Patent Application: US-201414182272-A

Abstract:
provided herein is a short - term myocardial infarction based test for identifying a compound , substance or drug that reduces the risk of myocardial infarction and optionally ischemic heart disease in a test subject . further provided is a method for preventing or treating myocardial infarction using the compound , substance or drug identified .

Description:
the present invention is based on the discovery of a short - term myocardial infarction - based test ( clinical trial ) which is designed to demonstrate if a test compound , e . g ., a cetp inhibitor , pcsk9 agent or other investigational drug , reduces the risk of myocardial infarction in a test subject . cetp inhibitors are members of a class of drugs that inhibit cholesteryl ester transfer protein ( cetp ). they are intended to reduce the risk of atherosclerosis by improving blood lipid levels . cholesteryl ester transfer protein normally transfers cholesterol from high density lipoprotein ( hdl ) cholesterol to very low density or low density lipoproteins ( vldl or ldl ). inhibition of this process results in higher hdl levels ( the so - called “ good ” cholesterol - containing particle ) and reduces ldl levels ( the so - called “ bad ” cholesterol ). examples of cetp inhibitors currently under development include anacetrapib ( merck ) and evacetrapib ( eli lilly & amp ; company ). the development of torcetrapib ( pfizer ), another cetp inhibitor , was halted in 2006 when phase iii studies showed excessive all - cause mortality in the treatment group receiving a combination of atorvastatin ( lipitor ) and torcetrapib . a “ pcsk9 agent ” is an agent that modulates the expression and / or synthesis of pcsk9 ( proprotein convertase subtilisin kexin 9 ). pcsk9 is a member of the subtilisin serine protease family that is involved with regulation of hepatic ldl receptor activity . pcsk9 agents may include but are not limited to the pcsk9 monoclonal antibodies , peptide mimics and anti - sense oligonucleotides . pcsk9 agents have been developed to prevent myocardial infarctions by lowering low - density lipoprotein ( ldl ) cholesterol . these agents generally are planned to be used to supplement statins . pcsk9 , a secreted protease , is involved with regulation of hepatic ldl receptor activity 41 , 42 blocking pcsk9 binding to the ldl receptor with a monoclonal antibody lowers ldl cholesterol in humans . 41 , 42 trials designed according to the present invention also detect if investigational or candidate drugs increase the risk of myocardial infarction in a test subject . the present invention is also directed to methods of reducing the risk of myocardial infarctions using a drug identified by the trials designed according to the methods disclosed herein . the participants used in the trials designed according to the methods of the present invention include subjects who will be undergoing elective percutaneous coronary interventions ( pci ) or are suffering from acute coronary syndromes ( acs / infarctions ). the standard treatment of elective pci and acs / infarction by administering a statin is incorporated into the invention . the test group is given a statin plus the experimental drug , and the control group is given only a statin . alternatively , the test group may be given the experimental drug and the control group is given only a placebo . in a particular embodiment , the test group and control group may be about the same size . as described in more detail below , it has been estimated that approximately 40 - 50 % of individuals who have undergone pci have a mild myocardial infarction . 1 , 2 the accepted course of treatment during and after pci involves administration of statins , which prevents about half of these myocardial infarctions . therefore , it would be expected that approximately 25 % of these patients will still experience a myocardial infarction , even when given a statin , in the days following the initial episode . with acs / myocardial infarction , there is a significant short - term mortality . the invention described herein describes a clinical trial wherein patients who will undergo elective pci , or have acs / infarction and are in need of therapy , would be given the experimental drug in addition to the normally administered statin ( the test group ). a control group is administered statin alone . the results ( e . g ., the ability of the test compound to inhibit myocardial infarctions in the pci group and inhibit mortality in the acs / infarction group ) are available in the short - term since the participants ( those having undergone pci or had acs / infarction ) are at acute risk for a myocardial infarction or acute mortality . for example , individual results are available in about one , two , or three days for subjects who have undergone pci . for an individual study of acs / infarction , results are available in about one , two or three weeks . in one embodiment , the invention provides relatively prompt overall results , e . g ., in six months or less , with multiple study centers . likewise , an increase of myocardial infarctions caused by the administration of the experimental drug is also apparent in the short - term . the invention is based on the principles that statins and the investigative drug operate additively and acutely by one basic mechanism . therefore , without being bound by any particular theory , it is useful to list these specific principles , as follows : 1 . risk factors directly induce myocardial infarction by expression of thrombosis / vasoconstriction it seems apparent that risk factors directly induce myocardial infarction by expression of thrombosis / vasoconstriction ; after all , thrombosis is the accepted , 3 and spasm is a proposed , 4 mechanism for the direct induction of myocardial infarction . there is clear evidence that multiple and diverse risk factors for ischemic hear disease ( ihd ) ( pharmaceutical and lifestyle ) express as thrombosis / vasoconstriction . 5 risk factors favor thrombosis / vasoconstriction through endothelial dysfunction and a separate tendency toward thrombosis such as platelet activation and / or sympathetic activation . 5 myocardial infarctions associated with cox - 2 inhibitors provide a specific example of the direct induction of myocardial infarction by risk factor - induced thrombosis / vasoconstriction and are generally attributed directly to thromboxane — which expresses thrombosis / vasoconstriction . 6 this evidence is of particular importance to the short - term test of the invention , as it is based on a drug . for the purpose of the short - term myocardial infarction - based test , no opinion is taken about whether thromboses or vasoconstriction directly induce myocardial infarctions — or whether anti - thrombosis or vasodilation directly prevents myocardial infarctions . the distinction is not relevant to this invention . thrombosis / vasoconstriction ( and anti - thrombosis / vasodilation ) tends to occur together as a unit 5 — and thromboses is the accepted , 3 and spasm a proposed , 4 mechanism for myocardial infarction . 3 . preventative factors , pharmaceutical and lifestyle , prevent myocardial infarctions through expression of anti - thrombosis / vasodilation there is clear evidence that multiple and diverse pharmaceutical and lifestyle preventative factors for ihd express anti - thromboses / vasodilation 5 — as part of pleiotrophic effects . if thromboses / vasoconstriction causes myocardial infarctions , reasonably , anti - thrombosis / vasodilation prevents myocardial infarctions . importantly , it generally is accepted that aspirin prevents myocardial infarctions through anti - thrombosis 7 — which reflects the standard paradigm that myocardial infarctions are due directly to thromboses . aspirin inhibits platelets , which express thrombosis / vasoconstriction . 7 there is inferential evidence that statins prevent myocardial infarctions through anti - thrombosis / vasodilatory effects . endothelial dysfunction favors thrombosis / vasoconstriction , 5 , 8 , 9 and statins improve endothelial dysfunction . 10 - 14 statins also depress the thrombotic arm of thrombosis / vasoconstriction . 15 , 16 further , statins suppress cox - 2 inhibitors 17 — which express thrombosis / vasoconstriction . 7 , 18 other pharmaceutical preventative agents for ihd improve thrombosis / vasoconstriction . significantly , aspirin 19 and angiotensin - converting enzyme inhibition 20 also improve endothelial dysfunction . in general , multiple pharmaceutical and lifestyle preventative factors express pleiotrophic effects , which expresses anti - thrombosis / vasodilation . 5 4 . risk factors act acutely to induce myocardial infarction ( through thrombosis / vasoconstriction ) there is evidence that risk factors act acutely to induce myocardial infarction . significantly , 82 . 2 % of myocardial infarctions in one series acutely followed “ triggering ” risk factors as acute stress , a heavy meal , and “ monday .” 21 this is interpreted as evidence that multiple risk factors ( which express thrombosis / vasoconstriction ) can act acutely . also significant , mental stress induced transient endothelial dysfunction ( which favors thrombosis / vasoconstriction ) in thirty minutes . 22 5 . preventative agents can prevent myocardial infarctions promptly ( supposedly through anti - thrombosis / vasodilation ) there is convincing evidence that acute statin therapy promptly reduces the incidence of periprocedural myocardial infarctions after percutaneous coronary interventions ( pci ), and reduces the incidence of short - term mortality with acute coronary syndromes ( acs / infarction ). the multiple studies of pci and acs treated with acute statin therapy show very impressive results — usually around or better than a 50 % improvement . individual studies of pci showed a significant reduction of periprocedural myonecrosis with statins over controls by 3 . 7 % vs . 9 . 4 %, 23 9 . 5 % vs . 15 . 8 %, 24 and 5 % vs . 18 %. 1 also , the incidence of large non - q - wave myocardial infarction was 8 % in the statin group and 15 . 6 % in the control group . 25 meta - analyses of statin treatment with pci showed similar results . there was a reduction of periprocedural myonecrosis over controls of 9 . 0 % vs . 17 . 5 % 2 and 7 . 7 % vs . 14 . 2 %. 26 another large study showed a 43 % reduction of post - procedural myocardial infarctions . 27 studies of acute statin use with acs / infarction showed reduction of in - hospital mortality and morbidity as compared to controls by 4 . 0 - 5 . 3 % vs . 15 . 45 28 and 5 % vs . 17 %. 29 meta - analyses of statin use with acs / infarctions showed a reduction of deaths at 7 days ( 0 . 4 % vs . 2 . 6 %) 30 and 30 days ( 0 . 5 % vs . 1 . 0 %). 31 finally , acute statin therapy with pci in cases of acs showed a lower rate of periprocedural myocardial injury over controls ( 5 . 8 % vs . 11 . 4 %). 32 there is evidence that statins act acutely to prevent myocardial infarctions through anti - thrombosis / vasodilatory effects ; statins improved endothelial dysfunction ( which favors thrombosis / vasoconstriction ) when measured at 60 minutes , 10 24 hours , 11 10 days , 12 2 weeks , 13 and 4 weeks . 14 also , anti - platelet effects ( anti - thrombosis / vasodilation ) of aspirin are measurable by 60 minutes . 7 further , angiotensin - converting inhibition improved endothelial dysfunction when measured at 4 weeks . 20 another study 33 showed that angiotensin converting enzyme inhibition prompted parasympathetic activation ( which improves endothelial dysfunction 5 ) when measured at 30 days . while measured at a month &# 39 ; s time , it seems reasonable that actual benefits occurred significantly earlier . the lability_of endothelial function can be used as evidence that preventative substances tend to act promptly to improve endothelial dysfunction . this liability is demonstrated by several parameters : the ability of mental stress to induce transient endothelial dysfunction by 30 minutes , 22 the ability of statins to promptly improve endothelial dysfunction , and the very beneficial effects of acute statin therapy with pci and acs / infarction . in this light , it is likely that angiotensin - converting enzyme inhibition improved endothelial dysfunction much more promptly than 4 weeks . it also is likely that other pharmaceutical agents that prevent myocardial infarction and improve endothelial function act acutely . that preventative agents act additively is commonly accepted . 3 as example , the combination of statins , angiotensin converting inhibitors , and aspirin reduced the risk of death in ihd by 71 %. 35 again , without wishing to be bound by any particular theory , the above evidence supports the tenet that preventative pharmaceutical agents operate acutely and additively , most likely by pleiotrophic anti - thrombosis / vasodilation . therefore , the short - term myocardial infarction - based test for investigative drugs is based on sound principles . if the combination of a preventative measure ( especially a statin ) plus an investigative drug act significantly more beneficially than a preventative measure ( e . g ., a statin ), this is evidence that the investigative drug reduces the risk of myocardial infarction . a second rationale can be used : as the preventative agent ( as a statin ) is given to both the test and control groups , the preventative agent cancels out . therefore , the test evaluates the ability of the investigative drug to act more beneficially than the control group . in one aspect of the present invention , individuals who are undergoing elective pci or are experiencing acs / acute myocardial infarction are separated into two groups , the test group and the control group . in a particular embodiment , the test group and the control group may be about the same size . the test group is given a statin plus the investigative drug , and the control group is given the usual statin ( e . g ., at about the same dose as the test group ). in a particular embodiment , statin therapy is given according to standard protocols for the treatment of elective pci and acs / acute myocardial infarction . generally , the investigative drug is given at the same time as the statin . alternatively , as set forth above , the test group is given the investigative drug and the control group is given a placebo . if there is a statistically significant lower incidence of myocardial infarction ( for the subjects who are undergoing elective pci ) and short - term mortality ( for the subjects with acs / acute myocardial infarction ) in the test group , this is prima facie evidence that the investigative drug reduces the risk of myocardial infarctions when used in the usual clinical setting . preferentially , statistically significant results should include about a 10 % or more reduction of infarctions between about one day to about seven days after undergoing the elective pci and / or about a 10 % or more reduction in mortality rate between about two weeks to about one month , two months , three months , four months , five months or six months after undergoing the elective pci . however , if the test group has a pronounced higher incidence of myocardial infarctions or mortality , it is likely that the drug causes myocardial infarctions . by giving all test group participants a statin , including the control group , all cases are treated as any individuals undergoing elective pci or treatment of acs / acute myocardial infarction would be treated under the current standard of care . because of the administration of the statin , both the test group and the control group are protected against myocardial infarction . as both the test and control groups are given about the same dose of a statin , in some embodiments , effects of the statin are balanced out , leaving only the effect of the experimental drug on pci and acs / infarction . the design of the clinical trials of the invention provide relatively prompt results as compared to accepted clinical trials of investigational drugs . in one embodiment , results of individual cases should be available , for example , in about one day , two , three , four , five , or six days , or a week for those who had elective pci ( measuring post - procedural myocardial infarctions ), and within about a week , two weeks , three weeks , or a month , for those who had acs / infarctions ( measuring short - term mortality ). also , because myocardial infarctions are highly concentrated , relatively small numbers of test subjects are necessary , e . g ., about 50 , 100 , 200 , 300 , 400 or 500 test subjects , for the methods of the invention . for individuals who have suffered from acs / infarction , about 100 % of cases have myocardial infarctions . with pci , incidence of periprocedural myocardial infarctions up to 40 - 50 % have been reported . 1 , 2 however , studies of pci reported above showed incidences of periprocedural myocardial infarctions in controls between 9 . 4 %, 23 15 . 6 %, 25 15 . 7 %, 24 and 18 %. 1 therefore , smaller numbers of cases are needed with acs / infarction than with pci to achieve statistical significance . however , total number of combined controls and test cases for pci have been rather small ( 153 , 1 668 , 24 383 , 23 and 451 25 ). periprocedural myocardial infarctions generally are mild and only detected by elevation of cardiac enzymes . 1 , 24 however , these mild infarctions are treated conventionally as genuine mild infarctions . in keeping with this , the incidence of large non - q - wave infarction after pci was 8 % in the statin group and 15 . 6 % in the control group 25 — findings similar to studies of periprocedural myonecrosis after pci . however , to solidify that the short - term myocardial infarction - based test directly predicts results of standard long - term phase iii tests , it is helpful to use both pci and acs models . the former model is based on preventing myocardial infarctions , and the latter model is based on reducing the impact of an acute acs / infarction . in some embodiments , dosage of statins for the short - term myocardial infarction - based test of the invention follows common practices with statin treatment of elective pci and with acs / infarction . the patient , in a specific embodiment , may be administered low ( 10 - 20 mg ), moderate ( 20 - 40 mg ) or high doses ( 40 - 80 mg ) of statin . for example , 80 23 , 24 and 40 1 mg per day of atorvastatin has been used with elective pci and can be used in the methods of the invention , although use of moderate doses of other statins is not excluded . for example , in an alternative embodiment , a “ high ” dose of 40 mg , “ moderate ” dose of 20 mg , “ low ” dose of 10 mg and “ very low ” dose of 5 mg of rosuvastatin may be used . also , in one embodiment , the statin therapy can be done in combination with one or more other effective preventative agents , such as angiotensin - converting enzyme inhibitors . also , use of preventative drugs other than statins are also included in some embodiments . although there is evidence that the acute effects of statins are manifested quickly in favoring anti - thrombosis / vasodilation , in one embodiment , there can be a period of pretreatment , for example to ensure full activation of the investigative drug . pretreatment with statins ( and the investigative drug ) for elective pci can be , for example , 12 hours to 31 days or more in advance . for example , pretreatment times of statins for pci have ranged from around 12 hours 23 to 31 days , 2 and most times have been about 7 days or more . 1 , 2 , 24 common practices for advance administration of the statin can be used in the methods of the invention . the investigative drug can also be administered in advance of pci . if there is concern that the investigative drug will take longer than statins to develop its full therapeutic effect , the dosing of the investigative drug for elective pci can begin significantly longer than a week prior to pci . for acs , to account for a possible tardy full effect of the investigative drug , evaluation of short - term mortality can be extended past 4 weeks , for example to 6 weeks or 8 weeks . doses of an investigative drug can be employed as used in other trials of the investigative drug or as determined by pre - clinical trials or determined based on dose of other like drugs . in general , investigative drugs can be used at high dosage , but moderate doses are not excluded . differences of incidences of periprocedural infarctions ( pci ) and short - term mortality ( acs / infarction ) between the test and control group are determined , using appropriate statistical methodology as is known in the art . incidences of periprocedural myocardial infarctions with pci is determined in test and control groups by standard methods for determining the occurrence of myocardial infarction . 36 in one embodiment , biomarker evaluation of myocardial infarction can be used . 36 , 37 the preferred biomarker for myocardial necrosis is cardiac troponin ( i or t ). 36 , 37 with pci , in one embodiment , measurement of cardiac enzymes is performed before or immediately after the procedure , and again at 6 - 12 and 18 - 24 hours . 36 for acs / infarction , in one embodiment , evaluation of the status of the myocardial infarction in test and control cases ( especially by cardiac enzymes ) is performed at admission , several times during the hospital stay , and when the protocol ends the trial , for example , at one week , one month , or six weeks . in particular , status of myocardial infarction may be determined to be improved in test subjects if there is a statistically significant reduction in cardiac enzymes in test subjects as compared to controls . current investigative cholesteryl ester transfer protein ( cetp ) inhibitor drugs ( for example , anacetrapib ( merck ) and evacetrapib ( eli lilly & amp ; company )) and other similar drugs are especially propitious drugs for testing by the short - term myocardial infarction - based test of the invention . the proposed uses of these drugs simulates the short - term myocardial infarction - based test . these drugs , which elevate high density lipoprotein ( hdl ) cholesterol , 38 - 39 are generally planned to be used to supplement drugs ( as statins ) which lower low density lipoprotein ( ldl ) cholesterol . trials of experimental cetp inhibitors used the following doses : anacetraapib 100 mg / day 38 and evacetrapib 30 , 100 , and 500 mg / day . 40 pcsk9 agents have been developed to prevent myocardial infarctions by lowering low - density lipoprotein ( ldl ) cholesterol . these agents may be used to supplement statins but could be used alone as well . pcsk9 , a secreted protease , is involved with regulation of hepatic blocking pcsk9 binding to the ldl receptor with a monoclonal antibody has been found to lower ldl cholesterol in humans . 41 , 42 the pcsk9 monoclonal antibody amg 145 ( amgen ) has been injected subcutaneously every four weeks at 350 mg . and 420 mg . 41 , 42 as well as subcutaneously every 2 weeks at 70 mg ., 105 mg ., and 140 mg . also , the monoclonal antibody regn727 / sar236553 ( regeneron / sanofi ) was injected subcutaneously every 4 weeks at doses of 200 or 300 mg ., or 150 mg every two weeks . 41 , 42 there are advantages to both the pci and the acs / acute infarction models . elective pci allows premedication . also , periprocedural infarctions after pci generally are mild , 1 , 24 thus limiting the risk of the study . post pci myocardial infarctions generally are asymptomatic , 1 and generally are defined as a three fold elevation of creatine kinase - myocardial isoenzyme . 24 also , if , as expected , the investigative drug reduces the risk of myocardial infarctions , this will aid half the cases ( the test group ). the acs / acute myocardial infarction model has a special advantage , as myocardial infarctions are serious and can result in significant short - term mortality . if the investigative drug reduces the risk of myocardial infarctions , the drug will give more protection against short - term mortality to half the cases ( the test group ). an important issue is the ability of the investigative drug to fare well with the test . that is , to prevent myocardial infarctions with individuals undergoing pci , and lower short - term mortality with individuals suffering from acs . importantly , the short - term myocardial infarction - based test of the invention simulates two separate clinical situations : the direct prevention of myocardial infarctions ( with individuals undergoing pci ) and limiting the acute term mortality of myocardial infarctions ( with individuals suffering from acs / infarctions ). if an investigative drug is effective in these situations , the drug will likely prevent infarctions in the clinical situation in high risk individuals in a clinical setting . 1 . pasceri v , patti g , nusca a , pristipino c , richichi g , di sciascio g et al . randomized trial of atorvastatin for reduction of myocardial damage during coronary intervention : results from the armyda ( atorvastatin for reduction of myocardial damage during angioplasty ) study . circulation 2004 ; 110 : 674 - 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14 . 40 . nicholls s j , brewer h b , kastelein j j , kreuger k a , wang m , shao m et al . effects of the cetp inhibitor evacetrapib administrated as monotherapy or in combination with statins on hdl and ldl cholesterol : a randomized controlled trial . jama 2011 ; 306 : 2099 - 109 . 41 . raal , f , scott , r , somaratne r , bridges i , li g , wasserman s m , stein e a . low - density lipoprotein cholesterol - lowering effects of amg 145 , a monoclonal antibody to proprotein convertase subtilisin / kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia : the reduction of ldl - c with pcsk9 inhibition in heterozygous familial hypercholesterolemia disorder ( rutherford ) randomized trial . 42 . stein e a , gipe d , gergeron j , gaudet d , weiss r , dufour r , wu r , pordy r . effect of a monoclonal antibody to pcsk9 , regn727 / sar236553 , to reduce low - density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy : a phase 2 randomised controlled trial . lancet 2012 ; 380 : 29 - 36 . this invention may be embodied in other forms or carried out in other ways without departing from the spirit or essential characteristics thereof . the present disclosure is therefore to be considered as in all aspects illustrate and not restrictive , and all changes which come within the meaning and range of equivalency are intended to be embraced therein . various publications are cited herein , the contents of which are hereby incorporated by reference in their entireties .