Patent Application
20080085911
The present invention is preferably directed to the utilization of HMG-CoA inhibitors and omega-3 fatty acids for reduction of Apo-B levels beyond that which is obtained with treatment of the HMG-CoA inhibitor alone. The methods of the present invention are especially useful for the treatment of one or more of the following: hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, vascular disease, atherosclerotic disease and related conditions, and/or for the prevention or reduction of cardiovascular and/or vascular events.
In preferred embodiments of the invention, a subject has baseline Apo-B levels of greater than 0.9 g/l, and the use of the invention reduces the Apo-B levels to less than 0.9 g/l.
In some embodiments, a subject has non-HDL-C levels of at least 130 mg/dl, more preferably at least 160 mg/dl, and the use of the invention reduces the Apo-B levels, preferably by at least 2% as compared to baseline and/or further than treatment with the HMG-CoA inhibitor alone.
In some embodiments, a subject has elevated LDL-C levels (e.g., at least 100 mg/dl, at least 100 mg/dl and less than 130 mg/dl, at least 130 mg/dl, or at least 160 mg/dl) and/or elevated triglyceride levels (e.g., at least 150 mg/dl, at least 200 mg/dl, 200-499 mg/dl, or at least 500 mg/dl) and, if both, can be qualified as a subject with mixed dyslipidemia.
In some embodiments, the invention provides a novel combination. In a preferred embodiment, the combination comprises omega-3 fatty acids and an HMG-CoA inhibitor, wherein the omega-3 fatty acids are administered simultaneous to administration of the HMG-CoA inhibitor, e.g., as a single fixed dosage pharmaceutical composition or as separate compositions administered at the same time.
In other preferred embodiments, the administration comprises omega-3 fatty acids and an HMG-CoA inhibitor, wherein the omega-3 fatty acids are administered apart from the administration of the HMG-CoA inhibitor, but in a concomitant treatment regime. For example, the HMG-CoA inhibitor may be administered once daily while the omega-3 fatty acids are administered twice daily. One skilled in the art with the benefit of the present disclosure will understand that the precise dosage and schedule for the administration of the omega-3 fatty acids and the HMG-CoA inhibitor will vary depending on numerous factors, such as, for example, the route of administration, the seriousness of the condition, other comorbidities, and the use of other medications.
In some embodiments, the claimed method of administration is a first-line therapy, meaning that it is the first type of therapy given for the condition or disease. In other embodiments, the claimed method of administration is a second-line therapy, meaning that the treatment is given when initial treatment (first-line therapy, e.g., HMG-CoA inhibitor or omega-3 fatty acid treatment alone) does not work adequately with respect to treatment goals, or ceases to be adequate, e.g. due to physiological changes in the patient or changes in CHD risk factors.
In some embodiments, the invention is suitable for primary prevention. In other embodiments, the invention is suitable for secondary prevention.
In preferred embodiments, the selected subject group was receiving HMG-CoA inhibitor therapy prior to the combination therapy of the HMG-CoA inhibitor and the omega-3 fatty acids. Other active agents (other than omega-3 fatty acids) may also have been employed prior to the combination therapy of the HMG-CoA inhibitor and the omega-3 fatty acids.
In preferred embodiments, the present invention includes a method of lipid therapy in a subject group comprising administering to the subject group an effective amount of an HMG-CoA inhibitor and omega-3 fatty acids, wherein after administration to the subject group the triglyceride level and an Apo-B level of the subject group are reduced as compared to a control group treated with the HMG-CoA inhibitor alone, and preferably an HDL-C level of the subject group is increased as compared to a control group treated with the HMG-CoA inhibitor alone and/or as compared to baseline. Preferably, the subject group has a baseline triglyceride level of 200 to 499 mg/dl.
In other preferred embodiments, the present invention includes a method of lipid therapy in a subject group comprising administering to the subject group an effective amount of an HMG-CoA inhibitor and omega-3 fatty acids, wherein after administration to the subject group the triglyceride level and an Apo-B level of the subject group are reduced as compared to a control group treated with the HMG-CoA inhibitor alone, preferably without increasing LDL-C more than 1% as compared to baseline. Preferably, the subject group has a baseline triglyceride level of 200 to 499 mg/dl.
In other preferred embodiments, the present invention includes a method of lipid therapy in a subject group, comprising administering to the subject group an effective amount of an HMG-CoA inhibitor and omega-3 fatty acids, wherein after administration to the subject group at least one of the following: (a) a non-HDL-C level, (b) a total cholesterol level, (c) a triglyceride level, and (d) an Apo-B level of the subject group is reduced as compared to a control group treated with the HMG-CoA inhibitor alone, and preferably an HDL-C level of the subject group is increased as compared to a control group treated with the HMG-CoA inhibitor alone, preferably without increasing LDL-C more than 1% as compared to baseline.
In other preferred embodiments, the present invention includes a method of lipid therapy in a subject group comprising administering to the subject group an effective amount of an HMG-CoA inhibitor and omega-3 fatty acids, wherein after administration to the subject group a non-HDL-C level of the subject group is reduced as compared to a control group treated with the HMG-CoA inhibitor alone. Preferably, the subject group has a baseline triglyceride level of 200 to 499 mg/dl.
In other preferred embodiments, the invention includes a method of reducing a triglyceride level and an Apo-B level in a subject group without increasing an LDL-C level in the subject group, comprising providing a subject group, and reducing the triglyceride level and the Apo-B level of the subject group by administering to the subject group a combination of an HMG-CoA inhibitor and omega-3 fatty acids in an amount effective to reduce the triglyceride level and the Apo-B level of the subject group as compared to treatment with an HMG-CoA inhibitor alone without increasing the LDL-C level.
The phrase “compared to treatment with HMG-CoA inhibitor alone” can refer to treatment of the same subject or subject group, or treatment of a comparable subject or subject group (i.e., subject(s) within the same class with respect to a particular blood protein, lipid, or marker, such as a cholesterol or triglyceride level) in a different treatment group. The terms “reduce” and “increase” in accordance with the embodimented methods are intended to mean a statistically significant reduction or increase in accordance with its general and customary meaning, i.e., a probability of chance of 5% or less (p=0.05 or less), more preferably 2.5% or less (p=0.025 or less). In embodiments of the invention, the HMG-CoA inhibitor alone statistically significantly reduces or increases certain levels (such as reducing Apo-B levels), and the combination therapy of the HMG-CoA inhibitor and the omega-3 fatty acids further statistically significantly reduces or increases the levels.
In addition to reducing Apo-B levels, the methods and compositions of the invention may also be used to reduce one or more of the following blood protein, lipid, or marker levels in a treated subject or subject group, as compared to treatment with the HMG-CoA inhibitor alone: non-HDL-C levels, triglyceride levels, VLDL-C levels, total C levels, RLP-C levels, Lp-PLA2 levels and/or Apo-C3 levels. The methods and compositions of the invention may also be used to increase HDL-C levels, as compared to treatment with the HMG-CoA inhibitor alone. Preferably, the methods and compositions of the invention are utilized without increasing LDL-C levels, as compared to baseline.
Preferably, non-HDL-C levels may be reduced at least about 5%, preferably at least about 7%, from baseline and/or at least about 5%, preferably at least about 7%, further than treatment with the HMG-CoA inhibitor alone.
Preferably, the triglyceride levels may be reduced by at least about 20%, preferably at least about 25%, as compared to baseline and/or at least about 10%, preferably at least about 15%, more preferably at least about 20%, further than treatment with the HMG-CoA inhibitor alone.
Preferably, the VLDL-C levels may be reduced by at least about 15%, preferably at least about 20%, more preferably at least about 25%, as compared to baseline and/or at least about 10%, preferably at least about 15%, more preferably at least about 20%, further than treatment with the HMG-CoA inhibitor alone.
Preferably, the total C levels may be reduced by at least about 3%, preferably at least about 5%, as compared to baseline and/or at least about 2%, preferably at least about 3%, further than treatment with the HMG-CoA inhibitor alone.
Preferably, the RLP-C levels may be reduced by at least about 15%, preferably at least about 20%, as compared to baseline and/or at least about 10%, preferably at least about 15%, further than treatment with the HMG-CoA inhibitor alone.
Preferably, the Lp-PLA2 levels may be reduced by at least about 5%, preferably at least about 7%, more preferably at least about 10%, as compared to baseline and/or at least about 3%, preferably at least about 5%, more preferably at least about 7%, further than treatment with the HMG-CoA inhibitor alone.
Preferably, the Apo-B levels may be reduced by at least about 3%, preferably at least about 4%, as compared to baseline and/or at least about 1%, preferably at least about 2%, further than treatment with the HMG-CoA inhibitor alone.
Preferably, the Apo-C3 levels may be reduced by at least about 5%, preferably at least about 7%, as compared to baseline and/or at least about 8%, preferably at least about 10%, further than treatment with the HMG-CoA inhibitor alone.
Preferably, the HDL-C levels may be increased by at least about 2%, preferably at least about 3%, as compared to baseline and/or to treatment with the HMG-CoA inhibitor alone.
Preferably, the present invention also decreases the ratio of total cholesterol to HDL-C, preferably by at least about 5%, more preferably at least about 10%, as compared to baseline and/or at least about 5%, preferably at least about 10%, further than treatment with the HMG-CoA inhibitor alone.
Generally, the effect of the HMG-CoA inhibitor is dose dependent, i.e., the higher the dose, the greater the therapeutic affect. However, the effect of each HMG-CoA inhibitor is different, and therefore the level of therapeutic effect of one HMG-CoA inhibitor cannot be necessarily be directly correlated to the level of therapeutic effects of other HMG-CoA inhibitors. However, those of ordinary skill in the art would understand the correct dosage to be given to a particular subject, based on experience and the seriousness of the condition.
As used herein, the term “omega-3 fatty acids” includes natural or synthetic omega-3 fatty acids, or pharmaceutically acceptable esters, derivatives, conjugates (see, e.g., Zaloga et al., U.S. Patent Application Publication No. 2004/0254357, and Horrobin et al., U.S. Pat. No. 6,245,811, each hereby incorporated by reference), precursors or salts thereof and mixtures thereof. Examples of omega-3 fatty acid oils include but are not limited to omega-3 polyunsaturated, long-chain fatty acids such as a eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and α-linolenic acid; esters of omega-3 fatty acids with glycerol such as mono-, di- and triglycerides; and esters of the omega-3 fatty acids and a primary, secondary or tertiary alcohol such as fatty acid methyl esters and fatty acid ethyl esters. Preferred omega-3 fatty acid oils are long-chain fatty acids such as EPA or DHA, triglycerides thereof, ethyl esters thereof and mixtures thereof. The omega-3 fatty acids or their esters, derivatives, conjugates, precursors, salts and mixtures thereof can be used either in their pure form or as a component of an oil such as fish oil, preferably purified fish oil concentrates. Commercial examples of omega-3 fatty acids suitable for use in the invention include Incromega F2250, F2628, E2251, F2573, TG2162, TG2779, TG2928, TG3525 and E5015 (Croda International PLC, Yorkshire, England), and EPAX6000FA, EPAX5000TG, EPAX4510TG, EPAX2050TG, K85TG, K85EE, K80EE and EPAX7010EE (Pronova Biocare a.s., 1327 Lysaker, Norway).
Preferred compositions include omega-3 fatty acids as recited in U.S. Pat. Nos. 5,502,077, 5,656,667 and 5,698,694, which are hereby incorporated herein by reference in their entireties.
Another preferred composition includes omega-3 fatty acids present in a concentration of at least 40% by weight, preferably at least 50% by weight, more preferably at least 60% by weight, still more preferably at least 70% by weight, most preferably at least 80% by weight, or even at least 90% by weight. Preferably, the omega-3 fatty acids comprise at least 50% by weight of EPA and DHA, more preferably at least 60% by weight, still more preferably at least 70% by weight, most preferably at least 80%, such as about 84% by weight. Preferably the omega-3 fatty acids comprise about 5 to about 100% by weight, more preferably about 25 to about 75% by weight, still more preferably about 40 to about 55% by weight, and most preferably about 46% by weight of EPA. Preferably the omega-3 fatty acids comprise about 5 to about 100% by weight, more preferably about 25 to about 75% by weight, still more preferably about 30 to about 60% by weight, and most preferably about 38% by weight of DHA. All percentages above are by weight as compared to the total fatty acid content in the composition, unless otherwise indicated. The percentage by weight may be based on the free acid or ester forms, although it is preferably based on the ethyl ester form of the omega-3 fatty acids even if other forms are utilized in accordance with the present invention.
The EPA:DHA ratio may be from 99:1 to 1:99, preferably 4:1 to 1:4, more preferably 3:1 to 1:3, most preferably 2:1 to 1:2. The omega-3 fatty acids may comprise pure EPA or pure DHA.
The omega-3 fatty acid composition optionally includes chemical antioxidants, such as alpha tocopherol, oils, such as soybean oil and partially hydrogenated vegetable oil, and lubricants such as fractionated coconut oil, lecithin and a mixture of the same.
The most preferred form of omega-3 fatty acids is the Lovaza™ omega-3 acid (K85EE, Pronova Biocare a.s., Lysaker, Norway) and preferably comprises the following characteristics (per dosage form):
The combination product of an HMG-CoA inhibitor and concentrated omega-3 fatty acids may be administered in a capsule, a tablet, a powder that can be dispersed in a beverage, or another solid oral dosage form, a liquid, a soft gel capsule, a coated soft gel capsule (see U.S. application Ser. No. 11/716,020, hereby incorporated by reference) or other convenient dosage form such as oral liquid in a capsule, as known in the art. In some embodiments, the capsule comprises a hard gelatin. The combination product may also be contained in a liquid suitable for injection or infusion.
The active ingredients of the present invention may also be administered with a combination of one or more non-active pharmaceutical ingredients (also known generally herein as “excipients”). Non-active ingredients, for example, serve to solubilize, suspend, thicken, dilute, emulsify, stabilize, preserve, protect, color, flavor, and fashion the active ingredients into an applicable and efficacious preparation that is safe, convenient, and otherwise acceptable for use.
Excipients include surfactants, such as propylene glycol monocaprylate, mixtures of glycerol and polyethylene glycol esters of long fatty acids, polyethoxylated castor oils, glycerol esters, oleoyl macrogol glycerides, propylene glycol monolaurate, propylene glycol dicaprylate/dicaprate, polyethylene-polypropylene glycol copolymer, and polyoxyethylene sorbitan monooleate, cosolvents such ethanol, glycerol, polyethylene glycol, and propylene glycol, and oils such as coconut, olive or safflower oils. The use of surfactants, cosolvents, oils or combinations thereof is generally known in the pharmaceutical arts, and as would be understood to one skilled in the art, any suitable surfactant may be used in conjunction with the present invention and embodiments thereof.
The omega-3 fatty acids can be administered in a daily amount of from about 0.1 g to about 10 g, more preferably about 1 g to about 8 g, and most preferably from about 2 g to about 6 g. In one embodiment, the omega-3 fatty acids are administered in an amount up to 4 g/day.
The HMG-CoA inhibitor may be administered in an amount more than, equal to or less than the conventional full-strength dose as a single-administered product. For example, the HMG-CoA inhibitor may be administered in an amount of from 10-100%, preferably about 25-100%, most preferably about 50-80%, of the conventional full-strength dose as a single-administered product. In one embodiment of the present invention, the HMG-CoA inhibitor can generally be present in an amount from about 0.5 mg to 80 mg, more preferably from about 1 mg to about 40 mg, and most preferably from about 2.5 mg to about 20 mg, per gram of omega-3 fatty acids. The daily dose may range from about 2 mg to about 320 mg, preferably about 4 mg to about 160 mg.
In some variations of the present invention, the combination of HMG-CoA inhibitor and the omega-3 fatty acids is formulated into a single administration or unit dosage.
Pravastatin, which is known in the market as Pravachol® manufactured by Bristol-Myers Squibb, Princeton, N.J., is hydrophilic. Pravastatin is best absorbed without food, i.e., an empty stomach. The dosage of pravastatin, in the combined administration of concentrated omega-3 fatty acids is preferably from 2.5 to 80 mg, preferably 5 to 60, and more preferably from 10 to 40 mg per dosage of concentrated omega-3 fatty acids. In one variation, the combination product using pravastatin is taken at or around bedtime, e.g., 10 pm.
Lovastatin, which is marketed under the name Mevacor® by Merck, Whitehouse Station, N.J., is hydrophobic. Unlike pravastatin, lovastatin should be taken with meals and accordingly, in some embodiments, the combination product of concentrated omega-3 fatty acids and lovastatin should be taken with food. The dosage of lovastatin, in the combined administration of concentrated omega-3 fatty acids is preferably from 2.5 to 100 mg, preferably 5 to 80 mg, and more preferably from 10 to 40 mg per dosage of concentrated omega-3 fatty acids.
Simvastatin, which is marketed under the name Zocor® by Merck, Whitehouse Station, N.J., is hydrophobic. The dosage of simvastatin, in the combined administration of concentrated omega-3 fatty acids is preferably from 1 to 80 mg per day, preferably 2 to 60 mg, and more preferably from 5 to 40 mg per dosage of concentrated omega-3 fatty acids.
Atorvastatin, which is marketed under the name Lipitor® by Pfizer, New York, N.Y., is hydrophobic and is known as a synthetic statin. The dosage of atorvastatin, in the combined administration of concentrated omega-3 fatty acids is preferably from 2.5 to 100 mg, preferably 5 to 80 mg, and more preferably from 10 to 40 mg per dosage of concentrated omega-3 fatty acids.
Fluvastatin, which is marketed under the name Lescole by Novartis, New York, N.Y., is hydrophilic and is known as a synthetic statin. The dosage of fluvastatin, in the combined administration of concentrated omega-3 fatty acids is from 5 to 160 mg, preferably 10 to 120 mg, and more preferably from 20 to 80 mg per dosage of concentrated omega-3 fatty acids.
Rosuvastatin is marketed under the name Crestor® by Astra Zeneca, Wilmington, Del. The dosage of rosuvastatin, in the combined administration of concentrated omega-3 fatty acids is from 1 to 80 mg, preferably 2 to 60 mg, and more preferably from 5 to 40 mg per dosage of concentrated omega-3 fatty acids.
Pitavastatin is currently marketed in Japan. The dosage of pitavastatin, in the combined administration of omega-3 fatty acids is from 0.25 to 20 mg, preferably 0.5 to 10 mg, and more preferably from 1 to 7.5 mg per dosage of omega-3 fatty acids.
The daily dosages of HMG-CoA inhibitor and concentrated omega-3 fatty acids can be administered together in from 1 to 10 dosages, with the preferred number of dosages from 1 to 4 times a day, most preferred 1 to 2 times a day. The administration is preferably oral administration, although other forms of administration that provides a unit dosage of HMG-CoA inhibitor and concentrated omega-3 fatty acids may be used.
In some embodiments, the formulations of the present invention allow for improved effectiveness of each active ingredient, with one or both administered as a conventional full-strength dose, as compared to the formulations in the prior art. In other embodiments, the formulations of the present invention may allow for reduced dosages of HMG-CoA inhibitor and/or omega-3 fatty acids, as compared to the formulations in the prior art, while still maintaining or even improving upon the effectiveness of each active ingredient.
The present combination of an HMG-CoA inhibitor and omega-3 fatty acids may allow for a greater effect than any expected combined or additive effect of the two drugs alone. Moreover, the combined or additive effect of the two drugs may depend on the initial level of triglycerides in the blood of a subject. For example, the triglyceride level of a subject is generally as normal if less than 150 mg/dL, borderline to high if within about 150-199 mg/dL, high if within about 200-499 mg/dL and very high if 500 mg/dL or higher. The present invention may be used to reduce the triglyceride level of a “very high” down to a “high” or “borderline to high” in less than 48 weeks, preferably within 24 weeks, more preferably within 12 weeks, and most preferably within 8 weeks. The present invention may also be used to reduce the triglyceride level of a “high” down to a “borderline to high” or “normal” in less than 48 weeks, preferably within 24 weeks, more preferably within 12 weeks, and most preferably within 8 weeks.
Clinical study: A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Combined Lovaza™ and Simvastatin Therapy in Hypertriglyceridemic Subjects
A randomized, double-blind, placebo-controlled clinical study was conducted to assess the efficacy and safety of combined treatment with Lovaza™ omega-3 fatty acids and simvastatin (Zocor®) in hypertriglyceridemic subjects. Patients were initially treated with 40 mg/day simvastatin for at least 8 weeks, whereupon baseline measurements were taken. Patients were eligible for enrollment and randomization if their baseline triglyceride levels were above normal (≧150 mg/dl) and their LDL-C at most 10% above the NCEP ATP III goal. A total of 259 patients were randomized and received at least one dose of either Lovaza™ omega-3 fatty acids or placebo, and 229 of these patients had baseline triglyceride levels between 200 and 499 mg/dl. Initial treatment was thereafter followed by an additional 8 week treatment with either 4 g/day Lovaza™ omega-3 fatty acids or placebo, while continuing statin therapy, in a double-blind fashion. 243 patients completed the study.
The following Table 1 shows the results obtained for changes in various lipid and inflammatory parameters and markers.
The following Tables 2 and 3 show the LDL-C goal achievement experienced in the study by those on Lovaza™ treatment and placebo, respectively.
A more detailed analysis of Apo-B reduction as function of baseline LDL-C and Non-HDL-C levels demonstrates the significant and increasing ability of Lovaza™ treatment to decrease Apo-B levels at increasing LDL-C and Non-HDL-C baseline levels, whereas placebo treatment results in random and insignificant changes in Apo-B levels.
Tables 4A, 4B and 5 show the Apo-B reduction and other lipid parameter changes with Lovaza™ or placebo treatment for specific LDL-C and Non-HDL-C patient subgroups. At higher LDL-C (≧100 mg/dL) and Non-HDL-C (≧130 mg/dL baseline levels, Lovaza™ reduces Apo-B while at lower baseline levels, Apo-B changes by Lovaza™ versus placebo are insignificant. Table 4B shows that the Apo-B reducing effect is even more profound at higher LDL-C baseline levels, and seems to be accompanied by a reduction in LDL-C levels.
†Variables typically not normally distributed, therefore statistical analyses were based on median values unless otherwise indicated
†Variables typically not normally distributed, therefore statistical analyses were based on median values unless otherwise indicated
Table 6 shows the Apo-B reduction and other lipid parameter changes with Lovaza™ or placebo treatment for above 200 mg/dL triglyceride baseline levels versus below this level. At higher triglyceride baseline levels (≧200 mg/dL), Lovaza™ reduces Apo-B while at lower baseline triglyceride levels, Apo-B changes by Lovaza™ versus placebo are insignificant.
†Variables typically not normally distributed, therefore statistical analyses were based on median values unless otherwise indicated
Tables 7 and 8 show the Apo-B reduction and other lipid parameter changes with Lovaza™ or placebo treatment for specific LDL-C/Triglyceride and Non-HDL-C/Triglyceride patient subgroups. At combined higher LDL-C (≧100 mg/dL) and triglyceride (≧200 mg/dL) baseline levels and at combined Non-HDL-C (≧130 mg/dL and triglyceride (≧200 mg/dL) baseline levels, Lovaza™ reduces Apo-B while at lower baseline levels, Apo-B changes by Lovaza™ versus placebo are insignificant.
†Variables typically not normally distributed, therefore statistical analyses were based on median values unless otherwise indicated
†Variables typically not normally distributed, therefore statistical analyses were based on median values unless otherwise indicated
All references cited herein are hereby incorporated by reference in their entirety.
The present application is a continuation-in-part of U.S. application Ser. No. 11/742,292, filed Apr. 30, 2007, and claims priority to provisional patent application Ser. No. 60/850,280, filed Oct. 10, 2006, the disclosures of which are hereby incorporated by reference.
| Number | Date | Country | |
|---|---|---|---|
| 60850280 | Oct 2006 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11742292 | Apr 2007 | US |
| Child | 11851867 | US |
