US20150004224A1 - Dpa-enriched compositions of omega-3 polyunsaturated fatty acids in free acid form - Google Patents

Dpa-enriched compositions of omega-3 polyunsaturated fatty acids in free acid form Download PDF

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US20150004224A1
US20150004224A1 US14/370,730 US201314370730A US2015004224A1 US 20150004224 A1 US20150004224 A1 US 20150004224A1 US 201314370730 A US201314370730 A US 201314370730A US 2015004224 A1 US2015004224 A1 US 2015004224A1
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amount
pharmaceutical composition
epa
acid
dpa
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Timothy J. MAINES
Bernardus Machielse
Bharat M. Mehta
Gerald Wisler
Michael Davidson
Peter Ralph WOOD
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Chrysalis Pharma AG
Omthera Pharmaceuticals Inc
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Chrysalis Pharma AG
Omthera Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • compositions rich in omega-3 (“ ⁇ -3” or “n-3”) polyunsaturated fatty acids (“PUFAs”) are being developed to treat a variety of clinical indications.
  • These products which are derived from natural sources, typically fish oils, are heterogeneous compositions, and comprise various species of omega-3 PUFAs, omega-6 PUFAs, and other minor components, including mono-unsaturated and saturated fatty acids.
  • the observed clinical effects are typically attributed to the composition as a whole, although the most prevalent of the PUFA species present in the mixture, usually EPA and DHA, are believed to contribute a substantial portion of the observed clinical effect.
  • the products are defined to include certain obligate polyunsaturated fatty acid species, each within a defined percentage tolerance range.
  • the compositions are further defined to limit certain undesired components, both those originating in the natural source, such as certain environmental contaminants, and those potentially created in the refining process.
  • the optimal composition likely differs as among intended clinical indications. Even for the first approved clinical indication, however, treatment of severe hypertriglyceridemia (TGs>500 mg/dl), the optimal composition has not yet been defined.
  • the first-approved pharmaceutical composition for treatment of severe hypertriglyceridemia comprises the omega-3 PUFA species eicosapentaenoic acid (“EPA”) and docosahexaenoic acid (“DHA”) in the form of ethyl esters in weight percentages of approximately 46:38 (EPA:DHA), with EPA and DHA together accounting for approximately 84% of all PUFA species in the composition.
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • Vascepa® previously known as AMR101
  • AMR101 is >96% pure EPA in the ethyl ester form, with substantially no DHA.
  • the nutraceutical product, OMAX3, sold as a dietary supplement and promoted in part to lower triglyceride levels comprises EPA and DHA in a weight ratio of about 4.1:1, wherein the EPA and DHA are likewise in the ethyl ester form, the formulation being more than 84% EPA and DHA by weight and more than 90% omega-3 fatty acids by weight.
  • DHA omega-3 PUFA species
  • EPA omega-3 PUFA species
  • LDL levels Mori et al., Am. J. Clin. Nutr. 71:1085-94 (2000), Grimsgaard et al., Am. J. Clin. Nutr. 66:649-59 (1997); elevation of LDL has been thought to be clinically disfavored in subjects with elevated cardiovascular risk.
  • omega-6 PUFA species arachidonic acid
  • AA arachidonic acid
  • the difficulty in defining an optimal composition is also due in part to enzymatic interconversion among certain omega-3 PUFA species, and to competition between omega-3 and omega-6 polyunsaturated fatty acids for shared enzymes in their respective biosynthetic pathways from medium chain dietary PUFAs (see FIG. 1 ).
  • a further challenge in designing an optimal composition is variation in bioavailability of orally administered PUFA compositions.
  • Absorption of PUFAs in the form of ethyl esters is known, for example, to depend on the presence of pancreatic lipase, which is released in response to ingested fats. Absorption of PUFA ethyl esters is therefore inefficient, and is subject to substantial variation, both among subjects and in any individual subject, depending on dietary intake of fat. See Lawson et al., “Human absorption of fish oil fatty acids as triacylglycerols, free acids, or ethyl esters,” Biochem Biophys Res Commun.
  • the refining process is designed to produce a final product having the obligate fatty acid components within pre-defined percentage tolerance ranges and to limit certain undesired components to levels below certain pre-defined tolerance limits, with sufficient yield to make the process commercially feasible and environmentally sustainable. Differences in the desired final composition dictate differences in the refining process.
  • urea inclusion complexation in the presence of ethanol is often used to remove saturated and mono-unsaturated long chain fatty acids, increasing the relative proportion of desired long chain omega-3 polyunsaturated fatty acids in the resulting composition. Too little urea reduces long chain omega-3 PUFA enrichment. Excess urea, however, can lead to concentration of unwanted components, and has the potential to lead, at any given temperature and reaction time, to increased production of ethyl carbamate, a carcinogen that is impermissible above certain defined low limits.
  • Existing alternatives to urea complexation present other difficulties.
  • the present disclosure provides DPA-enriched pharmaceutical compositions of omega-3 polyunsaturated fatty acids in free acid form. Enrichment in DPA content was an unintended and unexpected consequence of the commercial-scale production process. These DPA-enriched pharmaceutical compositions have been demonstrated to have exceptional pharmacological and clinical efficacy in in vitro experiments and in human clinical trials.
  • methods of treatment are provided.
  • methods of treating severe hypertriglyceridemia TGs>500 mg/dL
  • methods of treating hypertriglyceridemia 200 mg/dL-500 mg/dL
  • Further treatment methods include, inter alia, treatments to increase plasma EPA:AA ratios, treatments to decrease ApoCIII levels, and treatments to reduce or prevent resistance to platelet aggregation inhibitors.
  • compositions at commercial scale including methods that include a urea complexation step in which compositionally-constrained batches of transesterified intermediate feedstock are subjected to a urea complexation step using urea amounts within ranges determined by a new process algorithm.
  • FIG. 1 shows the known human pathways for biosynthesis of omega-3 and omega-6 long-chain polyunsaturated fatty acids from intermediate (medium) chain length essential fatty acids.
  • FIG. 2 is flow chart of an exemplary process for preparing an intermediate feedstock of PUFA ethyl esters.
  • FIG. 3A plots the average relative purification of classes of fatty acids by a urea complexation step in which algorithmically-determined amounts of urea are added to compositionally-defined intermediate feedstock of PUFA ethyl esters.
  • FIG. 3B illustrates the average differential purification of individual species of omega-3 and omega-6 PUFA ethyl esters when algorithmically-determined amounts of urea are added to compositionally-defined intermediate feedstock of PUFA ethyl esters.
  • FIG. 4 is a treatment flow diagram illustrating the design of the ECLIPSE clinical study further described in Example 7.
  • FIG. 5 compares the bioavailability of total EPA+DHA (baseline-adjusted change) following a single dose (4 g) of Lovaza® during the high-fat and low-fat diet periods.
  • FIG. 6 compares the bioavailability of total EPA+DHA (baseline-adjusted change) following a single dose (4 g) of Lovaza® (“EE-FA”) or Epanova®, a DPA-enriched composition of omega-3 PUFAs in free acid form (“FFA”), during the high-fat diet period.
  • EE-FA Lovaza®
  • Epanova® Epanova®
  • FFA free acid form
  • FIG. 7 compares the total plasma EPA+DHA concentrations (baseline-adjusted change) following a single dose (4 g) of Lovaza® or Epanova® during the low-fat diet period.
  • FIG. 8 compares the total plasma EPA concentrations (baseline-adjusted change) following a single dose (4 g) of Lovaza® or Epanova® during the low-fat diet period.
  • FIG. 9 compares the total plasma DHA concentrations (baseline-adjusted change) following a single dose of (4 g) of Lovaza® or Epanova® during the low-fat diet period.
  • FIGS. 10A and 10B present individual subject AUC 0-t responses during the low-fat and high-fat diets expressed as the ratio (%) of low-fat AUC 0-t to high-fat AUC 0-t . Negative ratios were not plotted.
  • FIG. 11 is a treatment flow diagram illustrating the design of the 14 day comparative bioavailability trial further described in Example 8 (timeline not to scale).
  • FIG. 12A plots the mean unadjusted total EPA+DHA concentrations versus time (linear scale) for treatment with Lovaza® vs. treatment with Epanova® in the 14 day comparative bioavailability trial further described in Example 8.
  • FIG. 12B is a histogram showing the difference in unadjusted EPA+DHA (nmol/mL) for the points bracketed in FIG. 12A .
  • FIG. 13 plots EPA+DHA mean base-line adjusted plasma total EPA+DHA concentrations versus time (linear scale) for treatment with Lovaza® vs. treatment with Epanova® in the 14 day comparative bioavailability study.
  • FIG. 14A is a histogram that plots the increases from baseline to steady state in unadjusted blood levels for EPA+DHA in the Lovaza® and Epanova® arms of the 14 day comparative bioavailability study.
  • FIG. 14B is a histogram that plots the increases from baseline to steady state in unadjusted C avg for EPA+DHA in the Lovaza® and Epanova® arms of the 14 day comparative bioavailability study.
  • FIG. 15A is a histogram that plots the increases from baseline to steady state for total blood levels of DHA in the Lovaza® and Epanova® arms of the 14 day comparative bioavailability study.
  • FIG. 15B is a histogram that plots the increases from baseline to steady state for DHA C avg levels in the Epanova® cohort compared to Lovaza® cohort in the 14 day comparative bioavailability study.
  • FIG. 16A is a histogram that plots the increases from baseline to steady state for total EPA levels in blood in the Lovaza® and Epanova® arms of the 14 day comparative bioavailability study.
  • FIG. 16B plots the increases from baseline to steady state for EPA C avg levels in the Epanova® and Lovaza® cohorts in the 14 day comparative bioavailability study.
  • FIG. 17 provides a treatment flow diagram illustrating the design of the EVOLVE study, further described in Example 10.
  • FIG. 18 summarizes the EVOLVE trial design in greater detail, further identifying the timing of study visits.
  • FIG. 19 shows the disposition of subjects in the EVOLVE trial.
  • FIGS. 20A-20D display average baseline and end-of-treatment (“EOT”) plasma levels (in ⁇ g/mL) for EPA ( FIG. 20A ), DHA ( FIG. 20B ), DPA ( FIG. 20C ) and AA ( FIG. 20D ), for each of the treatment arms in the EVOLVE trial.
  • EOT end-of-treatment
  • FIG. 20E compares average baseline and EOT EPA levels for the ECLIPSE trial described in Example 7, the 14-day bioavailability study described in Example 8, a statin drug-drug interaction study (“STATIN DDI”) described in Example 11, each treatment arm as well as the control arm of the EVOLVE trial described in Example 10, and values earlier reported in the literature for the unrelated JELIS trial (“JELIS”), which used a different omega-3 composition.
  • STATIN DDI statin drug-drug interaction study
  • JELIS unrelated JELIS trial
  • FIGS. 21A-21D plot median baseline and end-of-treatment (“EOT”) plasma levels (in ⁇ g/mL) for EPA ( FIG. 21A ), DHA ( FIG. 21B ), DPA ( FIG. 21C ), and AA ( FIG. 21D ) in the EVOLVE trial.
  • EOT end-of-treatment
  • FIGS. 22A and 22B plot change from baseline to EOT in absolute plasma levels (in ⁇ g/mL) of AA, DHA, EPA, and DPA, for each of the treatment arms of the EVOLVE trial.
  • FIG. 22A plots average changes;
  • FIG. 22B plots median changes.
  • FIG. 23A plots average change from baseline to EOT, as percentage of baseline value, for AA, DHA, EPA, and DPA in each of the treatment arms of the EVOLVE trial.
  • FIG. 23B plots median percent change from baseline to EOT.
  • FIGS. 24A-24I plot average baseline and EOT plasma levels (in mg/dL, with the exception of LpPLA2, shown in ng/mL) in the EVOLVE trial for triglycerides ( FIG. 24A ), Non-HDL-C ( FIG. 24B ), HDL-C ( FIG. 24C ), V-LDL-C ( FIG. 24D ), LDL-C ( FIG. 24E ), ApoB ( FIG. 24F ), ApoCIII ( FIG. 24G ), RLP ( FIG. 24H ), LpPLA2 ( FIG. 24I ).
  • FIGS. 25A-25I plot median baseline and EOT plasma levels (in mg/dL, with the exception of LpPLA2, shown in ng/mL) in the EVOLVE trial for triglycerides ( FIG. 25A ), Non-HDL-C ( FIG. 25B ), HDL-C ( FIG. 25C ), V-LDL-C ( FIG. 25D ), LDL-C ( FIG. 25E ), ApoB ( FIG. 25F ), ApoCIII ( FIG. 25G ), RLP ( FIG. 25H ), LpPLA2 ( FIG. 25I ).
  • FIGS. 26A and 26B plot change from baseline to EOT in absolute plasma levels (in mg/dL) in the EVOLVE trial of triglycerides (“TG”), Non-HDL-C (“NHDL-C”), HDL-C, VLDL-C, and LDL-C for each of the treatment arms of the EVOLVE trial, with FIG. 26A plotting average change and FIG. 26B showing median change.
  • TG triglycerides
  • NHDL-C Non-HDL-C
  • HDL-C high-HDL-C
  • VLDL-C VLDL-C
  • LDL-C LDL-C
  • FIG. 27 plots the percentage of subjects in the EVOLVE trial, given by the Y-axis, for whom triglyceride levels were reduced by the indicated percentage, given by the X-axis, for 2 g dose and 4 g dose of Epanova®.
  • FIG. 28A plots average change from baseline to EOT, as percentage of baseline value, for TG, non-HDL-c (“NHDL-C”), HDL-C, VLDL-C, LDL-C, ApoB, ApoCIII, LpLPA2, and RLP in each of the treatment arms of the EVOLVE trial, with FIG. 28B plotting median percent change from baseline to EOT.
  • NHDL-C non-HDL-c
  • HDL-C high-HDL-C
  • VLDL-C VLDL-C
  • LDL-C LDL-C
  • ApoB ApoB
  • ApoCIII LpLPA2
  • FIG. 29 plots the rate of change (absolute value) of the median percentage change from baseline in plasma levels of EPA, DHA, DPA, AA, TG, NHDL-C, and HDL-C between 2 g and 4 g doses of Epanova® in the EVOLVE trial.
  • FIG. 30 illustrates comparative data for Epanova®, as measured in the EVOLVE trial, and data reported by others for AMR-101 (Vascepa), at the indicated doses, with respect to TG levels.
  • FIG. 31 illustrates comparative data for Epanova®, as measured in the EVOLVE trial, and AMR-101 (Vascepa), with respect to various blood lipid parameters. Data for AMR-101 were reported by others. (*) indicates a p value of less than 0.05, (**) indicates a p value of less than 0.01, and (***) indicates a p value of less than 0.001.
  • FIG. 32 illustrates comparative data for Epanova® 2 g and 4 g doses, as determined in the EVOLVE trial, and Lovaza® 4 g dose, with respect to various blood lipid parameters. Data for Lovaza® were reported by others. (*) indicates a p value of less than 0.05, (**) indicates a p value of less than 0.01, and (***) indicates a p value of less than 0.001.
  • FIG. 33 illustrates comparative data for Epanova® 2 g and 4 g doses, as assessed in the EVOLVE trial, and Lovaza® 4 g dose, as reported by others, with respect to TG levels.
  • the superscripts indicate data sourced from (1) EVOLVE trial, (2) a meta-analysis from the Lovaza® New Drug Application (“NDA”) (3) Lovaza® FDA-approved product Label and (4) Takeda study.
  • (*) indicates a p value of less than 0.05
  • (**) indicates a p value of less than 0.01
  • (***) indicates a p value of less than 0.001.
  • FIG. 34 plots the correlation between percent change in LDL and percent change in ApoCIII, as measured in the EVOLVE trial.
  • FIG. 35 plots the least squares (LS) mean percentage change from baseline for the subset of EVOLVE trial subjects having TG baseline levels greater than or equal to 750 mg/dL, for the indicated treatment arms of the EVOLVE study, as further described in Example 10.
  • (*) indicates a p value of less than 0.05
  • (**) indicates a p value of less than 0.01
  • (***) indicates a p value of less than 0.001.
  • FIG. 36 plots the least squares (LS) mean percentage change from baseline for the subset of subjects having Type II diabetes, for the indicated treatment arms of the EVOLVE study, as described in Example 10.
  • (*) indicates a p value of less than 0.05
  • (**) indicates a p value of less than 0.01
  • (***) indicates a p value of less than 0.001.
  • FIG. 37 plots the least squares (LS) mean percentage change from baseline for the subset of subjects undergoing concurrent statin therapy, for the indicated treatment arms of the EVOLVE study, as described in Example 10.
  • (*) indicates a p value of less than 0.05
  • (**) indicates a p value of less than 0.01
  • (***) indicates a p value of less than 0.001.
  • FIG. 38 plots the least squares (LS) mean percentage difference relative to control for triglycerides (“TG”), non-HDL-cholesterol (“NHDL-C”), HDL-C, LDL-C, TC, VLDL-C, and TC/HDL-C, comparing subjects from the EVOLVE study described in Example 10 who either received (STATIN) or did not receive (NON-STATIN) statin therapy concurrent with treatment with the 2 g dose of Epanova®.
  • (*) indicates a p value of less than 0.05
  • (**) indicates a p value of less than 0.01
  • (***) indicates a p value of less than 0.001.
  • FIG. 39 plots the median percent change from baseline for TG, NHDL-C, HDL-C, LDL-C, TC, VLDL-C, and TC/HDL-C for the subset of subjects undergoing concurrent statin therapy, in the indicated treatment arms of the EVOLVE study, further described in Example 10.
  • (*) indicates a p value of less than 0.05
  • (**) indicates a p value of less than 0.01
  • (***) indicates a p value of less than 0.001.
  • FIG. 40 provides a treatment flow diagram illustrating the design of the ESPRIT study, further described in Example 12.
  • FIG. 41 shows the disposition of subjects in the ESPRIT trial.
  • FIGS. 42A and 42B plot the median LS percentage change from baseline for EPA ( FIG. 42A ) and DHA ( FIG. 42B ) from the ESPRIT study, further described in Example 12.
  • (*) indicates a p value of less than 0.05
  • (**) indicates a p value of less than 0.01
  • (***) indicates a p value of less than 0.001.
  • FIG. 43 plots mean LS percentage change from baseline for TG, Non-HDL-C, and HDL-C. Data shown are from the ESPRIT study, further described in Example 12. (*) indicates a p value of less than 0.05, (**) indicates a p value of less than 0.01, and (***) indicates a p value of less than 0.001.
  • FIG. 44 plots mean LS percentage change from baseline for ApoB, LDL-C, VLDL-C, and TC/HDL-C. Data shown are from the ESPRIT study, further described in Example 12. (*) indicates a p value of less than 0.05, (**) indicates a p value of less than 0.01, and (***) indicates a p value of less than 0.001.
  • FIG. 45 plots median percentage change from baseline for TG, with subjects grouped into tertiles by baseline TG levels, for subjects in the ESPRIT trial.
  • FIG. 46 plots median percentage change from baseline for Non-HDL-C, with subjects grouped into tertiles by baseline Non-HDL-C levels, for subjects in the ESPRIT trial.
  • FIG. 47 plots median percentage change from baseline for LDL-C, with subjects grouped into tertiles by baseline LDL-C levels, for subjects in the ESPRIT trial.
  • FIG. 48 plots median percentage change from baseline for TG for each of the treatment arms of the ESPRIT trial, with subjects grouped according to the identity of the statin taken in concurrent therapy.
  • FIG. 49 plots median percentage change from baseline for TG for each of the treatment arms of the ESPRIT trial, with subjects grouped into two groups according to low or high potency concurrent statin therapy.
  • FIG. 50 plots median percentage change from baseline for Non-HDL-C for each of the treatment arms of the ESPRIT trial, with subjects grouped according to low or high potency concurrent statin therapy.
  • FIG. 51 plots median percentage change from baseline for LDL-C for each of the treatment arms of the ESPRIT trial, with subjects grouped into two groups according to low or high potency concurrent statin therapy.
  • FIG. 52 plots median percentage change from baseline for TG, with subjects in each treatment arm of the ESPRIAT trial grouped into three groups according to high baseline TG, high baseline EPA, or concurrent rosuvastatin therapy.
  • FIG. 53 plots mean LS percentage change in particle size distribution from baseline for V-LDL particles grouped by size, as determined in the ESPRIT trial.
  • (*) indicates a p value of less than 0.05
  • (**) indicates a p value of less than 0.01
  • (***) indicates a p value of less than 0.001.
  • FIG. 54 plots mean LS percentage change in particle size distribution from baseline for LDL particles grouped by size for each of the treatment arms of the ESPRIT trial.
  • (*) indicates a p value of less than 0.05
  • (**) indicates a p value of less than 0.01
  • (***) indicates a p value of less than 0.001.
  • FIG. 55 plots LS median percentage change in LDL particle size, with subjects grouped into three groups according to ESPRIT EOT triglyceride levels.
  • FIG. 56A depicts baseline arachidonic acid (AA) plasma levels (in ⁇ g/mL) for subjects in the clinical trial further described in Example 11, grouped according to genotype at the rs174546 SNP.
  • FIG. 56B depicts percent change from baseline in AA plasma levels at day 15 of treatment with Epanova®, grouped according to genotype at the rs174546 SNP.
  • the interquartile range is indicated by a box
  • the median is indicated by a horizontal line in the interior of the interquartile box
  • the mean is represented by a diamond.
  • Outliers are represented by open circles. The whiskers extend to the minimum and maximum non-outlier value.
  • Score 1 identifies subjects who are homozygous at the major allele
  • Score 3 identifies subjects homozygous at the minor allele
  • Score 2 represents heterozygotes.
  • Urea inclusion complexation is a standard step often used in the refining of fish oils to remove saturated and mono-unsaturated long chain fatty acids, thus enriching for desired long chain omega-3 polyunsaturated fatty acids in the resulting composition.
  • clathration is a standard step often used in the refining of fish oils to remove saturated and mono-unsaturated long chain fatty acids, thus enriching for desired long chain omega-3 polyunsaturated fatty acids in the resulting composition.
  • Example 2 As described in Example 2, four exemplary production batches of polyunsaturated fatty acids in free acid form were prepared using a urea complexation step. Strict compositional controls were applied to the ethyl ester intermediate feedstock, using only batches in which specified species of polyunsaturated fatty acids fell within defined range limits, and urea amounts were used that fell within the range required by the urea calculator algorithm. All four production batches of the pharmaceutical composition were determined to meet the desired compositional specifications.
  • the urea complexation step substantially decreased the percentage of saturated fatty acids and mono-unsaturated fatty acids in the resulting composition, thereby substantially enriching for polyunsaturated fatty acids. See FIG. 3A .
  • performing urea complexation using urea amounts falling within the algorithmically-determined range had differential effects on enrichment of particular species of omega-3 polyunsaturated fatty acids and omega-6 polyunsaturated fatty acids.
  • DPA docosapentaenoic acid species
  • compositional analysis of 10 batches of API demonstrated reproducibly elevated levels of DPA in the final composition.
  • compositional analysis of 21 batches prepared using urea complexation demonstrated a reproducible 10-fold difference in the concentration of the omega-3 species, DPA, as compared to its omega-6 isomer, docosapentaenoic acid (C22:5 n-6).
  • DPA is the third most prevalent species of polyunsaturated fatty acid in the API, exceeded only by EPA and DHA. At this level, the DPA concentration is also approximately 10-fold greater than that reported for an earlier pharmaceutical composition of omega-3 polyunsaturated fatty acids in free acid form, termed Purepa, in which DPA was reported to be present at a level of 0.5%. See Belluzzi et al., Dig. Dis. Sci. 39(12): 2589-2594 (1994).
  • DPA is an intermediate in the biosynthetic pathway from EPA to DHA (see FIG. 1 ), surprisingly little is known about the DPA's specific biological effects.
  • gene expression profiling experiments were conducted using HepG2 hepatocarcinoma cells.
  • DPA's effects on hepatic cell gene expression predict greater clinical efficacy of DPA-enriched compositions.
  • DPA was observed to affect expression of genes in multiple metabolic pathways, including genes in categories known to be relevant to the clinical effects of omega-3 polyunsaturated fatty acids: genes involved in lipid metabolism, genes involved in cardiovascular physiology, and genes involved in inflammation. Significant second-order effects are also predicted, given the changes observed in the expression of genes that encode proteins that themselves affect gene expression, and in genes encoding proteins that affect post-transcriptional modification.
  • DPA DPA-driven upregulation of ACADSB, the short/branched chain acyl-CoA dehydrogenase, predicts lower serum triglyceride levels
  • DPA-driven downregulation of HMGCR analogous to inhibition of the encoded HMG-CoA-reductase enzyme by statins, would be predicted to lead to favorable decreases in the total cholesterol:HDL ratio
  • DPA downregulation of SQLE a rate-limiting step in sterol synthesis, analogously predicts reductions in total cholesterol levels.
  • the expression profiling experiments also demonstrated a dose threshold for DPA's effects.
  • the lower concentration tested chosen to mimic the 10-fold lower concentration of DPA in the earlier free acid omega-3 formulation, Purepa, affected the expression of 10-fold fewer genes than the higher DPA concentration, chosen to mimic the exposure expected from the pharmaceutical compositions described herein, demonstrating that the lower DPA concentration provides subthreshold exposure, and would be expected to provide a subtherapeutic dose in vivo.
  • Example 7 presents the results of the ECLIPSE clinical trial, an open-label, single dose, randomized 4-way-crossover study comparing the bioavailability of a 4 g dose of Lovaza® to bioavailability of a 4 g dose of the DPA-enriched pharmaceutical composition of omega-3 PUFA in free acid form described herein (hereinafter, “Epanova®”), under both high fat and low fat dietary conditions.
  • each 1-gram capsule of Lovaza® contains at least 900 mg of the ethyl esters of omega-3 fatty acids sourced from fish oils, predominantly a combination of ethyl esters of eicosapentaenoic acid (EPA—approximately 465 mg) and docosahexaenoic acid (DHA—approximately 375 mg).
  • the batch of Epanova® used in the trial comprised 57.3% (a/a) EPA, 19.6% (a/a) DHA, and 6.2% (a/a) DPA, each substantially in free acid form.
  • Epanova® over Lovaza® The superior fat-independent bioavailability of Epanova® over Lovaza® is clinically important, in view of the NCEP ATP III recommendation that subjects with hypertriglyceridemia and dyslipidemias adhere to a low-fat diet during adjunct therapy.
  • Example 8 presents results from a 14-day bioavailability study, which demonstrated that the increase in bioavailability observed in the single-dose ECLIPSE trial is maintained, even enhanced, over 2 weeks of dosing.
  • disaggregated subject-specific data demonstrated that the subject with least response to Epanova® still had a greater day-14 EPA+DHA Cmax than the subject with best response to Lovaza®.
  • Example 10 presents the results of the EVOLVE trial, a 12-week, double-blind, olive oil-controlled study of patients selected on the basis of high triglyceride levels, in the range of 500-2,000 mg/dL (severe hypertriglyceridemia).
  • the primary study endpoint was percent change in plasma triglyceride levels from baseline to end-of-treatment (“EOT”).
  • the secondary endpoint was percent change in plasma non-HDL cholesterol (“non-HDL-C”) from baseline to EOT.
  • the increase in EPA plasma levels with concomitant reduction in AA plasma levels caused a significant improvement in the EPA/AA ratio, from approximately 0.10 at baseline to approximately 0.67 (average) and 0.62 (median) at end-of-treatment (“EOT”) at the 4 g dose.
  • EOT end-of-treatment
  • the EPA/AA ratio has been reported to constitute an independent risk factor for coronary atherosclerosis, Nakamua & Maegawa, Endocrine Abstracts (2012) 29 OC19.1, with lower ratios associated with progression in coronary atherosclerosis in statin-treated patients with coronary artery disease, Nozue et al., Am J Cardiol. 2013 Jan. 1; 111(1):6-1 (ePub ahead of print).
  • Apolipoprotein CIII was significantly reduced by Epanova® treatment. Elevated levels of ApoCIII have been found to be an independent predictor for cardiovascular heart disease (CHD) risk, whereas genetically reduced levels of ApoCIII have been associated with protection from CHD, and have also been correlated with increase in longevity.
  • CHD cardiovascular heart disease
  • FIG. 29 plots the rate of change in the median percentage change from baseline in plasma levels of EPA, DHA, DPA, AA, TG, non-HDL-C, and HDL-C (absolute value) between 2 g and 4 g doses of Epanova®.
  • the rate of change (slope) in the median percentage change from baseline is near zero, predicting little further increase in DHA and DPA plasma levels would be achieved if dose is further increased. Similar plateauing of response was seen in triglyceride levels, HDL-C levels, and non-HDL-C levels (data not shown).
  • the rate of change for EPA remains high, with a slope of 0.59; further increase in EPA plasma levels is expected to be obtained by increasing Epanova® dosage above 4 g per day.
  • the rate of change (decrease) in AA levels upon doubling the Epanova® dose from 2 g to 4 g per day is even higher than that for EPA; further reductions in AA plasma levels are expected as Epanova® dosage is increased above 4 g/day.
  • Epanova® thus exhibits unprecedented potency in ability to elevate EPA levels, reduce AA levels, and improve the EPA:AA ratio.
  • a subset of subjects in the 2 g treatment arm of the EVOLVE trial who were receiving concurrent statin therapy displayed greater magnitudes of percentage changes (mean LS difference), relative to control, for TG, non-HDL-C, HDL-C, LDL-C, TC, VLDL-C, and TC/HDL-C, when compared to those subjects in the 2 g treatment arm who did not receive concurrent statin therapy.
  • Subjects receiving concurrent statin therapy showed a dose-dependent response to Epanova®, as shown in comparative data for Epanova® 2 g and Epanova® 4 g displayed in FIG. 39 .
  • Example 12 describes the ESPRIT clinical trial, which was conducted to study patients on baseline statin therapy with triglyceride levels between 200-500 mg/dL, lower than the patients with severe hypertriglyceridemia enrolled in the EVOLVE study described in Example 10.
  • FIGS. 45-52 illustrate that Epanova® is efficacious as an add-on to both low-potency and high-potency statins, in a range of baseline patient conditions.
  • FIG. 48 the reductions in TG levels were observed for patients who received concurrent rosuvastatin, atorvastatin, and simvastatin therapy.
  • Statistically significant effects on triglycerides, non-HDL-C, and LDL-C levels were observed regardless whether low potency or high potency statins were co-administered, as shown in FIGS. 49-51 .
  • compositions of polyunsaturated fatty acids (“PUFAs”) in free acid form are provided.
  • the composition is a pharmaceutical composition suitable for oral administration.
  • the composition is a neutraceutical composition suitable for oral administration.
  • composition comprises a plurality of species of omega-3 PUFA, each present substantially in free acid form.
  • the composition comprises eicosapentaenoic acid (C20:5 n-3) (“EPA,” also known as timnodonic acid), docosahexaenoic acid (C22:6 n-3) (“DHA,” also known as cervonic acid), and docosapentaenoic acid (C22:5 n-3) (“DPA”, also known as clupodonic acid), each substantially in free acid form.
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • DPA docosapentaenoic acid
  • the composition comprises EPA in an amount, calculated as a percentage by area on GC chromatogram of all fatty acids in the composition, of at least about 45% (“45% (a/a)”). In various embodiments, the composition comprises EPA in an amount of at least about 46% (a/a) 47% (a/a), 48% (a/a), 49% (a/a), or at least about 50% (a/a).
  • the composition comprises EPA in an amount of at least about 51% (a/a), at least about 52% (a/a), at least about 53% (a/a), at least about 54% (a/a), at least about 55% (a/a), at least about 56% (a/a), at least about 57% (a/a), at least about 58% (a/a), even at least about 59% (a/a), at least about 60% (a/a), at least about 61% (a/a), 62% (a/a), 63% (a/a), 64% (a/a), or 65% (a/a).
  • the composition comprises EPA in an amount of about 45 to about 65% (a/a). In particular embodiments, EPA is present in an amount of about 50 to about 60% (a/a). In various embodiments, EPA is present in an amount of about 52 to about 58.0% (a/a). In some embodiments, EPA is present in an amount of about 55% (a/a) to about 56% (a/a). In some embodiments, EPA is present in an amount of about 55% (a/a).
  • the composition comprises EPA in an amount, calculated as a percentage by mass of all fatty acids in the composition (“% (m/m)”), of about 50% (m/m) to about 60% (m/m). In certain embodiments, EPA is present in an amount of about 55% (m/m).
  • the composition comprises DHA in an amount of at least about 13% (a/a). In various embodiments, the composition comprises DHA in an amount of at least about 14% (a/a), at least about 15% (a/a), at least about 16% (a/a), at least about 17% (a/a), at least about 18% (a/a), at least about 19% (a/a), or at least about 20% (a/a). In selected embodiments, the composition comprises DHA in an amount of at least about 21% (a/a), at least about 22% (a/a), at least about 23% (a/a), at least about 24% (a/a), even at least about 25% (a/a).
  • the composition comprises DHA in an amount of about 13% (a/a) to about 25% (a/a). In certain embodiments, DHA is present in an amount of about 15% (a/a) to about 25% (a/a). In several embodiments, DHA is present in an amount of about 17% (a/a) to about 23% (a/a). In certain embodiments, DHA is present in an amount of about 19% (a/a) to about 20% (a/a).
  • compositions comprise DHA in an amount of about 15% (m/m) to about 25% (m/m). In certain embodiments, DHA is present in an amount of about 17% (m/m) to about 23% (m/m). In certain embodiments, DHA is present in an amount of about 20% (m/m).
  • the composition comprises DPA in an amount of at least about 1% (a/a). In various embodiments, the composition comprises DPA in an amount of at least about 1.5% (a/a), 2% (a/a), 2.5% (a/a), 3% (a/a), 3.5% (a/a), 4% (a/a), 4.5% (a/a), even at least about 5% (a/a). In selected embodiments, the composition comprises DPA in an amount of at least about 6% (a/a), at least about 7% (a/a), at least about 8% (a/a), or at least about 9% (a/a).
  • the composition comprises DPA in an amount of about 1% (a/a) to about 8% (a/a). In certain embodiments, the composition comprises DPA in an amount of about 2% (a/a) to about 7% (a/a). In selected embodiments, the composition comprises DPA in an amount of about 3% (a/a) to about 6% (a/a). In particular embodiments, the composition comprises DPA in an amount of about 4% (a/a) to about 5% (a/a).
  • the composition comprises DPA, calculated as a percentage by mass of all fatty acids in the composition, in an amount of no less than about 1% (m/m). In various embodiments, the composition comprises DPA in an amount of about 1% (m/m) to about 8% (m/m). In particular embodiments, the composition comprises DPA in an amount of no more than about 10% (m/m).
  • the composition comprises EPA and DHA in a total amount of at least about 60% (a/a). In various embodiments, the composition comprises EPA and DHA in a total amount of at least about 61% (a/a), 62% (a/a), 63% (a/a), 64% (a/a), 65% (a/a), 66% (a/a), 67% (a/a), 68% (a/a), 69% (a/a), or at least about 70% (a/a).
  • the composition comprise EPA and DHA in a total amount off at least about 71% (a/a), 72% (a/a), 73% (a/a), 74% (a/a), 75% (a/a), 76% (a/a), 77% (a/a), 78% (a/a), 79% (a/a), even at least about 80% (a/a).
  • the composition comprises EPA and DHA in total amount of at least about 81% (a/a), 82% (a/a), at least about 83% (a/a), 84% (a/a), even at least about 85% (a/a).
  • the composition comprises EPA and DHA in an amount of about 70.0% (m/m) to about 80.0% (m/m). In certain embodiments, the composition comprises about 75% (m/m) EPA plus DHA.
  • the composition comprises EPA, DHA, and DPA in a total amount of at least about 61% (a/a).
  • the composition comprises EPA, DHA, and DPA in a total amount of at least about 62% (a/a), 63% (a/a), 64% (a/a), 65% (a/a), 66% (a/a), at least about 67% (a/a), at least about 68% (a/a), at least about 69% (a/a), or at least about 70% (a/a).
  • the composition comprises EPA, DHA, and DPA in a total amount of at least about 71% (a/a), 72% (a/a), 73% (a/a), 74% (a/a), 75% (a/a), 76% (a/a), 77% (a/a), 78% (a/a), 79% (a/a), 80% (a/a), even at least about 81% (a/a), 82% (a/a), 83% (a/a), 84% (a/a), 85% (a/a), 86% (a/a), 87% (a/a), even at least about 88% (a/a).
  • the composition comprises EPA, DHA, and DPA in a total amount of between about 70% (a/a) to about 90% (a/a).
  • EPA is present in an amount of about 55% (a/a) to about 56% (a/a);
  • DHA is present in an amount of about 19% (a/a) to about 20% (a/a); and
  • DPA is present in an amount of about 4% (a/a) to about 5% (a/a).
  • the composition further comprises one or more omega-3 polyunsaturated fatty acid species selected from the group consisting of: ⁇ -linolenic acid (C18:3 n-3), moroctic acid (C18:4 n-3, also known as stearidonic acid), eicosatrienoic acid (C20:3 n-3), eicosatetraenoic acid (C20:4 n-3), and heneicosapentaenoic acid (C21:5 n-3).
  • omega-3 polyunsaturated fatty acid species selected from the group consisting of: ⁇ -linolenic acid (C18:3 n-3), moroctic acid (C18:4 n-3, also known as stearidonic acid), eicosatrienoic acid (C20:3 n-3), eicosatetraenoic acid (C20:4 n-3), and heneicosapentaenoic acid (C21:5 n-3).
  • the composition comprises EPA, DHA, DPA, and moroctic acid, each substantially in the free acid form.
  • the composition comprises EPA, DHA, DPA, moroctic acid, and heneicosapentaenoic acid, each substantially in the free acid form.
  • the composition comprises EPA, DHA, DPA, moroctic acid, heneicosapentaenoic acid, and eicosatetraenoic acid, each substantially in the free acid form.
  • the composition comprises EPA, DHA, DPA, ⁇ -linolenic acid (C18:3 n-3), moroctic acid (C18:4 n-3), eicosatrienoic acid (C20:3 n-3), eicosatetraenoic acid (C20:4 n-3), and heneicosapentaenoic acid (C21:5 n-3).
  • total omega-3 fatty acids defined as the sum of alpha-linolenic acid (C18:3 n-3), moroctic acid (C18:4 n-3), eicosatrienoic acid (C20:3 n-3), eicosatetraenoic acid (C20:4 n-3), eicosapentaenoic acid (EPA) (C20:5 n-3), heneicosapentaenoic acid (C21:5 n-3), docosapentaenoic acid (C22:5 n-3) and docosahexaenoic acid (DHA) (C22:6 n-3)—constitute from about 80% (a/a) to about 95% (a/a) of all fatty acids in the composition. In a variety of embodiments, total omega-3 fatty acids constitute from about 80-about 95% (m/m) of all fatty acids in the composition.
  • the composition further comprises one or more species of omega-6 PUFA, each present substantially in the free acid form.
  • the composition comprises one or more species of omega-6 PUFA selected from the group consisting of linoleic acid (C18:2 n-6), gamma-linolenic acid (C18:3 n-6), eicosadienoic acid (C20:2 n-6), dihomo-gamma-linolenic acid (C20:3 n-6) (“DGLA”), arachidonic acid (C20:4 n-6) (“AA”), and docosapentaenoic acid (C22:5 n-6, also known as osbond acid).
  • omega-6 PUFA selected from the group consisting of linoleic acid (C18:2 n-6), gamma-linolenic acid (C18:3 n-6), eicosadienoic acid (C20:2 n-6), dihomo-gamma-linolenic acid (C20:3 n-6) (“DGLA”), arachidonic acid (C20
  • the composition comprises linoleic acid (C18:2 n-6), gamma-linolenic acid (C18:3 n-6), eicosadienoic acid (C20:2 n-6), dihomo-gamma-linolenic acid (C20:3 n-6) (“DGLA”), arachidonic acid (C20:4 n-6) (“AA”), and docosapentaenoic acid (C22:5 n-6), each present substantially in the free acid form.
  • DGLA dihomo-gamma-linolenic acid
  • AA arachidonic acid
  • C22:5 n-6 docosapentaenoic acid
  • AA is present in an amount of no more than about 5% (a/a) of the fatty acids in the composition. In certain embodiments, AA comprises no more than about 4.5% (a/a) of the fatty acids in the composition. In particular embodiments, AA is present in an amount of no more than about 4% (a/a) of the fatty acids in the composition.
  • AA is present in an amount of no more than about 5% (m/m) of the fatty acids in the composition. In certain embodiments, AA comprises no more than about 4.5% (m/m) of the fatty acids in the composition. In particular embodiments, AA is present in an amount of no more than about 4% (m/m) of the fatty acids in the composition.
  • total omega-6 polyunsaturated fatty acids defined as the sum of linoleic acid (C18:2 n-6), gamma-linolenic acid (C18:3 n-6), eicosadienoic acid (C20:2 n-6), dihomo-gamma-linolenic acid (C20:3 n-6), arachidonic acid (C20:4 n-6) and docosapentaenoic acid (C22:5 n-6)—comprise no more than about 10% (a/a) of the fatty acids in the composition.
  • total omega-6 polyunsaturated fatty acids defined as the sum of linoleic acid (C18:2 n-6), gamma-linolenic acid (C18:3 n-6), eicosadienoic acid (C20:2 n-6), dihomo-gamma-linolenic acid (C20:3 n-6), arachidonic acid (C20:4 n-6) and docosapentaenoic acid (C22:5 n-6)—comprise no more than about 10% (m/m) of the fatty acids in the composition.
  • composition is given by Table 11, with each species of PUFA identified therein falling within the range of about ⁇ 3 SD to about +3 SD of the respectively recited average. In certain embodiments, each species of PUFA identified therein falls within the range of about ⁇ 2 SD to about +2 SD of the respectively recited average. In certain embodiments, each species falls within the range of about ⁇ 1 SD to about +1 SD of the respectively recited average.
  • composition is given by Table 13, with each species of PUFA identified therein falling within the range of about ⁇ 3 SD to about +3 SD of the respectively recited average. In certain embodiments, each species falls within the range of about ⁇ 2 SD to about +2 SD of the respectively recited average. In certain embodiments, each PUFA species falls within the range of about ⁇ 1 SD to about +1 SD of the respectively recited average.
  • polyunsaturated fatty acids other than omega-3 and omega-6 polyunsaturated fatty acids are present in an amount of no more than about 5% (a/a). In various embodiments, polyunsaturated fatty acids other than omega-3 and omega-6 polyunsaturated fatty acids are present in an amount of no more than about 5% (m/m).
  • At least 90% of each of the plurality of species of omega-3 PUFA in the composition is in the free acid form. In certain embodiments, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, even at least 99% of each species of omega-3 PUFA in the composition is present in the free acid form. In exemplary embodiments, at least 90% of the total omega-3 polyunsaturated fatty acid content in the composition is present in the free acid form.
  • At least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, even at least 99% of the total omega-3 polyunsaturated fatty acid content in the composition is present in the free acid form.
  • At least 90% of each of the plurality of species of omega-6 PUFA in the composition is in the free acid form. In certain embodiments, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, even at least 99% of each species of omega-6 PUFA in the composition is present in the free acid form. In exemplary embodiments, at least 90% of the total omega-6 polyunsaturated fatty acid content in the composition is present in the free acid form.
  • At least 90% of the total polyunsaturated fatty acid in the composition is present in the free acid form. In certain embodiments, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, even at least 99% of the total polyunsaturated fatty acid in the composition is present in the free acid form.
  • the composition comprises, in typical embodiments, no more than about 3.0% (a/a) saturated fatty acids and no more than about 5.0% (a/a) mono-unsaturated fatty acids. In various embodiments, the composition comprises no more than about 3.0% (m/m) saturated fatty acids and no more than about 5.0% (m/m) mono-unsaturated fatty acids.
  • the composition usefully further comprises an antioxidant.
  • the antioxidant is butylated hydroxyanisole (BHA).
  • BHA butylated hydroxyanisole
  • the antioxidant is alpha-tocopherol.
  • alpha-tocopherol is present in an amount of about 0.20-about 0.40% (m/m). In various embodiments, alpha-tocopherol is present in an amount of about 0.25-about 0.35% (m/m). In particular embodiments, alpha-tocopherol is present in an amount of about 0.27-about 0.33% (m/m).
  • the composition comprises no more than about 0.1 ppm ethyl carbamate. In some embodiments, the composition comprises no more than 0.1 ppm ethyl carbamate. In various embodiments, the composition comprises less than 0.1 ppm ethyl carbamate.
  • the composition comprises EPA in an amount, calculated as a percentage by area on GC chromatogram of all fatty acids in the composition, of about 45.0-about 65.0% (a/a). In certain embodiments, EPA is present in an amount of about 50.0-about 60.0% (a/a). In various embodiments, EPA is present in an amount of about 52.0-about 58.0% (a/a). In some embodiments, EPA is present in an amount of about 55.0% (a/a).
  • EPA is present in an amount of about 55.0-about 58.4% (a/a). In various embodiments, EPA is present in an amount of about 55.6-about 57.9% (a/a). In some embodiments, EPA is present in an amount of about 56.7% (a/a).
  • the composition comprises EPA in an amount, calculated as a percentage by mass of all fatty acids in the composition, of about 50.0-60.0% (m/m). In certain embodiments, EPA is present in an amount of about 55% (m/m).
  • the composition comprises DHA in an amount, calculated as a percentage by area on GC chromatogram of all fatty acids in the composition, of about 13.0-about 25.0% (a/a). In certain embodiments, DHA is present in an amount of about 15.0-about 23.0% (a/a). In various embodiments, DHA is present in an amount of about 17.0-about 21.0% (a/a). In certain embodiments, DHA is present in an amount of about 19.0-about 20.0% (a/a).
  • DHA is present in an amount of about 17.7-about 22.2% (a/a). In various embodiments, DHA is present in an amount of about 18.4-about 21.4% (a/a). In certain embodiments, DHA is present in an amount of about 19.9% (a/a).
  • the compositions comprises DHA, calculated as a percentage by mass of all fatty acids in the composition, in an amount of about 15.0-25.0% (m/m). In certain embodiments, DHA is present in an amount of about 20.0% (m/m).
  • the composition comprises EPA and DHA in a total amount, calculated as a percentage by area on GC chromatogram of all fatty acids in the composition, of about 67.0-about 81.0% (a/a). In certain embodiments, the composition comprises a total amount of EPA and DHA of about 69.0-about 79.0% (a/a). In various embodiments, the composition comprises a total amount of EPA plus DHA of about 71.0-about 77.0% (a/a). In certain embodiments, the composition comprises a total amount of EPA+DHA of about 74.0-about 75.0% (a/a).
  • the composition comprises EPA+DHA in a total amount, calculated as a percentage by mass of all fatty acids in the composition, of about 70.0-80.0% (m/m). In certain embodiments, the composition comprises about 75.0% (m/m) EPA plus DHA.
  • a-linolenic acid is present in an amount of about 0.07-about 1.10% (a/a). In certain embodiments, ⁇ -linolenic acid is present in an amount of about 0.24-about 0.91% (a/a). In various embodiments, ⁇ -linolenic acid is present in an amount of about 0.40-about 0.80% (a/a). In certain embodiments, ⁇ -linolenic acid is present in an amount of about 0.50 to about 0.600% (a/a).
  • moroctic acid is present in an amount of about 0.01-about 7.90% (a/a). In certain embodiments, moroctic acid is present in an amount of about 0.25-about 6.40% (a/a). In certain embodiments, moroctic acid is present in amount of about 1.70%-about 4.90% (a/a). In particular embodiments, moroctic acid is present in an amount of about 3.25% (a/a).
  • eicosatrienoic acid is present in an amount of about 0.75-about 3.50% (a/a). In certain embodiments, eicosatrienoic acid is present in an amount of about 1.20-about 3.00% (a/a). in various embodiments, eicosatrienoic acid is present in an amount of about 1.60-about 2.60% (a/a). In certain embodiments, eicosatrienoic acid is present in an amount of about 2.10% (a/a).
  • eicosatetraenoic acid is present in an amount of about 0.01-about 0.40% (a/a). In certain embodiments, eicosatetraenoic acid is present in an amount of about 0.01-about 0.30% (a/a). In some embodiments, eicosatetraenoic acid is present in an amount of about 0.03-about 0.22% (a/a). In some embodiments, eicosatetraenoic acid is present in an amount of about 0.12% (a/a).
  • heneicosapentaenoic acid is present in an amount of about 0.01-4.10% (a/a). In certain embodiments, heneicosapentaenoic acid is present in an amount of about 0.01-about 3.20% (a/a). In particular embodiments, heneicosapentaenoic acid is present in an amount of about 0.60-about 2.35% (a/a). In various embodiments, heneicosapentaenoic acid is present in an amount of about 1.50% (a/a).
  • DPA is present in an amount of about 0.90-about 7.60% (a/a). In a variety of embodiments, DPA is present in an amount of about 2.00-about 6.50% (a/a). In certain embodiments, DPA is present in an amount of about 3.10-about 5.40% (a/a). In various embodiments, DPA is present in an amount of about 4.25% (a/a).
  • DPA is present in an amount of about 2.13-about 8.48% (a/a). In certain embodiments, DPA is present in an amount of about 3.19-about 7.42% (a/a). In some embodiments, DPA is present in an amount of about 4.25-about 6.37% (a/a). In various embodiments, DPA is present in an amount of about 5.31% (a/a).
  • total omega-3 fatty acids comprise from about 80.0-about 95% (m/m) of all fatty acids in the pharmaceutical composition.
  • DGLA is present in an amount, calculated as a percentage by area on GC chromatogram of all fatty acids in the composition, of about 0.01-about 4.40% (a/a). In some embodiments, DGLA is present in an amount of about 0.01-about 3.30% (a/a). In certain embodiments, DGLA is present in an amount of about 0.01-about 2.20% (a/a). In some embodiments, DGLA is present in an amount of about 1.10% (a/a).
  • DGLA is present in an amount of about 0.28-about 0.61% (a/a). In certain embodiments, DGLA is present in an amount of about 0.33-about 0.56% (a/a). In some embodiments, DGLA is present in an amount of about 0.44% (a/a).
  • AA is present in an amount, calculated as a percentage by area on GC chromatogram of all fatty acids in the composition, of about 0.01-about 6.90% (a/a). In various embodiments, AA is present in an amount of about 0.01-about 5.40% (a/a). In certain embodiments, AA is present in an amount of about 0.70-about 3.80% (a/a). In a number of embodiments, AA is present in an amount of about 2.25% (a/a).
  • AA is present in an amount of about 1.41-about 4.87% (a/a). In certain embodiments, AA is present in an amount of about 1.99-about 4.30% (a/a). In a number of embodiments, AA is present in an amount of about 2.57-about 3.72% (a/a).
  • the composition comprises AA in an amount of no more than about 4.5% (a/a). In some embodiments, the composition comprises AA in an amount of no more than about 3.14% (a/a).
  • linoleic acid is present in an amount of about 0.25%-about 1.30% (a/a). In certain embodiments, linoleic acid is present in an amount of about 0.40%-about 1.20% (a/a). In various embodiments, linoleic acid is present in an amount of about 0.60%-about 0.95% (a/a). In particular embodiments, linoleic acid is present in an amount of about 0.80% (a/a).
  • gamma-linolenic acid is present in an amount of about 0.01-about 0.65% (a/a). In various embodiments, gamma-linolenic acid is present in an amount of about 0.03-about 0.51% (a/a). In certain embodiments, gamma-linolenic acid is present in an amount of about 0.15-about 0.40% (a/a). In several embodiments, gamma-linolenic acid is present in an amount of about 0.27% (a/a).
  • eicosadienoic acid is present in an amount of about 0.01-about 0.30 (a/a). In various embodiments, eicosadienoic acid is present in an amount of about 0.04-about 0.24% (a/a). In certain embodiments, eicosadienoic acid is present in an amount of about 0.09-about 0.20% (a/a). In some embodiments, eicosadienoic acid is present in an amount of about 0.14% (a/a).
  • docosapentaenoic acid is present in an amount of about 0.01-0.95% (a/a). In various embodiments, docosapentaenoic acid (C22:5 n-6) is present in an amount of about 0.01-about 1.05% (a/a). In some embodiments, docosapentaenoic acid (C22:5 n-6) is present in an amount of about 0.05-about 0.71% (a/a). In certain embodiments, docosapentaenoic acid (C22:5 n-6) is present in an amount of about 0.01-about 0.48% (a/a). In particular embodiments, docosapentaenoic acid (C22:5 n-6) is present in an amount of about 0.24% (a/a).
  • docosapentaenoic acid (C22:5 n-6) is present in an amount of about 0.01-about 1.19% (a/a). In certain embodiments, docosapentaenoic acid (C22:5 n-6) is present in an amount of about 0.16-about 0.98% (a/a). In particular embodiments, docosapentaenoic acid (C22:5 n-6) is present in an amount of about 0.57% (a/a).
  • the composition comprises no more than about 10.0% (a/a) total omega-6 fatty acids.
  • the composition comprises, in typical embodiments amongst these additional embodiments, no more than about 3.0% (a/a) saturated fatty acids, no more than about 5.0% (a/a) mono-unsaturated fatty acids, and no more than about 0.1 ppm ethyl carbamate. In some embodiments, the composition comprises no more than 0.1 ppm ethyl carbamate. In various embodiments, the composition comprises less than 0.1 ppm ethyl carbamate.
  • the pharmaceutical or neutraceutical composition of DPA-enriched omega-3 PUFAs in free acid form described in Section 5.2 above is usefully packaged in unit dosage forms for oral administration.
  • the dosage form is a capsule.
  • the dosage form is a gelatin capsule.
  • the gelatin capsule is a hard gelatin capsule.
  • the dosage form is a soft gelatin capsule.
  • the capsule comprises Type A gelatin. In some embodiments, the capsule comprises both Type A and Type B gelatin. Sources of collagen for the production of either type A or type B gelatin include, but are not limited to, cows, pigs and fish.
  • the capsule is a soft gelatin capsule comprising sufficient porcine Type A gelatin such that the capsule disintegrates within a time period of not more than 30 minutes in purified water at 37° C. after storage for at least 3 months at 40° C.
  • the capsule is a soft gelatin capsule comprising sufficient porcine Type A gelatin such that the capsule disintegrates within a time period of not more than 30 minutes in purified water at 37° C. after storage for 6 months at 40° C.
  • the capsule is a soft gelatin capsule comprising sufficient porcine Type A gelatin such that the capsule disintegrates within a time period of not more than 30 minutes in purified water at 37° C. after storage for 12 months at 40° C.
  • the capsule is a soft gelatin capsule comprising sufficient porcine Type A gelatin such that the capsule disintegrates within a time period of not more than 30 minutes in purified water at 37° C. after storage for at least 3 months at 30° C.
  • the capsule is a soft gelatin capsule comprising sufficient porcine Type A gelatin such that the capsule disintegrates within a time period of not more than 30 minutes in purified water at 37° C. after storage for 6 months at 30° C.
  • the capsule is a soft gelatin capsule comprising sufficient porcine Type A gelatin such that the capsule disintegrates within a time period of not more than 30 minutes in purified water at 37° C. after storage for 12 months at 30° C.
  • the capsule is a soft gelatin capsule comprising a mixture of porcine type A gelatin and a type B gelatin.
  • at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 40% even at least about 50% (w/w) of the gelatin is porcine type A gelatin.
  • at least about 55%, 60%, 65%, 70%, 75% (w/w) of the gelatin is porcine type A gelatin.
  • at least 80%, 85%, 90%, even 95% (w/w) of the gelatin is porcine type A gelatin.
  • the capsule is a soft gelatin capsule in which the gelatin consists essentially of porcine type A gelatin.
  • the capsule is a reduced cross-linked gelatin capsule, such as those described in U.S. Pat. No. 7,485,323, incorporated herein by reference in its entirety.
  • the capsule comprises succinylated gelatin.
  • capsules are made from substances that are not animal by-products, such as agar-agar, carrageenan, pectin, konjak, guar gum, food starch, modified corn starch, potato starch, and tapioca.
  • animal by-products such as agar-agar, carrageenan, pectin, konjak, guar gum, food starch, modified corn starch, potato starch, and tapioca.
  • Non-animal sources of materials that can be used to make capsules useful in the oral unit dosage forms described herein are described in U.S. Patent Publication No. 2011/0117180, incorporated herein by reference.
  • Vegicaps® Capsules Catalent are used.
  • the capsule is uncoated.
  • the capsule is coated.
  • the fatty acid composition is released in a time-dependent manner. In various embodiments, there is no substantial release of the PUFA composition for at least 30 minutes after ingestion. In certain embodiments, there is no substantial release of the PUFA composition for at least 30 minutes when release is tested in vitro. In certain embodiments, no more than about 20% of the PUFA composition is released within the first 30 minutes when tested in vitro. In selected embodiments, no more than about 25%, 30%, even no more than about 35% of the PUFA composition is released within the first 30 minutes, when tested in vitro. In particular embodiments, in vitro release properties are assessed according to the procedures described in provisional patent application No. 61/749,124, filed Jan. 4, 2013, titled “Method of release testing for omega-3 polyunsaturated fatty acids,” by Bharat Mehta, the disclosure of which is incorporated herein by reference in its entirety.
  • substantial quantities of the PUFA composition are released by about 60 minutes after ingestion. In certain embodiments, substantial quantities of the PUFA composition are released by about 60 minutes when tested in vitro. In selected embodiments, at least about 40% of the PUFA composition is released by about 60 minutes, when tested in vitro. In various embodiments, at least about 45%, 50%, 55%, 60%, even at least about 65% of the PUFA composition is released by about 60 minutes, when tested in vitro. In particular embodiments, in vitro release properties are assessed according to the procedures described in provisional patent application No. 61/749,124, filed Jan. 4, 2013, titled “Method of release testing for omega-3 polyunsaturated fatty acids,” by Mehta, the disclosure of which is incorporated herein by reference in its entirety.
  • capsules are coated as described in U.S. Pat. Nos. 5,792,795 and 5,948,818, the disclosures of which are incorporated herein by reference.
  • the coating is a poly(ethylacrylate-methylacrylate) copolymer.
  • the coating is Eudragit NE 30-D (Evonik Industries AG), which has an average molecular weight of about 800,000.
  • the capsule is coated with an enteric coating that protects the capsule from dissolution or disintegration in the stomach but dissolves at pH values encountered in the small intestine.
  • the oral unit dosage form contains from about 100 mg to about 2000 mg of the PUFA composition. In some embodiments, the oral dosage form contains about 250 mg of the PUFA composition. In some embodiments, the oral dosage form contains about 500 mg of the PUFA composition. In certain embodiments, the oral dosage form contains about 750 mg of the PUFA composition. In some embodiments, the oral dosage form contains about 1000 mg of the PUFA composition. In other embodiments, the oral dosage form contains about 1500 mg of the PUFA composition. In certain embodiments, the unit dosage form contains nonintegral weight amounts of PUFA composition between 100 mg and 2000 mg.
  • a plurality of unit dosage forms as above-described may usefully be packaged together in a dosage kit to increase ease of use and patient compliance.
  • the dosage kit is a bottle.
  • the plurality of dosage forms is packaged in blister packs, a plurality of which blister packs may optionally be packaged together in a box or other enclosure.
  • the plurality of unit dosage forms is sufficient for 30 days, 60 days, or 90 days of dosing.
  • the unit dosage form is a capsule containing approximately one gram of pharmaceutical composition as described above, and the dosage kit comprises 30, 60, 90, 120, 150, 180, 240, 270, or 300 such capsules.
  • the plurality of unit dosage forms is packaged under an inert gas, such as nitrogen or a noble gas, or is packaged under vacuum.
  • an inert gas such as nitrogen or a noble gas
  • the methods comprise orally administering the pharmaceutical composition described in Section 5.2 above to a patient having pre-treatment serum or plasma triglyceride levels ⁇ 500 mg/dL, in an amount and for a duration sufficient to reduce serum or plasma triglyceride levels below pre-treatment levels.
  • each dose of the pharmaceutical composition is administered as one or as a plurality of the unit dosage forms described in Section 5.3, above.
  • the pharmaceutical composition is administered in an amount and for a duration effective to reduce serum or plasma triglyceride levels by at least about 5%, 6%, 7%, 8%, or at least about 9% below pre-treatment levels. In certain embodiments, the composition is administered in an amount and for a duration effective to reduce serum or plasma triglyceride levels by at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18% or 19% below pre-treatment levels. In particular embodiments, the composition is administered in an amount and for a duration effective to reduce serum or plasma triglyceride levels by at least about 20% below pre-treatment levels. In various embodiments, the pharmaceutical composition is administered in an amount and for a duration effective to reduce serum or plasma triglycerides by at least about 25%, 30%, 35%, 40%, 45%, even at least about 50% below pre-treatment levels.
  • the pharmaceutical composition is administered in an amount and for a duration effective to reduce serum or plasma triglyceride levels by at least about 50 mg/dL, 60 mg/dL, 70 mg/dL, 80 mg/dL, 90 mg/dL, even at least about 100 mg/dL. In certain embodiments, the composition is administered in an amount and for a duration effective to reduce serum or plasma triglyceride levels by at least about 110 mg/dL, 120 mg/dL, 130 mg/dL, 140 mg/dL, even at least about 150 mg/dL.
  • the pharmaceutical composition is administered in an amount and for a duration effective to reduce serum or plasma triglyceride levels by at least about 160 mg/dL, 170 mg/dL, 180 mg/dL, even at least about 190 mg/dL or 200 mg/dL.
  • the pharmaceutical composition is administered in an amount and for a duration effective to decrease non-HDL-c levels by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, even at least about 10% below pre-treatment levels.
  • the pharmaceutical composition is administered in an amount and for a duration effective to increase HDL-c levels by at least about 1% above pre-treatment levels. In certain embodiments, the pharmaceutical composition is administered in an amount and for a duration sufficient to increase HDL-c by at least about 2%, 3%, 4%, even at least about 5%, 6%, 7%, 8%, 9%, or 10% above pre-treatment levels.
  • the pharmaceutical composition is administered in an amount and for a duration effective to reduce the total cholesterol:HDL-c (“TC/HDL”) ratio by at least about 1% below pre-treatment levels. In some embodiments, the pharmaceutical composition is administered in an amount and for a duration sufficient to reduce the TC/HDL ratio by at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, even at least about 9% or at least about 10% below pre-treatment levels.
  • TC/HDL total cholesterol:HDL-c
  • the pharmaceutical composition is administered in an amount and for a duration effective to decrease VLDL-c levels by at least about 5%, 6%, 7%, 8%, 9%, or at least about 10% below pre-treatment levels. In certain embodiments, the pharmaceutical composition is administered in an amount and for a duration sufficient to decrease VLDL-c levels by at least about 11%, 12%, 13%, 14%, 15%, 16%, 17%, even at least about 18%, 19%, or 20% below pre-treatment levels. In particular embodiments, the pharmaceutical composition is administered in an amount and for a duration sufficient to decrease VLDL-c levels by at least about 21%, 22%, 23%, 24%, even at least about 25% below pre-treatment levels.
  • the pharmaceutical composition is administered in an amount and for a duration effective to decrease ApoCIII levels. In certain embodiments, the pharmaceutical composition is administered in an amount and for a duration sufficient to decrease ApoCIII levels by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, even at least about 8%, 9% or 10% below pre-treatment levels.
  • the pharmaceutical composition is administered in an amount and for a duration effective to increase plasma EPA levels by at least 100% above pre-treatment levels. In certain embodiments, the pharmaceutical composition is administered in an amount and for a duration effective to increase plasma EPA levels by at least about 200%, 250%, 300%, even at least about 350%, 400%, 450% or at least about 500% above pre-treatment levels. In selected embodiments, the pharmaceutical composition is administered for a time and in an amount effective to increase plasma EPA levels by at least about 550%, 600%, 650%, even at least about 700% above pre-treatment levels.
  • the pharmaceutical composition is administered in an amount and for a duration effective to increase plasma DHA levels by at least about 50% above pre-treatment levels. In particular embodiments, the pharmaceutical composition is administered in an amount and for a duration effective to increase plasma DHA levels by at least about 55%, 60%, 65%, 70%, even at least about 75%, 80%, 85%, or 90% above pre-treatment levels.
  • the pharmaceutical composition is administered in an amount and for a duration effective to increase plasma DPA levels by at least about 50% above pre-treatment levels. In some embodiments, the pharmaceutical composition is administered in an amount and for a duration effective to increase plasma DPA levels by at least about 55%, 60%, 65%, 70%, 75%, even at least about 80%, 85%, 90%, 95%, or 100% above pre-treatment levels. In selected embodiments, the pharmaceutical composition is administered in an amount and for a duration effective to increase plasma DPA levels by at least about 110%, 120%, even at least about 125% above pre-treatment levels.
  • the pharmaceutical composition is administered in an amount and for a duration effective to reduce arachidonic acid (AA) concentration in plasma by at least about 5% below pre-treatment levels. In certain embodiments, the pharmaceutical composition is administered in an amount and for a duration effective to reduce arachidonic (AA) concentration in plasma by at least about 6%, 7%, 8%, 9%, 10%, even at least about 11%, 12%, 13%, 14%, even at least about 15%, 16%, 17%, 18%, 19%, 20%, or 21%, 22%, 23%, 24% even at least about 25% below pre-treatment levels.
  • the pharmaceutical composition is administered in an amount, and for a duration, effect to reduce plasma arachidonic acid concentration by at least about 25 ⁇ g/mL. In some embodiments, the pharmaceutical composition is administered in an amount and for a duration sufficient to reduce plasma AA levels by at least about 50 ⁇ g/mL, 55 ⁇ g/mL, 60 ⁇ g/mL, 65 ⁇ g/mL, even at least about 70 ⁇ g/mL, 75 ⁇ g/mL, 80 ⁇ g/mL, 85 ⁇ g/mL, 90 ⁇ g/mL, even at least about 95 ⁇ g/mL or 100 ⁇ g/mL.
  • the effective amount is at least about 2 g per day. In various embodiments, the effective amount is at least about 3 g per day. In particular embodiments, the effective amount is at least about 4 g per day. In typical embodiments, the effective amount is about 2 g per day. In certain embodiments, the effective amount is about 4 g per day.
  • the pharmaceutical composition is administered for at least 30 days. In certain embodiments, the pharmaceutical composition is administered for at least 60 days. In particular embodiments, the pharmaceutical composition is administered for at least 90 days, 120 days, 180 days, 240 days, or at least 360 days. In certain embodiments, the pharmaceutical composition is administered indefinitely.
  • the pharmaceutical composition is administered daily. In other embodiments, the pharmaceutical composition is administered every other day.
  • the daily dosage of pharmaceutical composition is administered in a single daily dose.
  • the pharmaceutical composition is administered in divided doses, with the daily dose divided into two administrations, three administrations, or even four administrations, over the course of the day.
  • the pharmaceutical composition is administered with food. In certain embodiments, the pharmaceutical composition is administered with a low fat meal. In other embodiments, the pharmaceutical composition is administered without food. In certain embodiments, the pharmaceutical composition is administered in the fasting state.
  • statin is selected from the group consisting of: pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, rosuvastatin, tenivastatin, and pitavastatin.
  • methods of treating patients who have pre-treatment serum or plasma triglyceride levels of about 200 mg/dL to about 500 mg/dL are provided.
  • the patients are already on statin therapy; in these patients, the pre-treatment serum or plasma triglyceride levels are those measured during statin treatment, prior to administration of the pharmaceutical compositions described in Section 5.2 above.
  • the method comprises orally administering an effective amount of a statin, and further administering the pharmaceutical composition described in Section 5.2 herein, orally, in an amount and for a duration sufficient to lower serum or plasma triglyceride levels below levels measured prior to treatment with the pharmaceutical composition described herein.
  • the pharmaceutical composition described in Section 5.2 and the statin need not be administered at the same time, with the same dosage schedule, or even on the same days. It is sufficient that the two be administered in sufficient temporal proximity that the patient receives therapeutic benefit concurrently from both.
  • the pharmaceutical composition described in Section 5.2 is administered in an amount and for a duration sufficient to reduce serum or plasma triglyceride levels by at least about 5% below pre-treatment levels. In various embodiments, the pharmaceutical composition is administered in an amount and for a duration sufficient to reduce serum or plasma triglyceride levels by at least about 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, even at least about 16%, 17%, 18%, 19%, or at least about 20% below pre-treatment levels.
  • the pharmaceutical composition described in Section 5.2 herein is administered in an amount and for a duration sufficient to reduce non-HDL-cholesterol by at least about 1%, at least about 2%, at least about 3%, 4%, 5%, even at least about 7%, 8%, 9%, or at least about 10% below pre-treatment levels.
  • the pharmaceutical composition described in Section 5.2 herein is administered in an amount and for a duration sufficient to raise HDL-c levels by at last about 1%, 2%, 3% or more above pre-treatment levels.
  • the pharmaceutical composition is administered in an amount and for a duration effective to increase plasma EPA levels by at least 100% above pre-treatment levels. In certain embodiments, the pharmaceutical composition is administered in an amount and for a duration effective to increase plasma EPA levels by at least about 200%, 250%, 300%, even at least about 350%, 400%, 450% or at least about 500% above pre-treatment levels. In selected embodiments, the pharmaceutical composition is administered for a time and in an amount effective to increase plasma EPA levels by at least about 550%, 600%, 650%, even at least about 700% above pre-treatment levels.
  • the pharmaceutical composition is administered in an amount and for a duration effective to increase plasma DHA levels by at least about 50% above pre-treatment levels. In particular embodiments, the pharmaceutical composition is administered in an amount and for a duration effective to increase plasma DHA levels by at least about 55%, 60%, 65%, 70%, even at least about 75%, 80%, 85%, or 90% above pre-treatment levels.
  • the pharmaceutical composition is administered in an amount and for a duration effective to increase plasma DPA levels by at least about 50% above pre-treatment levels. In some embodiments, the pharmaceutical composition is administered in an amount and for a duration effective to increase plasma DPA levels by at least about 55%, 60%, 65%, 70%, 75%, even at least about 80%, 85%, 90%, 95%, or 100% above pre-treatment levels. In selected embodiments, the pharmaceutical composition is administered in an amount and for a duration effective to increase plasma DPA levels by at least about 110%, 120%, even at least about 125% above pre-treatment levels.
  • the pharmaceutical composition is administered in an amount and for a duration effective to reduce arachidonic acid (AA) concentration in plasma by at least about 5% below pre-treatment levels. In certain embodiments, the pharmaceutical composition is administered in an amount and for a duration effective to reduce arachidonic (AA) concentration in plasma by at least about 6%, 7%, 8%, 9%, 10%, even at least about 11%, 12%, 13%, 14%, even at least about 15%, 16%, 17%, 18%, 19%, 20%, or 21%, 22%, 23%, 24% even at least about 25% below pretreatment levels.
  • the pharmaceutical composition is administered in an amount, and for a duration, effect to reduce plasma arachidonic acid concentration by at least about 25 ⁇ g/mL. In some embodiments, the pharmaceutical composition is administered in an amount and for a duration sufficient to reduce plasma AA levels by at least about 50 ⁇ g/mL, 55 ⁇ g/mL, 60 ⁇ g/mL, 65 ⁇ g/mL, even at least about 70 ⁇ g/mL, 75 ⁇ g/mL, 80 ⁇ g/mL, 85 ⁇ g/mL, 90 ⁇ g/mL, even at least about 95 ⁇ g/mL or 100 ⁇ g/mL.
  • the pharmaceutical composition described in Section 5.2 herein is administered in unit dosage forms as described in Section 5.3 above.
  • the pharmaceutical composition is administered in an amount of at least about 1 g per day. In some embodiments, the pharmaceutical composition is administered in an amount of at least about 2 g/day. In certain embodiments, the pharmaceutical composition is administered in an amount of at least about 3 g/day. In particular embodiments, the pharmaceutical composition is administered in an amount of at least about 4 g/day. In typical embodiments, the pharmaceutical composition is administered in an amount of about 2 g/day. In certain embodiments, the pharmaceutical composition is administered in an amount of about 3 g/day or about 4 g per day.
  • Methods are also provided for increasing the EPA:AA ratio, without regard to the patient's pre-treatment plasma triglyceride levels.
  • the methods comprise administering the pharmaceutical composition described in Section 5.2 herein to a patient having an EPA:AA ratio below about 0.25, in an amount and for duration sufficient to increase the patient's EPA:AA ratio to at least about 0.25.
  • the pharmaceutical composition is administered in an amount and for a duration sufficient to increase the patient's EPA:AA ratio to at least about 0.3, at least about 0.35, at least about 0.40, at least about 0.45, at least about 0.50, even to a level of at least about 0.55, 0.60, 0.61, 0.62, 0.63, 0.64, or 0.65.
  • the method comprises administering the pharmaceutical composition in an amount and for a duration effective to increase plasma EPA levels by at least 100% above pre-treatment levels.
  • the pharmaceutical composition is administered in an amount and for a duration effective to increase plasma EPA levels by at least about 200%, 250%, 300%, even at least about 350%, 400%, 450% or at least about 500% above Pre-treatment levels.
  • the pharmaceutical composition is administered for a time and in an amount effective to increase plasma EPA levels by at least about 550%, 600%, 650%, even at least about 700% above pre-treatment levels.
  • the pharmaceutical composition is administered in an amount and for a duration effective to increase plasma DHA levels by at least about 50% above pre-treatment levels. In particular embodiments, the pharmaceutical composition is administered in an amount and for a duration effective to increase plasma DHA levels by at least about 55%, 60%, 65%, 70%, even at least about 75%, 80%, 85%, or 90% above pre-treatment levels.
  • the pharmaceutical composition is administered in an amount and for a duration effective to increase plasma DPA levels by at least about 50% above pre-treatment levels. In some embodiments, the pharmaceutical composition is administered in an amount and for a duration effective to increase plasma DPA levels by at least about 55%, 60%, 65%, 70%, 75%, even at least about 80%, 85%, 90%, 95%, or 100% above pre-treatment levels. In selected embodiments, the pharmaceutical composition is administered in an amount and for a duration effective to increase plasma DPA levels by at least about 110%, 120%, even at least about 125% above pre-treatment levels.
  • the pharmaceutical composition is administered in an amount and for a duration effective to reduce arachidonic acid (AA) concentration in plasma by at least about 5% below pre-treatment levels. In certain embodiments, the pharmaceutical composition is administered in an amount and for a duration effective to reduce arachidonic (AA) concentration in plasma by at least about 6%, 7%, 8%, 9%, 10%, even at least about 11%, 12%, 13%, 14%, even at least about 15%, 16%, 17%, 18%, 19%, 20%, or 21%, 22%, 23%, 24% even at least about 25% below pre-treatment levels.
  • the pharmaceutical composition is administered in an amount, and for a duration, effect to reduce plasma arachidonic acid concentration by at least about 25 ⁇ g/mL. In some embodiments, the pharmaceutical composition is administered in an amount and for a duration sufficient to reduce plasma AA levels by at least about 50 ⁇ g/mL, 55 ⁇ g/mL, 60 ⁇ g/mL, 65 ⁇ g/mL, even at least about 70 ⁇ g/mL, 75 ⁇ g/mL, 80 ⁇ g/mL, 85 ⁇ g/mL, 90 ⁇ g/mL, even at least about 95 ⁇ g/mL or 100 ⁇ g/mL.
  • the pharmaceutical composition described in Section 5.2 herein is administered in unit dosage forms as described in Section 5.3 above.
  • the pharmaceutical composition is administered in an amount of at least about 1 g per day. In some embodiments, the pharmaceutical composition is administered in an amount of at least about 2 g/day. In certain embodiments, the pharmaceutical composition is administered in an amount of at least about 3 g/day. In particular embodiments, the pharmaceutical composition is administered in an amount of at least about 4 g/day. In typical embodiments, the pharmaceutical composition is administered in an amount of about 2 g/day. In certain embodiments, the pharmaceutical composition is administered in an amount of about 3 g/day or about 4 g per day.
  • Methods are also provided for increasing a patient's serum or plasma ApoCIII levels, without regard to the patient's pre-treatment plasma triglyceride levels.
  • the methods comprise administering the pharmaceutical composition described in Section 5.2 herein to a patient in need of lower ApoCIII levels, in an amount and for duration sufficient to decrease the patient's serum or plasma ApoCIII levels.
  • the patient is at risk for cardiovascular heart disease.
  • the pharmaceutical composition is administered in an amount and for a duration sufficient to decrease ApoCIII levels by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, even at least about 8%, 9% or 10% below pre-treatment levels.
  • compositions described herein is used to treat other disorders, including one or more of nonalcoholic steatohepatitis (NASH), hyperlipoproteinemia, including type III hyperlipoproteinemia, and metabolic syndrome.
  • NASH nonalcoholic steatohepatitis
  • hyperlipoproteinemia including type III hyperlipoproteinemia
  • metabolic syndrome including one or more of metabolic syndrome.
  • the pharmaceutical composition is used to reduce resistance to platelet aggregation inhibitors, such as Plavix, including use in the methods described in U.S. patent application Ser. No. 13/620,312, the disclosure of which is incorporated herein by reference in its entirety.
  • an improved process is presented for refining fish oil into pharmaceutical compositions comprising PUFAs in free acid form, and particularly for refining fish oil into the pharmaceutical compositions described in Section 5.2 herein.
  • the intermediate feedstock is prepared by transesterification of the body oil obtained from fish, for example fish from families Engraulidae, Clupeidae and Scombridae, by standard techniques well-known in the art, with process parameters adjusted so as to achieve a composition falling within the tolerances described in section 5.6.2 immediately below.
  • a crude triglyceride oil is extracted from fish, such as anchovy, sardine, mackerel and menhaden.
  • the crude triglyceride oil is then alkali refined, e.g. using sodium hydroxide, and deodorized, polished, and dried.
  • the PUFAs are then converted to esters, such as methyl esters or ethyl esters, by transesterification.
  • Transesterification can be performed, for example, by ethanolysis in the presence of ethanol and sodium ethoxide to produce ethyl esters. Transesterification is followed by at least one round, typically a plurality of rounds, of distillation.
  • triglyceride oil is alkali refined and deodorized, transesterified with ethanol, such as by ethanolysis in the presence of ethanol and sodium ethoxide, and then subject to one or more rounds of fractional distillation.
  • FIG. 2 presents a flow chart of an exemplary process for producing the intermediate feedstock.
  • fish are cooked in water and the resulting mixture of liquids and solids are filtered and the liquid portion centrifuged to remove the aqueous phase.
  • the oily fraction remaining from the preceding step is treated with alkali to neutralize any free fatty acids present, followed by water washing.
  • alkali refined fish oil in the triglyceride form is deodorized and environmental pollutants reduced, e.g. by distillation.
  • the dried deodorized fish oil is converted to the ethyl ester form using reaction with ethanol, catalyzed by the use of sodium ethoxide.
  • the excess ethanol is removed by distillation and the ethyl esters washed with a citric acid solution and then with water.
  • the ethyl esters are distilled to achieve the required concentration of EPA ethyl ester (EPA-EE) and DHA ethyl ester (DHA-EE) for use as an intermediate feedstock.
  • EPA-EE EPA ethyl ester
  • DHA-EE DHA ethyl ester
  • multiple rounds of distillation are performed. The exact conditions used are adjusted depending on the composition of the input ethyl ester composition in order to achieve the required concentration of EPA-EE and DHA-EE for the intermediate feedstock, as detailed in section 5.6.2 immediately below.
  • the intermediate feedstock composition comprises a plurality of species of omega-3 PUFAs, each present substantially in the form of an ethyl ester.
  • the intermediate feedstock composition comprises EPA, DHA, and DPA, each substantially in the form of an ethyl ester.
  • the intermediate feedstock composition comprises EPA ethyl ester (EPA-EE), DHA-EE, and DPA-EE, in an amount, calculated as a percentage by area on GC chromatogram of all fatty acid ethyl esters in the composition, falling within the range of ⁇ 3 SD to +3 SD of the averages respectively recited in Table 9.
  • each of EPA-EE, DHA-EE, and DPA-EE falls within ⁇ 2 SD to +2 SD of the respectively recited average.
  • each of EPA-EE, DHA-EE, and DPA-EE falls with ⁇ 1 SD to +1 SD of the respectively recited average.
  • the intermediate feedstock composition comprises EPA-EE, DHA-EE, and DPA-EE within the range set by their respective minima and maxima area percentages among the batches described in Table 8.
  • the composition further comprises one or more omega-3 polyunsaturated fatty acids, each substantially in the form of the ethyl ester, selected from the group consisting of: ⁇ -linolenic acid (C18:3 n-3), moroctic acid (C18:4 n-3), eicosatrienoic acid (C20:3 n-3), eicosatetraenoic acid (C20:4 n-3), and heneicosapentaenoic acid (C21:5 n-3).
  • omega-3 polyunsaturated fatty acids each substantially in the form of the ethyl ester, selected from the group consisting of: ⁇ -linolenic acid (C18:3 n-3), moroctic acid (C18:4 n-3), eicosatrienoic acid (C20:3 n-3), eicosatetraenoic acid (C20:4 n-3), and heneicosapentaenoic acid (C21:5
  • the one or more further species of omega-3-EE if present, is present in an amount, calculated as a percentage by area on GC chromatogram of all fatty acid ethyl esters in the composition, falling within the range of ⁇ 3 SD to +3 SD of the averages respectively recited in Table 9.
  • each species falls within ⁇ 2 SD to +2 SD of the respectively recited average.
  • each species falls with ⁇ 1 SD to +1 SD of the respectively recited average.
  • the one or more further species of omega-3-EE if present, is present in an amount, calculated as a percentage by area on GC chromatogram of all fatty acid ethyl esters in the composition, falling within the range set by their respective minima and maxima area percentages among the batches described in Table 8.
  • the intermediate feedstock composition also comprises at least one species of omega-6 PUFA.
  • the composition comprises ethyl esters of one or more omega-6 polyunsaturated fatty acid selected from the group consisting of: linoleic acid (C18:2 n-6), gamma-linolenic acid (C18:3 n-6), eicosadienoic acid (C20:3 n-6), dihomo-gamma-linolenic acid (“DGLA”) (C20:3 n-6), arachidonic acid (C20:4 n-6) (“AA”), and docosapentaenoic acid (C22:5 n-6).
  • omega-6 PUFA is present substantially in ethyl ester, form.
  • the one or more species of omega-6-EE if present, is present in an amount, calculated as a percentage by area on GC chromatogram of all fatty acid ethyl esters in the composition, falling within the range of ⁇ 3 SD to +3 SD of the averages respectively recited in Table 9.
  • each species falls within ⁇ 2 SD to +2 SD of the respectively recited average.
  • each species falls with ⁇ 1 SD to +1 SD of the respectively recited average.
  • the one or more further species of omega-3-EE if present, is present in an amount, calculated as a percentage by area on GC chromatogram of all fatty acid ethyl esters in the composition, falling within the range set by their respective minima and maxima area percentages among the batches described in Table 8.
  • the intermediate feedstock composition comprises EPA ethyl ester (EPA-EE) in an amount, calculated as a percentage by area on GC chromatogram of all fatty acid ethyl esters in the composition, of about 45.0-about 53.0% (a/a). In certain embodiments, EPA-EE is present in an amount of about 48.40-about 50.04% (a/a). In various embodiments, EPA-EE is present in an amount of about 48.67-about 49.77% (a/a). In some embodiments, the intermediate feedstock composition comprises EPA-EE in an amount of about 48.95-about 49.49% (a/a). In certain embodiments, the intermediate feedstock composition comprises EPA-EE in an amount of about 49.22% (a/a).
  • EPA-EE EPA ethyl ester
  • EPA-EE is present in an amount of about 44.20% (a/a)-about 46.92% (a/a). In some embodiments, EPA-EE is present in an amount of about 45.56% (a/a).
  • EPA-EE is present in an amount of about 425-460 mg/g.
  • the intermediate feedstock composition comprises DHA ethyl ester (DHA-EE) in an amount, calculated as a percentage by area on GC chromatogram of all fatty acid ethyl esters in the composition, of about 13.0-about 20.0% (a/a). In various embodiments, DHA-EE is present in an amount of about 16.43-about 18.28% (a/a). In various embodiments, the feedstock comprises DHA-EE in an amount of about 16.74-about 17.98% (a/a). In some embodiments, the intermediate feedstock composition comprises DHA-EE in an amount of about 17.05%-about 17.67% (a/a). In certain embodiments, the intermediate feedstock comprises DHA-EE in about 17.4% (a/a).
  • DHA-EE DHA ethyl ester
  • the intermediate feedstock comprises DHA in an amount of about 14.77% (a/a)-about 17.87% (a/a). In some embodiments, the intermediate feedstock comprises DHA in an amount of about 16.32% (a/a).
  • the intermediate feedstock comprises DHA in an amount of 150-170 mg/g.
  • DPA-EE is present in an amount of about 4.10 to about 6.74% (a/a). In some embodiments, DPA-EE is present in an amount of about 4.54 to about 6.30% (a/a). In various embodiments, DPA-EE is present in an amount of about 4.98 to about 5.86% (a/a). In certain embodiments, DPA-EE is present in an amount of about 5.42% (a/a).
  • DPA-EE is present in an amount of about 0.41 to about 0.70% (a/a). In certain embodiments, DPA-EE is present in an amount of about 0.56% (a/a).
  • the intermediate feedstock composition further comprises the ethyl ester of arachidonic acid (C20:4 n-6).
  • AA-EE is present in an amount of about 1.72 to about 2.81% (a/a).
  • arachidonic acid-EE is present in an amount of about 1.9 to about 2.63% (a/a).
  • arachidonic acid-EE is present in an amount of about 2.09 to about 2.45% (a/a).
  • arachidonic acid-EE is present in an amount of about 2.27% (a/a).
  • arachidonic acid-EE is present in an amount of no more than 3.0% (a/a). In some embodiments, arachidonic acid-EE is present in an amount of no more than 4.0% (a/a).
  • ⁇ -linolenic acid-EE is, in certain embodiments, present in an amount of about 0.3-about 0.45% (a/a). In some embodiments, ⁇ -linolenic acid-EE is present in an amount of about 0.4% (a/a).
  • ⁇ -linolenic acid-EE is present in an amount of about 0.24% (a/a)-0.62% (a/a).
  • ⁇ -linolenic acid-EE is present in an amount of about 0.43% (a/a).
  • moroctic acid-EE is present in an amount, calculated as a percentage by area on GC chromatogram of all fatty acid ethyl esters in the composition, of about 0.60-about 2.03% (a/a). In some embodiments, moroctic acid-EE is present in an amount of about 0.84 to about 1.80% (a/a). In various embodiments, moroctic acid-EE is present in an amount of about 1.10 to about 1.60% (a/a). In particular embodiments, moroctic acid-EE is present in an amount of about 1.32% (a/a).
  • moroctic acid-EE is present in an amount of about 0.64% to about 1.93% (a/a). In particular embodiments, moroctic acid-EE is present in an amount of about 1.28% (a/a).
  • eicosatrienoic acid-EE is present in an amount of less than about 0.1% (a/a). In some embodiments, eicosatrienoic acid-EE is present in an amount of less than about 0.4% (a/a).
  • eicosatetraenoic acid-EE is, in certain embodiments, present in an amount of about 1.57 to about 2.10% (a/a). In some embodiments, eicosatetraenoic acid-EE is present in an amount of about 1.66 to about 2.02% (a/a). In certain embodiments, eicosatetraenoic acid-EE is present in an amount of about 1.75 to about 1.93% (a/a). In specific embodiments, eicosatetraenoic acid-EE is present in an amount of about 1.84% (a/a).
  • eicosatetraenoic acid-EE is present in an amount of about 1.42 to about 2.49% (a/a). In some embodiments, eicosatetraenoic acid-EE is present in an amount of about 1.95% (a/a).
  • the heneicosapentaenoic acid-EE is present in an amount of about 2.25 to about 2.36% (a/a). In various embodiments, the heneicosapentaenoic acid-EE is present in an amount of about 2.27-about 2.34% (a/a). In some embodiments, the heneicosapentaenoic acid-EE is present in an amount of about 2.29 to about 2.32% (a/a). In particular embodiments, the heneicosapentaenoic acid-EE is present in an amount of about 2.31% (a/a).
  • the heneicosapentaenoic acid-EE is present in an amount of about 1.42 to about 2.76% (a/a). In particular embodiments, the heneicosapentaenoic acid-EE is present in an amount of about 2.09% (a/a).
  • linoleic acid-EE is present in an amount of about 0.53 to about 0.56% (a/a). In some embodiments, linoleic acid-EE is present in an amount of about 0.53 to about 0.55% (a/a). In some embodiments, linoleic acid-EE is present in an amount of about 0.54 to about 0.55% (a/a). In certain embodiments, linoleic acid-EE is present in an amount of about 0.54% (a/a).
  • linoleic acid-EE is present in an amount of about 0.38 to about 0.83% (a/a). In certain embodiments, linoleic acid-EE is present in an amount of about 0.60% (a/a).
  • gamma-linolenic acid-EE is present, in exemplary embodiments, in an amount less than 0.1% (a/a). In embodiments of the intermediate feedstock that further comprise the ethyl ester of gamma-linolenic acid (C18:3 n-6), gamma-linolenic acid-EE is present in an amount less than 0.4% (a/a).
  • eicosadienoic acid-EE is present in an amount of about 0.00 to about 0.63% (a/a) in various exemplary embodiments. In some embodiments, eicosadienoic acid-EE is present in an amount of about 0.00 to about 0.45% (a/a). In certain embodiments, eicosadienoic acid-EE is present in an amount of about 0.00 to about 0.27% (a/a). In particular embodiments, eicosadienoic acid-EE is present in an amount of about 0.09% (a/a).
  • eicosadienoic acid-EE is present in an amount of about 0.00 to about 0.54% (a/a). In particular embodiments, eicosadienoic acid-EE is present in an amount of about 0.25% (a/a).
  • DGLA-EE is present in an amount of about 0.35 to about 0.68% (a/a). In some embodiments, dihomo-gamma-linolenic acid-EE is present in an amount of about 0.41 to about 0.63% (a/a). In some embodiments, dihomo-gamma-linolenic acid-EE is present in an amount of about 0.46 to about 0.57% (a/a).
  • dihomo-gamma-linolenic acid-EE is present in an amount of about 0.26 to about 0.55% (a/a). In some embodiments, dihomo-gamma-linolenic acid-EE is present in an amount of about 0.40% (a/a).
  • docosapentaenoic acid C22:5 n-6
  • docosapentaenoic acid-EE is present in an amount of about 0.54 to about 0.80% (a/a). In some embodiments, docosapentaenoic acid-EE is present in an amount of about 0.59% to about 0.76% (a/a). In various embodiments, docosapentaenoic acid-EE is present in an amount of about 0.63% to about 0.72% (a/a). In particular embodiments, docosapentaenoic acid-EE is present in an amount of about 0.67% (a/a).
  • docosapentaenoic acid (C22:5 n-6)-EE is present in an amount of about 1.45% to about 7.21% (a/a). In some embodiments, docosapentaenoic acid (C22:5 n-6)-EE is present in an amount of about 4.33% (a/a).
  • Intermediate transesterified feedstock having a composition as above-defined is subjected to urea inclusion complexation.
  • the amount of urea used for complexation falls within an algorithmically-determined range.
  • an improved process for refining fish oil into pharmaceutical compositions comprising PUFAs in free acid form, particularly for refining fish oil into the pharmaceutical compositions described herein.
  • the improvement comprises subjecting an intermediate feedstock of transesterified fish oil comprising the ethyl esters of various omega-3 and omega-6 PUFA species in defined percentage ranges to a step of urea inclusion complexation, wherein the amount of urea used for complexation is within the range calculated according to (i) formula I(a), or (ii) according to formula I(b), or (iii) according to both formula I(a) and formula I(b) with the urea amount set to a value within the range set by, and inclusive of, the results of formulae I(a) and I(b), such as an average thereof, wherein the formulae are as follows:
  • the DHA and EPA target values are selected based on the desired final composition.
  • the enrichment factors, F enrichment-DHA and F enrichment-EPA can be the same or different. In a typical embodiment, F enrichment-DHA and F enrichment-EPA are the same, with a value of about 100/0.34, or about 300.
  • complexation is performed according to standard techniques. See, e.g., U.S. Pat. Nos. 4,377,526; 5,106,542; 5,243,046; 5,679,809; 5,945,318; 6,528,669; 6,664,405; 7,541,480; 7,709,668; and 8,003,813, the disclosures of which are incorporated herein by reference.
  • the intermediate feedstock is mixed with a solution of urea in ethanol.
  • the complexation is carried out at 60° C.-80° C., the mixture is then cooled, and the mixture is thereafter filtered or centrifuged to remove urea complexes. Ethanol is removed by distillation and the oil washed several times with water.
  • the uncomplexed PUFA esters are hydrolyzed to free fatty acids by standard techniques.
  • the composition is further purified by distillation, either before or after hydrolysis, and further finished using one or more of the following standard techniques: treatment with active carbon, chromatographic purification, solvent removal, bleaching, e.g. with bleaching earth, and supercritical extraction.
  • Antioxidants such as BHA or ⁇ -tocopherol, are added.
  • Urea inclusion complexation is a standard step often used in the refining of fish oils to remove saturated and mono-unsaturated long chain fatty acids, thus enriching for desired long chain omega-3 polyunsaturated fatty acids in the resulting composition.
  • U.S. Pat. No. 4,377,526 studies designed to characterize the effects of various physiochemical parameters on the process (see, e.g., Hayes et al., “Triangular Phase Diagrams To Predict The Fractionation Of Free Fatty Acid Mixtures Via Urea Complex Formation,” Separation Sci. Technol.
  • compositional requirements for the intermediate ethyl ester feedstock are presented in Section 5.6.2 and Examples 2 and 4. See Tables 3-6, 8-9.
  • the optimal amount of urea required to be used was found to be determined by (i) formula I(a), or (ii) according to formula I(b), or (iii) according to both formula I(a) and formula I(b), with the urea amount set to a value within the range set by, and inclusive of, the results of formulae I(a) and I(b), such as the average of the two results, wherein the formulae are as follows:
  • the enrichment factors, F enrichment-DHA and F enrichment-EPA can be the same or different.
  • composition of the intermediate transesterified feedstock and the final pharmaceutical composition (“active pharmaceutical ingredient”, or “API”), was determined by gas chromatography. Results are compiled in Tables 3-6, below.
  • the urea complexation step substantially decreased the percentage of saturated fatty acids and mono-unsaturated fatty acids in the resulting composition, thereby substantially enriching for polyunsaturated fatty acids. See Tables 3-6, and FIG. 3A . Unexpectedly, however, performing urea complexation using urea amounts falling within the algorithmically-determined range had a differential effect on enrichment of individual species of omega-3 polyunsaturated fatty acids and omega-6 polyunsaturated fatty acids.
  • Table 7 provides a qualitative assessment of enrichment of various species of polyunsaturated fatty acid, comparing prevalence in the ethyl ester intermediate feedstock to that in the free acid API, averaged across the four production batches described in Tables 3-6. See also FIG. 3B .
  • omega-3 polyunsaturated fatty acids are substantially enriched, the effect of urea complexation on omega-6 PUFAs, as a class, is not as predictable.
  • the omega-6 species DGLA and docosapentaenoic acid are reduced in prevalence; gamma-linolenic acid and arachidonic acid are increased; and there is little or no effect on linolenic acid and eicosadienoic acid.
  • omega-3 docosapentaenoic acid species DPA (C22:5 n-3)
  • DPA docosapentaenoic acid
  • C22:5 n-6 docosapentaenoic acid
  • omega-3 docosapentaenoic acid species DPA
  • omega-6 docosapentaenoic acid species is present at an average concentration of 0.46% (a/a).
  • DPA is the third most prevalent species of polyunsaturated fatty acid in the API, exceeded only by EPA and DHA. At this level, the DPA concentration is also 10-fold greater than that reported for an earlier pharmaceutical composition of omega-3 polyunsaturated fatty acids in free acid form, termed Purepa, in which DPA was reported to be present at a level of 0.5%. See Belluzzi et al., Dig. Dis. Sci. 39(12): 2589-2594 (1994).
  • DPA omega-3 docosapentaenoic acid species
  • DPA is the third most prevalent species of polyunsaturated fatty acid in the pharmaceutical compositions analyzed in the examples above, and is present at a concentration 10-fold that in Purepa, an earlier pharmaceutical composition of omega-3 polyunsaturated fatty acids in free acid form.
  • DPA is an intermediate in the biosynthetic pathway from EPA to DHA (see FIG. 1 )
  • gene expression profiling experiments were conducted.
  • Hep G2 hepatocarcinoma cells were cultured in serum-free Dulbecco's Modified Eagle's Medium (DMEM) (Sigma-Aldrich) with 4.5 g/l glucose, 1-glutamine, NaHCO 3 and pyridoxine HCl supplemented with 1% (vol/vol) nonessential amino acids, 1% Na-pyruvate, 1% penicillin/streptomycin, and 10% (vol/vol) fatty acid-free bovine serum albumin (BSA), all purchased from Gibco BRL.
  • DMEM Dulbecco's Modified Eagle's Medium
  • BSA bovine serum albumin
  • Ratios of EPA (at 100 ⁇ M), DHA (at 40 ⁇ M), and DPA (at 11 ⁇ M) were chosen to approximate the ratios of EPA, DHA, and DPA in the pharmaceutical compositions (API) described in Section 5.2 and Example 5 (see Tables 12 and 13). Absolute concentrations were chosen to best approximate—within the constraint imposed by the desired compositional ratios and constraints imposed by the culture conditions—the plasma ranges observed in the 2 g and 4 g treatment arms of the EVOLVE trial (see Example 10).
  • the lower DPA concentration (1 ⁇ M) was chosen to approximate the systemic exposure that would be expected from use of the earlier pharmaceutical composition of omega-3 polyunsaturated fatty acids in free acid form, termed Purepa, in which DPA was reported to be present at a level 1/10 that seen in the current pharmaceutical composition.
  • the HepG2 cells were incubated with the identified fatty acid (EPA, DHA, DPA, or specified mixtures) for a total of 48 hours prior to cell harvest and RNA extraction.
  • the identified fatty acid EPA, DHA, DPA, or specified mixtures
  • DPA is an intermediate in the biosynthetic pathway from EPA to DHA, and although DPA is known to retroconvert to EPA in vivo, Kaur et al., Prog. Lipid Res. 50:28-34 (2011), we observed markedly different effects on hepatic cell gene expression after incubating with DPA, as compared to effects seen with EPA and with DHA.
  • DPA concentration of DPA was assessed. As noted above, the higher DPA concentration (at 11 ⁇ M), was chosen so that ratios of EPA (at 100 ⁇ M), DHA (at 40 ⁇ M), and DPA (at 11 ⁇ M) would approximate the ratios of EPA, DHA, and DPA in the pharmaceutical compositions (API) described in Section 5.2 and Example 5, with absolute concentrations chosen to best approximate—within the constraint imposed by the desired compositional ratio and constraints imposed by the culture conditions—the plasma ranges observed in the treatment arms of the EVOLVE trial (see Example 10).
  • API pharmaceutical compositions
  • the lower DPA concentration (1 ⁇ M) was chosen to approximate the systemic exposure that would be expected from use of the earlier pharmaceutical composition of omega-3 polyunsaturated fatty acids in free acid form, termed Purepa, in which DPA was reported to be present at a level 1/10 that seen in the current pharmaceutical composition.
  • the threshold dose effect can also be seen by focusing on three categories of genes known to be relevant to the clinical effects of omega-3 polyunsaturated fatty acids: genes involved in lipid metabolism, genes involved in cardiovascular physiology, and genes involved in inflammation (assignment of genes to the identified categories performed automatically by the iReportTM software). Results are tabulated in Table 24, below.
  • the 11 ⁇ M in vitro concentration is lower than the ⁇ 90 ⁇ M plasma concentration observed in the 4 g/day EVOLVE patients. See Example 10.
  • the results thus predict that a clinically-relevant dose of the DPA-enriched compositions described in Section 5.2 and Example 5 (see Table 12 and 13) will have significant metabolic effects, including effects on lipid metabolism, cardiovascular physiology, and inflammation. Few, if any, of these DPA-specific effects would be expected at the 10-fold lower DPA levels seen in the earlier Purepa preparation.
  • the 22 lipid metabolism genes that demonstrate statistically significant changes in expression at the 11 ⁇ M DPA concentration, but not 1 ⁇ M concentration, are identified in Table 25, below.
  • DPA's effects on expression of several of these genes suggest that DPA, at analogous in vivo concentration, should lead to improvement in various clinically-relevant lipid parameters.
  • DPA at 11 ⁇ M upregulates ACADSB, the short/branched chain acyl-CoA dehydrogenase.
  • the ACADSB gene product is involved in breakdown of triglycerides; upregulation would be expected to result in lower serum triglyceride levels.
  • HMGCR which is downregulated, encodes HMG-CoA reductase, the rate-limiting enzyme for cholesterol synthesis and the target for statin inhibition.
  • statin action downregulation of expression of the HMGCR gene by DPA should lead to favorable decreases in the total cholesterol:HDL ratio.
  • SQLE which is also downregulated, encodes squalene epoxidase, which catalyzes the first oxygenation step in sterol biosynthesis and is thought to be one of the rate-limiting enzymes in this pathway. Downregulation of SQLE should also lead to reduced total cholesterol levels.
  • DPA affects expression of genes in multiple metabolic pathways, including genes in categories known to be relevant to the clinical effects of omega-3 polyunsaturated fatty acids: genes involved in lipid metabolism, genes involved in cardiovascular physiology, and genes involved in inflammation. Significant second-order effects are expected, given the changes we observed in the expression of genes that encode proteins that themselves affect gene expression, and in genes encoding proteins that affect post-transcriptional modification.
  • DPA DPA-driven upregulation of ACADSB, the short/branched chain acyl-CoA dehydrogenase, expected to result in lower serum triglyceride levels; downregulation of HMGCR, which, like treatment with statins, should lead to favorable decreases in the total cholesterol:HDL ratio; and downregulation in SQLE, which should analogously lead to reduced total cholesterol levels.
  • ACADSB the short/branched chain acyl-CoA dehydrogenase
  • STUDY DRUG (Epanova®)—Type A porcine soft gelatin capsules coated with Eudragit NE 30-D (Evonik Industries AG) were prepared, each containing one gram of a PUFA composition in which the polyunsaturated fatty acids are present in the form of free fatty acids (“API”).
  • the encapsulated API had the composition set forth in Table 26.
  • FIG. 4 provides a treatment flow diagram illustrating the design of the study: briefly, after a washout period, subjects were randomized to one of two treatment sequences:
  • Low-fat period meals (periods 1 and 2): no breakfast (fasting); no-fat lunch (0 g fat; 600 kcal) after the 4-hour blood draw; low-fat dinner (9 g fat; 900 kcal) after the 12-hour blood draw.
  • Low-fat food items were: fat-free yogurt, fruit cup, fat-free Fig Newtons, Lean Cuisine meal.
  • High-fat period meals (periods 3 and 4): high-fat breakfast (20 g fat; 600 kcal) immediately after the 0.5 hour blood draw; high-fat lunch (30 g fat; 900 kcal) after the 4-hour blood draw; and high-fat dinner (30 g fat; 900 kcal) after the 12-hour blood draw.
  • High-fat food items were: breakfast sandwich & powdered mini-donuts; cheese pizza; potato chips; and cheese and ham panini.
  • Pre-trial screening washout requirements were: 60 days for fish oil, EPA or DHA supplements or fortified foods; 7 days for fish, flaxseed, perilla seed, hemp, spirulina, or black currant oils, statins, bile acid sequestrants, cholesterol absorption inhibitors or fibrates.
  • the crossover washout period was at least 7 days.
  • the primary determinants of bioavailability ln-transformed area under the plasma concentration versus time curve (AUC t ) and maximum measured plasma concentration (C max ) over a 24-hour interval for the baseline-adjusted change in total and individual EPA and DHA concentrations.
  • Plasma concentrations were baseline-adjusted prior to the calculation of pharmacokinetic parameters. Figures are plotted for the baseline-adjusted change in geometric means (ln-transformed).
  • ANOVA Analysis of variance
  • Ratios of means were calculated using the least square means for ln-transformed AUC 0-t , AUC 0-inf , and C max .
  • the ratios of means and their 90% confidence intervals are to lie above the upper limit of 125.00% for AUC 0-t , AUC 0-inf and C max in order to show Epanova® has superior relative bioavailability compared to Lovaza® with regards to diet.
  • Study population The study enrolled 54 healthy adults, 41 males (75.9%) and 13 females (24.1%), aged 21 to 77. All of the treatment periods were completed by 51 subjects (94.4%), with 53 subjects (98.1%) completing the low fat portion of the study. The population was predominantly Black or African-American (66.7%) with 31.5% White and 1.8% Asian.
  • FIG. 5 compares the bioavailability of total EPA+DHA (baseline-adjusted change) following a single dose (4 g) of Lovaza® during the high-fat and low-fat periods (fasted dose conditions), confirming that the bioavailability of Lovaza® is significantly decreased with the low-fat diet.
  • the baseline-adjusted change in total plasma EPA+DHA levels show that the AUC t for Lovaza® in the low-fat meal period is decreased by 83.3% compared to Lovaza® in the high-fat meal period: 661.6 vs 3959.5 nmol-h/mL, respectively (p ⁇ 0.0001) (LS mean data in Table 27, below).
  • FIG. 6 compares the bioavailability of total EPA+DHA (baseline-adjusted change) during the high-fat period following a single dose (4 g) of Lovaza® versus a single dose (4 g) of Epanova®, demonstrating that in the high-fat meal periods, in which the bioavailability of Lovaza® was confirmed to be greatest, the bioavailability EPA+DHA was nonetheless significantly greater when administered in free fatty acid form (Epanova®) than as the corresponding ethyl ester omega-3 composition (Lovaza®) (p ⁇ 0.0007).
  • FIG. 7 compares the bioavailability of total EPA+DHA (baseline-adjusted change) following a single dose of Epanova® vs. Lovaza® during the low-fat diet period, demonstrating that the baseline-adjusted change in total plasma EPA+DHA levels show a 4.6-fold greater AUC t for Epanova® than Lovaza® during low-fat meal periods: 3077.8 vs. 668.9 nmol-h/mL, respectively (p ⁇ 0.0001) (LS mean data in Table 28, below).
  • FIG. 8 compares the bioavailability of EPA (baseline-adjusted change) following a single dose of Epanova® vs. Lovaza® during the low-fat diet period, showing a 13.5-fold greater AUC t for Epanova® than Lovaza® during low-fat meal periods: 578.2 vs. 42.7 ⁇ g ⁇ h/mL, respectively (p ⁇ 0.0001) (LS mean data are presented in Table 29, below).
  • FIG. 9 compares the bioavailability of DHA (baseline-adjusted change) following a single dose of Epanova® vs. Lovaza® during the low-fat diet period, showing a 2.2-fold greater AUC t for Epanova® than Lovaza® during low-fat meal periods: 383.1 vs 173.4 ⁇ g ⁇ hr/mL, respectively (p ⁇ 0.0001) (LS mean data presented in Table 30, below).
  • the 2.2-fold greater DHA bioavailability in Epanova® vs Lovaza® occurred despite there being 42% less DHA in the Epanova® formulation.
  • FIGS. 10A and 10B present individual subject AUC 0-t responses during the low-fat and high diets expressed as the ratio (%) of low-fat AUC 0-t to high-fat AUC 0-t . Negative ratios were not plotted. The data show that during the low-fat diet period, 30 of 54 (56%) subjects on Epanova® (free fatty acids) versus 3 of 52 (6%) on Lovaza® (ethyl esters) maintained an AUC t that was ⁇ 50% of the respective high-fat diet period AUC t .
  • FIG. 11 is a treatment flow diagram illustrating the design of the 14 day comparative bioavailability trial, in which study drug (Lovaza® or Epanova®) was consumed with a low fat breakfast. In contrast, doses were given fasting in the low fat arm of the original ECLIPSE trial described in Example 7.
  • FIG. 12A plots the mean un-adjusted total EPA+DHA concentrations versus time (linear scale), both for treatment with Lovaza® and treatment with Epanova®.
  • FIG. 12B is a histogram showing the difference in unadjusted EPA+DHA (nmol/mL) for the time points bracketed in FIG. 12A .
  • FIGS. 12A and 12B demonstrate that after 14-days of dosing, accumulation of EPA+DHA from Epanova® was 2.6 fold higher than Lovaza® in subjects maintained on a low-fat diet.
  • FIG. 13 plots mean baseline-adjusted plasma total EPA+DHA concentrations versus time (linear scale) for treatment with Lovaza® vs. treatment with Epanova® in the 14 day comparative bioavailability study, demonstrating that after 14-days of dosing with a low-fat meal, EPA+DHA levels (AUC 0-24 ) from Epanova® were 5.8 fold higher than Lovaza® in subjects maintained on a low-fat diet.
  • FIG. 14A is a histogram that plots the increases from baseline to steady state in unadjusted blood levels for EPA+DHA in the Lovaza® and Epanova® arms of the 14 day comparative bioavailability study, demonstrating that blood levels of EPA+DHA increased 316% from baseline to steady-state in the Epanova® cohort compared to 66% in the Lovaza® cohort.
  • FIG. 14A is a histogram that plots the increases from baseline to steady state in unadjusted blood levels for EPA+DHA in the Lovaza® and Epanova® arms of the 14 day comparative bioavailability study, demonstrating that blood levels of EPA+DHA increased 316% from baseline to steady-state in the Epanova® cohort compared to 66% in the Lovaza® cohort.
  • 14B is a histogram that plots the increases from baseline to steady state in unadjusted C avg for EPA+DHA in the Lovaza® and Epanova® arms of the 14 day comparative bioavailability study, demonstrating that average concentration (C avg ) levels of EPA+DHA increased 448% from baseline in the Epanova® cohort compared to 90% in the Lovaza® cohort.
  • FIG. 15A is a histogram that plots the increases from baseline to steady state for total blood levels of DHA in the Lovaza® and Epanova® arms of the 14 day comparative bioavailability study, demonstrating that levels of DHA increased 109% from baseline to steady-state in the Epanova® cohort compared to 34% in the Lovaza® cohort.
  • FIG. 15B plots the increases from baseline to steady state for DHA C avg levels in the Epanova® cohort compared to Lovaza® cohort in the 14 day comparative bioavailability study, and demonstrates that average concentration (C avg ) levels of DHA increased 157% from baseline in the Epanova® cohort compared to 47% in the Lovaza® cohort.
  • FIG. 16A is a histogram that plots the increases from baseline to steady state for total EPA levels in blood in the Lovaza® and Epanova® arms of the 14 day comparative bioavailability study, and demonstrates that Levels of EPA increased 1021% from baseline to steady-state in the Epanova® cohort compared to 210% in the Lovaza® cohort.
  • FIG. 16B plots the average concentration increases from baseline to steady-state, and demonstrates that C avg levels of EPA increased 1,465% from baseline in the Epanova® cohort compared to 297% in the Lovaza® cohort.
  • the Sprague Dawley rat was selected for this study because it was the rat strain used in the toxicology program conducted with Lovaza®, and thus permitted direct comparison of the data from the present study with Epanova® to publicly available rat toxicity data in the Lovaza® Summary Basis of Approval.
  • the Sprague Dawley rats provide a model that is recognized to predict the effects of omega-3 PUFAs on lipid changes for triglycerides and total cholesterol in human subjects. Results at 13 weeks are shown in Table 32, below.
  • Epanova® provided not only markedly higher maximum plasma concentrations (C max ) of DHA and EPA than Lovaza®, but also provided markedly higher AUC (0-t) for the two omega-3 species; AUC (0-t) is a measure of systemic exposure.
  • C max maximum plasma concentrations
  • AUC (0-t) is a measure of systemic exposure.
  • the greater bioavailability and long term systemic exposure of these two omega-3 PUFA species with Epanova® therapy resulted in long term differences in lipid lowering efficacy, with Epanova® effecting substantially greater reductions in plasma triglycerides and in total cholesterol than was seen with LOVAZA®.
  • the compositions described herein thus provide greater efficacy with respect to two clinically important cardiovascular parameters.
  • STUDY DRUG (Epanova®)—Type A porcine soft gelatin capsules were prepared, each containing one gram (1 g) of a PUFA composition comprising omega-3 PUFAs in free acid form (“API”). The capsules were coated with Eudragit NE 30-D (Evonik Industries AG). The API had the composition given in batch 2 of Table 10 (see Example 4, above).
  • PLACEBO Capsules were prepared containing olive oil for use as a control.
  • a 12-week double-blind, olive oil-controlled, study was performed in the United States, Denmark, Hungary, India, Netherlands, Russia, and Ukraine. Subjects were selected on the basis of high triglyceride levels, in the range of 500-2,000 mg/dL. Subjects were randomly selected to receive 2, 3, or 4 grams of Epanova®, or 4 grams of olive oil as placebo.
  • the general trial design is illustrated in FIG. 17 , with FIG. 18 providing a more detailed treatment flow diagram further identifying the timing of study visits.
  • the primary study endpoint was percent change in plasma triglyceride levels from baseline to end-of-treatment (“EOT”).
  • the secondary endpoint was percent change in plasma non-HDL-cholesterol (“Non-HDL-C”) from baseline to EOT.
  • FIG. 19 shows the disposition of all subjects, with “AE” abbreviating “adverse event” and “SAE” abbreviating “serious adverse event.”
  • Table 33 shows average triglyceride (TG) and cholesterol measurements for the subjects at randomization (prior to treatment), in comparison to desirable levels as described by the Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), produced by the National Heart Lung and Blood Institute.
  • Epanova® achieved the primary endpoint of triglyceride reduction and the secondary endpoint of reduction of non-HDL cholesterol (total cholesterol level minus the level of HDL-cholesterol) (“non-HDL-C”) at all doses, and produced statistically significant reductions in multiple established markers of atherogenicity: Apo B, Apo CIII, RLP, and LpPLA2.
  • Epanova® provided additive efficacy on key lipid parameters: TG; non-HDL-C; HLD-c; total cholesterol (TC); and TC/HDL-C.
  • Plasma levels of EPA, DHA, and DPA the three species of omega-3 lc-PUFA in greatest abundance in Epanova®—were measured at baseline and at end-of treatment (EOT), as were plasma levels of the omega-6 lc-PUFA, arachidonic acid (AA).
  • Table 34 below, separately tabulates average baseline, median baseline, average end-of-treatment (EOT), and median EOT plasma levels for EPA, DHA, DPA, and AA, as well as TG, NHDL-C, HDL-C, VLDL-C, and LDL-C.
  • EPA:AA ratios at baseline were about 0.10 (see Table 37, below).
  • FIGS. 20A-20E plot the average baseline and end-of-treatment (“EOT”) plasma levels (inn/mL) for EPA ( FIG. 20A ), DHA ( FIG. 20B ), DPA ( FIG. 20C ) and AA ( FIG. 20D ), for each of the treatment arms in the EVOLVE trial.
  • FIG. 20E compares average baseline and EOT EPA levels for each treatment arm and the control (olive oil) arm to values earlier reported for ECLIPSE (see Example 7), 14-day bioavailability study(see Example 8), a statin drug-drug-interaction study (Statin DDI), and the unrelated JELIS trial conducted by others with a different omega-3 PUFA formulation (“JELIS”).
  • EOT end-of-treatment
  • FIGS. 21A-21D plot median baseline and end-of-treatment (EOT) plasma levels (in ⁇ g/mL) for EPA ( FIG. 21A ), DHA ( FIG. 21B ), DPA ( FIG. 21C ), and AA ( FIG. 21D ).
  • EOT end-of-treatment
  • Table 35 tabulates the average change and the median change in absolute plasma levels from baseline to EOT for EPA, DHA, DPA, and AA, as well as TG, NHDL-C, HDL-C, VLDL-C, and LDL-C.
  • FIGS. 22A , 22 B, 26 A, and 26 B plot the data in the table above, showing the change from baseline to EOT in absolute plasma levels (in ⁇ g/mL) of AA, DHA, EPA, and DPA for each of the treatment arms of the EVOLVE trial, with FIG. 22A plotting average change and FIG. 22B showing median change from baseline.
  • Table 36A separately tabulates average, median, and least squares mean percentage change from baseline to EOT in plasma levels of EPA, DHA, DPA, and AA, as well as TG, NHDL-C, HDL-C, VLDL-C, and LDL-C, for each of the treatment arms of the EVOLVE trial.
  • Table 21B separately tabulates percentage change from baseline to EOT and LS mean change in the average and median plasma levels of ApoB, ApoCIII, LpPLA2, and RLP, for each of the treatment arms of the EVOLVE trial.
  • FIG. 23A plots the average change from baseline to EOT, as percentage of baseline value, for AA, DHA, EPA, and DPA in each of the treatment arms of the EVOLVE trial, and FIG. 23B plots the median percent change from baseline to EOT.
  • Table 37 below presents EPA/AA ratios at beginning and end-of-treatment for each of the treatment arms of the EVOLVE trial.
  • FIG. 26A and FIG. 26B which plot the average and median, respectively, for the absolute change from baseline.
  • FIG. 27 illustrates the percentage of subjects who exhibited 0-10% reduction in TG, 10-20% reduction in TG, 20-30% reduction in TG, 30-40% reduction in TG, 40-50% reduction in TG, and greater than 50% reduction in TG, for Epanova® 2 g and 4 g doses.
  • FIG. 26A and FIG. 26B also show that non-HDL-C and VLDL-C were reduced, while HDL-C was elevated. LDL-C levels were also elevated, a measurement that is likely due to an increase in LDL particle size upon treatment (discussed further in Example 12). Average and median percentage changes are displayed in FIG. 28A and FIG. 28B , respectively.
  • Absolute average baseline and EOT levels are plotted in FIGS. 24A-24I for TG ( FIG. 24A ), Non-HDL-C ( FIG. 24B ), HDL-C ( FIG. 24C ), V-LDL-C ( FIG. 24D ), LDL-C ( FIG. 24E ), ApoB ( FIG. 24F ), ApoCIII. ( FIG. 24G ), RLP ( FIG. 24H ), and LpPLA2 ( FIG. 24I ).
  • Absolute median baseline and EOT levels are plotted in FIGS. 25A-25I for TG ( FIG. 25A ), Non-HDL-C ( FIG. 25B ), HDL-C ( FIG. 25C ), V-LDL-C ( FIG. 25D ), LDL-C ( FIG. 25E ), ApoB ( FIG. 25F ), ApoCIII ( FIG. 25G ), RLP ( FIG. 25H ), and LpPLA2 ( FIG. 25I ).
  • FIG. 29 plots the rate of change in the median percentage change from baseline in plasma levels of EPA, DHA, DPA, AA, TG, non-HDL-C, and HDL-C (absolute value) between 2 g and 4 g doses of Epanova®.
  • Table 38 tabulates the results:
  • the rate of change for EPA remains high, with a slope of 0.59; further increase in EPA plasma levels is expected to be obtained by increasing Epanova® dosage above 4 g/day.
  • the rate of change in AA levels upon doubling the Epanova® dose from 2 g to 4 g per day is even higher than that for EPA; further reductions in AA plasma levels are expected as Epanova® dosage is increased above 4 g/day.
  • Epanova® thus exhibits unprecedented potency in ability to reduce AA levels.
  • Apolipoprotein CIII (ApoCIII) was significantly reduced by Epanova® treatment.
  • ApoCIII inhibits lipoprotein lipase activity and hepatic uptake of triglyceride-rich lipoproteins. Elevated levels of ApoCIII have been found to be an independent predictor for cardiovascular heart disease (CHD) risk while genetically reduced ApoCIII is associated with protection from CHD.
  • CHD cardiovascular heart disease
  • Omega-3 fatty acid formulations containing DHA have been shown to increase LDL-C in patients with severe hypertriglyceridemia (Kelley et al., 2009 , J Nutrition, 139(3):495-501). This effect on LDL-C is postulated to be a result of increased lipoprotein particle size (Davidson et al., 2009 , J. Clin. Lipidology, 3(5):332-340).
  • FIG. 34 shows the correlation between percent change in LDL and percent change in ApoCIII for data from the EVOLVE trial.
  • a Pearson correlation coefficient of ⁇ 0.28 was obtained when these data were fit using a linear regression, demonstrating that increases in LDL correlated with decreases in ApoCIII upon treatment with Epanova®.
  • LPL Type 1 lipoprotein lipase
  • STUDY DRUG (Epanova®)—Type A porcine soft gelatin capsules were prepared, each containing one gram (1 g) of a PUFA composition comprising omega-3 PUFAs in free acid form (“API”). The capsules were coated with Eudragit NE 30-D (Evonik Industries AG). The API had the composition given in batch 3 of Table 9 (see Example 4, above).
  • STUDY DRUG (Zocor)—40 mg tablets of simvastatin produced by Merck Sharp & Dohme Ltd. were obtained from a commercial source.
  • STUDY DRUG (Aspirin®)—81 mg enteric-coated tablets produced by Bayer HealthCare Pharmaceuticals were obtained from a commercial source.
  • Treatment condition “A” consisted of co-administration of an oral dose of 40 mg of simvastatin (1 tablet), 81 mg of aspirin (1 tablet) and 4 g (4 capsules) of Epanova®, once a day (every 24 hours) with 240 mL of water on the mornings of Days 1 to 14, for a total of 14 doses, under fasting conditions.
  • Treatment condition “B” consisted of administration of an oral dose of 40 mg of simvastatin (1 tablet) and 81 mg of aspirin (1 tablet) once a day (every 24 hours) with 240 mL of water on the mornings of Days 1 to 14, for a total of 14 doses, under fasting conditions. There was a 14 day washout between treatments.
  • Blood was drawn for plasma fatty acid levels (EPA, DHA, AA) at check-in (day ⁇ 1) and at check-out (day 15) following the treatment arm with Epanova® (treatment “A”).
  • Genotyping was performed at various previously identified SNPs, including SNPs in the FADS1 gene (e.g. rs174546), including a SNP associated with conversion of DGLA to AA (SNP rs174537), the FADS2 gene, and Scd-1 gene.
  • EOT end-of-treatment
  • FIG. 56 shows arachidonic acid (AA) plasma levels for subjects grouped according to genotype at the rs174546 SNP, at (A) baseline (in ⁇ g/mL), and (B) day 15 of treatment with Epanova® (in percent change from baseline).
  • AA arachidonic acid
  • the interquartile range is indicated by a box
  • the median is indicated by a horizontal line in the interior of the interquartile box
  • the mean is represented by a diamond.
  • Outliers are represented by open circles. The whiskers extend to the minimum and maximum non-outlier value.
  • Score 1 identifies subjects who are homozygous at the major allele
  • Score 3 identifies subjects homozygous at the minor allele
  • Score 2 represents heterozygotes.
  • TT genotype In response to treatment with Epanova®, a substantial increase in EPA was observed, with the largest percent increase in the TT genotype (TT: 1054%, CT:573%, CC:253%).
  • STUDY DRUG (Epanova®)—Type A porcine soft gelatin capsules were prepared, each containing one gram (1 g) of a PUFA composition comprising omega-3 PUFAs in free acid form (“API”). The capsules were coated with Eudragit NE 30-D (Evonik Industries AG). The API had the composition given in batch 3 of Table 9 (see Example 4, above).
  • PLACEBO Capsules were prepared containing olive oil for use as a control.
  • a subset of subjects in the 2 g treatment arm of the EVOLVE trial who were receiving concurrent statin therapy displayed greater magnitudes of percentage changes (mean LS difference), relative to control, for TG, non-HDL-C, HDL-C, LDL-C, TC, VLDL-C, and TC/HDL-C, when compared to those subjects in the 2 g treatment arm who did not receive concurrent statin therapy.
  • Subjects receiving concurrent statin therapy showed a dose-dependent response to Epanova®, as shown in comparative data for Epanova® 2 g and Epanova® 4 g displayed in FIG. 39 .
  • the ESPRIT clinical trial was conducted to study patients on baseline statin therapy. As shown in FIG. 40 , patients were selected for the ESPRIT study based on TG levels between 200-500 mg/dL and baseline statin therapy. Of the 660 patients who were selected for the trial, 220 were treated with olive oil placebo, 220 were treated with Epanova® 2 g dose, and 220 were treated with Epanova® 4 g dose. All placebo and Epanova® treatments were administered in addition to the baseline statin therapy.
  • Table 41 shows the baseline levels for TG, HDL-C, LDL-C, non-HDL-C, and VLDL-C for subjects in the ESPRIT trial, in comparison to desirable levels as described by the Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), issued by the National Heart Lung and Blood Institute.
  • FIG. 41 illustrates the patient disposition for the ESPRIT trial, showing that 6 patients were withdrawn from the placebo arm, 6 patients were withdrawn from the 2 g treatment arm, and 12 patients were withdrawn from the 4 g treatment arm.
  • the number of patients who experienced adverse effects (AE) was low overall, with 2 in the placebo arm, 3 in the 2 g treatment arm, and 7 in the 4 g treatment arm.
  • FIGS. 45-52 Further details of the results of the ESPRIT trial are presented in FIGS. 45-52 , demonstrating that Epanova® is efficacious as an add-on to both low-potency and high-potency statins, in a range of baseline patient conditions.
  • FIG. 45 shows the results for median TG percentage change from baseline for three tertiles of patients, partitioned by baseline TG levels.
  • FIG. 46 shows the results for median non-HDL-C percentage change from baseline for three tertiles of patients, partitioned by baseline non-HDL-C levels.
  • FIG. 47 shows the results for median LDL-C percentage change from baseline for three tertiles of patients, partitioned by baseline LDL-C levels.
  • FIG. 52 compares median percentage changes from baseline for triglycerides for (A) patients having higher TG baseline levels ( ⁇ 294 mg/dL), (B) patients having high EOT EPA levels ( ⁇ 26.58 ⁇ g/mL), and (C) patients receiving concurrent rosuvastatin therapy.
  • the results show that the Epanova® 2 g dose works similarly to the 4 g dose in those patient populations shown in FIG. 52 .

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