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Pharmaceutical formulations, methods, and dosing regimens for the treatment and prevention of acute coronary syndromes

Pharmaceutical formulations, methods, and dosing regimens for the treatment and prevention of acute coronary syndromes description/claims

This application is related to U.S. Provisional Application Ser. Nos. 60/513,116 (filed Oct. 20, 2003), 60/517,016 (filed Nov. 3, 2003) and 60/571,129 (filed May 14, 2004), each of which is incorporated herein by reference in its entirety.

The invention provides novel formulations and methods to treat or prevent acute coronary syndromes. In a preferred embodiment, the formulations are single unit dosages that have a specified pH osmolality and purity. In a preferred method the formulation is administered weekly, monthly or yearly in a dose range of about 1 mg/kg to about 100 mg/kg per administration. Additionally, doses and dosing regimens are disclosed as well as specific diseases for which the doses or dosing regimens are intended to be used. The formulations and methods employ an Apolipoprotein A-I Milano: phospholipid complex.

The management and treatment of myocardial infarction has changed dramatically since the first half of the 20th century, progressing from an era of bed rest and observation, to an emphasis on technology, including hemodynamic monitoring and balloon catheters, to an increased focus on thrombolytic therapy. (Antman and Braunwald, “Acute Myocardial Infarction” in Heart Disease, A Textbook of Cardiovascular Medicine, 61 edition, vol. 2, Braunwald et al., eds, 2001, W.B. Saunders Company, Philadelphia). Therapeutic approaches to treating cardiovascular diseases have evolved tremendously in the last 100 years accompanied by greater understanding of the underlying pathology.

Almost all myocardial infarctions result from coronary atherosclerosis, generally with superimposed coronary thrombosis. Slowly accumulating plaques can be asymptomatic due to the development of collateral vessels. However, atherosclerotic plaques, especially those rich in lipids, are prone to abrupt plaque rupture. Plaque rupture and associated endothelial injury cause the release of mediators such as thromboxane A2, serotonin, adenosine diphosphate, thrombin, platelet activating factor, tissue factor and oxygen-derived free radicals. These mediators promote platelet aggregation and mechanical obstruction often leading to thrombus formation which interferes with blood flow and oxygen supply. Persistent and severe interferences with myocardial oxygen supply can lead to acute myocardial infarction. (See, Rioufol et al., 2002, Circulation 106:804, Timmis, 2003, Heart 89:1268-72).

The mainstay of atherosclerotic pharmacotherapy has been chronic therapy to prevent or slow the development of atherosclerotic plaques primarily by focusing on lowering LDL or “bad cholesterol” as a therapeutic endpoint. Statin therapy, for example, has greatly contributed to improved cardiovascular health; however, adverse effects such as rhabdomyolysis, remain an impediment. Furthermore, statins do little in an acute situation, for example, to reduce vulnerable, unstable atherosclerotic plaque during an ischemic episode. Acute treatment has largely relied on thrombolytics (such as tPA) and surgical intervention such a percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft (CABG). While thrombolytics provide relief by decreasing or eliminating an occluding thrombus, they do not alter the underlying pathology. Interventions such as PTCA carry their own risks and are often unsuitable for patients in acute conditions. Hence current pharmacologic therapies do little to help patients once unstable plaque presents as a risk. (See, Newton and Krause 2002, Atherosclerosis S3:31-38).

HDL therapy is emerging as a new treatment paradigm for dyslipidemia and atherosclerosis. Id. Apolipoprotein A-I Milano (Apo A-I Milano) has been of interest due to the paradoxical finding that carriers of the variant form of this apolipoprotein have low HDL (“good cholesterol”) levels and decreased risk of cardiovascular disease. (See, Franceschini et al., 1980, J. Clin. Invest. 66:892-900, Weisgraber et al., 1983, J. Biol. Chem. 258: 2508-2513, Franceschini et al., 1985, Atherosclerosis 58: 159-174, Franceschini et al., 1987, Arteriosclerosis 7:426-435). Apo A-I Milano homodimers were found to reduce intimal thickening in cholesterol fed rabbits (Ameli et al., 1994, Circulation, 90: 1935-41 and Soma et al., 1995, Cir. Res. 76:405-11). In ApoE deficient mice, atherosclerotic lesions were reduced by both multiple low dose and single high dose Apo A-I Milano: lipid complexes (Shah et al., 1998, Circulation 97: 780-85 and Shah et al., 2001, Circulation 103:3047-50). Plaque regression in rabbits was also demonstrated with single local infusions of Apo A-I Milano:phospholipid complexes in doses of 500 mg and 1000 mg of protein per rabbit. (Chiesa et al., 2002, Cir. Res. 90:974-80). The lesions induced in the rabbit model are largely comprised of macrophages and not representative of the more complex lesions in humans. Therefore, it is uncertain if analogous treatments would be effective for the complicated plaques found in human atherosclerosis. (Li et al., 1999, Arterioscler Thromb Vasc Biol 19:378-383 and Shah et al., 2001, Circulation 103:3047-50).

Yet despite the improved understanding of the pathophysiology of myocardial infarction and developments in HDL therapy, safe and effective doses, dosing regimens and pharmaceutical formulations for the prophylactic and therapeutic use of Apo A-I Milano or Apo A-I Milano: lipid complexes in humans are still desired.

The invention provides methods and pharmaceutical formulations for the treatment and prevention of cardiovascular disease or related disorders including atherosclerosis, acute coronary syndromes, ischemia, ischemic reperfusion injury, angina and myocardial infarction and the reduction or stabilization of atherosclerotic plaque, the reduction of plaque in occluded vessels and promotion of cholesterol efflux. The invention thus encompasses doses and dosing regimens for the use of Apo A-I Milano:phospholipid complex and pharmaceutical formulations of Apo A-I Milano: phospholipid complex to treat or prevent cardiovascular disease or related disorders including atherosclerosis, acute coronary syndromes, ischemic reperfusion injury, angina and myocardial infarction, and the reduction or stabilization of atherosclerotic plaque, the reduction of plaque in occluded vessels and promotion of cholesterol efflux. The method and formulations described herein cause rapid reduction or stabilization of unstable atherosclerotic plaques which, if left untreated or treated by conventional methods, can rupture and lead to ischemic events including acute coronary syndromes.

Applicants have determined that an exogenously produced HDL mimetic, such as Apo A-I Milano, preferably as an Apo A-I Milano:phospholipid complex, offers a unique approach for the treatment and prevention of cardiovascular disease or related disorders; such disorders include but are not limited to atherosclerosis, acute coronary syndromes, ischemia, ischemic reperfusion injury, angina and myocardial infarction, or the reduction or stabilization of atherosclerotic plaque in narrowed or occluded vessels. The methods including the doses and dosing regimens and pharmaceutical formulations of the invention provide safe, effective and non-surgical treatment which rapidly promotes cholesterol efflux and mobilization from atherosclerotic plaques. The promotion of rapid cholesterol efflux reduces atheroma volume in one or more affected vessels. Reduced atheromas (the mass of plaque of degenerated thickened arterial intima occurring in atherosclerotic vessels) allow greater blood flow and reduces the risk of ischemia, including unstable angina, myocardial infarctions and acute coronary syndromes.

Prior to this invention which provides pharmaceutical formulations of Apo A-I M and specific doses for the treatment and prevention of cardiovascular disease, including acute coronary syndromes, atherosclerosis, angina, myocardial infarction, and ischemic reperfusion injury, conventional atherosclerotic therapy focused on lowering LDL or “bad cholesterol” as a therapeutic endpoint. These conventional LDL therapies, for example, treatment with statins, can require months of treatment before LDL serum levels are decreased in a subject. In acute or emerging cardiovascular disorders, conventional therapy has largely relied on surgical intervention such as percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft (CABG). However, surgical intervention is often contraindicated in some patients in an emergent situation, particularly patients in poor overall health. Moreover, these conventional methods do not provide a non-surgical pharmacologic treatment effective in an acute situation. Furthermore, conventional therapies focused on treating the symptoms of cardiovascular disease and acute coronary syndromes especially in the circulatory system. Conventional therapies as described above and in more detail below, have focused on reducing LDL cholesterol, reducing blood clot formation and lowering blood pressure which do not treat or prevent the underlying cause of cardiovascular disease and acute coronary syndromes, the stabilization, reduction and modification of the plaque within the vessel wall.

The pharmaceutical formulations and methods, including the doses and dosing schedules provided herein are safe, effective and act rapidly to reduce or stabilize atherosclerotic plaque. The doses described herein are rapid acting, providing reduction of atherosclerotic plaque in as little as a few weeks by promoting cholesterol mobilization. In certain embodiments, the doses described herein can be used to treat a subject suffering from acute coronary syndromes or disorders associated with ischemia or vessel occlusion. In certain embodiments, the doses described herein can be used to prevent disease progression once atherosclerotic plaques present a risk to the subject. The disease progression prevented can be further occlusion of a vessel or to prevent the rupture of an unstable atherosclerotic plaque which can lead to ischemic conditions including acute coronary syndromes and ischemic reperfusion injury.

The methods and pharmaceutical formulations provided herein are so effective that a single dose of 45 mg/kg can stimulate cholesterol mobilization from an atherosclerotic plaque. In certain embodiments, a single high dose, for example about 45 mg/kg, of the Apo A-I Milano:phospholipid complex or pharmaceutical formulation thereof, can be administered to a subject. In certain embodiments, one or more high doses of the Apo A-I Milano:phospholipid complex or pharmaceutical formulation thereof, can be administered to a subject followed by one or more of the same dose (45 mg/kg) or lower doses, for example, about 1 mg/kg, about 3 mg/kg, about 5 mg/kg, about 10 mg/kg or about 15 mg/kg. For example, a subject may be administered two doses of 45 mg/kg and then additional doses of 10 mg/kg. Additionally, the oppose regimen of low dose followed by high dose may be used. Of course, for acute disease condition the higher doses are preferably used first. In certain embodiments, the subject can be treated once weekly for several weeks with the Apo A-I Milano:phospholipid complex or pharmaceutical formulation thereof and then treated on an intermittent bases, for example, twice yearly, yearly or every two years, as needed to maintain patent and non-occluded vessels, and to reduce the risk of plaque rupture and adverse vascular events.

In certain embodiments, the methods for the treatment or prevention of acute coronary syndromes comprise administering Apo A-I Milano: phospholipid complexes or pharmaceutical formulations thereof about every day, about every other day, about every 3 days, about every 4 days, about every 5 days, about every 6 days, about every 7 days, about every 8 to 10 days or about every 11 to 14 days to a subject in need thereof. In a preferred embodiment, the Apo A-I Milano: phospholipid complexes or pharmaceutical formulations thereof can be administered about every 7 days. In certain embodiments, administration of the Apo A-I Milano: phospholipid complexes or pharmaceutical formulations thereof can be a one time administration. In certain embodiments, administration can continue for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7-12 weeks, about 13-24 weeks or about 25-52 weeks. In certain preferred embodiments, administration of the Apo A-I Milano: phospholipid complexes or pharmaceutical formulations thereof is about every 7 days for about 5 weeks. In certain embodiments, administration can be intermittent after, for example, about 5 weeks. For example, a subject can be treated once a week for about 5 weeks and then treated about 3 to about 4 times over the following year. In certain embodiments, the pharmaceutical formulations described herein can be administered to the subject intermittently to maintain the patency of a vessel. For example, a dose of about 15 mg/kg can be administered to the pharmaceutical formulation administration about every 10 days for about 7 weeks and then treated, for example, about 26 weeks later or about 52 weeks later. Other embodiments, including dosing schedules and use of the methods in combination with conventional drug therapy and surgical interventions are described hereinbelow.

The invention provides pharmaceutical formulations for administration of Apolipoprotein A-I Milano (Apo A-I Milano) for the treatment or prevention of acute coronary syndromes and ischemic reperfusion injury. In a preferred embodiment the Apo A-I Milano is complexed with a lipid for the methods described herein. For example, the lipid can be a phospholipid, preferably 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (also termed, 1-palmitoyl-2-oleoyl-phosphatidylcholine or POPC). In a most preferred embodiment, the Apo A-I Milano: POPC complex can be a pharmaceutical formulation. In another preferred embodiment, the Apo A-I Milano: phospholipid complex or a pharmaceutical formulation thereof can be administered in a dose of about 1 mg of protein/kg to about 100 mg of protein/kg to a subject in need thereof.

In certain embodiments, the methods can comprise administering doses of the Apo A-I Milano:phospholipid complexes or injectable or liquid pharmaceutical formulations thereof for the treatment of acute coronary syndromes. In a preferred embodiment, the ApoA I M:phospholipid complexes or pharmaceutical formulations thereof can be administered in a dose of about 1 mg (protein)/kg to about 100 mg (protein)/kg to a subject in need thereof. In certain embodiments, the method can comprise treatment or prevention of acute coronary syndromes by the administration of Apo A-I Milano:phospholipid complexes or pharmaceutical formulations thereof as an intravenous infusion. In certain embodiments, the methods can comprise administration as a intravenous push infusion. By intravenous push infusion, it is meant that the Apo A-I Milano: phospholipid or pharmaceutical formulations thereof are administered intravenously over a short time period such as up to 5 minutes, for example, 2-5 minutes. In certain embodiments, administration of the Apo A-I Milano: phospholipid complexes or pharmaceutical formulations thereof can comprise a continuous intravenous infusion. By continuous intravenous infusion it is meant that Apo A-I Milano: phospholipid complexes or pharmaceutical formulations thereof are administered continuously over a period of time longer than 2-5 minutes, for example, about 30 minutes to about 3 hours. Continuous intravenous infusions can be administered with the aid of an infusion pump or device. In certain embodiments, administration of the Apo A-I Milano: phospholipid or pharmaceutical formulations thereof can be a combination of continuous intravenous infusions and intravenous push infusions (“bolus doses”) of the Apo A-I Milano: phospholipid complexes or pharmaceutical formulations thereof. The bolus doses can be administered before, after or during the continuous infusion. In certain embodiments the administration of the Apo A-I Milano or lipid complexes or pharmaceutical formulations thereof can be in combination with other drugs that treat or prevent cardiovascular disease, concomitant or comorbid diseases or provide symptomatic relief. The administration of other drugs can be concurrent or sequential.

The methods provide for intravenous infusion of the pharmaceutical formulations described herein. Any suitable vessel can be used for infusion, including peripheral vessels such as the vessels in the antecubital fossa of the arm or a central line into the chest. In preferred embodiments, the pharmaceutical formulation is infused into the cephalic or median cubital vessel at the antecubital fossa in the arm of a subject.

In certain embodiments, the methods can comprise administration of a pharmaceutical formulation of the Apo A-I Milano: phospholipid complex at high or low doses or a combination thereof. As described hereinbelow, a high dose of the pharmaceutical formulation over a short dosing interval can safely and effectively reduce atheroma volume in subjects with partially or fully occluded vessels. In certain embodiments, the pharmaceutical formulation can be administered before, during or after a surgical intervention such as PTCA to unblock an occluded vessel. In certain embodiments, one or more intermittent doses can be administered to the subject to maintain the patency of a previously occluded vessel (“maintenance dose”).

This invention provides a novel approach to the treatment or prevention of ischemic reperfusion injury, that is, the use of the pharmaceutical formulations or doses of Apo A-I Milano complex described herein for the treatment of ischemic reperfusion. Doses useful for this treatment include doses up to 100 mg/kg of the Apo A-I Milano: phospholipid complex administered to a subject in need thereof. In certain embodiments, the methods can comprise administration of a pharmaceutical composition of the Apo A-I Milano: phospholipid complex at a dose of about 1 mg/kg to about 100 mg/kg of a subject's body weight. In particular embodiments, the methods can comprise administration of a pharmaceutical composition of the Apo A-I Milano: phospholipid complex at a dose of about 10 mg/kg to about 50 mg/kg. In a preferred embodiment, the methods can comprise administration of a pharmaceutical composition of the Apo A-I Milano: phospholipid complex at a specific dose of about 15 mg/kg. In another preferred embodiment, the methods can comprise administration of a pharmaceutical composition of the Apo A-I Milano: phospholipid complex at a specific dose of about 45 mg/kg. The invention also preferably includes the use of 15 mg/kg alone or in combination with the 45 mg/kg dose. Similarly, the 45 mg/kg dose can be used alone or in combination with the 15 mg/kg dose for the treatment or prevention of ischemic reperfusion injury.

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