WO2011083465A1 - Treatment with vb-201 - Google Patents
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- WO2011083465A1 WO2011083465A1 PCT/IL2011/000008 IL2011000008W WO2011083465A1 WO 2011083465 A1 WO2011083465 A1 WO 2011083465A1 IL 2011000008 W IL2011000008 W IL 2011000008W WO 2011083465 A1 WO2011083465 A1 WO 2011083465A1
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Definitions
- the present invention in some embodiments thereof, relates to the field of pharmacology and more particularly, but not exclusively, to a novel dosage form and treatment regimen of the oxidized phospholipid VB-201, which can be efficiently used to treat or prevent inflammation associated diseases and disorders such as, for example, atherosclerosis and related disorders, and autoimmune diseases or disorders such as psoriasis, arthritis, multiple sclerosis and inflammatory bowl disease.
- inflammation associated diseases and disorders such as, for example, atherosclerosis and related disorders, and autoimmune diseases or disorders such as psoriasis, arthritis, multiple sclerosis and inflammatory bowl disease.
- Oxidized phospholipids have been previously described as useful in the treatment of medical conditions such as, for example, cardiovascular diseases, cerebrovascular diseases and inflammatory diseases and disorders.
- CI-201 l-hexadecyl-2-(4'-carboxybutyl)- glycerol-3-phosphocholine; also referred to in the art as VB-201).
- PCT/IL05/000735 Publication No. WO 06/006161
- PCT/IL02/00005 Publication No. WO 02/053092
- PCT/IL08/000013 Publication No. WO 08/084472
- the present inventors have thus uncovered that the elimination half-life of VB- 201 is in a range of about 27 to 51 hours (i.e., longer than one day), and that plasma concentrations of VB-201 are relatively stable when VB-201 is administered once per day.
- the present inventors have further uncovered that daily dosages of 80 mg VB-201 per day or less are safe and well-tolerated, that a substantial percentage of VB-201 is absorbed into the bloodstream, and that absorption is not strongly affected by whether the subject has recently eaten.
- the present inventors have further uncovered that daily dosages of 80 mg VB-201 and less are effective at inhibiting inflammatory processes.
- a pharmaceutical composition unit dosage form comprising between 1 mg and 100 mg VB-201 and a pharmaceutically acceptable carrier, the pharmaceutical composition unit dosage form being formulated for oral administration.
- VB-201 in the manufacture of a unit dosage form of a medicament for treating or preventing an inflammatory disease or disorder, the unit dosage form comprising from 1 mg to 100 mg VB-201 and being formulated for oral administration.
- a method of treating or preventing an inflammatory disease or disorder comprising orally administering to a subject in need thereof a therapeutically effective amount of VB-201, wherein the therapeutically effective amount ranges from 1 mg per day to 100 mg per day.
- a method of treating or preventing psoriasis comprising orally administering to a subject in need thereof a therapeutically effective amount of VB-201, wherein the therapeutically effective amount ranges from 1 mg per day to 100 mg per day.
- a method of treating or preventing rheumatoid arthritis comprising orally administering to a subject in need thereof a therapeutically effective amount of VB-201, wherein the therapeutically effective amount ranges from 1 mg per day to 100 mg per day.
- a method of treating or preventing an inflammation selected from the group consisting of inflammation of a carotid artery and inflammation of an aorta comprising orally administering to a subject in need thereof a therapeutically effective amount of VB-201, wherein the therapeutically effective amount ranges from 1 mg per day to 100 mg per day.
- a method of treating or preventing an inflammatory disease or disorder comprising orally administering to a subject in need thereof a therapeutically effective amount of VB-201, wherein the administering is effected once or twice a day.
- a method of treating or preventing psoriasis comprising orally administering to a subject in need thereof a therapeutically effective amount of VB-201, wherein the administering is effected once or twice a day.
- a method of treating or preventing rheumatoid arthritis comprising orally administering to a subject in need thereof a therapeutically effective amount of VB-201, wherein the administering is effected once or twice a day.
- a method of treating or preventing an inflammation selected from the group consisting of inflammation of a carotid artery and inflammation of an aorta comprising orally administering to a subject in need thereof a therapeutically effective amount of VB-201, wherein the administering is effected once or twice a day.
- the unit dosage form comprises 10 mg VB-201.
- the unit dosage form comprises 20 mg VB-201.
- the unit dosage form comprises 30 mg VB-201.
- the unit dosage form comprises 40 mg VB-201. According to some embodiments of the invention, the unit dosage form comprises 50 mg VB-201.
- the unit dosage form comprises 60 mg VB-201.
- the unit dosage form comprises 70 mg VB-201.
- the unit dosage form comprises 80 mg VB-201.
- the unit dosage form comprises 90 mg VB-201.
- the unit dosage form comprises 100 mg VB-201.
- the unit dosage form comprises from 10 mg to 30 mg VB-201.
- the unit dosage form comprises from 15 mg to 25 mg VB-201.
- the unit dosage form comprises from 18 mg to 22 mg VB-201.
- the unit dosage form comprises from 70 mg to 90 mg VB-201.
- the unit dosage form comprises from 75 mg to 85 mg VB-201.
- the pharmaceutical composition unit dosage form is packaged in a packaging material and identified in print, in or on the packaging material, for use in the treatment or prevention of an inflammatory disease or disorder.
- the pharmaceutical composition unit dosage form is identified for use once per day.
- the pharmaceutical composition unit dosage form is identified for use such that a daily dose consists of one or two units of the pharmaceutical composition unit dosage form. According to some embodiments of the invention, the pharmaceutical composition unit dosage form is identified for use such that a daily dose consists of one unit of the pharmaceutical composition unit dosage form.
- the pharmaceutical composition unit dosage form is identified for use during, or after a meal.
- the therapeutically effective amount of VB-201 is administered once per day.
- the therapeutically effective amount ranges from 1 mg per day to 100 mg per day.
- the therapeutically effective amount is 10 mg VB-201 per day.
- the therapeutically effective amount is 20 mg VB-201 per day.
- the therapeutically effective amount is 30 mg VB-201 per day.
- the therapeutically effective amount is 40 mg VB-201 per day.
- the therapeutically effective amount is 50 mg VB-201 per day.
- the therapeutically effective amount is 60 mg VB-201 per day.
- the therapeutically effective amount is 70 mg VB-201 per day.
- the therapeutically effective amount is 80 mg VB-201 per day.
- the therapeutically effective amount is 90 mg VB-201 per day.
- the therapeutically effective amount is 100 mg VB-201 per day.
- the therapeutically effective amount is in a range of from 10 mg to 30 mg VB-201 per day. According to some embodiments of the invention, the therapeutically effective amount is in a range of from 15 mg to 25 mg VB-201 per day.
- the therapeutically effective amount is in a range of from 18 mg to 22 mg VB-201 per day.
- the therapeutically effective amount is in a range of from 70 mg to 90 mg VB-201 per day.
- the therapeutically effective amount is in a range of from 75 mg to 85 mg VB-201 per day.
- a method described herein comprises administering one or two units of a pharmaceutical composition unit dosage form described herein.
- a method described herein comprises administering one unit of a pharmaceutical composition unit dosage form described herein.
- 201 is administered during, or after a meal.
- the inflammatory disease or disorder is associated with an endogenous oxidized lipid.
- the inflammatory disease or disorder is selected from the group consisting of an idiopathic inflammatory disease or disorder, a chronic inflammatory disease or disorder, an acute inflammatory disease or disorder, an autoimmune disease or disorder, an infectious disease or disorder, an inflammatory malignant disease or disorder, an inflammatory transplantation-related disease or disorder, an inflammatory degenerative disease or disorder, a disease or disorder associated with a hypersensitivity, an inflammatory cardiovascular disease or disorder, an inflammatory cerebrovascular disease or disorder, a peripheral vascular disease or disorder, an inflammatory glandular disease or disorder, an inflammatory gastrointestinal disease or disorder, an inflammatory cutaneous disease or disorder, an inflammatory hepatic disease or disorder, an inflammatory neurological disease or disorder, an inflammatory musculoskeletal disease or disorder, an inflammatory renal disease or disorder, an inflammatory reproductive disease or disorder, an inflammatory systemic disease or disorder, an inflammatory connective tissue disease or disorder, an inflammatory tumor, necrosis, an inflammatory implant-related disease or disorder, an inflammatory aging process, an immunode
- the inflammatory disease or disorder is selected from the group consisting of psoriasis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, atherosclerosis, inflammation of a carotid artery and inflammation of an aorta.
- FIG. 1 is a graph showing mean VB-201 plasma concentrations as a function of time following a single-dose oral administration of 1 mg (Cohort 1), 3 mg (Cohort 2), 10 mg (Cohort 3), 30 mg (Cohort 4), and 50 mg (Cohort 7) VB-201 capsules;
- FIG. 2 is a graph showing mean VB-201 plasma concentrations as a function of time on day 1 and day 14, following a daily oral administration of 5 mg (Chrt 1), 10 mg (Chrt 2), 20 mg (Chrt 3b) and 30 mg (Chrt 4) VB-201;
- FIG. 3 is a graph showing mean VB-201 plasma concentrations as a function of time following a single-dose administration of one (1x10) or two (10+10) 10 mg capsules, for either enteric coated capsules (Coat) and uncoated capsules (UnCoat), and either to fasting subjects (Fast) or to fed subjects (Fed);
- FIG. 4 is a graph showing mean VB-201 plasma concentrations as a function of time on day 1 and day 14, following a daily oral administration of 40 mg VB-201 (Cohort 1), and on day 14, following a daily oral administration of 80 mg VB-201 (Cohort 2);
- FIGs. 5A-5C are graphs showing mean C-reactive protein (CRP) plasma levels before (day 0) and after (day 14 or day 28) daily oral administration of 40 mg VB-201 for 14 days (FIG. 5A), 80 mg VB-201 for 14 days (FIG. 5B) or 80 mg VB-201 for 28 days (FIG. 5C), as determined by high sensitivity CRP (hsCRP) assay (N indicates number of subjects tested, and % reduction in CRP levels are shown);
- CRP C-reactive protein
- FIGs. 6A-6D are graphs showing interleukin-23 (IL-23) plasma levels (FIGs. 6A and 6C) and interferon- ⁇ (IFN- ⁇ ) levels (FIGs. 6B and 6D) in subjects who had pre- dosing (day 0) detectable levels of IL-23 and were administered 40 mg VB-201 per day for 14 days (FIGs. 6A-6B) and 80 mg VB-201 per day for 28 days (FIGs. 6C-6D); and
- FIG. 7 is a graph showing the degree of migration (expressed as the number of migrated cells), over the course of 3.5 hours, of human CD14 cells (pre-treated for 30 minutes with 8 ⁇ VB-201 or with control solvent) towards RANTES (100 ng/ml), MIP- 1 a (50 ng/ml), MCP-1 (50 ng/ml) or MCP-3 (50 ng/ml).
- the present invention in some embodiments thereof, relates to a novel dosage form and treatment regimen of the oxidized phospholipid VB-201, which can be efficiently used to treat or prevent inflammatory diseases and disorders such as, for example, atherosclerosis and related disorders, inflammatory bowel diseases and autoimmune diseases or disorders such as psoriasis and arthritis.
- inflammatory diseases and disorders such as, for example, atherosclerosis and related disorders, inflammatory bowel diseases and autoimmune diseases or disorders such as psoriasis and arthritis.
- VB-201 (also referred to herein and in the art as CI-201) has shown considerable promise as a therapeutically active agent in various in vitro models and in vivo animal models of inflammatory conditions.
- the present inventors have studied in detail the safety, tolerability and pharmacokinetics of VB-201 in human subjects. To this effect, the present inventors have put ample efforts in devising pharmacological assays for determining the safety, tolerability and pharmacokinetics of VB-201 in human subjects. The protocols of these assays are described in detail in the Examples section that follows. Based on the data obtained in the clinical studies conducted, the present inventors have developed optimal treatment regimens and unit dosage forms.
- FIG. 1 shows the time profile of plasma concentrations of VB-201 (also referred to herein as a "concentration-time curve") following oral administration of 1 to 50 mg VB-201.
- Table 1 presented in the Examples section provides values of various pharmacokinetic parameters derived from concentration-time curves. Table 1 shows, for example, that a substantial percentage of VB-201 is absorbed into the bloodstream
- FIG. 2 shows concentration-time curves on day 1 and on day 14 of a regimen of daily oral administration of 5-30 mg VB-201.
- the accumulation of VB-201 in the blood is clearly shown therein.
- Table 2 presented in the Examples section provides values of various pharmacokinetic parameters for both day 1 and day 14.
- FIG. 3 shows that plasma concentration levels of VB-201 were not significantly affected by whether the subject was administered VB-201 when fed or when fasting.
- FIG. 3 further shows that enteric coatings on VB-201 capsules reduced the amount of VB-201 which was absorbed, and that enteric coatings delayed absorption of VB-201, particularly when the subject was fed prior to administration.
- Table 3 presented in the Examples section provides values of various pharmacokinetic parameters for both fed and fasting subjects, and for both coated and non-coated capsules.
- FIG. 4 shows concentration-time curves on day 14 of a regimen of daily oral administration of 40 or 80 mg VB-201.
- the concentration-time curve on day 1 is shown for 40 mg per day VB-201, such that the accumulation of VB-201 in the blood is clearly shown therein.
- Table 4 presented in the Examples section provides values of various pharmacokinetic parameters derived from the data for day 1 and day 14.
- FIGs. 1-4 and Tables 1-4 further show that plasma concentrations of VB-201 are relatively linearly proportional to the administered dose of VB-201.
- FIGs. 2 and 4 further show that plasma concentrations of VB-201 are relatively stable during over the course of a day when VB-201 is regularly administered once- daily.
- minimum concentrations during a 24-hour period were at least about 66.7 % of the maximum concentrations during the same time period.
- FIGs. 5A-5C show that administration of 40 mg per day and 80 mg per day VB- 201 considerable reduces C-reactive protein levels, a marker of inflammation.
- FIGs. 6A-6D show that administration of 40 or 80 mg per day VB-201 reduces levels of the pro -inflammatory cytokines interleukin-23 and interferon- ⁇ . These results indicate that the dosages described herein are effective at inhibiting inflammatory processes.
- a method of treating or preventing an inflammatory disease or disorder comprising orally administering to a subject in need thereof a therapeutically effective amount of VB-201.
- the therapeutically effective amount ranges from 1 mg per day to 100 mg per day.
- the therapeutically effective amount ranges from 10 mg per day to 100 mg per day.
- the therapeutically effective amounts described herein refer to therapeutically effective amounts for administration to adult subjects.
- amounts of VB-201 to be administered a child are adjusted, for example, according to body weight of the child.
- the therapeutically effective amounts described herein are absolute, and do not depend on the body weight of the subject, with the optional exception of subjects with a body weight far from the adult average (e.g., children).
- the therapeutically effective amounts described herein are considered suitable for a subject of average body weight (e.g., 70 kg), and the amount to be administered is adjusted according to the body weight of the subject receiving VB-201.
- a dose of 100 mg per day recited herein is optionally understood to refer to a dose of 100 mg per day per 70 kg body weight (i.e., 1.43 mg/kg per day).
- the elimination half-life ( ⁇ /2 ) of VB-201 is in a range of about 27 to 51 hours (i.e., longer than one day).
- the VB-201 enters the blood stream gradually following administration, with peak plasma concentrations usually occurring approximately 6-11 hours after administration.
- the plasma concentrations of VB-201 are relatively stable when VB-201 is administered once per day, and are expected to be even more stable when VB-201 is administered twice per day.
- a method of treating or preventing an inflammatory disease or disorder comprising orally administering to a subject in need thereof a therapeutically effective amount of VB-201, wherein administration of the VB-201 is effected once or twice a day.
- the administration of VB-201 is effected once a day.
- Regimens including administration of a therapeutically effective agent once or twice a day (and particularly for administration once a day) are particularly convenient and useful, when the pharmacokinetics of the agent is suitable for such a regimen, as the administration is readily incorporated in a daily routine. Consequently, forgetting to administer the agent is less likely to occur.
- once or twice daily administration of an agent is not particularly burdensome on either the subject or any other person (e.g., medical professional administering) administering the agent. Consequently, refusal to accept and/or provide administration is less likely to occur.
- a regimen of once or twice daily administration is likely to induce high compliance to the regimen.
- a regimen of once daily administration is particularly likely to induce high compliance.
- the therapeutically effective amount of VB- 201 is in a range of 1 mg per day to 100 mg per day, optionally in a range of 10 mg per day to 100 mg per day, and administering this amount is effected once or twice per day, depending on the unit dosage form utilized, as detailed hereinafter, and is optionally effected once per day.
- the therapeutically effective amount is 10 mg per day, in some embodiments it is 20 mg per day, in some embodiments it is 30 mg per day, in some embodiments it is 40 mg per day, in some embodiments it is 50 mg per day, in some embodiments it is 60 mg per day, in some embodiments it is 70 mg per day, in some embodiments it is 80 mg per day, in some embodiments it is 90 mg per day, and in some embodiments it is 100 mg per day. Any integer between 1 to 100 mg per day is also contemplated.
- the therapeutically effective amount is approximately 20 mg per day (e.g., in a range of from 10 mg per day to 30 mg per day).
- the amount is in a range of from 15 mg per day to 25 mg per day, and optionally in a range of from 18 mg per day to 22 mg per day.
- the therapeutically effective amount is approximately 80 mg per day (e.g., in a range of from 70 mg per day to 90 mg per day).
- the amount is in a range of from 75 mg per day to 85 mg per day, and optionally in a range of from 88 mg per day to 92 mg per day.
- the therapeutically effective amount of VB- 201 is administered during a meal or after a meal.
- the term “during” refers to a period of time from 60 minutes before the beginning of the meal, optionally 30 minutes before the meal, optionally 10 minutes before the meal, and optionally 5 minutes before the meal, until 60 minutes after the meal ends, optionally 30 minutes after the meal, optionally 10 minutes after the meal, and optionally 5 minutes after the meal.
- the phrase "after a meal” refers to a period of time lasting until 6 hours after the end of the meal, optionally, 4 hours after the meal, optionally 3 hours after the meal, and optionally 2 hours after the meal.
- "after a meal” encompasses a period of time during which the subject feels a sensation of a "full stomach” rather than an "empty stomach”. Without being bound by any particular theory, it is believed that administration during or after a meal reduces the chances of experiencing possible side effects of VB- 201.
- VB-201 may be administered within a coating (e.g., an enteric coating).
- a coating e.g., an enteric coating.
- Exemplary materials for forming a coating include Eudragit®, Opadry® (e.g., Opadry ® amb) and Acryl-Eze®, which may be used alone or in combination to form an enteric coating.
- the coating may be used, for example, for protecting a portion of the digestive system (e.g., the stomach) from the VB-201 (e.g., in order to minimize side effects) or any substance (e.g., carrier) co-administered with the VB-201, to mask a taste of VB- 201 or any substance (e.g., carrier) co-administered with the VB-201 (e.g., to enhance palatability), and/or to control release and/or uptake (e.g., delaying release and/or uptake) of VB-201 (e.g., in order to provide for more stable plasma concentrations of VB-201).
- an enteric coating delays uptake of VB-201 most significantly when the VB-201 is administered to a fed subject. Consequently, in embodiments wherein a coating (e.g., an enteric coating) is intended to delay uptake, the VB-201 is optionally administered during or after a meal.
- a coating e.g., an enteric coating
- VB-201 can be administered either to a fasting subject or to a fed subject.
- the relatively narrow range of doses found to be suitable according to embodiments of the present invention allows for the production of unit dosage forms of a medicament (e.g., a pharmaceutical composition) designed for easy and convenient administration of a therapeutically effective amount of VB-201 described herein. It may be beneficial for the therapeutically effective amount to consist of no more than two unit dosage forms, as administration of more than two dosage forms at any one time may be more difficult. For example, it is commonly difficult to swallow more than two solid unit dosage forms (e.g., pills, tablets, capsules, etc.). Moreover, administration of more than two unit dosage forms at any one time increases the likelihood of confusion and administration of an inappropriate dose. Hence, according to optional embodiments, the method comprises administering one or two units of a unit dosage form at each administration. Optionally, one unit of the unit dosage form is administered per administration.
- a medicament e.g., a pharmaceutical composition
- the method comprises administering one or two units of a unit dosage form at each administration.
- one unit of the unit dosage form is administered per administration.
- the method is effected by administering one or two units (optionally one unit) of a unit dosage form described herein.
- VB-201 in the manufacture of a unit dosage form of a medicament (e.g., a pharmaceutical composition) for treating or preventing an inflammatory disease or disorder, the unit dosage form comprising from 1 mg to 100 mg VB-201, and being formulated for oral administration.
- the unit dosage form comprises from 10 mg to 100 mg VB-201.
- the VB-201 can be utilized either per se or as a part of a pharmaceutical composition, which further comprises a pharmaceutically acceptable carrier.
- a pharmaceutical composition unit dosage form comprising between 1 mg and 100 mg of VB-201 and a pharmaceutically acceptable carrier.
- the pharmaceutical composition unit dosage form is formulated for oral administration.
- the pharmaceutical composition unit dosage form comprises between 10 mg and 100 mg of VB-201.
- such a pharmaceutical composition unit dosage form is packaged in a packaging material and identified in print, in or on the packaging material, for use in the treatment or prevention of an inflammatory disease or disorder.
- a plurality of unit dosage forms is packaged in a packaging material and identified in print, in or on the packaging material, for use in the treatment or prevention of an inflammatory disease or disorder. Suitable inflammatory diseases and disorders are discussed in more detail elsewhere herein.
- a "pharmaceutical composition” refers to a preparation of VB-
- 201 (as active ingredient), or physiologically acceptable salts or prodrugs thereof, with other chemical components, including, but not limited to, physiologically suitable carriers, excipients, lubricants, buffering agents, antibacterial agents, bulking agents (e.g. mannitol), antioxidants (e.g., ascorbic acid or sodium bisulfite), and the like.
- physiologically suitable carriers including, but not limited to, physiologically suitable carriers, excipients, lubricants, buffering agents, antibacterial agents, bulking agents (e.g. mannitol), antioxidants (e.g., ascorbic acid or sodium bisulfite), and the like.
- the purpose of the pharmaceutical composition is to facilitate administration of VB-201 to a subject.
- unit dosage form describes physically discrete units, each unit containing a predetermined quantity of VB-201 calculated to produce the desired therapeutic effect, in association with at least one pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.
- physiologically acceptable carrier and “pharmaceutically acceptable carrier”, which are used interchangeably, describe a carrier or a diluent that does not cause significant irritation to the subject and does not abrogate the biological activity and properties of the VB-201.
- carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered.
- excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient.
- compositions for use in accordance with the present invention thus may be formulated for oral administration in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the compounds into preparations which can be used pharmaceutically.
- a pharmaceutical composition unit dosage form according to some embodiments can be formulated readily by combining VB-201 with pharmaceutically acceptable carriers well known in the art.
- the active ingredient (VB-201) is formulated, for example, as sachets, pills, caplets, capsules, tablets, dragee- cores or discrete (e.g., separately packaged) units of powder, granules, or suspensions or solutions in water or non-aqueous media.
- Thickeners, diluents, flavorings, dispersing aids, emulsifiers or binders may be desirable.
- Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores.
- Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl- cellulose, sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).
- disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
- Dragee cores are provided with suitable coatings.
- suitable coatings For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
- Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active doses.
- compositions which can be used orally, include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
- the push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers.
- the active ingredient may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
- stabilizers may be added.
- formulations for oral administration further include a protective coating, aimed at protecting or slowing enzymatic degradation of the preparation in the GI tract.
- Composition unit dosage forms according to the present embodiments may, if desired, be presented in a pack or dispenser device, such as an FDA (the U.S. Food and Drug Administration) approved kit, which may contain one or more unit dosage forms containing VB-201.
- the pack or dispenser device may, for example, comprise metal or plastic foil, such as, but not limited to a blister pack.
- the pack or dispenser device may be accompanied by instructions for administration.
- the pack may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions for human administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.
- Composition unit dosage forms comprising VB-201 formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an inflammatory disease or disorder, as defined herein.
- the unit dosage for is identified (e.g., in the abovementioned instructions for administration) for use once or twice per day, optionally once per day.
- the unit dosage form is identified (e.g., in the abovementioned instructions for administration) for use such that a daily dose consists of one or two units of the unit dosage form, and optionally one unit of the unit dosage form.
- the unit dosage form is identified (e.g., in the abovementioned instructions for administration) for use during, or after a meal, as described herein.
- the unit dosage form comprises 10 mg VB-201.
- a unit dosage form is particularly suitable for administering 10 mg VB-201 per day or 20 mg VB-201 per day (e.g., by administering one unit dosage form twice per day or administering 2 unit dosage forms once a day).
- Such unit dosage forms are also relatively suitable for administering 30 mg or 40 mg VB-201 per day (e.g., by administering 3 or 4 unit dosage forms per day, optionally by administering 1 or 2 unit dosage forms twice a day).
- the unit dosage form comprises 20 mg VB-201.
- a unit dosage form is particularly suitable for administering 20 mg VB-201 per day or 40 mg VB-201 per day (e.g., by administering one unit dosage form twice per day or administering 2 unit dosage forms once a day).
- Such unit dosage forms are also relatively suitable for administering 60 mg or 80 mg VB-201 per day (e.g., by administering 3 or 4 unit dosage forms per day, optionally by administering 1 or 2 unit dosage forms twice a day).
- the unit dosage form comprises 30 mg VB-201.
- a unit dosage form is particularly suitable for administering 30 mg VB-201 per day or 60 mg VB-201 per day (e.g., by administering one unit dosage form twice per day or administering 2 unit .dosage forms once a day).
- Such unit dosage forms are also relatively suitable for administering 90 mg VB-201 per day (e.g., by administering 3 unit dosage forms per day, optionally by administering 1 or 2 unit dosage forms twice a day).
- the unit dosage form comprises 40 mg VB-201.
- Such a unit dosage form is particularly suitable for administering 40 mg VB-201 per day or 80 mg VB-201 per day (e.g., by administering one unit dosage form twice per day or administering 2 unit dosage forms once a day).
- the unit dosage form comprises 50 mg VB-201.
- Such a unit dosage form is particularly suitable for administering 50 mg VB-201 per day or 100 mg VB-201 per day (e.g., by administering one unit dosage form twice per day or administering 2 unit dosage forms once a day).
- the unit dosage form comprises 60 mg VB-201.
- Such a unit dosage form is particularly suitable for administering 60 mg VB-201 per day.
- the unit dosage form comprises 70 mg VB-201, in some embodiments it comprises 80 mg VB-201, in some embodiments it comprises 90 mg VB-201, and in some embodiments it comprises 100 mg VB-201.
- Such unit dosage forms are particularly suitable for administering 70 mg per day, 80 mg per day, 90 mg per day, and 100 mg per day, respectively, of VB-201.
- the unit dosage form comprises 80 mg VB-201.
- Such a unit dosage form is particularly suitable for administering 80 mg VB-201 per day, once a day.
- the unit dosage form comprises approximately 20 mg VB-201 (e.g., in a range of from 10 mg to 30 mg).
- the amount of VB-201 in the unit dosage form is in a range of from 15 mg to 25 mg, and optionally in a range of from 18 mg to 22 mg.
- the therapeutically effective amount is approximately 80 mg (e.g., in a range of from 70 mg to 90 mg).
- the amount of VB-201 in the unit dosage form is in a range of from 75 mg to 85 mg, and optionally in a range of from 88 mg to 92 mg.
- a unit dosage form is designed so as to facilitate division of a unit dosage form into two half-unit dosage forms.
- a pill, tablet or caplet may be scored so as to be readily broken in half.
- VB-201 (l-hexadecyl-2-(4'-carboxybutyl)-glycerol-3-phosphocholine) according to embodiments of the present invention may be a chiral enantiomer of l-hexadecyl-2- (4'-carboxybutyl)-glycerol-3-phosphocholine, i.e., either the (R)- enantiomer ((R)-l- hexadecyl-2-(4'-carboxybutyl)-5 «-glycerol-3-phosphocholine) or the (S)- enantiomer ( 5')-l-hexadecyl-2-(4'-carboxybutyl)-glycerol-3-phosphocholine), or a mixture
- the inflammatory disease or disorder treatable according to embodiments of the present invention is an inflammatory disease or disorder associated with an endogenous oxidized lipid.
- an endogenous oxidized lipid refers to one or more oxidized lipids that are present or formed in vivo, as a result of inflammatory and other cell- or humoral-mediated processes.
- Oxidized low-density lipoprotein oxidized-LDL
- Oxidized-LDL Oxidized low-density lipoprotein
- Inflammatory diseases or disorders treatable according to exemplary embodiments of the present invention include psoriasis (e.g., plaque psoriasis), rheumatoid arthritis, and atherosclerosis and related conditions, such as inflammation of an artery (e.g., inflammation of a carotid artery and/or inflammation of an aorta).
- psoriasis e.g., plaque psoriasis
- rheumatoid arthritis e.g., atherosclerosis and related conditions, such as inflammation of an artery (e.g., inflammation of a carotid artery and/or inflammation of an aorta).
- inflammatory diseases or disorders treatable according to exemplary embodiments of the present invention include multiple sclerosis and inflammatory bowel disease (e.g., chronic inflammatory bowel disease).
- Representative inflammatory diseases and disorders treatable according to embodiments of the present invention include, for example, idiopathic inflammatory diseases or disorders, chronic inflammatory diseases or disorders, acute inflammatory diseases or disorders, autoimmune diseases or disorders, infectious diseases or disorders, inflammatory malignant diseases or disorders, inflammatory transplantation-related diseases or disorders, inflammatory degenerative diseases or disorders, diseases or disorders associated with a hypersensitivity, inflammatory cardiovascular diseases or disorders, inflammatory cerebrovascular diseases or disorders, peripheral vascular diseases or disorders, inflammatory glandular diseases or disorders, inflammatory gastrointestinal diseases or disorders, inflammatory cutaneous diseases or disorders, inflammatory hepatic diseases or disorders, inflammatory neurological diseases or disorders, inflammatory musculo-skeletal diseases or disorders, inflammatory renal diseases or disorders, inflammatory reproductive diseases or disorders, inflammatory systemic diseases or disorders, inflammatory connective tissue diseases or disorders, inflammatory tumors, necrosis, inflammatory implant-related diseases or disorders, inflammatory aging processes, immunodeficiency diseases or disorders, proliferative diseases and disorders and inflammatory pulmonary diseases or disorders, as is detailed herein
- hypersensitivities include Type I hypersensitivity,
- Type II hypersensitivity Type III hypersensitivity, Type IV hypersensitivity, immediate hypersensitivity, antibody mediated hypersensitivity, immune complex mediated hypersensitivity, T lymphocyte mediated hypersensitivity, delayed type hypersensitivity, helper T lymphocyte mediated hypersensitivity, cytotoxic T lymphocyte mediated hypersensitivity, TH1 lymphocyte mediated hypersensitivity, and TH2 lymphocyte mediated hypersensitivity.
- Non-limiting examples of inflammatory cardiovascular disease or disorder include occlusive diseases or disorders, atherosclerosis, a cardiac valvular disease, stenosis, restenosis, in-stent-stenosis, myocardial infarction, coronary arterial disease, acute coronary syndromes, congestive heart failure, angina pectoris, myocardial ischemia, thrombosis, Wegener's granulomatosis, Takayasu's arteritis, Kawasaki syndrome, anti-factor VIII autoimmune disease or disorder, necrotizing small vessel vasculitis, microscopic polyangiitis, Churg and Strauss syndrome, pauci-immune focal necrotizing glomerulonephritis, crescentic glomerulonephritis, antiphospholipid syndrome, antibody induced heart failure, thrombocytopenic purpura, autoimmune hemolytic anemia, cardiac autoimmunity, Chagas' disease or disorder, and anti-helper T lymphocyte autoimmunity.
- Stenosis is an occlusive disease of the vasculature, commonly caused by atheromatous plaque and enhanced platelet activity, most critically affecting the coronary vasculature.
- Restenosis is the progressive re-occlusion often following reduction of occlusions in stenotic vasculature.
- in-stent-stenosis may occur, re-occluding the treated vessel.
- cerebrovascular diseases or disorders include stroke, cerebrovascular inflammation, cerebral hemorrhage and vertebral arterial insufficiency.
- Non-limiting examples of peripheral vascular diseases or disorders include gangrene, diabetic vasculopathy, ischemic bowel disease, thrombosis, diabetic retinopathy and diabetic nephropathy.
- Non-limiting examples of autoimmune diseases or disorders include all of the diseases caused by an immune response such as an autoantibody or cell-mediated immunity to an autoantigen and the like.
- Representative examples are chronic rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma, mixed connective tissue disease, polyarteritis nodosa, polymyositis/dermatomyositis, Sjogren's syndrome, Bechet's disease, multiple sclerosis, autoimmune diabetes, Hashimoto's disease, psoriasis, primary myxedema, pernicious anemia, myasthenia gravis, chronic active hepatitis , autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, uveitis, vasculitides and heparin induced thrombocytopenia.
- Non-limiting examples of inflammatory glandular diseases or disorders include pancreatic diseases or disorders, Type I diabetes, thyroid diseases or disorders, Graves' disease, thyroiditis, spontaneous autoimmune thyroiditis, Hashimoto's thyroiditis, idiopathic myxedema, ovarian autoimmunity, autoimmune anti-sperm infertility, autoimmune prostatitis and Type I autoimmune polyglandular syndrome.
- Non-limiting examples of inflammatory gastrointestinal diseases or disorders include colitis, ileitis, Crohn's disease, chronic inflammatory intestinal disease, inflammatory bowel syndrome, inflammatory bowel disease, celiac disease, ulcerative colitis, an ulcer, a skin ulcer, a bed sore, a gastric ulcer, a peptic ulcer, a buccal ulcer, a nasopharyngeal ulcer, an esophageal ulcer, a duodenal ulcer and a gastrointestinal ulcer.
- Non-limiting examples of inflammatory cutaneous diseases or disorders include acne, an autoimmune bullous skin disease, pemphigus vulgaris, bullous pemphigoid, pemphigus foliaceus, contact dermatitis and drug eruption.
- Non-limiting examples of inflammatory hepatic diseases or disorders include autoimmune hepatitis, hepatic cirrhosis, and biliary cirrhosis.
- Non-limiting examples of inflammatory neurological diseases or disorders include multiple sclerosis, Alzheimer's disease, Parkinson's disease, myasthenia gravis, motor neuropathy, Guillain-Barre syndrome, autoimmune neuropathy, Lambert-Eaton myasthenic syndrome, paraneoplastic neurological disease or disorder, paraneoplastic cerebellar atrophy, non-paraneoplastic stiff man syndrome, progressive cerebellar atrophy, Rasmussen's encephalitis, amyotrophic lateral sclerosis, Sydeham chorea, Gilles de la Tourette syndrome, autoimmune polyendocrinopathy, dysimmune neuropathy, acquired neuromyotonia, arthrogryposis multiplex, Huntington's disease, AIDS associated dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis, stroke, an inflammatory retina
- Non-limiting examples of inflammatory connective tissue diseases or disorders include autoimmune myositis, primary Sjogren's syndrome, smooth muscle autoimmune disease or disorder, myositis, tendinitis, a ligament inflammation, chondritis, a joint inflammation, a synovial inflammation, carpal tunnel syndrome, arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, a skeletal inflammation, an autoimmune ear disease or disorder, and an autoimmune disease or disorder of the inner ear.
- Non-limiting examples of inflammatory renal diseases or disorders include autoimmune interstitial nephritis and/or renal cancer.
- Non-limiting examples of inflammatory reproductive diseases or disorders include repeated fetal loss, ovarian cyst, or a menstruation associated disease or disorder.
- Non-limiting examples of inflammatory systemic diseases or disorders include systemic lupus erythematosus, systemic sclerosis, septic shock, toxic shock syndrome, and cachexia.
- Non-limiting examples of infectious disease or disorder include chronic infectious diseases or disorders, a subacute infectious disease or disorder, an acute infectious disease or disorder, a viral disease or disorder, a bacterial disease or disorder, a protozoan disease or disorder, a parasitic disease or disorder, a fungal disease or disorder, a mycoplasma disease or disorder, gangrene, sepsis, a prion disease or disorder, influenza, tuberculosis, malaria, acquired immunodeficiency syndrome, and severe acute respiratory syndrome.
- Non-limiting examples of inflammatory transplantation-related diseases or disorders include graft rejection, chronic graft rejection, subacute graft rejection, acute graft rejection hyperacute graft rejection, and graft versus host disease or disorder.
- Exemplary implants include a prosthetic implant, a breast implant, a silicone implant, a dental implant, a penile implant, a cardiac implant, an artificial joint, a bone fracture repair device, a bone replacement implant, a drug delivery implant, a catheter, a pacemaker, an artificial heart, an artificial heart valve, a drug release implant, an electrode, and a respirator tube.
- Non-limiting examples of inflammatory tumors include a malignant tumor, a benign tumor, a solid tumor, a metastatic tumor and a non-solid tumor.
- Non-limiting examples of inflammatory pulmonary diseases or disorders include asthma, allergic asthma, emphysema, chronic obstructive pulmonary disease or disorder, sarcoidosis and bronchitis.
- An example of a proliferative disease or disorder is cancer.
- a compound or “at least one compound” may include a plurality of compounds, including mixtures thereof.
- range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
- method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
- treating includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.
- VB-201 concentrations in plasma was performed using an HPLC-MS/MS (high performance liquid chromatography with tandem mass spectrometric detection) assay. Calibration was for a range of from 5 to 500 ng/ml for low doses and from 50 to 5000 ng/ml for high doses.
- Pharmacokinetic parameters were estimated by using a non-compartmental method, except for the AUC (area under curve), which was determined using a (log-) trapezoidal rule as the area above the previous trough level.
- CRP C-reactive protein
- Plasma levels of interleukin-23 (IL-23) and interferon- ⁇ (IFN- ⁇ ) were determined using the FlowCytomix human simplex kits (Bender Medsystems) for the aforementioned cytokines according to the manufacturer instructions. Acquisition of samples was performed using FacsCalibur (Becton Dickinson). Results were analyzed with the FlowCytomix Pro 2.2 Software.
- CD14 + cells Human monocytes (CD14 + cells) were isolated from whole blood of healthy donors. Following PBMC (peripheral blood mononuclear cell) separation from whole blood using Ficoll-Paque and leucosep tubes, CD14 + cells were separated using specific CD14 micro beads (Miltenyi Biotech). Purity of the CD14 + population was validated using specific monoclonal CD14 antibody by FACS analysis.
- PBMC peripheral blood mononuclear cell separation from whole blood using Ficoll-Paque and leucosep tubes. Purity of the CD14 + population was validated using specific monoclonal CD14 antibody by FACS analysis.
- RANTES 100 ng/ml
- ⁇ - ⁇ macrophage inflammatory protein- la
- MCP-1 macrophage chemotactic protein- 1; 50 ng/ml
- MCP-3 50 ng/ml
- CD14+ cells were pre- incubated for 30 minutes with solvent (1 % ethanol/PBS) or VB-201 at 8 ⁇ (or different concentrations ranging between 1.7-17 ⁇ , not shown).
- Migration assay was conducted by seeding 300,000 treated cells in the upper chamber, followed by incubated for 3-4 hours, after which the number of migrated cells was determined by FACS (fluorescence activated cell sorting).
- vital signs systolic and diastolic blood pressure, heart rate, respiratory rate, body temperature;
- Treatment-emergent adverse events were defined as any adverse event that started on or after administration of the first dose of VB-201, and no more than 30 days after administration of the last dose, or are ongoing at the time of the first dose and worsened in severity or frequency during treatment.
- VB-201 was formulated in gelatin capsules enterocoated with Eudragit®.
- the log-transformed values of the primary target parameters were subject to an analysis of variance (ANOVA) model with the effects: sequence, subjects within sequence, period and treatment. Based on the ANOVA, 90 % confidence intervals for the treatment were calculated.
- Table 1 Pharmacokinetic parameters of VB-201 in plasma following a single-dose administration of 1, 3, 10, 30, and 50 mg VB-201 (results are presented as mean ⁇ standard deviation, with range in parentheses)
- Vz/F 88 ⁇ 10 79 ⁇ 21 93 ⁇ 32 74 ⁇ 22 63 ⁇ 25 liters (76-102) (47-109) (60-151) (51-111) (30-92)
- AUC(0-168) area under concentration-time curve from 0 hours to 168 hours
- AUC(0-last non-BLQ) area under concentration-time curve, from 0 hours to last measurement which was not below the limit of quantification
- AUC(O-infinity) area under concentration-time curve from 0 hours to infinity
- C aVg (0-168) average concentration from 0 hours to 168 hours
- Tmax time until maximum plasma concentration is reached
- Vz/F apparent volume of distribution during terminal phase after oral administration
- the pharmacokinetics of VB-201 was dose- linear and nearly dose-proportional with regard to AUC (area under concentration-time curve) and C max (maximum plasma concentration).
- T max values were relatively independent of dose levels (ranging from 6 to 8 hours). VB-201 plasma levels rose generally linearly until T max was reached. The mean half life (Ti /2 ) was 37 to 51 hours.
- the clearance parameters mean transit time (MTT), apparent clearance (Cl/F), and apparent volume of distribution (Vz/F) were relatively independent of dose levels.
- treatment-emergent adverse events were reported in 27 out of 40 subjects. 32 treatment-emergent adverse events in 12 subjects were considered drug-related. All treatment-emergent adverse events were of mild or moderate intensity and no event was of severe intensity. The incidence of adverse events did not appear to be dose-related.
- Adverse events and laboratory abnormalities were even less frequent in the 2 subjects with very high VB-201 exposure compared to the other subjects.
- a randomized, double-blind, placebo-controlled study was performed to in order to investigate the safety, tolerability and pharmacokinetics of VB-201 at a repeated, daily dose taken orally.
- the subjects were all healthy volunteers. Cohorts of six subjects each received a daily dose 5, 10, 20 and 30 mg VB-201 in the morning, following at least 10 hours of fasting, for 14 days. 10 subjects received a placebo.
- the VB-201 was formulated in gelatin capsules enterocoated with Opadry AMB and Acryleze White.
- the 20 mg dose was originally in the form of 20 mg capsules. Due to significantly reduced absorption and delayed uptake when using 20 mg capsules, the data were invalidated and the 20 mg cohort was repeated using administration of four 5 mg capsules to new subjects.
- Concentration-time curves were constructed for a time period of 24 hours on each of days 1 and 14. Mean plasma concentrations of VB-101 during days 1 and 14 are shown in FIG. 2.
- AUC(0-24) area under concentration-time curve from 0 hours to 24 hours after administration
- AUC(O-infinity) area under concentration-time curve from 0 hours to infinity
- Tmax time until maximum plasma concentration is reached
- AUMC(0-24) area under the moment curve of the concentration-time curve from 0 hours to 24 hours after administration
- Vd/F volume of distribution
- AUC area under concentration-time curve
- Cma maximum plasma concentration
- This variation is possibly a result of gastric emptying following ingestion of respectively four 5 mg capsules (for a 20 mg dosage) and six 5 mg capsules (for a 30 mg dosage).
- the average accumulation rate was approximately 5, but was slightly higher for a 30 mg dosage.
- Terminal elimination half-lives could not be reliably calculated over the 0-24 hour range because of the long Ti/ 2 for the compound. More reliable measurements were calculated from the recovery phase (days 14-22).
- the clearance parameters Cl/F (clearance) and MTT (mean transit time) were relatively independent of dose. MTT values were similar for all dosage levels tested. Clearance values at dosages of 5 mg and 10 mg were similar (especially when 2 outliers were discounted). Clearance values were somewhat higher at dosages of 20 and 30 mg. The differences between Day 1 values and Day 14 values may be artifacts of the long half-lives, which affect both calculations.
- VB-201 capsules were investigated in a double-blind, placebo-controlled study in healthy subjects. Cohorts of six subjects each received a single dose of 10 mg, 2x10 mg or 20 mg VB-201 in the morning. For each dosage level, one cohort received enteric coated capsules and one cohort received non-coated capsules. 12 subjects received a placebo.
- Subjects were randomly assigned to receive the drug when fed (i.e., following completion of a standardized high fat meal) or when fasting (i.e., fasting for at least 10 hours). Blood samples were drawn 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 48, 72, 96, 120 and 144 hours post-dose. Subjects then underwent an additional 8 day washout period, after which subjects underwent a second administration. Subjects who received the first administration when fasting, received the second administration when fed, and subjects who received the first administration when fed, received the second administration when fasting. Following the second administration, blood samples were taken at the same times post-dose as previously.
- Concentration-time curves were constructed for time periods of up to 144 hours. Pharmacokinetic parameters were calculated based on data for the first 24 hours and for the whole 144 hours. Parameters calculated from data covering 144 hours provide a more accurate estimate of metabolic parameters. Nevertheless, parameters were also calculated from data covering the first 24 hours in order to compare parameters with previous studies.
- FIG. 3 Various pharmacokinetic parameters calculated from the data are presented in Table 3 below.
- Table 3 Effect of fasting and enteric coating on mean pharmacokinetic parameters of VB-201 in plasma following single administration of 10, 2x10 and 20 mg VB-201
- AUC(0-24) area under concentration-time curve from 0 hours to 24 hours after administration
- AUC(0-144) area under concentration-time curve from 0 hours to 144 hours after administration
- AUC(0-infinity, from 24) area under concentration-time curve from 0 hours to infinity, as calculated based on data from 0 to 24 hours
- AUC(0-infinity, from 144) area under concentration-time curve from 0 hours to infinity, as calculated based on data from 0 to 144 hours
- Ti/2 (from 144) elimination half-life calculated based on data from 0 to 144 hours
- AUMC(0-24) area under the moment curve of the concentration-time curve from 0 hours to 24 hours after administration
- AUMC(0-infinity) area under the moment curve of the concentration-time curve from
- MTT (0-24) mean transit time calculated over 0 to 24 hours
- MTT mean transit time calculated based on data from 0 to 144 hours
- Ke (from 24) elimination rate constant calculated based on data from 0 to 24 hours
- Ke (from 144) elimination rate constant calculated based on data from 0 to 144 hours
- Cl/F (0-24) clearance calculated over 0 to 24 hours after administration
- Vd/F (0-24) volume of distribution over 0 to 24 hours after administration
- Vd/F (from 144) volume of distribution calculated based on data from 0 to 144 hours
- Vd/F (from 144) volume of distribution calculated based on data from 0 to 144 hours
- AUC and C max values were proportional to the dose, indicating a linear dose response.
- coated capsules significantly lowered AUC and Cmax values.
- enteric coatings increased T max .
- fasting subjects exhibited a considerably smaller coating-induced increase in T max than did fed subjects.
- terminal elimination half-lives and mean transit times (MTT) were not affected by dose level, coating or feeding.
- enteric coated and non-coated capsules with 10 to 20 mg VB-201 are as safe and tolerable as placebo, whether taken while fasting or following feeding.
- a randomized, double-blind, placebo-controlled study was performed to in order to investigate the safety, tolerability and pharmacokinetics of VB-201 at a repeated, daily dose taken orally.
- the subjects were all healthy volunteers. Cohorts of six subjects each received a daily dose of 40 or 80 mg VB-201 in the morning, following at least 10 hours of fasting, for 14 days. 6 subjects received a placebo.
- the VB-201 was formulated in non-enterocoated capsules.
- Plasma samples obtained on day 0 (pre-dosing) and on day 14 from the subjects in each cohort (40 mg for 14 days, 80 mg for 14 days, and 80 mg for 28 days), and on day 28 from the subjects of the cohort receiving 80 mg VB-201 for 28 days, were assayed for C-reactive protein (CRP) by the high sensitivity CRP assay described hereinabove.
- CRP C-reactive protein
- Mean plasma concentrations of VB-201 during 24 hour time periods following administration were determined for days 1 and 14 of the 40 mg cohort, and for day 14 of the 80 mg cohort, and pharmacokinetic parameters were determined for the data representing each of these time periods.
- the mean plasma concentrations are shown in FIG. 4.
- Table 4 Pharmacokinetic parameters of VB-201 in plasma on days 1 and 14 following daily administration of 40 and 80 mg VB-201 (results are presented as: mean ⁇ standard deviation)
- AUC(0-24) area under concentration-time curve from 0 hours to 24 hours after administration
- AUC(0-infinity) area under concentration-time curve from 0 hours to infinity
- Tmax time until maximum plasma concentration is reached
- MTT(0-24) mean transit time calculated over 0 to 24 hours
- MTT(0-infinity) mean transit time calculated over 0 hours to infinity
- Vd/F(0-24) volume of distribution calculated over 0 to 24 hours after administration
- Vd/F(0-infinity) volume of distribution calculated over 0 hours to infinity
- AUC and C ma x values on day 14 were proportionate to the dosage level.
- the observed accumulation ratio between day 14 and day 1 was approximately 3 (only the 40 mg cohort was measured).
- T 2 elimination half-lives
- MTT mean transit times
- CRP C-reactive protein
- CRP C-reactive protein
- Interleukin-23 (IL-23) is an important part of the inflammatory response against infection, and promotes production of numerous inflammatory molecules. IL-23 plays an important role in the development of symptoms of multiple sclerosis and inflammatory bowel disease, highlighting the importance of IL-23 in inflammatory disease pathways.
- Interferon- ⁇ (IFN-y)_ is a cytokine which is expressed by Thl cells and suppresses activity of Th2 cells. IFN- ⁇ promotes leukocyte migration. IFN- ⁇ expression is associated with a number of auto-inflammatory and autoimmune diseases.
- administration of 40 mg per day VB-201 considerably reduced IL-23 levels in both subjects which exhibited detectable pre-dose IL-23 levels.
- administration of 40 mg per day VB-201 considerably reduced IFN- ⁇ levels in one subject, whereas the second subject had no detectable IFN- ⁇ levels before or after administration.
- VB-201 is effective against inflammatory diseases and disorders such as multiple sclerosis and inflammatory bowel disease.
- VB-201 was previously shown to be effective in the in vivo animal models of adjuvant-induced arthritis and collagen-induced arthritis. VB-201 has also been shown to have immunomodulatory effects which may slow progression of rheumatoid arthritis (RA). The efficacy of VB-201 in treating RA in humans is therefore investigated.
- a randomized, double blind, Phase II study is performed in subjects with active RA receiving VB-201 with concomitant methotrexate (MTX) compared to subjects receiving MTX alone.
- MTX methotrexate
- Diagnosis of RA is based on the 1987 Revised American Rheumatism Association Criteria for the Classification of Rheumatoid Arthritis. Subjects already receiving MTX (at least 12.5 mg per week, for at least 6 months) are selected. The number of subjects enrolled with a history of previous RA treatment with biologies (e.g., TNF-a inhibitors, T-cell inhibitors, and B-cell inhibitors) is limited to 30 % of all subjects.
- biologies e.g., TNF-a inhibitors, T-cell inhibitors, and B-cell inhibitors
- eligible subjects are randomly assigned to receive 20 mg per day VB-201, 80 mg per day VB-201, or placebo, for a period of 12 weeks. Doses are administered orally at breakfast time. All subjects continue to receive MTX at the same dose utilized prior to study entry.
- the maximal dose of VB-201 (80 mg/day) was determined according to the tolerability results presented in Example 4.
- Efficacy of each dosage level of VB-201 relative to placebo and MTX only groups is determined by measuring mean change from baseline for each of ACR components and percentage of patients achieving ACR20, ACR50 and ACR70 responses (as defined by the American College of Rheumatology) at weeks 2, 4, 8, 12 and 16.
- Additional criteria include the percentage of subjects requiring rescue intervention, and the percentage of subjects achieving low disease activity (score of 3.2 or less), remission (score of ⁇ 2.6), "good” response or “moderate” response, as calculated according to the Disease Activity Score 28 (DAS28) at weeks 2, 4, 8, 12 and 16.
- DAS28 Disease Activity Score 28
- Safety of VB-201 administration is evaluated as described hereinabove by physical examination, incidence of adverse effects, vital signs, clinical chemistry, hematology, urinalysis and electrocardiograms.
- a randomized, double-blind Phase II study is performed in subjects with moderate to severe plaque psoriasis, in order to determine the efficacy of VB-201 in treating this condition.
- Patients are selected with moderate (i.e., scoring at least 3 on a 0 to 5 point Physician Global Assessment (PGA)) to severe, stable and active plaque psoriasis vulgaris affecting at least 10 % of the body surface and with a Psoriasis Area and Severity Index (PASI) score of at least 12. Patients must undergo a wash-out period following any previous treatments. After screening and establishment of a baseline, eligible subjects are randomly assigned to receive 20 mg per day VB-201, 80 mg per day VB-201 or a daily placebo, for a period of 12 weeks. Doses are administered orally at breakfast time with food.
- moderate i.e., scoring at least 3 on a 0 to 5 point Physician Global Assessment (PGA)
- PGA Physician Global Assessment
- PASI Psoriasis Area and Severity Index
- the maximal dose of VB-201 (80 mg/day) was determined according to the tolerability results presented in Example 4.
- Efficacy of each dosage level of VB-201 relative to placebo is determined according to the percentage of patients which achieve at least a 50 % or 75 % improvement over baseline PASI score at week 12.
- Additional criteria include change in affected body surface area from baseline to week 12, change in PGA score from baseline to week 12, any change relative to baseline PASI score, and change in Patient Psoriasis Global Assessment score from baseline to week 12.
- Blood samples are taken at weeks 4, 8 and 12, in order to assess VB-201 pharmacokinetics, as well as plasma cytokine levels.
- Safety of VB-201 administration is evaluated as described hereinabove by physical examination, incidence of adverse effects, vital signs, clinical chemistry, hematology, urinalysis and electrocardiograms.
- Inflammation is measured by positron emission computed tomography (PET-CT) to quantify 18 FDG ( 18 F- fludeoxyglucose) uptake as a target to background ratio (TBR). ;
- Subjects are scanned by PET-CT to determine baseline 18 FDG uptake, and those with a TBR of at least 1.6 in either the carotid artery or the ascending aorta are selected for study. After screening and establishment of a baseline, eligible subjects are randomly assigned to receive 20 mg per day VB-201, 80 mg per day VB-201 or a daily placebo, for a period of 12 weeks. Doses are administered orally at breakfast time with food.
- the maximal dose of VB-201 (80 mg day) was determined according to the tolerability results presented in Example 4.
- the TBR of each subject is determined again by PET-CT at week 12 of the treatment. Efficacy is determined by comparing TBR values obtained before and after treatment.
- This subjects of this study can be a subset of subjects of a second study (e.g., the study described in Example 7), and the study can be performed concomitantly with the second study.
- Cell migration is an essential process during many phases of development and adult life. Cells can either migrate as individuals or move in the context of tissues. Movement is controlled by internal and external signals, which activate complex signal transduction cascades resulting in highly dynamic and localized remodeling of the cytoskeleton, cell-cell and cell-substrate interactions. Chemoattractants induce cell migration through the activation of a distinct family of structurally related heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors.
- G protein structurally related heterotrimeric guanine nucleotide-binding protein
- Chemokines or chemotactic cytokines are 8- to 10-kDa secreted proteins that regulate migration and activation of not only leukocytes, including the DC, but also of stromal cells. Chemoattraction occurs in response to a local gradient of chemokines in the extracellular space.
- VB-201 was tested in vitro as described hereinabove for possible effects on migration of human primary monocytes towards inflammatory chemokines using a trans-well assay.
- chemoattractants which serve as ligands for different chemokine receptors were used.
- Two assays were performed in triplicates for each chemoattractant.
- VB-201 significantly (P ⁇ 0.05) reduced migration of human primary monocytes towards all of the following monocytes attractants: MCP-1, MCP-3, ⁇ -1 ⁇ and RANTES. Similar response was observed when human endothelial cell medium was used as an attractant.
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BRBR112012016543-7A BR112012016543A2 (en) | 2010-01-05 | 2011-01-05 | Vb-201 Treatment |
AU2011204406A AU2011204406B2 (en) | 2010-01-05 | 2011-01-05 | Treatment with VB-201 |
US13/520,719 US20130172294A1 (en) | 2010-01-05 | 2011-01-05 | Treatment with VB-201 |
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CA2786060A CA2786060A1 (en) | 2010-01-05 | 2011-01-05 | Treatment with vb-201 |
NZ60122411A NZ601224A (en) | 2010-01-05 | 2011-01-05 | Treatment with vb-201 |
KR1020127020564A KR20120133375A (en) | 2010-01-05 | 2011-01-05 | Treatment with vb-201 |
JP2012547586A JP2013516455A (en) | 2010-01-05 | 2011-01-05 | Treatment with VB-201 |
ZA2012/05425A ZA201205425B (en) | 2010-01-05 | 2012-07-19 | Treatment with vb-201 |
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PCT/IL2011/000008 WO2011083465A1 (en) | 2010-01-05 | 2011-01-05 | Treatment with vb-201 |
PCT/IL2011/000010 WO2011083467A1 (en) | 2010-01-05 | 2011-01-05 | Combined treatment utilizing vb-201 |
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EP (2) | EP2521454A4 (en) |
JP (2) | JP2013516455A (en) |
KR (1) | KR20120133375A (en) |
CN (1) | CN102834011B (en) |
AU (1) | AU2011204406B2 (en) |
BR (1) | BR112012016543A2 (en) |
CA (1) | CA2786060A1 (en) |
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NZ (1) | NZ601224A (en) |
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Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8563534B2 (en) | 2000-11-24 | 2013-10-22 | Vascular Biogenics Ltd. | Methods employing and compositions containing defined oxidized phospholipids for prevention and treatment of atherosclerosis |
US8569529B2 (en) | 2007-01-09 | 2013-10-29 | Vascular Biogenics Ltd. | High-purity phospholipids |
WO2013121300A3 (en) * | 2012-02-16 | 2013-12-27 | Vascular Biogenics Ltd. | Methods for treating psoriasis and vascular inflammation |
US8759557B2 (en) | 2004-07-09 | 2014-06-24 | Vascular Biogenics Ltd. | Process for the preparation of oxidized phospholipids |
KR20140078641A (en) * | 2011-09-01 | 2014-06-25 | 바스큘라 바이오제닉스 리미티드 | Formulations and dosage forms of oxidized phospholipids |
US8999960B2 (en) | 2008-10-08 | 2015-04-07 | Vascular Biogenics Ltd. | Oxidized thiophospholipid compounds and uses thereof |
US9006217B2 (en) | 2007-01-09 | 2015-04-14 | Vascular Biogenics Ltd. | High-purity phospholipids |
US9206206B2 (en) | 2008-11-06 | 2015-12-08 | Vascular Biogenics Ltd. | Oxidized lipid compounds and uses thereof |
US9771385B2 (en) | 2014-11-26 | 2017-09-26 | Vascular Biogenics Ltd. | Oxidized lipids |
US10022388B2 (en) | 2014-11-26 | 2018-07-17 | Vascular Biogenics Ltd. | Oxidized lipids and treatment or prevention of fibrosis |
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US20150320773A1 (en) * | 2011-12-12 | 2015-11-12 | Vascular Biogenics Ltd. | Treatment of inflammation |
US9763992B2 (en) | 2014-02-13 | 2017-09-19 | Father Flanagan's Boys' Home | Treatment of noise induced hearing loss |
WO2017173203A1 (en) * | 2016-03-31 | 2017-10-05 | Mayo Foundation For Medical Education And Research | Methods and materials for assessing intestinal permeability |
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AU1846102A (en) * | 2000-11-24 | 2002-06-03 | Cardimmune Ltd | Methods employing and compositions containing defined oxidized phospholipids forprevention and treatment of atherosclerosis |
WO2006006161A2 (en) * | 2004-07-09 | 2006-01-19 | Vascular Biogenics Ltd. | Improved process for the preparation of oxidized phospholipids |
US8084209B2 (en) * | 2005-07-22 | 2011-12-27 | Children's Hospital & Research Center Oakland | HMGCR isoforms in prediction of efficacy and identification of cholesterol-modulating compounds |
US20090074720A1 (en) * | 2005-10-28 | 2009-03-19 | Sabbadini Roger A | Methods for decreasing immune response and treating immune conditions |
US8137977B2 (en) * | 2006-04-24 | 2012-03-20 | Children's Hospital & Research Center At Oakland | Lipidomic approaches to determining drug response phenotypes in cardiovascular disease |
EA201070656A1 (en) * | 2007-11-28 | 2010-12-30 | Тева Фармасьютикал Индастриз, Лтд. | METHOD OF DELAYING THE BEGINNING OF MANIFESTATION OF CLINICALLY DEFINED SCATTERED SCLEROSIS |
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2011
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- 2011-01-05 CN CN201180009408.XA patent/CN102834011B/en not_active Expired - Fee Related
- 2011-01-05 WO PCT/IL2011/000012 patent/WO2011083469A1/en active Application Filing
- 2011-01-05 MX MX2012007807A patent/MX2012007807A/en not_active Application Discontinuation
- 2011-01-05 NZ NZ60122411A patent/NZ601224A/en not_active IP Right Cessation
- 2011-01-05 EP EP11731734.7A patent/EP2521454A4/en not_active Withdrawn
- 2011-01-05 US US13/520,719 patent/US20130172294A1/en not_active Abandoned
- 2011-01-05 CA CA2786060A patent/CA2786060A1/en not_active Abandoned
- 2011-01-05 US US13/520,713 patent/US20120329758A1/en not_active Abandoned
- 2011-01-05 WO PCT/IL2011/000008 patent/WO2011083465A1/en active Application Filing
- 2011-01-05 JP JP2012547588A patent/JP2013516457A/en active Pending
- 2011-01-05 AU AU2011204406A patent/AU2011204406B2/en not_active Ceased
- 2011-01-05 EP EP11731736.2A patent/EP2521569B1/en active Active
- 2011-01-05 WO PCT/IL2011/000010 patent/WO2011083467A1/en active Application Filing
- 2011-01-05 KR KR1020127020564A patent/KR20120133375A/en not_active Application Discontinuation
- 2011-01-05 ES ES11731736.2T patent/ES2654944T3/en active Active
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2012
- 2012-07-19 ZA ZA2012/05425A patent/ZA201205425B/en unknown
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2013
- 2013-03-14 US US13/828,643 patent/US20130225525A1/en not_active Abandoned
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Patent Citations (1)
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US20070099868A1 (en) * | 2003-05-27 | 2007-05-03 | Dror Harats | Oxidized lipids and uses thereof in the treatment of inflammatory diseases and disorders |
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Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8563534B2 (en) | 2000-11-24 | 2013-10-22 | Vascular Biogenics Ltd. | Methods employing and compositions containing defined oxidized phospholipids for prevention and treatment of atherosclerosis |
US8759557B2 (en) | 2004-07-09 | 2014-06-24 | Vascular Biogenics Ltd. | Process for the preparation of oxidized phospholipids |
US8802875B2 (en) | 2004-07-09 | 2014-08-12 | Vascular Biogenics Ltd. | Process for the preparation of oxidized phospholipids |
US9006217B2 (en) | 2007-01-09 | 2015-04-14 | Vascular Biogenics Ltd. | High-purity phospholipids |
US8569529B2 (en) | 2007-01-09 | 2013-10-29 | Vascular Biogenics Ltd. | High-purity phospholipids |
US9566288B2 (en) | 2007-01-09 | 2017-02-14 | Vascular Biogenics Ltd. | High-purity phospholipids |
US8999960B2 (en) | 2008-10-08 | 2015-04-07 | Vascular Biogenics Ltd. | Oxidized thiophospholipid compounds and uses thereof |
US9206206B2 (en) | 2008-11-06 | 2015-12-08 | Vascular Biogenics Ltd. | Oxidized lipid compounds and uses thereof |
KR20140078641A (en) * | 2011-09-01 | 2014-06-25 | 바스큘라 바이오제닉스 리미티드 | Formulations and dosage forms of oxidized phospholipids |
JP2014525463A (en) * | 2011-09-01 | 2014-09-29 | バスキュラー バイオジェニックス リミテッド | Oxidized phospholipid formulations and dosage forms |
US9254297B2 (en) | 2011-09-01 | 2016-02-09 | Vascular Biogenics Ltd. | Formulations and dosage forms of oxidized phospholipids |
KR101939430B1 (en) * | 2011-09-01 | 2019-01-16 | 바스큘라 바이오제닉스 리미티드 | Formulations and dosage forms of oxidized phospholipids |
WO2013121300A3 (en) * | 2012-02-16 | 2013-12-27 | Vascular Biogenics Ltd. | Methods for treating psoriasis and vascular inflammation |
US9771385B2 (en) | 2014-11-26 | 2017-09-26 | Vascular Biogenics Ltd. | Oxidized lipids |
US10022388B2 (en) | 2014-11-26 | 2018-07-17 | Vascular Biogenics Ltd. | Oxidized lipids and treatment or prevention of fibrosis |
US10206936B2 (en) | 2014-11-26 | 2019-02-19 | Vascular Biogenics Ltd. | Oxidized lipids and treatment or prevention of fibrosis |
US10464957B2 (en) | 2014-11-26 | 2019-11-05 | Vascular Biogenics Ltd. | Oxidized lipids and methods of use thereof |
Also Published As
Publication number | Publication date |
---|---|
ZA201205425B (en) | 2015-07-29 |
EP2521454A1 (en) | 2012-11-14 |
CN102834011B (en) | 2016-01-13 |
US20120329758A1 (en) | 2012-12-27 |
KR20120133375A (en) | 2012-12-10 |
MX2012007807A (en) | 2012-10-03 |
CA2786060A1 (en) | 2011-07-14 |
BR112012016543A2 (en) | 2015-09-01 |
WO2011083467A1 (en) | 2011-07-14 |
ES2654944T3 (en) | 2018-02-15 |
EP2521569A4 (en) | 2013-05-22 |
CN102834011A (en) | 2012-12-19 |
US20160008381A1 (en) | 2016-01-14 |
AU2011204406B2 (en) | 2015-05-07 |
US20130172294A1 (en) | 2013-07-04 |
WO2011083469A1 (en) | 2011-07-14 |
JP2013516457A (en) | 2013-05-13 |
US20130225525A1 (en) | 2013-08-29 |
EP2521454A4 (en) | 2013-06-26 |
NZ601224A (en) | 2015-03-27 |
JP2013516455A (en) | 2013-05-13 |
AU2011204406A1 (en) | 2012-08-02 |
EP2521569A1 (en) | 2012-11-14 |
EP2521569B1 (en) | 2017-11-01 |
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