034 ]
`“ Clinical evidence of cardiovascular disease ” may
`be present when the subject fulfils at least one criterion
`selected from the group consisting of
`[ 0035 ]
`a ) prior myocardial infarction ,
`[ 0036 ]
`b ) prior stroke or transient ischaemic attack ( TIA ) ,
`[ 0037 ]
`c ) prior coronary , carotid or peripheral arterial
`revascularisation ,
`[ 0038 ]
`d ) > 50 % stenosis on angiography or imaging of
`coronary , carotid or lower extremity arteries ,
`[ 0039 ]
`e ) history of symptomatic coronary heart disease
`( e . g documented by eg positive exercise stress test or any
`cardiac imaging or unstable angina with ECG changes ) ,
`100401 f ) asymptomatic cardiac ischemia ( e . g . docu
`mented by positive nuclear imaging test or exercise test or
`stress echo or any cardiac imaging ) ,
`[ 0041 ]
`g ) heart failure New York Heart Association
`( NYHA ) class and
`[ 0042 ]
`h ) chronic renal impairment ( e . g . documented
`( prior to screening ) by estimated glomerular filtration rate
`( eGFR < 60 mL / min / 1 . 73 m² per MDRD ) .
`[ 0043 ]
`In some embodiments clinical evidence of cardio
`vascular disease is prior myocardial infarction . In some
`embodiments clinical evidence of cardiovascular disease is
`prior stroke or transient ischaemic attack ( TIA ) . In some
`embodiments clinical evidence of cardiovascular disease is
`prior coronary , carotid or peripheral arterial revascularisa
`tion . In some embodiments clinical evidence of cardiovas
`cular disease is > 50 % stenosis on angiography or imaging of
`coronary , carotid or lower extremity arteries . In some
`embodiments clinical evidence of cardiovascular disease is
`history of symptomatic coronary heart disease ( e . g . docu
`mented by positive exercise stress test or any cardiac imag -
`ing or unstable angina with ECG changes ) . In some embodi
`ments clinical evidence of cardiovascular disease is
`asymptomatic cardiac ischemia ( e . g . documented by posi
`tive nuclear imaging test or exercise test or stress echo or
`any cardiac imaging ) . In some embodiments clinical evi
`dence of cardiovascular disease is heart failure New York
`Heart Association ( NYHA ) class In some embodiments
`clinical evidence of cardiovascular disease is chronic renal
`impairment ( e . g . , documented ( prior to screening ) by esti
`mated glomerular filtration rate ( eGFR ) < 60 mL / min / 1 . 73
`m² per MDRD ) .
`
`[ 0044 ] “ Subclinical evidence of cardiovascular disease ”
`may be present when the subject fulfils at least one criterion
`selected from the group consisting of
`[ 0045 ]
`i ) persistent microalbuminuria ( e . g . 30 - 299 mg / g )
`or proteinuria ,
`[ 0046 ]
`j ) hypertension and left ventricular hypertrophy by
`ECG or imaging ,
`[ 0047 ]
`k ) left ventricular systolic or diastolic dysfunction
`( e . g . by imaging ) , and
`10048 ]
`1 ) ankle / brachial index < 0 . 9 .
`[ 0049 ]
`In some embodiments subclinical evidence of car
`diovascular disease is persistent microalbuminuria ( 30 - 299
`mg / g ) or proteinuria . In some embodiments subclinical
`evidence of cardiovascular disease is hypertension and left
`ventricular hypertrophy by ECG or imaging . In some
`embodiments subclinical evidence of cardiovascular disease
`is left ventricular systolic or diastolic dysfunction by imag
`ing . In some embodiments subclinical evidence of cardio
`vascular disease is ankle / brachial index < 0 . 9 .
`100501 .
`In some embodiments the term “ prior ” refers to
`before initiating administration of semaglutide .
`10051 ]
`In some embodiments characteristics of the subject
`described herein , such as BMI or age , refers to before
`initiating administration of semaglutide or at the time of
`initiating administration of semaglutide .
`[ 0052 ]
`In some embodiments the subject is at least 50
`years of age , such as at least 60 years of age . In some
`embodiments the subject is less than 60 years of age . In
`some embodiments the subject ( i ) is at least 50 years of age
`and has clinical evidence of cardiovascular disease , and / or
`( ii ) is at least 60 years of age and has subclinical evidence
`of cardiovascular disease .
`[ 0053 ]
`In some embodiments the subject has HbA , , of at
`least 7 . 0 % , e . g . prior to receiving semaglutide administra
`tion . In some embodiments the subject has HbAle of at least
`9 . 0 % , e . g . prior to receiving semaglutide administration . In
`some embodiments the subject has HbAlc in the range from
`7 . 0 % to 15 . 0 % , e . g . prior to receiving semaglutide admin
`istration . HbA , , may be determined according to methods
`known in the art , for example as a percentage determined
`according to the method defined by the Diabetes Control and
`Complications Trial ( DCCT ) , see New Engl J Med 1993 ;
`329 : 977 - 986 .
`[ 0054 ] In some embodiments the subject is , except for
`semaglutide , anti - diabetic drug naive or treated with one or
`more oral anti - diabetic drugs ( OADs ) or treated with human
`NPH insulin or long - acting insulin analogue or premixed
`insulin , alone or in combination with one or two OAD ( S ) .
`The subject may be anti - diabetic drug naive . The subject
`may be treated with one or more oral anti - diabetic drugs
`( OADs ) . The subject may be treated with human NPH
`insulin or long - acting insulin analogue or premixed insulin ,
`alone or in combination with one or two OAD ( s ) . In some
`embodiments the OAD may be selected from the group
`consisting of sulfonylureas , insulin secretagogues , thiazoli
`dinediones , alpha - glucosidase inhibitors , dipeptidyl pepti
`dase - 4 inhibitors , sodium - glucose co - transporter - 2 inhibi
`tors , and combinations thereof . In some embodiments the
`OAD is sulfonylurea ( e . g . glimepiride , glipizide , glyburide ) .
`In some embodiments the OAD is insulin secretagogues
`( e . g . biguanides such as metformin or meglitinides such as
`nateglinide ) . In some embodiments the OAD is thiazolidin
`ediones ( e . g . pioglitazone , rosiglitazone ) . In some embodi
`ments the OAD is alpha - glucosidase inhibitors ( e . g . acar
`
`MPI EXHIBIT 1295 PAGE 7
`
`

`

`US 2019 / 0134162 A1
`
`May 9 , 2019
`
`bose , miglitol , voglibose ) . In some embodiments the OAD
`is sodium - glucose co - transporter - 2 inhibitors ( e . g . dapagli
`flozin , canagliflozin , empagliflozin ) . In some embodiments
`the OAD is dipept