CN118019529A

CN118019529A - Methods of inhibiting progression of oxidative retinal disease

Info

Publication number: CN118019529A
Application number: CN202280063750.6A
Authority: CN
Inventors: K·施密特; M·什切平诺夫
Original assignee: Baiojiwa Co ltd
Current assignee: Baiojiwa Co ltd
Priority date: 2021-07-22
Filing date: 2022-07-22
Publication date: 2024-05-10

Abstract

A method of inhibiting progression of an oxidative retinal disease is disclosed. The method comprises administering to a patient in need thereof deuterated docosahexaenoic acid or an ester thereof.

Description

Methods of inhibiting progression of oxidative retinal disease

Cross Reference to Related Applications

U.S. provisional patent application Ser. No. 63/224690 filed on 7/22 of 2021; U.S. provisional patent application Ser. No. 63/224679 filed on 7/22 of 2021; and U.S. provisional patent application Ser. No. 63/224674 filed on 7.22 of 2021, the entire contents of each of which are incorporated herein by reference.

Technical Field

Disclosed are methods of inhibiting progression of an oxidative retinal disease in a human. The method comprises a dosing regimen for treating a patient suffering from neurodegenerative eye disease with deuterated docosahexaenoic acid (DHA) or a prodrug thereof. In particular, the dosing regimen allows the therapeutic concentration of deuterated DHA in the body to rapidly reach a level at which the progression of the disease is reduced despite the progressive increase in metabolic absorption of the compound in the patient being treated.

Background

Humans have many oxidative retinal diseases, most of which are incurable, which can lead to vision impairment and, in many cases, blindness. Typically, at the time of early diagnosis, the attending physician will instruct the patient to stop smoking, establish a healthy lifestyle, and take vitamins and/or antioxidants to slow down the rate of disease progression. See, for example, mayocic.org/treatments-conditions/dry-maulatar-degeneration/diagnosties-treatment/drc-20350381.

Recent advances in understanding the underlying etiology of these diseases have shown that oxidative stress is an important component. However, ocular inflammation, age, and immune system are also identified as contributors. See, e.g., knickelbein et al, clinical international ophthalmology (int.ophtalmol. Clin.), 2015:55 (3) 63-78.

Despite years of research and understanding of the underlying etiology, many, if not most, oxidative retinal diseases remain difficult to treat. For example, current standard treatments for macular degeneration include periodic intraocular injections of anti-VEGF antibodies. See, e.g., moutray et al, progression of chronic disease treatment (Ther. Adv. Chron. Dis.) 2 (5): 325-311 (2011) ]. However, the fact that such treatment requires intraocular injection has limited its widespread use. Thus, there is a need for new treatments for oxidative retinal diseases, including macular degeneration. The novel treatment is preferably non-invasive and even more preferably orally administrable.

Summary of The Invention

The retina contains very high levels of docosahexaenoic acid, which is found in the highest concentration in the disc membrane of the extracellular segment of photoreceptors, including rod cells that help convert light into electrical and chemical signals of the brain. Docosahexaenoic acid accounts for the majority of the total amount of polyunsaturated fatty acid groups in the photoreceptor cell rod extracellular segment membrane phospholipids. This ratio is higher than in any other tissue of the human body.

Peroxidation of docosahexaenoic acid occurs in the retina, especially in rod cells, due to an imbalance between the regular production of reactive oxygen species ("ROS") and subsequent detoxification. Docosahexaenoic acid (DHA) has the following structure:

Is a 22 carbon chain omega-3 polyunsaturated fatty acid ("PUFA") with 6 sites of cis unsaturation. There are 5 bisallylmethylene groups between these 6 positions. These groups are particularly susceptible to oxidative damage by ROS. Furthermore, due to the stacking nature in rod cells, oxidation of the bis-allyl position in the first DHA results in an oxidative cascade of adjacent DHA, known as lipid self-peroxidation (LPO). This cascade can cause severe damage to the retina and negatively impact its activity. In addition, oxidized DHAs results in oxidation of membrane proteins and conversion to a large number of highly reactive carbonyl compounds. The continued imbalance in the oxidation process results in continued degeneration of the retina of the patient's eye.

Recently, shchepinov, U.S. patent No. 10058522, discloses that oxidative retinal diseases can be treated by administering deuterated docosahexaenoic acid or esters thereof. After administration, a portion of the deuterated docosahexaenoic acid binds to the retina, including rod cells, thereby stabilizing the rod cells from oxidative damage. This stabilization is due to the enhanced stability of the carbon-deuterium bond relative to the carbon-hydrogen bond. However, the time required for deuterated docosahexaenoic acid to reach therapeutic concentrations in the retina is long, measured in months. This is because the substitution of deuterated DHA for non-deuterated DHA in rod cells is gradual, which results in a considerable period of time from the beginning of the treatment to the production of therapeutic levels of deuterated DHA in the retina. Of course, during this period, the patient's ocular disease progresses with a loss of visual function.

As mentioned above, many retinal diseases involve progressive deterioration of a patient's vision due to uncontrolled disease pathology. For example, macular degeneration initially manifests as darkening and distortion of the patient's vision, followed by further deterioration, ultimately leading to blindness. Given the progressive nature of these diseases, coupled with the goal of maintaining as much vision as possible for as long a period of time, it is desirable that the therapeutic concentration of docosahexaenoic acid in the body be reached as quickly as possible. However, the administration of any deuterated DHA is complicated by several factors. These include, for example, body limitations on how much polyunsaturated fatty acids (including deuterated DHA) can be absorbed per day; the amount of PUFAs taken per patient per day varies, often exceeding the maximum amount of PUFAs that can be absorbed; the amount of PUFA absorbed varies for each patient; patient compliance; and patients suffering from conditions that interfere with PUFA intake (e.g., clostridium difficile infection and concomitant antibiotic-associated diarrhea).

All of the above evidence suggests that there is a current need to provide a dosing regimen that allows for rapid uptake of deuterated docosahexaenoic acid into the body (particularly in the retina) that is universally applicable to patients with varying metabolism, body weight and degree of retinal degeneration due to disease.

In one embodiment, the present disclosure provides a dosing regimen that allows for the ingestion of deuterated docosahexaenoic acid or esters thereof in an amount that can accelerate the onset of therapeutic concentrations within the retina and reduce the rate of disease progression. In one embodiment, the decrease is based on the difference in the extent of disease progression in patients receiving treatment compared to patients receiving placebo-controlled treatment over a 6 month, or 12 month, or 18 month, or 24 month interval between the onset of treatment and the assessment of disease progression. In one embodiment, this difference in the extent of disease progression in patients receiving treatment is about 20% compared to patients receiving placebo treatment over a 6 month, or 12 month, or 18 month or 24 month interval between the initiation of treatment and the assessment of disease progression, as detected by reduced geographic atrophy progression.

In one embodiment, a dosing regimen is provided that includes periodic daily administration of unit doses of deuterated docosahexaenoic acid or an ester thereof. The unit dose is selected to provide for accelerated (rapid) uptake of deuterated docosahexaenoic acid in the retina. Unit doses may be divided into 1, 2,3 or 4 subunits, each subunit being administered on the same day.

In one embodiment, a method of treating an oxidative retinal disease in a patient in need thereof is provided, the method comprising periodically administering to the patient from about 100 mg/day to about 1000 mg/day of a composition comprising deuterated docosahexaenoic acid or an ester thereof, wherein the administration achieves a therapeutic concentration of deuterated docosahexaenoic acid in the retina while the rate of progression of the oxidative retinal disease is reduced. In one embodiment, the periodic administration to the patient is from about 100 mg/day to about 350 mg/day. In another embodiment, the periodic administration to the patient is from about 350 mg/day to about 650 mg/day. In another embodiment, the periodic administration to the patient is from about 650 mg/day to about 1000 mg/day. In some cases, the periodic administration to the patient may be in the range of about 100 mg/day to about 1250 mg/day.

The methods described herein provide an accelerated onset of therapeutic concentration of deuterated docosahexaenoic acid in vivo to minimize unnecessary visual loss in a treated patient suffering from an oxidative retinal disease.

In one embodiment, the periodic administration of the unit dose comprises at least 5 days per week, preferably 7 days per week.

In one embodiment, the periodic administration of the unit dose comprises administration of at least about 70% of the days per month, preferably at least about 80% of the days per month.

In one embodiment, the deuterated docosahexaenoic acid ester is a C ₁-C₆ alkyl ester, preferably ethyl ester.

In one embodiment, the daily dose of 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; or about 825 mg/day; or about 850 mg/day; or about 875 mg/day; or about 900 mg/day; or about 925 mg/day; or about 950 mg/day; or about 975 mg/day; or about 1000 mg/day, and includes any range between any two of the numbers recited. The exact dosage used will be determined by the attending clinician based on factors such as the age, weight, sex and extent of progression of the oxidative eye disease of the patient.

In one embodiment, the methods described herein use a composition comprising deuterated docosahexaenoic acid or esters thereof wherein at least about 80% of the hydrogens on all of the diallyl sites are replaced with deuterium and wherein the average deuterium on the monoallyl sites is from about 1 to about 35% based on all available monoallyl sites. The compositions are suitable for use in the dosing regimens described herein. Deuterium addition to the bis-allylic position stabilizes the deuterated docosahexaenoic acid against oxidative damage. This in turn prevents the cascade of Lipid Peroxidation (LPO), thereby minimizing damage to retinal cells. When the concentration of the deuterated docosahexaenoic acid in the retina reaches a therapeutic level, the disease progression is significantly reduced. Furthermore, the level of deuteration at the monoallyl site is necessarily related to deuteration at the bis-allyl site, and there is evidence that deuteration during synthesis progresses to high levels at the bis-allyl site. Furthermore, it has been found that the addition of deuterium to deuterated docosahexaenoic acid does not cause functional interference or adverse effects on the patient.

In a preferred embodiment, the composition used in the dosing regimen comprises a population of deuterated docosahexaenoic acid and/or esters thereof having an average of at least 90% of the hydrogen atoms on the bis allyl groups exchanged for deuterium atoms. The composition has a remarkable anti-LPO protective effect in vivo. In addition, deuterated compositions also contain detectable amounts of deuteration at the monoallyl site. In particular, the average level of hydrogen atoms exchanged for deuterium atoms at all monoallyl sites within the composition is from about 1% to about 35%. Surprisingly, the addition of deuteration at the monoallyl site does not interfere with the protection provided by deuteration at the bis-allyl site.

In one embodiment, the onset of therapeutic concentration is within 50 days, preferably within 40 days, more preferably within 30 days, after initiation of treatment.

In one embodiment, the periodic administration of docosahexaenoic acid or an ester thereof comprises administering daily doses of docosahexaenoic acid or an ester thereof for at least 5 days per week during the treatment period. In another embodiment, the periodic administration of docosahexaenoic acid or an ester thereof comprises administering a daily dose of docosahexaenoic acid or an ester thereof once daily for 7 days per week during the treatment period.

In one embodiment, the rate of decrease in disease progression is based on the following formula:

a) Determining the average disease progression rate for the group of treated patients by detecting the extent of geographic atrophy of the retina of each patient at the beginning of the treatment and at 6 or 12 months, or at 18 or 24 months after the beginning of the treatment, obtaining an average of the differences, assigning a first value to the average difference, and assigning the value to "a";

b) Determining the average disease progression rate for the untreated patient group by detecting the extent of geographic atrophy of the retina of each patient at the beginning of the treatment and at 6 or 12 months, or at 18 or 24 months after the beginning of the treatment, obtaining an average value of the differences, assigning a second value to the average difference, and assigning the value to "B";

c) Calculating the difference between A and B and assigning the value to "C";

d) If B is greater than A, assigning C to be a positive value;

e) If A is greater than B, assigning C to be negative; and

F) Dividing C by B and multiplying by 100.

The implementation of this calculation is illustrated below:

Patients receiving treatment showed an average increase in the degree of geographic atrophy of 0.15____ over 6 months of treatment defined as a;

Patients receiving placebo treatment showed an average increase in pattern atrophy of 0.24__ over 6 months defined as B.

The difference between a and B is 0.09, designated as "C";

According to d) above, this value is given a positive number; and

Dividing C by B (0.09/0.24) and multiplying by 100 gives a reduction in disease progression rate of 37.5.

In one embodiment, such a rate of decrease for a given patient is determined as described above, but the results are used in individuals by replacing the queue-based A.

In one embodiment, the patient is placed in a diet that limits the intake of excess PUFA compounds to maximize the body's intake of deuterated docosahexaenoic acid. In general, limitations lead to excessive intake of dietary components by PUFAs. These dietary ingredients include, for example, fish oil pellets and salmon, as well as patients who have had excessive PUFA intake using conventional feeding tubes. In a preferred embodiment, the methods described herein include both the above dosing regimen and placing the patient in a restricted diet to avoid ingestion of excessive amounts of PUFA ingredients.

Detailed Description

A method of treating an oxidative eye disease is disclosed that slows the rate of disease progression in a patient. In one embodiment, the methods of the invention comprise a dosing regimen that effectively and rapidly provides therapeutic levels of deuterated docosahexaenoic acid in the eye.

Before discussing the present invention in more detail, the following terms will first be defined. Undefined terms give their definitions in the context or give their medically acceptable definitions.

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

As used herein, the term "about" when used before a numerical designation (e.g., temperature, time, amount, concentration, etc.) means that there may be a variation of (+) or (-) 10%, 5%, 1% or an approximation of any subrange or sub-value therebetween. Preferably, the term "about" when used with respect to a dose means that the dose may vary by +/-10%.

As used herein, the terms "comprising" or "comprises" are intended to mean that the compositions and methods include the recited elements, but do not exclude other elements.

As used herein, the term "consisting essentially of … …" when used in defining compositions and methods shall mean excluding other elements that have any significance to the combination of the stated purposes. Thus, a composition consisting essentially of the elements defined herein will not exclude other materials or steps that do not materially affect the basic and novel characteristics of the claimed invention.

As used herein, the term "consisting of … …" shall mean excluding other ingredients and substantial process steps above the trace elements. The embodiments defined in each of the transition terms are within the scope of the invention.

As used herein, the term docosahexaenoic acid refers to a compound having the following known structure:

Esters of docosahexaenoic acid are formed by substitution of the-OH group with-OR. Such esters are defined below.

As used herein, unless the context dictates otherwise, the term "deuterated docosahexaenoic acid or ester thereof" refers to a docosahexaenoic acid or ester compound having an average of at least 80% of the hydrogen atoms exchanged for deuterium atoms at the bis-allyl position and an average of no more than about 35% of the hydrogen atoms exchanged for deuterium atoms at the mono-allyl position. In a preferred embodiment, the average value of the hydrogen atoms exchanged for deuterium at the bis allyl position and the average value of the hydrogen atoms exchanged for deuterium at the mono allyl position are as follows.

In one embodiment, the deuterated DHA described herein can be represented by formula I:

Wherein each Y is independently hydrogen or deuterium, provided that at least about 80% of all said Y groups are deuterium; and

Each X and X ¹ is independently hydrogen or deuterium, provided that the sum of all X and X ¹ groups contains at least about 1% to about 35% deuterium, including all subranges found therebetween.

In one embodiment, the sum of the two X groups comprises about 5% to about 30% deuterium, including all subranges between the two numbers, while the sum of the two X ¹ groups comprises about 1% to about 10% deuterium, including all subranges between the two numbers.

Exemplary deuterated DHA combinations described herein are provided in table 1 below, with reference to formula I above:

TABLE 1

As used herein, unless the context indicates otherwise, the term "esters thereof" refers to C ₁-C₆ alkyl esters, glycerides (including mono-, di-and tri-glycerides), sucrose esters, phosphate esters, and the like. The particular ester used is not critical as long as the ester is pharmaceutically acceptable (non-toxic and biocompatible).

As used herein, the term "phospholipid" refers to any and all phospholipids that are components of cell membranes. The term includes phosphatidylcholine, lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and sphingomyelin.

As used herein, the term "patient" refers to a human patient or a cohort of human patients suffering from an oxidative retinal disease that can be treated by administration of a composition comprising deuterated docosahexaenoic acid or an ester thereof.

As used herein, the term "pharmaceutically acceptable salt" of a compound disclosed herein is within the scope of the methods described herein and includes acid or base addition salts that retain the desired pharmacological activity and are not biologically undesirable (e.g., the salt is not overly toxic, allergenic or irritating, and is bioavailable). When the compound has a basic group, such as an amino group, pharmaceutically acceptable salts may be formed with inorganic acids (e.g., hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., alginates, 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, naphthalenesulfonic acid, and p-toluenesulfonic acid), or acidic amino acids (e.g., aspartic acid and glutamic acid). When the compound has an acidic group, such as a carboxylic acid group, it may form a salt with a metal (e.g., alkali and alkaline earth metals (e.g., na ⁺、Li⁺、K⁺、Ca²⁺、Mg²⁺、Zn²⁺)), ammonia, or an organic amine (e.g., dicyclohexylamine, trimethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine), or a basic amino acid (e.g., arginine, lysine, and ornithine). Such salts may be prepared in situ during isolation and purification of the compound, or by reacting the purified free base or the free acid form of the compound with a suitable acid or base, respectively, and isolating the salt thus formed.

Preparation of Compounds

Deuterated docosahexaenoic acid is prepared by the synthetic method described in U.S. patent No. 10730821, incorporated herein by reference in its entirety. Specifically, table 1 of said patent shows a single run of the synthetic scheme described therein, which provides an average deuterium exchange at the bis-allylic position of about 96% and an average deuterium exchange at the mono-allylic position of about 26%.

The esters of these deuterated fatty acids are prepared by conventional techniques well known in the art.

Methodology of

The methods described herein require the sustained dosage levels described herein to achieve therapeutic concentrations in the eye (particularly in retinal rod cells) and to maintain such concentrations. The dosages used herein take into account the variability of metabolism of individual patients with respect to maximum daily PUFA intake, the percentage of deuterated docosahexaenoic acid or esters thereof comprising the PUFA intake moiety, the particular disease that impairs PUFA intake, and other factors well known in the art. In addition, the gradual increase in the in vivo concentration of docosahexaenoic acid and its relatively long half-life provide a "holiday" for patient administration, provided that at least 70% of the days per month are administered, such as 5 days per week, 6 days per week, and 3 weeks of 4 weeks are 7 days per week. In one embodiment, at least 85% of the days per month (e.g., at least 6 days per week) are administered. Thus, patients who intentionally or unintentionally miss daily dosing still conform to the overall dosing regimen, as opposed to traditional medications.

The dosing regimen employs a daily dose or unit dose of from about 100 mg/day to about 1000 mg/day, regardless of the BMI of the patient, the severity of the disease condition, or the overall health condition of the patient. In one embodiment, the daily dose is from about 100 mg/day to about 350 mg/day. In another embodiment, the daily dose is from about 350 mg/day to about 650 mg/day. In another embodiment, the daily dose is from about 650 mg/day to about 1000 mg/day. In a specific embodiment, deuterated docosahexaenoic acid or an ester thereof is present 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 about 850 mg/day; or about 875 mg/day; or about 900 mg/day; or about 925 mg/day; or about 950 mg/day; or about 975 mg/day; or about 1000 mg/day. The administered dose may be any value or subrange within the stated range.

Diagnosis and progression of oxidative eye disease is assessed by any of a variety of conventional diagnostic tools known in the art. For example, please refer to the verywellhealth.com/how-magnetic-degeneration-is-diagnosed-4160590. In one embodiment, the rate of decrease in patient disease progression is assessed by comparing the ocular test results after initiation of treatment to the results obtained at the initiation of diagnosis/treatment or to any previously assessed test results. The data indicate 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 50% or more when using the methods of administration described herein. The amount of reduction may be any value or subrange within the range, including the endpoints. Typically, a comparison is made between the known rate of disease progression and the rate of disease progression experienced by the patient, and at any time from 1 to 24 months after initiation of treatment (e.g., about 6 months, or 12 months, or 18 months, or 24 months after initiation of treatment), and then periodically (e.g., every 6 months). In one embodiment, the known rate of disease progression may be based on a geographic atrophy progression rate in a patient cohort receiving placebo treatment over the same period of time.

In another embodiment, the efficacy of a treatment regimen can be assessed by comparing the extent of progression of geographic atrophy in the treated population or individuals to the placebo population. In this comparison, efficacy was determined by statistically significant reduction in progression of geographic atrophy in the treatment population compared to the placebo population. Preferably, the degree of reduction is at least about 20%, or at least about 30%, or at least about 40%, or at least 50% or more when using the methods of administration described herein.

The methods described herein are also based in part on the discovery that when the lipid membrane of retinal cells is stabilized against LPO, the progression of oxidative retinal disease is significantly reduced. Without being limited by theory, it is believed that this is because the substitution of hydrogen atoms with deuterium atoms in deuterated docosahexaenoic acid renders these carbon-deuterium bonds significantly more stable to ROS than carbon-hydrogen atoms. As described above, this stability appears to reduce the lipid autoxidation cascade, thereby limiting the rate of disease progression.

Combination of two or more kinds of materials

The treatment described herein may be combined with conventional treatment of the oxidized retina, provided that such treatment is performed on an orthogonal mechanism of action associated with inhibition of lipid autoxidation. Drugs suitable for use in combination include, but are not limited to, antioxidants such as edaravone, edezone, mitoquinone, mitoquinoline, vitamin C or vitamin E, provided that none of these antioxidants is directed to riluzole that inhibits lipid autoxidation, preferentially blocks TTX-sensitive sodium channels, conventional pain relief drugs, and the like.

Pharmaceutical composition

The particular dosage of deuterated docosahexaenoic acid or ester thereof is achieved by any number of acceptable modes of administration. As mentioned above, the actual amounts, i.e. the active ingredients, to be taken in daily or regular doses according to the method of the invention are described in detail above. The drug may be administered at least once daily, preferably once or twice or three or more times daily.

The present invention is not limited to any particular composition or pharmaceutical carrier as they may vary. In general, the compounds of the present invention will be administered as pharmaceutical compositions by any of a variety of known routes of administration. However, oral 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, it is preferred to divide the daily or regular unit dose into subunits having many tablets, pills, capsules, etc. In a particularly preferred embodiment, the docosahexaenoic acid or ester thereof is administered in the form of a pure oil in a gel capsule.

Pharmaceutical dosage forms of the compounds of the present invention may be manufactured by any method known in the art, for example by conventional mixing, tabletting, encapsulation, etc. The compositions of the present invention may include one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecule into a pharmaceutical formulation.

The composition may comprise a drug in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, facilitate administration, and do not adversely affect the therapeutic benefit of the claimed compounds. Such excipients may be any solid, liquid or semi-solid commonly available to those skilled 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 the Lemington pharmaceutical sciences (Mark publication, 18 th edition, 1990) edited by E.W. Martin.

If desired, the compositions of the present invention may be provided in packages or sub-packaging units, each containing daily or regular unit doses of the medicament containing the desired number of subunits. For example, such a package or device may, for example, comprise a metal or plastic foil, such as a blister pack, vial or any other type of container. The packaging or dispensing device may be accompanied by instructions for administration, including, for example, instructions for taking all of the subunits contained therein that make up daily or periodic doses.

The amount of drug in the formulation may vary depending on the number of subunits required for daily or periodic administration. Typically, the formulation will contain about 10 to 100 weight percent of drug based on the total formulation, excluding the weight of the capsule carrier, on a weight percent (wt%) basis, with the balance being one or more suitable pharmaceutically acceptable excipients. Preferably, the compound is present at a level of about 50 to 99 weight percent.

In a preferred embodiment, the drug is encapsulated within a capsule without the need for any pharmaceutical excipients, such as stabilizers, antioxidants, colorants, and the like.

Examples

The invention will be further understood by reference to the following examples, which are intended to be purely exemplary of the invention. The scope of the invention is not limited by the exemplary embodiments, which are intended as illustrations of a single aspect of the invention. Any functionally equivalent method is within the scope of the invention. Various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims. In these embodiments, the following terms are used herein and have the following meanings.

Example 1 preparation of deuterated Ethyl docosahexaenoic acid

According to the procedure of U.S. patent No. 10730821, a composition comprising ethyl docosahexaenoate was prepared having an average deuteration of greater than 80% at the bis-allyl position and an average deuteration of less than 35% at the mono-allyl position.

EXAMPLE 2 reduction of disease progression Rate

This example illustrates the reduction in the rate of progression of yellow spot degeneration in a patient population treated with deuterated ethyl docosahexaenoate similar to example 1 compared to a placebo patient population. Specifically, 250 mg/day of deuterated ethyl docosahexaenoic acid or 250 mg/day of safflower oil was administered to the treatment population. Patients maintained this dosing regimen throughout the course of the clinical study. Periodic measurements of further progression of geographic atrophy were obtained.

Administration is continued for 6 months or 12 months, or 18 months or 24 months. The average extent of progression of geographic atrophy was then examined for each population. The efficacy of the treatment regimen was assessed by comparing the extent of progression of geographic atrophy in the treatment population with that in the placebo population. In particular, the methods described herein statistically significantly reduce the rate of disease progression.

Example 3-determination of reduction of disease progression Using treated and untreated patient populations

In this example, the decrease in disease progression is determined as follows:

a) Determining the average rate of disease progression for a patient population treated with deuterated ethyl docosahexaenoate by detecting the extent of geographic atrophy of each patient's retina at the beginning of the treatment and at 6, 12, 18 or 24 months after the beginning of the treatment, determining the difference between the extent of atrophy at the beginning of the treatment and at a later point in time, then obtaining an average of the differences, and assigning a first value to the average difference and assigning the value as "a";

b) Determining the average rate of progression of the disease in the patient population treated with placebo (safflower oil) by detecting the extent of geographic atrophy of each patient's retina at the beginning of the treatment and at 6, 12, 18 or 24 months after the beginning of the treatment, determining the difference between the extent of atrophy at the beginning of the treatment and at a later point in time, then obtaining an average of the differences, and assigning a second value to the average difference and assigning the value as "B";

c) Calculating the difference between B and ase:Sub>A and assigning the value to "C" (e.g., B-a=c);

d) If B is greater than A, assign a positive value to "C";

e) If B is less than A, assign a negative value to "C"; and

F) Dividing C by B and multiplying by 100[ (C/B) x 100].

According to this example, the geographic atrophy of the treated patient is statistically significant reduced by a positive percentage, preferably at least a positive 20%. That is, if any value of ase:Sub>A is 40 and any value of B is 60, B-a=c gives ase:Sub>A C value of 20. Then dividing by C/B gives 20/60 and multiplying this value by 100=33%.

Example 4-determination of reduction of disease progression Using treated and untreated patient populations

Or the disease progression rate of an individual patient can be assessed by:

a) Determining the disease progression rate of said individual patient by detecting the extent of geographic atrophy of the patient's retina at the beginning of the treatment and at 6, 12, 18 or 24 months after the beginning of the treatment, and assigning a third value "D" to the difference;

b) Determining the average rate of disease progression for the patient population treated with placebo (safflower oil) by detecting the extent of geographic atrophy of each patient's retina at the beginning of the treatment and at 6, 12, 18 or 24 months after the beginning of the treatment, determining the difference between the extent of atrophy at the beginning of the treatment and at a later point in time, then obtaining an average of the differences, and assigning a second value "E" to the average difference;

c) Calculating the difference between D and E and assigning the value to "F" (e.g., E-d=f);

d) If E is greater than D, assign a positive value to "F";

e) If E is less than D, assign a negative value to "F"; and

F) Divide F by E and multiply by 100[ (F/E) x 100].

According to this example, the geographic atrophy of the treated patient is statistically significant reduced by a positive percentage, preferably at least a positive 20%. That is, if any value of D is 50 and any value of E is 100. Then E-d=f gives an F value of 50. Then dividing by F/E gives 50/100 and multiplying this value by 100=50%.

Claims

1. A method for reducing the rate of disease progression of an oxidative retinal disease in a retina of a patient, the method comprising periodically administering to the patient a composition comprising deuterated docosahexaenoic acid or an ester thereof in an amount of about 100 mg/day to about 350 mg/day, wherein the administration achieves a therapeutic concentration of deuterated docosahexaenoic acid in the retina while reducing the rate of progression of the oxidative retinal disease.

2. The method of claim 1, wherein the periodic administration of the composition comprises at least 5 days per week.

3. The method of claim 1 or 2, wherein the deuterated docosahexaenoic acid or ester thereof in the composition comprises an average deuteration at the bis-allylic position of at least about 80% based on all available bis-allylic positions and an average deuteration at the mono-allylic position of from about 1% to about 35% based on all available mono-allylic positions.

4. The method of claim 3, wherein the average deuterium at the bis-allylic position is at least about 90% and the average deuterium at the mono-allylic position is about 1% to about 25%.

5. The method of any one of claims 1 to 4, wherein the onset of the therapeutic concentration of docosahexaenoic acid in the retina of the patient is within 50 days after initiation of the treatment.

6. The method of claim 5, wherein the onset of the therapeutic concentration of docosahexaenoic acid in the retina of the patient is within 40 days after initiation of the treatment.

7. The method of claim 5, wherein the onset of the therapeutic concentration of docosahexaenoic acid in the retina of the patient is within 30 days after initiation of the treatment.

8. The method of claim 1, wherein the decrease in rate of progression is compared to an average decrease in rate of disease progression in a treated patient population, the average decrease rate determined by comparing the average decrease in rate of progression of the oxidative retinal disease in the treated patient population to the average decrease in rate of progression in a placebo-treated patient population using the formula of example 2.

9. The method of claim 1, wherein the average rate of decrease in disease progression in the treated patient is determined by comparing his or her decrease in the rate of progression of the oxidative retinal disease with the average rate of progression in a placebo-treated patient population using the formula of example 3.

10. The method of claim 8, wherein day 0 is prior to treatment with deuterated docosahexaenoic acid or an ester thereof.

11. The method of claim 9, wherein day 0 is prior to treatment with placebo.

12. The method of any one of claims 8 to 11, wherein the period of time is 6 months or 12 months.

13. The method of any one of claims 1 to 7, wherein the decrease in the rate of progression of the patient's oxidative retinal disease is determined based on a comparison to the rate of progression of the patient's retina prior to treatment.

14. The method of any one of claims 1 to 13, wherein the ester is a C ₁-C₆ alkyl ester, a monoglyceride, a diglyceride, a triglyceride, a sucrose ester, or a phosphate ester.

15. The method of claim 14, wherein the ester is ethyl ester.

16. The method of any of claims 1 to 15, further comprising placing the patient in a diet that limits intake of non-deuterated polyunsaturated fatty acids.