Classifications

• • 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
  • A61K31/21—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
  • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
  • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents

Definitions

• the methods include a dosing regimen to treat a patient suffering from a neurodegenerative ocular disease treatable with a deuterated docosahexaenoic acid (DHA) or a prodrug thereof.
• DHA deuterated docosahexaenoic acid
• the dosing regimen provides for rapid onset to a therapeutic concentration in vivo of deuterated DHA at a level where the progression of the disease is reduced notwithstanding the gradual increase in metabolic uptake of this compound in the treated patient.
• the retina contains very high levels of docosahexaenoic acid which is found in the highest concentrations in the disk membranes of the outer segments of photoreceptor ceils including rods that help convert light into electrical and chemical signals for the brain.
• Docosahexaenoic acid accounts for most of the total polyunsaturated fatty acid groups present in the phospholipids of rod’s outer segment membranes of the photoreceptor cells. This represents a proportion higher than is found in any other tissues in the human body.
• DHA docosahexaenoic acid
• PUFA polyunsaturated fatty acid
• oxidation of a bis-allylic position in a first DHA leads to an oxidative cascade of neighboring DHAs known as lipid auto-peroxidation (LPO).
• LPO lipid auto-peroxidation
• This cascade generates significant damage to the retina and negatively affects the viability of the retina.
• the oxidized DHAs lead to oxidation of membrane proteins as well as being converted into a large number of highly reactive carbonyl compounds. The ongoing imbalance in the oxidative process leads to continued degradation in the retina of the patient's eyes.
• this disclosure provides for dosing protocols that allow for the uptake of deuterated docosahexaenoic acid or an ester thereof in amounts that provide for an accelerated onset of a therapeutic concentration in the retina and reduction in the rate of disease progression.
• a reduction is based on the differential in the extent of the disease progression in treated patients as compared to patients treated with placebo control at 6 months, or at 12 months, or at 18 months, or at 24 months interval between initiation of therapy and evaluation of disease progression.
• this differential in the extent of disease progression in treated patients as compared to patients treated with placebo is about 20% as measured by reduced geographic atrophy expansion over a 6 or 12, or 18, or 24 month interval between initiation of therapy and evaluation of disease progression.
• a dosing protocol which comprises the periodic administration of a unit dose of deuterated docosahexaenoic acid or an ester thereof per day.
• the unit dose is selected to provide for an accelerated (rapid) uptake of the deuterated docosahexaenoic acid in the retina.
• the unit dose can be split into 1, 2, 3 or 4 subunits each administered on the same day.
• a method for treating an oxidative retinal disease in a patient in need thereof comprises the periodic administration to said patient of from about 100 mg/day to about 1,000 mg/day of a composition comprising a deuterated docosahexaenoic acid or ester thereof wherein said administration results in a therapeutic concentration of deuterated docosahexaenoic acid in the retina coupled with a reduction in the rate of progression of said oxidative retinal disease.
• the periodic dosing to the patient is from about 100 mg/day to about 350 mg/day.
• the periodic dosing to the patient is from about 350 mg/day to about 650 mg/day.
• the periodic dosing to the patient is from about 650 mg/day to about 1.000 mg/day. In some cases, the periodic dosing to the patient can range from about 100 mg/day to about 1,250 mg/day.
• the methods described herein provide for an accelerated onset of a therapeutic concentration of deuterated docosahexaenoic acid in vivo to minimize unnecessary loss of vision functionality in the treated patients suffering from an oxidative retinal disease.
• said periodic administration of the unit dose comprises administration for at least 5 days per week and preferably 7 days a week.
• said periodic administration of the unit dose comprises administration for at least about 70% of the days per month and preferably at least about 80% of the days per month.
• the deuterated docosahexaenoic acid ester is a C1-C6 alkyl ester and preferably an ethyl ester.
• the per day dosing of the deuterated docosahexaenoic acid or ester thereof is about 100 mg/day; or about 125 mg/day; or about 150 mg/day; or about 175 mg/day; or about 200 mg/day; or about 225 mg/day; or about 250 mg/day; or about 275 mg/day; or about 300 mg/day; or about 325 mg/day; or about 350 mg/day; or about 375 mg/day, or about 400 mg/day; or about 425 mg/day; or about 450 mg/day; or about 475 mg/day; or about 500 mg/day; or about 525 mg/day; or about 550 mg/day; or about 575 mg/day; or about 600 mg/day; or about 625 mg/day; or about 650 mg/day; or about 675 mg/day; or about 700 mg/day; or about 725 mg/day; or about 750 mg/day; or about 775 mg/day; or about 800 mg/day;
• the methods described herein employ compositions comprising deuterated docosahexaenoic acid or ester thereof with at least about 80 percent replacement of hydrogen of all of the bis-allylic sites with deuterium and with an average deuteration at the mono-allylic sites of from about 1 to about 35 percent based on all of the available mono-allylic sites.
• Such compositions are suitable for use in the dosing protocols described herein.
• the inclusion of deuterium in the bis-allylic sites stabilizes the deuterated docosahexaenoic acid against oxidative damage. This, in turn, stops the cascade of lipid peroxidation (LPO) thereby minimizing damage to the retinal cells.
• LPO lipid peroxidation
• compositions used in the dosing protocol comprise a population of deuterated docosahexaenoic acids and/or esters thereof having on average at least 90% of the bis-allylic hydrogen atoms exchanged to deuterium atoms.
• Such compositions impart significant protection against LPO in vivo.
• the deuterated compositions contain a measurable amount of deuteration at the mono-allylic sites as well.
• the average level of hydrogen atoms exchanged for deuterium atoms at all mono-allylic sites ranges from about 1 to about 35% in the composition.
• the inclusion of deuteration at the mono- allylic sites does not interfere with the protection accorded by deuteration at the bis-allylic sites.
• the onset of a therapeutic concentration is within 50 days from the start of treatment, preferably within 40 days, and more preferably, within 30 days.
• the periodic administration of docosahexaenoic acid or esters thereof comprises administration of a daily dose of docosahexaenoic acid or an ester thereof for at least 5 days per week during therapy.
• the periodic administration of docosahexaenoic acid or esters thereof comprises administration of a daily dose of docosahexaenoic acid or an ester thereof once a day for 7 days per week during therapy.
• the rate of reduction in disease progression is based on the following formula: a) determine the average rate of disease progression for a cohort of treated patients by measuring the extent of geographic atrophy in each of the patient's retina at the start of therapy and at 6 months or 12 months, or 18 months or 24 months post start of therapy, obtaining an average for that differential and assigning a first value to that average differential and assign "A" to that value; b) determine the average rate of disease progression for a cohort of untreated patients by measuring the extent of geographic atrophy in each of the patient's retina at the start of therapy and at 6 months or 12 months, or 18 months or 24 months post start of therapy, obtaining an average for that differential and assigning a second value to that average differential and assign "B" to that value; c) calculate the delta between A and B and assign "C" to that value; d) assign a positive value to C if B is greater than A; e) assign a negative value to C if A is greater than B; and f) divide C by B
• this rate of reduction for a given patient is determined as above but by replacing A based on the cohort and using the result for the individual.
• the patients are placed on a diet that restricts intake of excessive amounts of PUFA compounds to maximize the uptake of the deuterated docosahexaenoic acid by the body.
• dietary components that contribute to excessive amounts of PUFA consumed are restricted.
• Such dietary components include, for example, fish oil pills, and salmon, and patients on conventional feeding tubes that result in excessive PUFA intake.
• the methods described herein include both the dosing regimen described above as well as placing the patients on a restrictive diet that avoids excessive ingestion of PUFA components.
• the methods of this invention include a dosing regimen that efficiently and rapidly provides a therapeutic level of deuterated docosahexaenoic acid in the eyes.
• the term “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.
• the term “about” when used with regard to a dose amount means that the dose may vary by +/- 10%.
• compositions and methods are intended to mean that the compositions and methods include the recited elements, but not excluding others.
• compositions and methods when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention.
• docosahexaenoic acid refers to the compound having the known structure as follows:
• Esters of docosahexaenoic acid are formed by replacing the -OH group with -OR.
• esters are as defined herein below.
• the term “deuterated docosahexaenoic acid or an ester thereof’ refers to docosahexaenoic acid or ester compounds having on average at least 80 percent of the hydrogen atoms at the bis-allylic sites exchanged to deuterium atoms with on average no more than about 35 percent of the hydrogen atoms at the mono-allylic sites exchanged to deuterium atoms.
• the average of hydrogen atoms at the bis-allylic sites exchanged to deuterium and the average of hydrogen atoms at the mono-allylic sites exchanged to deuterium are provided below
• deuterated DHA as described herein can be represented by formula I: where each Y is independently hydrogen or deuterium provided that at least about 80% of all of said Y groups are deuterium; and each X and X 1 is independently hydrogen or deuterium provided that the aggregate of all X and X 1 groups contain at least about 1% to about 35% of deuterium including all subranges found there between.
• the aggregate of both X groups contains from about 5% to about 30% of deuterium including all subranges between these two numbers whereas the aggregate of both X 1 groups contains from about 1% to about 10% of deuterium including all subranges between these two numbers.
• an ester thereof refers to a C1-C6 alkyl ester, glycerol ester (including monoglycerides, diglycerides and triglycerides), sucrose esters, phosphate esters, and the like.
• the particular ester employed is not critical provided that the ester is pharmaceutically acceptable (non-toxic and biocompatible).
• phospholipid refers to any and all phospholipids that are components of the cell membrane. Included within this term are phosphatidylcholine, lysophosphatydylcholine, phosphatidylethanolamine, phosphatidylserine, and sphingomyelin.
• the term “patient” refers to a human patient or a cohort of human patients suffering from an oxidative retinal disease treatable by administration of a compositions comprising deuterated docosahexaenoic acid or an ester thereof.
• the term “pharmaceutically acceptable salts” of compounds disclosed herein are within the scope of the methods described herein and include acid or base addition salts which retain the desired pharmacological activity and is not biologically undesirable (e.g., the salt is not unduly toxic, allergenic, or irritating, and is bioavailable).
• pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., alginate, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalene sulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid).
• inorganic acids such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid
• organic acids e.g., alginate, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, ox
• the compound When the compound has an acidic group, such as for example, a carboxylic acid group, it can form salts with metals, such as alkali and earth alkali metals (e.g., Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+ ), ammonia or organic amines (e.g., dicyclohexylamine, trimethylamine, trimethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e.g., arginine, lysine, and ornithine).
• metals such as alkali and earth alkali metals (e.g., Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+ ), ammonia or organic amines (e.g., dicyclohexylamine, trimethylamine, trimethylamine, pyridine, picoline, ethanolamine, diethanol
• Deuterated docosahexaenoic acid is prepared by the synthetic methods set forth in
• Esters of these deuterated fatty acids are prepared by conventional techniques well known in the art.
• the methods described herein entail the sustained dosing levels described herein to both achieve a therapeutic concentration and to maintain such a concentration in the eye and, specifically, in the rods of the retina.
• the dosing employed herein accounts for the variability of individual patients' metabolism with regard to the daily maximum PUFA uptake, the percent that the deuterated docosahexaenoic acid or ester thereof constitutes part of the PUFA uptake, specific conditions that compromise the PUFA uptake, and other factors well known in the art.
• the gradual increase in the in vivo concentration of docosahexaenoic acid and its relatively long half-life allows for patient medication "holidays" provided that the drug is administered at least 70% of the days per month, such as 5 days per week, 6 days per week, as well as 7 days per week for 3 weeks out of 4.
• the drug is administered at least 85% of the days per month (e.g., at least six days per week). Therefore, a patient who intentionally or inadvertently misses a daily dose of the drug is still compliant with the overall dosing protocol which is quite dissimilar to conventional drugs.
• the dosing regimen employs a daily or unit dose of from about 100 mg/day to about 1,000 mg/day without regard to the patient's BMI, severity of the disease condition, or the otherwise overall health of the patient.
• the daily dose is from about 100 mg/day to about 350 mg/day.
• the daily dose is from about 350 mg/day to about 650 mg/day.
• the daily dose is from about 650 mg/day to about 1,000 mg/day.
• the deuterated docosahexaenoic acid or ester thereof is administered at about 100 mg/day; or about 125 mg/day; or about 150 mg/day; or about 175 mg/day; or about 200 mg/day; or about 225 mg/day; or about 250 mg/day; or about 275 mg/day; or about 300 mg/day; or about 325 mg/day; or about 350 mg/day; or about 375 mg/day, or about 400 mg/day; or about 425 mg/day; or about 450 mg/day; or about 475 mg/day; or about 500 mg/day; or about 525 mg/day; or about 550 mg/day; or about 575 mg/day; or about 600 mg/day; or about 625 mg/day; or about 650 mg/day; or about 675 mg/day; or about 700 mg/day; or about 725 mg/day; or about 750 mg/day; or about 775 mg/day; or about 800 mg/day; or about 825 mg/day; or
• the diagnosis and progression of the oxidative ocular disease is evaluated by any one of a number of conventional diagnostic tools well known in the art. See, e.g., verywellhealth.com/how-macular-degeneration-is-diagnosed-4160590.
• the rate of reduction in a patient's disease progression is evaluated by comparing the ocular tests results subsequent to start of therapy to those obtained at the time of the original diagnosis / start of therapy or to the test results from any prior evaluation.
• the data suggest that the rate of disease progression in an individual patient will be reduced by at least about 20%, or at least about 30%, or at least about 40%, or at least about 50% or more when the dosing methods described herein are employed.
• the amount of reduction may be any value or subrange within the recited ranges, including endpoints.
• the comparison is between the known rate of disease progression and that experienced by the patient and is made at any time from 1 to 24 months, such as about 6, or 12, or 18, or 24 months after initiation of therapy and then periodically thereafter (e.g., every 6 months).
• the known rate of disease progression can be based on the rate of geographic atrophy progression in a cohort of patients treated with placebo over the same period of time.
• the efficacy of the treatment protocol can be evaluated by comparing the extent of geographic atrophy progression in a treated population or individual against a placebo population. In such a comparison, efficacy is established by a statistically significant reduction in geographic atrophy progression in the treated population as compared to the placebo population.
• the degree of reduction is at least by at least about 20%, or at least about 30%, or at least about 40%, or at least about 50% or more when the dosing methods described herein are employed.
• the methods described herein are also based, in part, on the discovery that when the lipid membrane of the retinal cells is stabilized against LPO, there is a substantial reduction in the progression of the oxidative retinal disease. Without being limited by theory, it is believed this is because replacement of hydrogen atoms with deuterium atoms at the deuterated docosahexaenoic acid renders these carbon-deuterium bonds significantly more stable to ROS than the carbon-hydrogen atoms. As above, this stability manifests itself in reducing the cascade of lipid auto-oxidation and, hence, limiting the rate of disease progression.
• the therapy provided herein can be combined with conventional treatment of used with oxidative retinal provided that such therapy is operating on an orthogonal mechanism of action relative to inhibition of lipid auto-oxidation.
• Suitable drugs for use in combination include, but not limited to, antioxidants such as edaravone, idebenone, mitoquinone, mitoquinol, vitamin C, or vitamin E provided that none of these antioxidants that are directed to inhibiting lipid auto-oxidation, nluzole which preferentially blocks TTX-sensitive sodium channels, conventional pain relief mediations, and the like.
• the specific dosing of deuterated docosahexaenoic acid or an ester thereof is accomplished by any number of the accepted modes of administration.
• the actual amount of the drug used in a daily or periodic dose per the methods of this invention, i.e., the active ingredient, is described in detail above.
• the drug can be administered at least once a day, preferably once or twice or three or more times a day.
• compositions or pharmaceutical carrier are not limited to any particular composition or pharmaceutical carrier, as such may vary.
• compounds of this invention will be administered as pharmaceutical compositions by any of a number of known routes of administration. However, orally delivery is preferred typically using tablets, pills, capsules, and the like.
• the particular form used for oral delivery is not critical but due to the large amount of drug to be administered, a daily or periodic unit dose is preferably divided into subunits having a number of tablets, pills, capsules, and the like.
• the docosahexaenoic acid or an ester thereof is administered in a gel capsule as a neat oil.
• compositions of this invention may be manufactured by any of the methods well-known in the art, such as, by conventional mixing, tableting, encapsulating, and the like.
• the compositions of this invention can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use.
• compositions can comprise the drug in combination with at least one pharmaceutically acceptable excipient.
• Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the claimed compounds.
• excipient may be any solid, liquid, or semi-solid that is generally available to one of skill in the art.
• Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
• Other suitable pharmaceutical excipients and their formulations are described in Remington ’s Pharmaceutical Sciences , edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
• compositions of this invention may, if desired, be presented in a pack or dispenser device each containing a daily or periodic unit dosage containing the drug in the required number of subunits.
• a pack or device may, for example, comprise metal or plastic foil, such as a blister pack, a vial, or any other type of containment.
• the pack or dispenser device may be accompanied by instructions for administration including, for example, instructions to take all of the subunits constituting the daily or periodic dose contained therein.
• the amount of the drug in a formulation can vary depending on the number of subunits required for the daily or periodic dose of the drug.
• the formulation will contain, on a weight percent (wt %) basis, from about 10 to 100 weight percent of the drug based on the total formulation outside of the weight of the capsule carrier with the balance being one or more suitable pharmaceutical excipients.
• the compound is present at a level of about 50 to 99 weight percent.
• the drug is encapsulated inside a capsule without the need for any pharmaceutical excipients such as stabilizers, antioxidants, colorants, etc.
• This example illustrates the reduction in the rate of macular degeneration progression in a cohort of patients treated with deuterated docosahexaenoic acid ethyl ester similar to that of Example 1, as compared to a cohort of placebo patients.
• the treated cohort is administered 250 mg/day of deuterated docosahexaenoic acid ethyl ester or 250 mg/day of safflower oil.
• the patients are maintained on this dosing regimen throughout the clinical study. Periodic measurements of further geographic atrophy development are obtained.
• Dosing is continued for 6 or 12, or 18 or 24 months. At that time, the average extent of geographic atrophy progression is measured for each cohort. The efficacy of the treatment protocol is evaluated by comparing the extent of geographic atrophy progression in a treated population against a placebo population. Specifically, the methods describe herein provide a statistically significant reduction in the rate of disease progression.
• the reduction in disease progression is determined as follows: a) determine the average rate of disease progression for a cohort of patients treated with the deuterated docosahexaenoic acid ethyl ester by measuring the extent of geographic atrophy in each of the patient's retina at the start of therapy and at 6, 12, 18 or 24 months post start of therapy, determining the difference between the extent of atrophy at the start of therapy and at the later time point, and then obtaining an average for that differential and assigning a first value designated as "A" to that average differential; b) determine the average rate of disease progression for a cohort of patients treated with placebo (safflower oil) by measuring the extent of geographic atrophy in each of the patient's retina at the start of therapy and at 6, 12, 18 or 24 months post start of therapy, determining the difference between the extent of atrophy at the start of therapy and at the later time point, and then obtaining an average for that differential and assigning
• A C); d) assign a positive value to "C” if B is greater than A; e) assign a negative value to "C” if B is less than A; and 1) divide C by B and multiply by 100 [(C/B) x 100]
• the rate of disease progression for an individual patient can be assessed by the following: a) determine the rate of disease progression for said individual patient by measuring the extent of geographic atrophy in the patient's retina at the start of therapy and at 6, 12,18 or 24 months post start of therapy and assigning a third value "D" to that differential; b) determine the average rate of disease progression for a cohort of patients treated with placebo (safflower oil) by measuring the extent of geographic atrophy in each of the patient's retina at the start of therapy and at 6, 12, 18 or 24 months post start of therapy, determining the difference between the extent of atrophy at the start of therapy and at the later time point, and then obtaining an average for that differential and assigning a second value designated as "E" to that average differential; c) calculating the difference between D and E and assign "F" to that
• a treated patient will have a positive percent reduction in geographic atrophy that is statistically significant and preferably at least a positive 20 percent reduction.

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