Pharmaceutical compositions of D10-docosahexaenoic acid or its esters

Abstract

A method is disclosed for assessing the presence or absence of therapeutic levels of deuterated docosahexaenoic acid during treatment of a patient with a retinal oxidative disease or a neuronal oxidative disease.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 403,670, filed September 2, 2022, which is incorporated herein by reference in its entirety.

[0002] Pharmaceutical compositions are disclosed that contain about 100 mg to about 1250 mg of D-10-docosahexaenoic acid, preferably about 250 mg, about 500 mg, or about 1,000 mg of D-10-docosahexaenoic acid. The D-10-docosahexaenoic acid can be delivered as the acid ("active"), as an ester, or as a pharmaceutically acceptable salt thereof (collectively "D-DHA" unless the context dictates otherwise). These compositions are useful for treating oxidative diseases mediated at least in part by lipid peroxidation, such as neuronal and retinal oxidative diseases. The amount of active D-DHA in these compositions is designed to achieve an in vivo therapeutic steady-state concentration of D-DHA (acid), regardless of the amount of docosahexaenoic acid (DHA) ingested by the patient. [Background technology]

[0003] DHA is an essential fatty acid. The main source of DHA is food, especially oily seafood, which is rich in DHA. On average, about 90% of adults over 50 years old in the United States consume food containing 70 milligrams (average) to 130 milligrams (90% level) of docosahexaenoic acid (DHA) per day. Only 10% of adults exceed the daily intake of 130 milligrams (mg) (Papanikolaou, Nutrition Journal, 13:31-37 (2014), which is incorporated herein by reference in its entirety). Only 5% of the same population consumes more than 180 mg of DHA per day, i.e., the 95th percentile, increasing their daily intake of DHA up to approximately 180 mg / day of DHA (USDA, Agricultural Research Service, 2021 "Usual Nutrient Intake from Food and Beverages, by Gender and Age, What We Eat in America - http: / / www.ars.usda.gov / nea / bhnrc / fsrg), which is incorporated herein by reference in its entirety. As is well known, DHA is the major structural polyunsaturated fatty acid component in the phospholipid membranes of neurons and the rods and cones of the retina.

[0004] DHA peroxidation, including that occurring in neurons or retina, is the cause of multiple destructive degenerative diseases.For example, retinal oxidative diseases include, but are not limited to, wet and atrophic age-related macular degeneration (including associated geographic atrophy), retinal degeneration, cataract, retinitis pigmentosa, diabetic retinopathy, glaucoma, and Stargardt's disease.Such neuron oxidative diseases include, but are not limited to, amyotrophic lateral sclerosis (ALS), Jacobson's syndrome, spinal muscular atrophy, multiple system atrophy, Alzheimer's disease (AD) and mild cognitive impairment, Huntington's disease, infantile axonal disease (INAD), Parkinson's disease, and progressive supranuclear palsy (PSP).

[0005] The use of certain deuterated polyunsaturated fatty acids or esters thereof to treat these diseases is disclosed in U.S. Patent No. 10,058,522 (incorporated herein by reference in its entirety). Although the underlying etiologies of these diseases differ, the resulting pathology all involves lipid peroxidation of polyunsaturated fatty acids (PUFAs), such as DHA, with oxidation initiating at one or more bis-allylic positions of these PUFAs. Once initiated, the first oxidation site then initiates the oxidation of adjacent sites on adjacent PUFAs in a chain reaction, a process defined as lipid peroxidation.

[0006] Treatment of oxidative diseases, such as retinal and neuronal oxidative diseases, with D-DHA is complicated by the fact that it can take weeks to months after initiation of treatment to reach therapeutic concentrations at target sites within the body (e.g., neurons or retina). Furthermore, once such therapeutic concentrations are reached, patients are required to continue treatment for the remainder of their lives to maintain those concentrations to treat the underlying chronic disease state.

[0007] Furthermore, unlike most therapeutic agents, D-DHA as a drug is meant to supplement naturally occurring essential fatty acids, but most therapeutic agents do not have naturally occurring counterparts. This means that clinicians must balance the amount of D-DHA delivered to patients to achieve a therapeutically effective ratio between the amount of D-DHA taken up in vivo at target sites such as neurons and the retina and the amount of naturally occurring DHA. Balancing this dichotomy is complicated by at least four important factors: 1) variable patient intake levels of naturally occurring DHA, 2) patient noncompliance with medication, 3) determining the relative proportions of naturally occurring DHA and D-DHA in a patient at any given time to achieve therapeutic concentrations of D-DHA in target tissues or cells, and 4) ensuring that such therapeutic concentrations are maintained.

[0008] The relative percentage of a fixed amount of deuterated DHA (D-DHA) to the total amount of DHA, including D-DHA, is not 100% due to dietary intake and dilution of natural DHA. This means that for a fixed dose of D-DHA, the percentage of D-DHA absorbed and incorporated into the body by a patient is controlled by the total pool of DHA ingested by the patient. In other words, the more naturally occurring DHA ingested during treatment, the lower the relative percentage of the fixed dose of D-DHA administered. Therefore, the percentage of D-DHA absorbed and incorporated into the body depends on the amount of DHA ingested. Furthermore, oily marine products and fish oil contain high levels of natural DHA. For patients whose diets include significant amounts of such marine products and / or who use fish oil-based medications or dietary supplements, increasing the amount of DHA poses a problem because it significantly increases the average daily amount of DHA ingested. As mentioned above, this reduces the relative percentage of the fixed dose of D-DHA ingested and then incorporated into the body as part of the total DHA pool.

[0009] Furthermore, apart from food frequency questionnaires that determine average intakes in large populations, there is no reliable, direct method for determining the average amount of DHA consumed by individual patients before starting treatment. Therefore, for patients starting D-DHA therapy, clinicians can only estimate the amount of DHA consumed in their diets based on detailed food questionnaire analyses of their past diets. While these may be generally predictable for some patients, in most cases, such analyses will not be predictable for all patients, as patients typically lack sufficient memory of their diets, including both the content and quantity. Furthermore, the diet of any given patient varies from day to day and from hour to hour, making the patient's average DHA intake a continuously moving variable, adding an additional level of complexity and unpredictability. Therefore, results indicating that a drug is ineffective for a patient may be linked to the patient's excessive DHA intake, non-compliance, or both. In either case, the results for that patient indicate that D-DHA was ineffective, but the failure may not have been due to the drug but to factors unrelated to it.

[0010] Regarding patient compliance, it is well known that non-compliance (not taking medication on multiple days per month) occurs in approximately 50% or more of patients treated with chronic diseases.See, for example, uspharmacist.com / article / medication-adherence-the-elephant-in-the-room, the entire contents of which are incorporated herein by reference.This reduces the apparent efficacy of the drug, potentially causing the otherwise beneficial drug to be deemed ineffective.Currently, non-compliance with medication during the treatment of chronic diseases is a serious problem.

[0011] Finally, it is extremely difficult to determine a reliable running average of in vivo DHA concentrations for a given patient and then balance this with the required amount of D-DHA administered to achieve therapeutic concentrations in, for example, neurons and the retina. This is due to the number of variables mentioned above, and in particular the lack of available assays to assess the amount of DHA found in blood samples, and the lack of access to neurons and the retina in living patients. As noted above, the amount of active D-DHA absorbed by a patient from a fixed dose of D-DHA depends on the amount of DHA contained in the patient's diet. In other words, the more DHA consumed, the lower the percentage of active D-DHA that reaches the target tissues. Therefore, drug developers and clinicians rely on published statistical average data for target populations at the start of treatment, but cannot determine whether the dose of D-DHA provided to a patient will always be sufficient to effectively treat the condition when administered chronically.

[0012] Therefore, there is an urgent need to provide a pharmaceutical composition that eliminates the amount of DHA ingested by a patient as a factor in whether D-DHA is effective, reduces the impact of non-compliance on the validity of the results obtained, and then provides a means to test the relative ratio of active D-DHA to DHA in treated patients to ensure that patients achieve and maintain therapeutic levels of active D-DHA. Summary of the Invention

[0013] Pharmaceutical compositions and related methods are disclosed that include a therapeutically effective amount of D-DHA, wherein the average amount of DHA ingested by a patient is independent of the daily dose of D-DHA initially provided to the patient, resulting in consistent variability in the amount of DHA ingested across all patients at the start of treatment.

[0014] Also disclosed are methods for analyzing the ratio of a patient's active D-DHA to the total amount of DHA present in the patient's blood. These methods are performed after the initiation of treatment, with the first analysis preferably occurring approximately 14-45 days after the initiation of treatment (the steady-state concentration of active D-DHA in plasma is reached approximately 14 days after the initiation of treatment and in red blood cells approximately 45 days after the initiation of treatment). In these methods, approximately 14-45 days after the initiation of treatment, a clinician can determine the in vivo concentrations of both active D-DHA and DHA by minimally invasive analysis of the patient's plasma or red blood cells. Specifically, by knowing the daily dose of D-DHA administered to the patient, the clinician can determine the amount of active D-DHA in the blood (plasma or red blood cells). Then, by correlating that amount with the relative amount of DHA to the known amount of active D-DHA, the clinician can extrapolate the average in vivo amount of DHA ingested by the patient. When used in combination, the attending clinician can adjust the amount of D-DHA in the pharmaceutical composition or ask the patient to adjust their diet (e.g., by reducing the patient's intake of oily fish) as needed. Thus, the compositions and methods provided herein can treat patients with a therapeutic dose of D-DHA, regardless of the patient's DHA intake at the start of treatment. Furthermore, periodic analysis of the ratio of active D-DHA to DHA in the patient's blood allows the clinician to determine whether the treated patient is maintaining a therapeutic ratio of active D-DHA to DHA. If not, the clinician can increase the dose of D-DHA, administer a bolus injection of D-DHA, or instruct the patient to reduce their intake of DHA, such as oily fish, or to improve medication compliance. Furthermore, the clinician can re-evaluate all patients at subsequent time points to ensure that all patients are maintaining a therapeutic ratio of active D-DHA to DHA.

[0015] Furthermore, when steady-state concentrations of active D-DHA are achieved in vivo in major organs and tissues, such as skeletal muscle and liver, the amount of D-DHA in the disclosed pharmaceutical compositions can be adjusted to accommodate non-compliance of several days to several weeks per month, as summarized in Tables 5-7.

[0016] The compositions and methods disclosed herein are based on two specific molecular characteristics of D-DHA: (i) D-DHA has a higher molecular weight than DHA, which allows for quantitative analysis of D-DHA in the presence of native DHA using standard analytical methods, and (ii) active D-DHA and DHA have the same absorption, distribution, and elimination rates, which are either fixed or variable for a given patient and / or vary from patient to patient, involving multiple factors, including: Each patient's blood can be analyzed to determine the total concentration of DHA (including active D-DHA) as well as the ratio of active D-DHA to DHA. Correlate whether a patient's average intake of DHA results in a therapeutic ratio of active D-DHA to DHA for a given dose of D-DHA, recognizing that the variability in DHA intake for that patient may vary from day to day, week to week, and season to season. Identifying that portion of treated patients who are taking too much DHA and therefore not achieving therapeutic levels or who are non-compliant. Patients who consume more than the average amount of oily seafood (i.e., multiple meals) per week can be identified. Determine the therapeutic in vivo ratio of active D-DHA to DHA, then correlate that ratio with the daily dose of D-DHA, allowing for a wide variability in the average amount of DHA ingested by patients per day; and Recognize levels of medication non-compliance and how to address it while maintaining effective treatment outcomes.

[0017] Until now, there has been no internal standard for measuring DHA, so it has not been possible to directly determine the average daily intake of DHA.In other words, clinicians can quantify the amount of DHA in blood, but because some of the DHA present in body tissues is constantly recycled and redistributed through blood circulation in the human body, its exact correlation to daily dietary intake cannot be quantified.The present invention is based in part on the discovery that D-DHA has a dual function as a therapeutic agent and at the same time as an internal standard that can be distinguished from natural DHA by its molecular weight.Therefore, initially administering a fixed dose of D-DHA to a patient based on the statistical average of the average daily intake of DHA in the target patient population allows clinicians to evaluate the blood concentrations of both active D-DHA and DHA in patients after a steady-state concentration of active D-DHA is reached in the blood (i.e., plasma or red blood cells). Furthermore, once the concentration of active D-DHA in a patient's plasma or red blood cells reaches a steady state, determining the amount of active D-DHA in a blood sample allows a clinician to determine the average amount of DHA ingested per day by that patient based on the known daily dose of D-DHA administered.

[0018] In one embodiment, there is provided a method for assessing the average daily intake of DHA in a patient, comprising: a) administering to a patient a fixed daily dose of D-DHA for a period of time sufficient to achieve a steady-state concentration in the patient's blood or a component thereof; b) obtaining samples of the patient's blood or components thereof at successive time intervals and assessing the amount of active D-DHA in the samples based on the fixed daily amount of D-DHA administered and the ratio of active D-DHA to DHA; and c) correlating the ratio of active D-DHA to DHA with the amount of active D-DHA found in the blood or a component thereof to obtain a value for DHA in the blood over time.

[0019] In some embodiments, the blood component being tested is plasma, and a fixed daily dose administered to a patient reaches a steady state concentration in plasma in about 14 days.

[0020] In some embodiments, the blood component being tested is red blood cells, and a fixed daily dose of D-DHA administered to a patient reaches a steady-state concentration in these cells in about 45 days.

[0021] As shown in the Examples below, it has been shown that in vivo, a concentration of active D-DHA to DHA of at least about 1:4 (at least about 20% of the total DHA in plasma is active D-DHA) is sufficient to produce a therapeutic reduction in lipid peroxidation, with a ratio of active D-DHA to DHA of preferably at least about 1:1 providing near-maximal results. Based on the average daily amount of DHA ingested by the patient and the concentration of active D-DHA in the patient's blood relative to the total amount of DHA (including active D-DHA), a clinician can maintain the same dose of D-DHA or adjust (increase / decrease) the dose to reach the in vivo target ratio of active D-DHA to DHA to provide a therapeutic result for the patient.

[0022] Because D-DHA is well tolerated with minimal adverse events, concentrations up to or exceeding 1250 mg / day can be used. This allows for dosing regimens using about 50 mg / day to about 1250 mg / day or more, or 100 mg / day to 1,000 mg / day. Given the considerable variability in diet over time and the wide therapeutic range of D-DHA, it is preferred that the target ratio of active D-DHA to D-DHA be at least about 1:3, or at least about 2:3, or at least about 1:1, or at least about 2:1 or more to account for such variability, provided that the preferred maximum dose is 1,250 mg / day or less.

[0023] In another aspect, there is provided a method for treating an oxidative neurodegenerative or retinal disease in a patient, comprising: a) administering to a patient a fixed daily dose of D-DHA for a period of time sufficient to achieve a steady-state concentration in the patient's blood or a component thereof; b) obtaining samples of the patient's blood or components thereof at successive time intervals and assessing the amount of active D-DHA in the samples based on the fixed daily amount of D-DHA administered and the ratio of active D-DHA to DHA; c) correlating the ratio of active D-DHA to DHA with the amount of active D-DHA found in blood or a component thereof to obtain levels of DHA in the blood over time; d) adjusting the amount of the fixed daily dose of D-DHA as needed to achieve a steady state concentration of active D-DHA to DHA of at least about 1:4 in the patient; e) maintaining a controlled, fixed daily dose of D-DHA to treat the disease.

[0024] In some embodiments, patients being treated with D-DHA are scheduled to have regular blood samples analyzed to confirm that the target ratio of active D-DHA to DHA is maintained. Such regular blood draws can be performed monthly, quarterly, semi-annually, annually, or at any interval deemed appropriate by the treating clinician. Additionally, by confirming maintenance of the targeted ratio of active D-DHA to DHA, such periodic testing can assess whether the daily amount of DHA being ingested is still substantially the same (+ / - 20%) as seen in previous tests, or whether the patient is complying with medication.

[0025] In some embodiments, the adjusted fixed daily dose of D-DHA is set to achieve a steady-state blood concentration of active D-DHA to DHA of about 1:3, or about 2:3, or about 1:1, or about 2:1, or more. In a preferred embodiment, the fixed daily dose of D-DHA assigned by the clinician at the start of treatment is set to a concentration that is therapeutic for at least about 90% of the adult population in the United States. USDA analysis of the diets of a large number of male volunteers over the age of 50 established that the average daily intake of DHA consumed by 90% (90th percentile) of these adults was up to about 130 mg / day. Considering that men tend to eat more than women, it can be reasonably concluded that this level of DHA intake consumed more than 90% of all patients, including women. By extrapolation, much of the remaining 10% of patients with higher daily DHA intakes can be consumed by treating them using an initial fixed daily dose of about 250 mg, about 500 mg, or about 1,000 mg / day of D-DHA. The larger the initial fixed dose, the greater the number of patients that will be enrolled.

[0026] In some embodiments, the oxidative neurodegenerative disease is amyotrophic lateral sclerosis (ALS), Jacobson's syndrome, spinal muscular atrophy, multiple system atrophy, Alzheimer's disease (AD) and mild cognitive impairment, Huntington's disease, infantile neuroaxonal disease (INAD), Parkinson's disease, or progressive supranuclear palsy (PSP).

[0027] In some embodiments, the oxidative retinal disease is wet and dry age-related macular degeneration (including its associated geographic atrophy), retinal degeneration, cataracts, retinitis pigmentosa, diabetic retinopathy, glaucoma, or Stargardt's disease.

[0028] In some embodiments, the present disclosure provides pharmaceutical compositions comprising D-DHA in an amount sufficient to provide a D-DHA to DHA ratio of at least about 1:4 in a patient after a steady-state concentration of active D-DHA in the blood is reached. In some embodiments, such pharmaceutical compositions comprise a fixed amount of about 50 mg D-DHA, or about 100 mg D-DHA, or about 250 mg D-DHA, or about 500 mg D-DHA, or about 1,000 mg DHA, and an optional pharmaceutically acceptable carrier.

[0029] It should be noted that the initial administration of D-DHA to patients is based on published statistical data without any assay, but may include a completed dietary questionnaire regarding which foods are consumed and how frequently. Such a questionnaire may include questions regarding the amount and type of seafood consumed. Upon reviewing the questionnaire, the clinician may advise reducing the intake of DHA-containing dietary supplements or oily fish, or select a dose of D-DHA that best corresponds to the patient's actual diet. For example, as shown in the Examples, a patient receiving 250 mg of D-DHA per day and consuming an average of approximately 130 mg of DHA per day will have a D-DHA to DHA ratio of approximately 1.92 to 1 when steady-state concentrations are reached in plasma, red blood cells, and large organs such as the liver and skeletal muscle tissue. As the average amount of DHA consumed by the patient decreases from 130 mg / day, this ratio increases in favor of D-DHA. Similarly, for patients receiving 130 mg / day of DHA but assigned a higher dose of D-DHA, a higher D-DHA to DHA ratio is obtained.

[0030] The exact dose initially assigned to a patient by the treating clinician can be predicted based on the target ratio of active D-DHA to DHA that is appropriate for that patient based on age, weight, sex, and the specific oxidative disease being treated. Once the average daily amount of DHA ingested by the patient is determined, the clinician can then adjust the dose of D-DHA to achieve the target ratio, all within the skill of the treating clinician. Generally, a dose of either 250 mg / day of D-DHA or 500 mg / day of D-DHA, or a dose of 1,000 mg / day of D-DHA, when administered at 250 mg / day, is considered adequate to therapeutically treat more than 95% of all patients, and a dose of 1,000 mg / day is considered adequate to therapeutically treat more than 99% of all patients treated.

[0031] Thus, in another aspect, there is provided a pharmaceutical composition comprising a dose of at least about 250 mg of D-DHA (or about 250 mg of D-DHA) in one or more pharmaceutically acceptable units, and optionally in the presence of a pharmaceutically acceptable carrier.

[0032] In some embodiments, pharmaceutical compositions are provided that include a unit dose of at least about 500 mg of D-DHA (or about 500 mg of D-DHA) in one or more pharmaceutically acceptable units, and optionally in the presence of a pharmaceutically acceptable carrier.

[0033] In some embodiments, pharmaceutical compositions are provided that contain at least about 1,000 mg of D-DHA (or about 1,000 mg of D-DHA) in one or more pharmaceutically acceptable units, optionally in the presence of a pharmaceutically acceptable carrier.

[0034] In some embodiments, the administered D-DHA is an ester of docosahexaenoic acid, hi another embodiment, the ester is a C1-C6 alkyl ester, preferably an ethyl ester.

[0035] In some embodiments, knowing that the average daily intake of DHA is linked to the amount of D-DHA administered, a clinician can use a standardization curve (see, e.g., Figures 2, 3, 4, 5, and 6) to ascertain what the concentration of active D-DHA should be in a patient at different times after initiation of treatment. Such a curve allows the clinician to monitor and assess the overall accumulation of active D-DHA in target tissues or cells for a given patient. If a patient fails to achieve the predicted concentration of active D-DHA in either plasma or red blood cells from a given day after initiation of treatment based on the standardization curve for the dose of D-DHA used, the clinician can decide to provide the patient with a bolus of D-DHA, limit or further limit the amount of DHA ingested by the patient to an average of 130 mg / day or less, and / or increase the dose of D-DHA.

[0036] Furthermore, the steady-state concentration of active D-DHA in either plasma or red blood cells correlates well with the steady-state concentration in the body. For example, the steady-state concentration of active D-DHA in neurons and the retina is reached approximately 4 to 7 months after the start of treatment. Furthermore, if a target steady-state concentration in the blood is achieved for a given dose of D-DHA, it becomes clear that continued administration of D-DHA to the treated patient will subsequently achieve the desired concentration of active D-DHA in those target tissues / organs compared to the administered dose of D-DHA. Furthermore, if the steady-state concentration is maintained in the blood over the above-mentioned period, clinicians can confirm that the steady-state concentration also correlates with the therapeutic concentration in the retina and neurons. As also shown in the Examples, the steady-state concentration of active D-DHA (the ratio of D-DHA to DHA) is the same in all tissues.

[0037] Thus, in another aspect, there is provided a method for monitoring a patient for active D-DHA uptake, the method comprising: administering a fixed dose of D-DHA to the patient; obtaining one or more blood or blood component samples from the patient at set points after initiation of treatment; assessing the ratio of active D-DHA to DHA in the sample relative to the total amount of DHA; comparing the assessed amount of active D-DHA to a standard concentration curve based on the particular dose of D-DHA, the average daily amount of DHA ingested by the patient, the blood or blood component being assessed, and the length of time since the start of treatment; determining whether the patient is achieving a target active D-DHA to DHA ratio based on the curve; This includes increasing the dose of D-DHA as needed to reach or exceed a target active D-DHA to DHA ratio and / or limiting the amount of DHA ingested by the patient.

[0038] In some embodiments, any substantial deviation in the ratio of active D-DHA to DHA from the patient's previous results should be examined to determine which factors may have contributed to such results. For example, the clinician can inquire about the patient's diet immediately prior to a blood test and, if appropriate, instruct the patient to abstain from fats, such as oily seafood or fish oil, for at least 7 days prior to the subsequent blood test. The clinician can also inquire about whether the patient has discontinued treatment for a period of time that is sufficiently longer than the explicable days of non-compliance provided herein.

[0039] In some embodiments, the blood component being evaluated is plasma.

[0040] In some embodiments, the blood component being evaluated is a red blood cell.

[0041] In some embodiments, the time from initiation of treatment to the first blood test is about 14 to about 120 days. In some embodiments, the time from initiation of treatment to the first blood test is at least about 14 days. In other embodiments, the time from initiation of treatment to the first blood test is at least about 30 days or at least about 90 days.

[0042] In some embodiments, the method for monitoring a patient for active D-DHA uptake uses D-DHA at a dose of about 250 mg / day, or about 500 mg / day, or about 1,000 mg / day of D-DHA.

[0043] In a further aspect, compositions are provided comprising a plasma or red blood cell sample from a patient treated with D-DHA, wherein the sample contains a mixture of D-DHA and DHA, and the absolute amount of each component in the sample can be assessed. In some embodiments, the sample may be obtained after the concentration of D-DHA has reached steady state in the patient. [Brief explanation of the drawings]

[0044] [Figure 1] Figure 1 shows the detected increase in the concentration of D-DHA using three different markers (plasma, erythrocytes, and retina) at four different time points (8, 19, 38, and 77 days after initial D-DHA exposure) in a cohort of mice fed a customized rodent diet containing 0.5% w / w D-DHA. [Figure 2] Normalized curves modeled from the data in FIG. 1 show the increase in D-DHA concentrations using different markers (plasma, red blood cells, and retina) for five different dosing regimens over the time course from treatment initiation to steady state in patients with an average dietary intake of approximately 130 mg of DHA per day. [Figure 3] Normalized curves modeled from the data in FIG. 1 show the increase in D-DHA concentrations using different markers (plasma, red blood cells, and retina) for five different dosing regimens over the time course from treatment initiation to steady state in patients with an average dietary intake of approximately 130 mg of DHA per day. [Figure 4]Normalized curves modeled from the data in FIG. 1 show the increase in D-DHA concentrations using different markers (plasma, red blood cells, and retina) for five different dosing regimens over the time course from treatment initiation to steady state in patients with an average dietary intake of approximately 130 mg of DHA per day. [Figure 5] Normalized curves modeled from the data in FIG. 1 show the increase in D-DHA concentrations using different markers (plasma, red blood cells, and retina) for five different dosing regimens over the time course from treatment initiation to steady state in patients with an average dietary intake of approximately 130 mg of DHA per day. [Figure 6] Normalized curves modeled from the data in FIG. 1 show the increase in D-DHA concentrations using different markers (plasma, red blood cells, and retina) for five different dosing regimens over the time course from treatment initiation to steady state in patients with an average dietary intake of approximately 130 mg of DHA per day. [Figure 7] The data in Figure 1 show the variation in D-DHA concentrations with dietary DHA intake at D-DHA to DHA ratios ranging from about 1.4:1 to about 3.6:1, modeled from the data, and representing the difference between the mean (70 mg / day), 90th percentile (130 mg / day), and 95th percentile (180 mg / day) dietary DHA intakes in elderly men in the United States. DETAILED DESCRIPTION OF THE INVENTION

[0045] Pharmaceutical compositions comprising D-DHA or an ester or pharmaceutically acceptable salt thereof ("D-DHA"), and methods related thereto, are disclosed. Before describing these compositions and methods in more detail, the following terms are defined. Terms not defined are given their definition in context or their medically accepted definition.

[0046] 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.

[0047] As used herein, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes instances when the event or circumstance occurs or does not occur.

[0048] As used herein, the term "about," when used before numerical designations such as temperature, time, amount, concentration, and such others, including ranges, indicates an approximation that may vary by (+) or (-) 10%, 5%, 1%, or any subrange or subvalue therebetween. Preferably, the term "about," when used in reference to a dose, means that the dose may vary by + / - 5%.

[0049] 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 others.

[0050] As used herein, the term "consisting essentially of," when used to define compositions and methods, shall mean excluding other elements of any essential importance to the combination for the described purpose. Thus, a composition consisting essentially of the elements defined herein does not exclude other materials or steps that do not materially affect the basic and novel characteristics of the claimed invention.

[0051] As used herein, the term "consisting of" is intended to mean excluding more than trace amounts of other ingredients and other substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.

[0052] As used herein, unless the context requires otherwise, the term "ester thereof" refers to a C1-C 10 It refers to any one of alkyl esters, glycerol esters (defined herein and including monoglycerides, diglycerides, and triglycerides), sucrose esters, phosphate esters, and the like. The particular ester group used is not critical, so long as the ester is pharmaceutically acceptable (non-toxic and biocompatible). In some embodiments, the ester is a C1-C6 alkyl ester, preferably an ethyl ester.

[0053] As used herein, the term "alkyl" refers to straight-chain, branched-chain and cyclic alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, 2-methylcyclopropyl, n-pentyl, cyclopentyl, n-hexyl, cyclohexyl, and the like.

[0054] As used herein, the term "steady-state ratio" refers to the ratio of active D-DHA to DHA in vivo that is maintained at about 90% to 110% of its maximum value based on the dose of D-DHA administered and the patient's average daily DHA intake. As noted above, a patient consuming an average of 130 mg / day of DHA and receiving about 250 mg / day of D-DHA has a D-DHA to DHA ratio of about 1.92 to 1. Thus, in this case, the steady-state concentration of D-DHA to DHA is about 1.73:1 to about 2.11:1.

[0055] Since the average daily intake ratio of DHA varies from day to day, the steady-state ratio will fluctuate slightly based on the amount of DHA ingested.In addition, the amount of D-DHA administered is unlikely to be the same at the same time every day, and in fact, patients may be non-compliant on certain days.Figure 7 is intended to show the fluctuations in the steady-state ratio of D-DHA to DHA when administered at 250mg / day to a hypothetical patient who has an average DHA intake of 130mg / day, while having a minimum intake of DHA of about 70mg / day and a maximum intake of about 180mg / day.In Figure 7, the slight increase in the ratio of D-DHA to DHA at steady state indicates that less DHA is ingested per day over a period of several weeks, and the slight decrease in the ratio of D-DHA to DHA indicates that more DHA is ingested per day over a period of several weeks.

[0056] As used herein, the terms "deuterated DHA," "D-DHA," or "deuterated docosahexaenoic acid or ester thereof" refer to docosahexaenoic acid and its esters having deuteration as described below. In vivo, the ester is first hydrolyzed to yield its corresponding acid ("active D-DHA"), which is then incorporated into structural features such as glycerol esters. Before describing deuteration, the structure of docosahexaenoic acid and specific moieties therein are provided below in Formula A. [ka]

[0057] Deuteration is described as an average based on a population of such DHA compounds that contain at least about 80 percent total deuteration at the bis-allylic sites (80% of the hydrogen atoms at these sites are replaced with deuterium atoms) and no more than about 30% total deuteration at the two mono-allylic sites (no more than about 30% of the four hydrogen atoms at the two mono-allylic sites are replaced with deuterium).

[0058] In a preferred embodiment, the substitution of hydrogen with deuterium at the bis-allylic moieties is from about 92 to about 96 percent, where total deuteration exists as follows: a) about 87 percent to about 92 percent of the CD2 moieties in bis-allylic sites; b) greater than about 6 percent to about 12 percent CHD moieties in bis-allylic moieties, and c) about 2 percent or less of CH moieties in bis-allylic sites; However, the total number of hydrogens and deuteriums in the bis-allylic positions is equal to 10.

[0059] In another preferred embodiment, the bis-allylic moieties of D-DHA have about 93 to about 96 percent total deuteration at the bis-allylic moieties, where total deuteration is expressed as follows: a) about 87 to about 92 percent of the CD2 moiety in the bis-allylic moiety; b) about 6.5 to about 12 percent CHD moieties in bis-allylic moieties, and c) about 1.5 percent or less of CH moieties in bis-allylic sites; However, the total number of deuterium and hydrogen atoms in the bis-allylic positions is equal to 10.

[0060] In yet another preferred embodiment, the bis-allylic moieties of D-DHA have about 92 to about 95 percent total deuteration at the bis-allylic moieties, where the total deuteration is present as follows: a) approximately 88-92 percent of the CD2 moiety in bis-allylic sites; b) about 6.5 to 12 percent CHD moieties in bis-allylic sites; c) about 1.5 percent or less CH2 moieties in bis-allylic moieties; and d) a total deuteration of 25% or less on average at both mono-allylic sites; However, the total number of hydrogens and deuteriums in the bis-allylic positions is equal to 10.

[0061] The degree of deuteration at the two mono-allylic sites varies due to steric hindrance imparted by the carboxyl or carboxyl ester. In some embodiments, the degree of deuteration at the proximal mono-allylic site is about 0.5% to about 5%. In other embodiments, the degree of deuteration at the proximal mono-allylic site is about 1% to about 5%. Stated another way, on average, only about 0.5% to about 5%, or 1% to about 5%, of the hydrogen atoms found at the proximal mono-allylic site of a composition comprising a population of D-DHA are replaced with deuterium.

[0062] In some embodiments, the level of deuteration at the distal mono-allylic site is about 10% to about 20%. In some embodiments, the level of deuteration at the distal mono-allylic site is about 12% to about 18%. Stated another way, on average, only about 10% to about 20% or 12% to about 18% of the hydrogen atoms found at the distal mono-allylic site of a composition comprising a plurality of D-DHAs are replaced with deuterium.

[0063] In some embodiments, the deuterated docosahexaenoic acid or ester thereof comprises a population of compounds of formula (I): [ka] wherein R is hydrogen, C1-C 10 alkyl or a pharmaceutically acceptable salt thereof; each X is independently hydrogen or deuterium, and the sum of the amounts of deuterium defined by both X groups is such that, on average, the total amount of deuteration on carbon atoms is less than about 5%; each X 1 are independently hydrogen or deuterium, and both X 1 The total amount of deuterium, defined by 1 an amount such that less than about 25% of the groups are deuterium, the remainder being hydrogen; Each Y is independently hydrogen or deuterium, and a particular value of each Y is, on average: a) about 87 to about 92 percent of the Y groups on each carbon atom are deuterium; b) greater than about 5 percent to about 12 percent of the Y groups on each carbon atom are substituted with a single hydrogen and a single deuterium; and c) less than about 2 percent of the Y groups at each carbon atom are replaced with two hydrogen atoms; d) However, the sum of all Y groups is equal to 10.

[0064] In some embodiments, compositions comprising compounds of Formula (I) have less than 1.5 percent of the carbon atoms in the bis-allylic moiety substituted with two hydrogen atoms.

[0065] In some embodiments, the compositions described herein do not replace hydrogen with deuterium at any site other than the mono-allylic and bis-allylic sites, and therefore the level of deuterium found at the remaining sites of DHA is its natural abundance.

[0066] Exemplary deuterated DHA compositions described herein are provided in Table 1 below and refer to formula (I) above. [Table 1]

[0067] In one preferred embodiment, both X groups together contain from about 5% to about 30% deuterium, including all subranges between these two numbers, while both X groups together contain from about 1% to about 10% deuterium, including all subranges between these two numbers.

[0068] In some embodiments, the deuterated DHA is provided as a pharmaceutical composition comprising an effective amount of deuterated DHA or an ester or pharmaceutically acceptable salt thereof as described herein, and optionally a pharmaceutically acceptable carrier.

[0069] When describing ex vivo populations, the term "D-DHA or drug" refers to deuterated docosahexaenoic acid or its ester or a pharmaceutically acceptable salt thereof. When describing in vivo populations, the ester is hydrolyzed in the gastrointestinal tract, and in the retinal environment, docosahexaenoic acid is incorporated into glycerol esters such as cardiolipin, plasmalogens, and phospholipids, including those of formula (II): [ka] [In the formula, R 1 is a fatty acid residue or a docosahexaenoic acid residue, and R 2 is a docosahexaenoic acid residue, and R 3 where R is choline, ethanolamine, serine, inositol, or hydrogen, monovalent or divalent salts. Unlike fatty acids found elsewhere in the body, the retina contains R 1 and R 2 and R can contain a residue of deuterated docosahexaenoic acid. 1 is selected from the residue of a saturated fatty acid or the residue of docosahexaenoic acid, and R 2 is a residue of docosahexaenoic acid. With respect to the terms "residue of a fatty acid" or "residue of docosahexaenoic acid," each of these refers to an ester bond formed between the carboxyl and hydroxyl groups of glycerol combined with elimination of water.

[0070] In a preferred embodiment, deuteration at other sites on docosahexaenoic acid or its esters is unaffected, and therefore the level of deuteration at sites other than the bis-allylic and mono-allylic sites is at natural abundance.

[0071] The term "naturally occurring docosahexaenoic acid" refers to any and all sources of DHA, where the deuterium abundance is based on its natural abundance.

[0072] As used herein, the term "phospholipid" refers to any and all phospholipids that are components of cell membranes. This term includes phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and sphingomyelin. In motor neurons, the cell membrane is rich in phospholipids containing arachidonic acid.

[0073] The term "bis-allylic moiety" refers to the methylene group (CH2) separating two double bonds.

[0074] The term "mono-allylic moiety" further includes a methylene group on the opposite side.

[0075] The term "oxidized PUFA products" refers to any oxidized form of polyunsaturated fatty acids, as well as any and all metabolic products formed from oxidized PUFAs, including reactive aldehydes, ketones, alcohols, and carboxyl derivatives that are toxic to cells when found in phospholipids, lipid bilayers, or as enzyme substrates.

[0076] As used herein, the term "disease etiology" refers to the underlying cause(s) of a disease. The term "disease pathology" refers to the development, structural / functional changes, and natural history associated with the disease after it has been caused. The disease pathology includes a decline in cellular function.

[0077] The term "therapeutic concentration" refers to a concentration of active D-DHA that reduces the rate of oxidative disease mediated at least in part by lipid peroxidation. As shown in the Examples below, such concentrations are based on replacing at least about 20%, preferably at least about 33%, preferably at least about 50%, more preferably at least about 75%, and most preferably at least about 80% of the DHA in target tissues or cells with the D-DHA described herein. To achieve this level of replacement, active D-DHA must be administered over a period of time (weeks to months) because it is slowly replaced in vivo.

[0078] In some embodiments, the target tissue is the retina, and in particular the rods and cones of the retina, particularly in the treatment of oxidative retinal diseases, including, but not limited to, wet and dry age-related macular degeneration (including its associated geographic atrophy), retinitis pigmentosa, diabetic retinopathy, cataracts, and Stargardt's disease.

[0079] In some embodiments, neurons are targeted, including but not limited to, motor neurons and memory neurons, where lipid peroxidation leads to oxidative neuronal diseases, including, but not limited to, amyotrophic lateral sclerosis (ALS), Jacobson's syndrome, spinal muscular atrophy, multiple system atrophy, atherosclerotic vascular disease, Alzheimer's disease (AD) and mild cognitive impairment, Huntington's disease, infantile neuroaxonal disease (INAD), Parkinson's disease, and progressive supranuclear palsy, to name a few.

[0080] As used herein, the terms "blood" or "blood or components thereof" refer to either red blood cells or plasma.

[0081] As used herein, the term "non-compliance" means that the patient is non-compliant with medication at a rate that fails to achieve and / or maintain a steady-state ratio of D-DHA to DHA of at least about 1:4 during treatment.

[0082] As used herein, the term "accountable days of patient noncompliance" or "accountable days of medication noncompliance" means that the D-DHA dosing regimen is sufficient to account for or tolerate the number of days of patient noncompliance per month while maintaining a D-DHA to DHA ratio of at least about 1:4 for the patient during treatment. The degree of accountable days of noncompliance per month depends on the dose used and the amount of DHA ingested. Because higher doses of D-DHA result in a higher ratio of active D-DHA to DHA at steady state in liver and skeletal muscle tissue, regardless of the average daily intake of DHA, clinicians may choose to administer doses of about 250 mg / day, or 500 mg / day, or 1,000 mg / day of D-DHA to patients, thereby extending the number of explainable days of noncompliance by at least about 4 days / month at 250 mg / day and by at least about 7 days / month at 500 mg / day (both starting in patients with a DHA intake of about 130 mg / day or less).

[0083] For patients with an average DHA intake of about 260 mg / day or less, consuming an average of one oily seafood meal per week increases the dose of D-DHA or its esters or pharmaceutically acceptable salts to about 500 mg / day, resulting in at least about 7 days of explainable non-compliance per month. At a dose of about 1,000 mg / day of D-DHA, the number of explainable non-compliance days per month is at least about 10 days.

[0084] In a preferred embodiment, the available days of explainable noncompliance can be at least 2.5 months long after initiation of treatment, based on the initial achievement of therapeutic steady-state concentrations of D-DHA in large DHA storage organs, such as skeletal muscle. Thus, the explainable days of noncompliance preferably occur thereafter and are associated with chronic treatments where noncompliance is particularly acute.

[0085] The finding that the compositions and methods described herein can account for non-compliance days is unexpected and medically important, and correlates with the faster effectiveness of drugs.In other words, non-compliance is an ongoing medical problem, especially for chronic diseases that require treatment for the rest of patients' lives.Generally, non-compliance is found in both short-term compliance (less than about 2.5 months) and long-term or chronic compliance (more than about 2.5 months).

[0086] Generally, short-term compliance is estimated to be in the range of 70-80%, with shorter compliance being associated with higher percentages. In contrast, long-term compliance is estimated to be in the range of approximately 40-50%. See, for example, ncbi.nlm.nih.gov / pmc / articles / PMC2503662 / , the entire contents of which are incorporated herein by reference. Thus, the initial stage of a patient's treatment is reached when a steady-state concentration of active D-DHA is achieved in key tissues, such as skeletal muscle tissue, which occurs approximately 11 weeks (2.5 months) after the start of treatment. See, for example, Table 2 below. [Table 2]

[0087] During this initial compliance period, noncompliance is less of a problem. This is because patients who are informed that they have a devastating disease, such as macular degeneration or ALS, are significantly more likely to maintain compliance during the first 2.5 months of treatment. However, with lifelong chronic therapy, compliance drops significantly when transitioning to long-term medication, especially when the disease progression remains essentially unchanged from day to day. During this phase of treatment, the benefit of accountable days of noncompliance is particularly important.

[0088] Without being limited to any theory, D-DHA exhibits a wide therapeutic window, allowing administration of up to approximately 1250 mg / day, and once a steady-state concentration is reached in skeletal muscle tissue, it is stored in the body for a long period of time, resulting in explainable non-compliance days. Specifically, as shown in Table 2 above, the elimination half-life of active D-DHA in skeletal muscle tissue is approximately 15.4 days, in the liver approximately 14.2 days, and in plasma approximately 23.7 days. This means that if a steady-state concentration of active D-DHA is achieved in tissues with significant DHA storage capacity, such as the liver and skeletal muscle tissue, these tissues will act as significant active D-DHA drug depots.

[0089] Again, without being limited to any theory, for a target in vivo ratio of active D-DHA to DHA of 1:4, where the patient is consuming an average of about 200 mg / day of DHA and is being treated with 50 mg / day of D-DHA, the patient should achieve a ratio of active D-DHA to DHA in skeletal muscle tissue of about 0.2:1 at about day 75. If such a ratio were the minimum ratio to achieve therapeutic results, there would be no explainable days of noncompliance.

[0090] Example 7 provides a theoretical example of how the ratio of active D-DHA to DHA can vary based on the amount of DHA ingested per day.

[0091] As used herein, the term "patient" refers to a human patient or cohort of human patients suffering from a neurodegenerative disease treatable by administration of deuterated DHA. The term "subject" refers to a mammalian subject.

[0092] As used herein, the term "pharmaceutically acceptable salts" of the compounds 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 salts are not overly toxic, allergenic, or irritating and are bioavailable). If the compound has a basic group, such as an amino group, pharmaceutically acceptable salts can be formed with inorganic acids (e.g., hydrochloric acid, hydrobromic 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, naphthalenesulfonic acid, and p-toluenesulfonic acid), or acidic amino acids (e.g., aspartic acid and glutamic acid). If the compound has an acidic group, such as a carboxylic acid group, pharmaceutically acceptable salts can be formed with alkali and alkaline earth 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). Such salts can be prepared in situ during the isolation and purification of the compound, or by separately reacting the purified compound in its free base or free acid form with the appropriate acid or base, respectively, and isolating the salt thus formed.

[0093] The term "pharmaceutical unit" means that the drug is delivered daily in one or more pills, tablets, capsules, liquid formulations, etc. The specific form of the pharmaceutical unit is not important and is within the discretion of the clinician. In one preferred embodiment, the drug is encapsulated as a liquid in a capsule without the addition of any pharmaceutical excipients. In another preferred embodiment, the drug is encapsulated as a liquid in a capsule using pharmaceutical excipients such as biologically acceptable oils (e.g., olive oil, sunflower oil, coconut oil, etc.).

[0094] The term "oily fish" refers to fish containing at least 500 mg of DHA per 3 ounce serving, including, but not limited to, salmon, herring, tuna, trout, etc.

[0095] Compound synthesis The deuterated DHA compositions described herein are obtained according to US Pat. No. 10,577,304, which is incorporated herein by reference in its entirety. [ka] In the formula, R, X, X 1 , and Y are as defined above.

[0096] With respect to Scheme 1, the reaction can be carried out in a suitable inert solvent using docosahexaenoic acid ethyl ester (or any other suitable ester), compound 1, a stoichiometric excess of deuterium oxide, in the presence of a ruthenium catalyst, as described in U.S. Pat. No. 10,577,304, the entire contents of which are incorporated herein by reference.

[0097] As shown in Example 1, the total amount of deuteration at the bis-allylic moieties ranges from about 92 to about 97 percent. Stated another way, after deuteration, the 10 hydrogen atoms at the bis-allylic moieties are replaced, on average, with about 9.2 to about 9.7 deuterium atoms, leaving only about 0.3 to 0.8 hydrogen atoms. Furthermore, high-field NMR establishes that, on average, about 87 to about 92 percent of the carbon atoms at the bis-allylic moieties have two deuterium atoms, and greater than about 5 to about 12 percent of the carbon atoms at the bis-allylic moieties have one hydrogen and one deuterium substitution, with the remainder being CH2 moieties.

[0098] In view of the above, it has been determined that even if complete deuteration of the bis-allylic moieties is not achieved, the presence of CHD groups at these moieties provides greater stability against lipid peroxidation than CH groups. By limiting the reaction conditions so that, on average, no more than about 2% of the carbon atoms at the bis-allylic moieties are CH groups, the resulting composition still provides excellent control against LPO (lipid peroxidation) in vivo.

[0099] pathology The pathology resulting from each oxidative disease (such as retinal oxidative disease and neurooxidative disease) differs from the underlying etiology of other oxidative diseases, but progresses through a common pathology. That is, regardless of the diverse conditions that cause each of these oxidative diseases (etiologies), once triggered, the pathology of these diseases involves the accumulation of oxidized DHA products. By limiting oxidative damage, the disease pathology is addressed and the harmful effects on patients are reduced. For example, in the case of AMD, animal studies have demonstrated that the loss of vision induced by retinal lipid peroxidation resulting from ferroptosis is significantly limited by treating animals with deuterated DHA compared to untreated animals.

[0100] Without being limited to any theory, in the case of oxidative diseases, the incorporation of deuterated DHA into the outer segments of the retina's rods and cones and surrounding retinal tissue limits the extent of oxidation by reactive oxygen species, thereby protecting cells within the retina from the damage and destruction that is typical in retinal oxidative diseases (e.g., AMD).

[0101] Additionally, without being limited to any theory, in neurological disorders, incorporation of D-DHA into neuronal cell membranes limits the extent of oxidation by reactive oxygen species, thereby limiting cellular dysfunction or cell death.

[0102] Administration The method described herein involves periodically administering D-DHA as described herein to achieve therapeutic concentration and maintain such concentration in vivo.Dosage used herein takes into account the variability of individual patient's diet for daily dosing of D-DHA.In addition, due to the gradual increase in D-DHA concentration in vivo and its relatively long half-life, clinicians can account for the days of non-compliance with dosing regimen, but the results for that patient will still be considered to indicate the effectiveness of the drug.

[0103] Thus, a patient who intentionally or inadvertently misses their daily dose of medication is still adhering to an overall medication protocol that is quite different from conventional medication.

[0104] The dosing regimen uses a daily dose or unit dose of about 100 mg / day to about 1250 mg / day, regardless of the patient's BMI, the severity of the disease state, or otherwise the patient's general health, or the initial intake level of DHA as described above.

[0105] Diagnosis and progression of oxidative eye disease can be assessed by any one of several conventional diagnostic tools known in the art. See, for example, verywellhealth.com / how-macular-degeneration-is-diagnosed-4160590. In some embodiments, the rate of decline in a patient's disease progression is assessed by comparing eye exam results after treatment initiation with those obtained at the time of initial diagnosis / treatment initiation or with exam results from any previous assessment. These data suggest that when the dosing methods described herein are used, the rate of disease progression in an individual patient can be reduced by at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or more. The amount of decline can be any value or subrange within the recited range, including the endpoints. Generally, the comparison is made between the known rate of disease progression and the rate experienced by the patient, and is made at any time between 1 and 24 months, such as about 6, 12, 18, or 24 months after treatment initiation, and periodically thereafter (e.g., every 6 months). In some embodiments, the known rate of disease progression can be based on the rate of geographic atrophy progression in a cohort of patients treated with a placebo over the same period of time.

[0106] In another embodiment, the efficacy of a treatment protocol can be assessed by comparing the extent of geographic atrophy progression in a treated population or individual with a placebo population. In such a comparison, efficacy is established by a statistically significant reduction in geographic atrophy progression in the treated population compared to the placebo population. Preferably, the extent of reduction is at least about 20%, or at least about 25%, or at least about 30%, or at least about 50% or more when the dosing methods described herein are used.

[0107] Furthermore, the method described herein is based in part on the discovery that when the lipid membranes of cells, such as neurons, are stabilized against LPO, there is a substantial reduction in the progression of oxidative neuronal diseases.Without being limited by theory, it is believed that this is because the replacement of hydrogen atoms with deuterium atoms in the deuterated docosahexaenoic acid bis-allylic moiety makes these carbon-deuterium bonds significantly more stable against ROS (reactive oxygen species) than carbon-hydrogen atoms.As mentioned above, this stability is manifested in reducing the cascade of lipid autoxidation, thus limiting the rate of disease progression.

[0108] combination The treatment provided herein can be combined with any other treatment used for oxidative retinal disease, provided that such treatment does not interfere with the treatment described herein.For macular degeneration, drugs such as bevacizumab, ranibizumab, aflibercept and brolucizumab are all prescribed to reduce disease progression, and can be used in combination with the therapy described herein.

[0109] In another embodiment, the combination therapy can use a drug that acts via an orthogonal mechanism of action to the methods described herein. Suitable drugs for use in combination include, but are not limited to, flavonoids, resveratrol, carotenoids, cyanines, antioxidants such as edaravone, idebenone, mitoquinone, mitoquinol, vitamin C, or vitamin E, riluzole, which preferentially blocks tetrodotoxin-sensitive sodium channels (TTX-sensitive sodium channels), and conventional pain relievers.

[0110] Pharmaceutical Composition The specific dosing of deuterated docosahexaenoic acid or its esters described herein can be achieved by any number of accepted modes of administration. As noted above, the actual amount of drug (i.e., active ingredient) used in the daily or periodic doses according to the methods of the present invention is described in detail above. The drug can be administered at least once daily, preferably once, twice, three or more times daily.

[0111] The present invention is not limited to any particular composition or pharmaceutical carrier, which may vary. Generally, the compounds of the present invention are administered as pharmaceutical compositions by any of a number of known administration routes. However, oral delivery is typically preferred, using tablets, pills, capsules, etc. The specific form used for oral delivery is not critical, but due to the large amount of drug administered, the daily or periodic dose is preferably divided into subunits, such as multiple tablets, pills, capsules, etc. In a particularly preferred embodiment, docosahexaenoic acid or its ester is administered as a neat oil in a gel capsule.

[0112] Pharmaceutical dosage forms of the compounds of the present invention can be prepared by any method known in the art, such as conventional mixing, tabletting, encapsulation, etc. The compositions of the present invention can include one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecule into preparations for pharmaceutical use.

[0113] The composition can contain a drug in combination with at least one pharmaceutically acceptable excipient.Acceptable excipients are non-toxic, aid in administration, and do not adversely affect the therapeutic utility of the claimed compound.Such excipients can be any solid, liquid, or semi-solid excipients commonly available to those skilled in the art.

[0114] 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, etc. 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).

[0115] The compositions of the present invention can, if desired, be presented in a pack or dispenser device containing each daily or regular unit dose containing the drug in the required number of subunits. Such a pack or device can, for example, comprise metal or plastic foil, such as a blister pack, a vial, or any other type of container. The pack or dispenser device can be accompanied by instructions for administration, including, for example, instructions for taking all of the subunits making up the daily or regular dose contained therein.

[0116] The amount of drug in the formulation can vary depending on the number of subunits required for a daily or periodic dose of the drug. Typically, the formulation contains, on a weight percent (wt%) basis, about 10 to 100 weight percent of the drug based on the total formulation outside the weight of the capsule carrier, with the remainder being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 50 to 99 weight percent.

[0117] In a preferred embodiment, the drug is encapsulated within the capsule without the need for any pharmaceutical excipients such as stabilizers, antioxidants, colorants, etc.

[0118] In a preferred embodiment, the D-DHA administered to a patient is a docosahexaenoic acid ester (eg, a C1-C6 alkyl ester, preferably the ethyl ester).

[0119] method In some embodiments, the methods described herein involve administering D-DHA to a patient suffering from an oxidative retinal or neuronal disease. The drug is delivered to the patient at a dose prescribed by the treating clinician. Typically, such a dose is about 100 to about 1,250 milligrams per day. The accumulation of active DHA in the body can be monitored, for example, by blood testing, to ensure that the patient is accumulating active DHA consistent with achieving a therapeutic outcome. If the blood test indicates insufficient levels of active D-DHA, the clinician can determine whether dietary intake of DHA needs to be adjusted, medication needs to be increased, or the patient needs to be evaluated for termination of medication.

[0120] In preferred embodiments, D-DHA is administered to a patient in an amount sufficient to achieve a steady-state concentration of active D-DHA in the blood of at least about 25% (a 1:3 ratio of D-DHA to DHA), or at least about 33% (a 1:2 ratio), or at least about 50% (a 1:1 ratio), or at least about 66% (a 2:1 ratio), or at least about 80% (a 4:1 ratio), based on the total amount of DHA, including active D-DHA, found therein. In embodiments, the percentage of active DHA compared to total DHA in the patient (e.g., in red blood cells, plasma, and / or retinal cells) can be from about 25% to about 80%, from about 33% to about 70%, or from about 50% to about 66%.

[0121] Testing Protocol Once administered, the attending clinician will need to monitor the rate of absorption of active D-DHA into the target tissue or cells. Because physical access to the retina or neurons is not feasible in living animals, the methods described in the Examples demonstrate that either plasma or red blood cells (RBCs) can be used as surrogates to assess whether absorption is proceeding appropriately within the retina. This is because both plasma and RBCs reach steady-state concentrations, which occur at different times after the start of treatment, but nevertheless allow the clinician to conclude that the patient will reach steady-state concentrations in the target tissue or cells at a later time, as described above in Table 2.

[0122] It is well established in the art to carry out blood tests of plasma or RBC for the presence of individual components contained in plasma or RBC.However, in the art, it has not been possible to establish the correlation between the presence and amount of DHA in blood and the daily dietary intake of DHA.Here, the following example will demonstrate one method for such assessment.Specifically, active D-DHA is used as a marker compound, and is administered at a specific fixed dose for a sufficient time to establish the steady-state concentration in blood based on this dose, and the amount of DHA provided by patient's diet can be evaluated by combining the ratio of active D-DHA to DHA established by assay, and then correlating the amount of DHA based on the amount of active D-DHA produced by the fixed dose with the ratio of deuterated DHA in blood.

[0123] However, at the start of treatment, the attending clinician can only roughly estimate the amount of DHA ingested by the patient based on a detailed analysis of the patient's diet and assuming that the reported diet accurately reflects what the patient actually ingests. Given this uncertainty and the effort required, the compositions and methods provided herein start from a different perspective (one that does not rely on an approximate average daily intake rate of DHA). Rather, the clinician starts with a dose of D-DHA sufficient to capture the average daily dose of DHA ingested by about 90% of patients, or about 95% of patients, or about 99% or more of patients. Specifically, the clinician can start treatment with about 150 mg / day of D-DHA (for about 90% or more of patients), or about 200 or 250 mg / day of D-DHA (for about 95% or more of patients), or about 500 mg / day of D-DHA (to further increase the proportion of patients who have intake), or about 1,000 mg / day (to achieve intake by about 99% or more of treated patients).

[0124] Then, clinicians can use this approach to assess the average amount of DHA that patients take in per day by testing blood samples for the DHA concentration found in the blood samples after reaching a steady-state concentration of active D-DHA in blood.Once this amount is determined, clinicians can either maintain the dose of D-DHA or adjust the dose to an amount that produces a target ratio of active D-DHA to DHA that will be therapeutic.In addition, as mentioned above, clinicians can target the dose to a level that exceeds the therapeutic ratio of active D-DHA to DHA, in order to account for the days of non-compliance by patients.

[0125] Furthermore, such testing can assess whether a patient is complying with medication instructions provided by their clinician. In some embodiments, if a blood test indicates that the patient is not achieving the target concentration of active D-DHA, the methods described herein include restricting the patient's dietary DHA intake (e.g., to about 100 mg / day or less), increasing the dose of D-DHA, or both, during treatment with D-DHA. In some embodiments, the methods include restricting the patient's dietary DHA intake to about 70 mg / day or less during treatment with D-DHA. In some embodiments, the methods include restricting the patient's dietary DHA intake to about 60 mg / day or less during treatment with D-DHA. In some embodiments, the methods include restricting the patient's dietary DHA intake to about 50 mg / day or less during treatment with D-DHA. In some embodiments, dietary DHA intake is limited to about 50 mg to about 130 mg per day, or about 60 mg to about 120 mg per day, or about 60 mg to about 110 mg per day.

[0126] The actual method of testing for active D-DHA concentration and the ratio of active D-DHA to DHA in blood samples is not critical, as long as the test analysis is performed using a fixed dose of D-DHA over at least 14 days, and the test is then performed using patient plasma based on patients who fasted for at least 8 hours before blood was drawn. Testing for active D-DHA in red blood cells does not require fasting, but requires a long period (typically at least about 6 weeks after initiation of treatment) before a steady-state condition is reached in these cells.

[0127] In addition to the above, standardization curves can be generated for each dose of DHA to establish the time and concentration to reach steady state in the blood for different dosing regimens of D-DHA (see Figures 3, 4, 5, and 6). As shown in the examples, standardization curves for determining the time between the start of treatment and steady-state concentration are provided for two different markers (plasma and RBC) using two different dosing regimens. Using this procedure, a standardization curve can be established for any dosing concentration of D-DHA.

[0128] For testing, a clinician can obtain a composition comprising a plasma or red blood cell sample from a patient, where the patient has been administered D-DHA over a period of time, preferably after a steady-state concentration of D-DHA has been reached in the sample. As described herein, the clinician can assess the concentration of both active D-DHA and DHA in the sample. If the concentration of D-DHA is deemed insufficient to provide the desired level of treatment, the clinician can adjust the amount of D-DHA administered and / or the amount of DHA ingested by the patient (e.g., by adjusting the daily D-DHA dose or dietary intervention as appropriate). [Example]

[0129] The present invention will be further understood by reference to the following examples, which are intended to be purely exemplary of the invention. The present invention is not limited in scope by the exemplified embodiments, which are intended only as illustrations of single aspects of the invention. Any methods that are functionally equivalent are within the scope of the present invention. Various modifications of the present 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 fall within the scope of the appended claims.

[0130] As used herein, the following abbreviations have the following definitions: Terms not defined have their accepted scientific definitions. AMD = age-related macular degeneration DHA = Docosahexaenoic acid D-10 DHA = A DHA composition having, on average, DHA compounds containing at least about 80 percent total deuteration at the bis-allylic sites (80% of the hydrogen atoms at these sites are replaced with deuterium atoms) and about 30% or less total deuteration at the two mono-allylic sites (about 30% or less of the four hydrogen atoms at the two mono-allylic sites are replaced with deuterium). mg = milligram

[0131] Example 1 - Preparation of deuterated docosahexaenoic acid ethyl ester Following the procedures of U.S. Patent No. 10,730,821, a composition was prepared containing docosahexaenoic acid ethyl ester deuterated at the bis-allylic positions to an average level of greater than 80% and deuterated at the mono-allylic positions to an average level of less than 35%. The details of the deuteration are described in formula (I) (described above and reproduced below). [ka] where R is hydrogen, C1-C 10 alkyl or a pharmaceutically acceptable salt thereof; each X is independently hydrogen or deuterium, and the sum of the amounts of deuterium defined by both X groups is such that, on average, the total amount of deuteration on carbon atoms is less than about 5%; each X 1 are independently hydrogen or deuterium, and both X 1 The total amount of deuterium, defined by 1 an amount such that less than about 25% of the groups are deuterium, the remainder being hydrogen; Each Y is independently hydrogen or deuterium, and a particular value of each Y is, on average: a) about 87 to about 92 percent of the Y groups on each carbon atom are deuterium; b) greater than about 5 percent to about 12 percent of the Y groups on each carbon atom are substituted with a single hydrogen and a single deuterium; and c) less than about 2 percent of the Y groups at each carbon atom are replaced with two hydrogen atoms; However, the sum of all Y groups is selected to be equal to 10.

[0132] Example 2 - Methods of reducing the rate of disease progression It has been established that oxidative stress plays a central role in AMD. Iron, a potent generator of hydroxyl radicals via the well-known Fenton reaction, has been implicated in AMD. DHA is the most abundant PUFA in the retinal photoreceptor membrane, and its bis-allylic position is readily oxidized to produce toxic oxidation products, such as carboxyethylpyrrole adducts, which are elevated in the retina of AMD patients.

[0133] In this example, two cohorts of adult male wild-type C57BL / 6J mice (Jackson Labs) were used. Both cohorts were fed the same diet containing 0.25% or 0.5% D-DHA or a matching amount of DHA as a control. After 4 weeks, the mice were intravitreally injected with 1 microliter of 0.5 mmol / L ammonium ferric citrate diluted in 0.9% saline (test) or 1 microliter of 0.9% saline (control). The mice were then continued to receive the respective diets for 4 weeks after injection to evaluate whether D-DHA can protect against AMD-related geographic atrophy.

[0134] Subsequent BAF and IRAF images showed low AF in the superior retina of the test mice, as well as geographic atrophy. Meanwhile, test mice were completely protected from geographic atrophy when the concentration of D-DHA was at least 50% of the total DHA in the retina. Protection was achieved at lower concentrations of D-DHA vs. DHA, but at a rate that correlated with the relative concentration of D-DHA (the lower the D-DHA concentration, the less protection).

[0135] These results clearly show that D-DHA inhibits the oxidation of bis-allylic site, which is essential for AMD.Furthermore, these results show that protection is observed at a ratio of D-DHA to DHA of about 1:4, but maximum protection is achieved at a ratio of D-DHA to DHA of at least about 1:1.Liu, et al., Aging Cell, 2022, provides the complete experiment of this example, which is incorporated herein by reference in its entirety.

[0136] Based on the above experiments, the following shows the proposed evaluation of the reduction in the rate of progression of macular degeneration in a cohort of patients treated with deuterated docosahexaenoic acid ethyl ester compared to a cohort of test patients treated with placebo. Specifically, the treatment cohort is administered 250 mg / day of deuterated docosahexaenoic acid ethyl ester or 250 mg / day of safflower oil. Patients are maintained on this dosing regimen throughout this clinical trial. Further periodic measurements of geographic atrophy progression are obtained.

[0137] Medication is continued for 6 or 12, or 18 or 24 months. At that time, the average progression of geographic atrophy is measured for each group.The effectiveness of treatment protocol is evaluated by comparing the progression of geographic atrophy in treatment group with placebo group.Specifically, the method described herein results in a statistically significant reduction in the rate of disease progression.

[0138] Example 3 - Determining Reduction in Disease Progression In this example, a reduction in disease progression can be determined as follows. a) determining the average rate of disease progression for a cohort of patients treated with deuterated docosahexaenoic acid ethyl ester by measuring the degree of geographic atrophy in each of the patient's retinas at the start of treatment and at 6, 12, 18, or 24 months after the start of treatment, determining the difference between the degree of atrophy at the start of treatment and the degree of atrophy at each subsequent time point, then taking the average of the differences, and assigning a first value designated "A" to that average difference; b) for a cohort of patients treated with a placebo (e.g., safflower oil), determining the average rate of disease progression by measuring the degree of geographic atrophy in each of the patients' retinas at the start of treatment and at 12, 18, or 24 months after the start of treatment, determining the difference between the degree of atrophy at the start of treatment and the degree of atrophy at the subsequent time points, then taking the average of the differences, and assigning a second value designated "B" to that average difference; c) Calculate the difference between B and A and assign the value "C" (e.g., BA=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". f) Divide C by B and multiply by 100 [(C / B) × 100].

[0139] According to this example, treated patients will have a statistically significant positive reduction in geographic atrophy area, preferably at least 20-25%. That is, if A has an arbitrary value of 45 and B has an arbitrary value of 60, then BA=C, and C is 15. Then, dividing C / B gives 15 / 60, which is multiplied by 100 to get 25%.

[0140] Example 4 - Determining Reduction in Disease Progression Alternatively, the rate of disease progression for an individual patient with oxidative retinal disease can be assessed by: a) For each patient treated with 1,000 mg of D-DHA, determine the rate of disease progression by measuring the degree of geographic atrophy in the patient's retina at the start of treatment and 6, 12, 18, or 24 months after the start of treatment and assigning a third value, "D," to the difference; b) for a cohort of patients treated with placebo (safflower oil), determining the average rate of disease progression by measuring the degree of geographic atrophy in each of the patients' retinas at the start of treatment and at 6, 12, 18, or 24 months after the start of treatment, determining the difference between the degree of atrophy at the start of treatment and the degree of atrophy at each subsequent time point, then taking the average of those differences, and assigning a second value designated "E" to that average difference; c) Calculate the difference between D and E and assign "F" to that value (e.g., ED=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". f) Divide F by E and multiply by 100 [(F / E) × 100].

[0141] According to this example, treated patients have a statistically significant positive reduction in geographic atrophy, preferably at least a positive 20% reduction. That is, if D has an arbitrary value of 50 and E has an arbitrary value of 75, then ED=F, which gives F a value of 25. Then, dividing F / E gives 50 / 100, which is multiplied by 100 to get 33.3%.

[0142] Methods for calculating disease progression in oxidative neurological disorders are well known, including those described in U.S. Pat. No. 11,351,143 and U.S. patent application Ser. No. 17 / 408,285, both of which are incorporated herein by reference in their entireties.

[0143] Example 5 - Determination of D-DHA Levels Adult C57BL / 6J mice were fed a customized rodent diet containing 0.5% w / w D-DHA but no native DHA for 77 days. Animals were sacrificed, and plasma, red blood cells, and retinal tissue were dissected on study days 8, 19, 38, and 77 (six animals per time point, three males and three females). Active D-DHA and DHA were extracted from the samples and derivatized to methyl esters using a mixture of heptane / toluene (63:37 by volume) and methanol / dimethoxypropane / sulfuric acid (85:11:4 by volume) with gentle shaking at 80°C for 2 hours. The organic phase was then separated and dried under nitrogen. D-DHA and DHA methyl esters were structurally identified and quantified by gas chromatography coupled with tandem mass spectrometry detection, and D-DHA substitution levels (percent of total DHA) were calculated. The results are presented in Table 3 and graphed in Figure 1. The measured data revealed that the active D-DHA replacement rate follows first-order kinetics, i.e., a 50% increase from the previous measurement at regular intervals (hereafter referred to as cumulative half-lives) in each sample type (approximately every 2.7 days in plasma, approximately every 8.75 days in red blood cells, and approximately every 23.42 days in retina), with maximum concentrations (steady state) reached sooner in plasma and red blood cells (available in human subjects by simple blood sampling) than in retina (not available in living human subjects). With known cumulative half-lives, steady-state concentrations can be calculated by single-point and / or multipoint measurements without the need to wait until steady state is actually reached. [Table 3]

[0144] Example 6 - Prediction of retinal D-DHA concentrations In contrast to controlled experimental diets, naturally occurring DHA is ingested by patients treated with D-DHA, which may dilute the relative proportion of administered D-DHA absorbed along with the total DHA pool, and its final steady-state concentration in blood and ultimately in target tissues such as the retina.With the above data and standard curve, the retinal steady-state active D-DHA concentration can be determined with reasonable accuracy by calculating the D-DHA / total DHA ratio in plasma and / or erythrocytes.Table 4 illustrates this by using an average daily dietary intake of approximately 130 mg of DHA per day.This represents the 90th percentile of the average normal DHA intake for men over 51 years old in the United States.

[0145] Figures 3, 4, 5, and 6 show how measurements of plasma and erythrocyte active D-DHA concentrations can be used to predict expected retinal steady-state concentrations. Measuring the active D-DHA replacement rate at a known fixed daily dose and steady state also allows for approximation and monitoring of an individual patient's average dietary DHA intake, allowing for timely adjustment of either the D-DHA daily dose or dietary intervention to reduce natural DHA intake until a desired therapeutic active D-DHA replacement level, preferably about 50% or greater, can be achieved. [Table 4]

[0146] As shown in Table 4, in each case, first-order kinetics reveals that a 250 mg dose of D-DHA results in a steady-state ratio of active D-DHA based on the total DHA concentration present. Extrapolating back from the case of Table 4, a dose of at least 130 mg / day of D-DHA would result in a 1:1 ratio of active D-DHA to DHA. This ratio has been shown above to be therapeutic. Doses of 250 mg or greater result in a ratio of 1.9:1 or greater, which provides a margin for non-compliance, as described herein above.

[0147] Example 7 Figure 7 is intended to illustrate the variation in the steady-state ratio of D-DHA to DHA based on a hypothetical patient receiving 250 mg of D-DHA ethyl ester per day and consuming an average of approximately 130 mg or less of DHA per day. As shown in Figure 7, the patient's daily ratio of active D-DHA to DHA will vary at steady state due to the normal waxing and waning of the amounts of DHA and D-DHA ingested / administered, regardless of the rate at which they are absorbed. This is evident by the non-uniformity of the curves.

[0148] Specifically, at approximately 24-25 weeks after initiation of treatment, patients achieve steady-state concentrations of active D-DHA to DHA in all major body tissues, including plasma, liver, and skeletal muscle tissue. Active D-DHA plasma levels are approximately 66%, and the ratio of D-DHA to DHA in plasma is predicted to be approximately 1.92:1.

[0149] After the end of the 25th week, the patient reduces their dietary DHA intake to about 70 mg DHA per day for two weeks. Thereafter, the patient increases their dietary DHA intake to about 180 mg DHA per day for three weeks, and then resumes their previous DHA intake at about 130 mg / day. Since the ratio of active D-DHA to DHA at the start of treatment is about 1.92:1 (about 66% of the active D-DHA plasma level), reducing the amount of DHA consumed increases the ratio of active D-DHA to DHA. This increases the relative proportion of active D-DHA as a function of total DHA consumed to about 78% after two weeks. This is evident by the increase in the active D-DHA to DHA ratio to about 3.6:1. Subsequent increased DHA intake reduces the active D-DHA plasma level to about 58% after three weeks, which is equivalent to an active D-DHA to DHA ratio of about 1.4:1. The patient then reduced her DHA intake to approximately 130 mg / day, and after two weeks, her active D-DHA plasma levels returned to 66%, with an active D-DHA to DHA ratio of 1.92:1, as shown in Figure 7, where again the variation in the curve indicates the change in the amount of DHA ingested.

[0150] The same periodic monitoring scheme will reveal when active D-DHA levels fall below the intended therapeutic threshold, eg, below 59% or below 20% D-DHA.

[0151] Tables 5, 6, and 7 are based on Table 2 and describe the time required for plasma D-DHA levels to fall below 50% or below 20% at five different daily doses of D-DHA for the following examples: (i) a patient at the 90th percentile of daily intake consuming up to 130 mg DHA (Table 5), (ii) a patient at the 95th percentile of daily intake with a maximum of 180 mg DHA (Table 6), and (iii) a patient consuming more than one oily fish meal per week with a maximum daily DHA intake of 260 mg. [Table 5] [Table 6] [Table 7] *:USDA,Agricultural Research Service,2021”Usual Nutrient Intake from Food and Beverages,by Gender and Age,What We Eat in America- http: / / www.ars.usda.gov / nea / bhnrc / fsrg

[0152] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0153] The invention illustratively described in this disclosure can suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms "comprising," "including," "containing," etc., shall be read expansively and without limitation. In addition, the terms and expressions used herein are used as terms of description and not of limitation, and the use of such terms and expressions is not intended to exclude any equivalents of the illustrated and described features or portions thereof, but recognizes that various modifications are possible within the scope of the present disclosure as claimed.

[0154] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety to the same extent as if each were individually incorporated by reference. In case of conflict, the present specification, including definitions, will control.

[0155] While the present disclosure has been described in conjunction with the above embodiments, it should be understood that the foregoing description and examples are intended to illustrate, but not limit, the scope of the present disclosure. Other aspects, advantages, and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which this disclosure pertains.

Claims

1. 1. A method for assessing the average daily intake of DHA in a patient, comprising: a) administering to said patient a fixed daily dose of D-DHA for a period sufficient to reach a steady state concentration in said patient's blood or a component thereof; b) obtaining a sample of the patient's blood or a component thereof and assessing the amount of active D-DHA in the sample based on the fixed daily amount of D-DHA administered and the ratio of active D-DHA to DHA; c) correlating the ratio of active D-DHA to DHA with the amount of D-DHA found in the blood or a component thereof to obtain a value for DHA in the blood; d) adjusting the dose of D-DHA depending on the level of DHA in the blood.

2. 10. The method of claim 1, wherein the blood component being tested is plasma and the fixed daily dose of D-DHA administered to the patient reaches a steady-state concentration in the plasma in about 14 days.

3. 10. The method of claim 1, wherein the blood component being tested is a population of red blood cells, and the fixed daily dose of D-DHA administered to the patient reaches a steady-state concentration in these cells in about 45 days.

4. 1. A method for treating an oxidative neurodegenerative or retinal disease in said patient, comprising: a) administering to said patient a fixed daily dose of D-DHA for a period sufficient to reach a steady state concentration in said patient's blood or a component thereof; b) obtaining a sample of the patient's blood or a component thereof and assessing the amount of active D-DHA in the sample based on the fixed daily amount of D-DHA administered and the ratio of active D-DHA to DHA; c) correlating the ratio of active D-DHA to DHA with the amount of active D-DHA found in the blood or a component thereof to obtain a value for DHA in the blood; d) adjusting the amount of said fixed daily dose of D-DHA as needed to achieve a therapeutically effective amount; e) continuing an adjusted or maintained fixed daily dose of D-DHA to treat said disease.

5. 5. The method of claim 4, wherein the patient undergoes serial blood tests to ensure that the therapeutically effective amount is maintained.

6. 6. The method of claim 5, wherein the serial blood tests are performed monthly, quarterly, semi-annually, yearly, or at any interval deemed appropriate by the treating clinician.

7. 5. The method of claim 4, wherein the oxidative neurodegenerative disease is amyotrophic lateral sclerosis (ALS), Jacobson's syndrome, spinal muscular atrophy, multiple system atrophy, Alzheimer's disease (AD) and mild cognitive impairment, Huntington's disease, infantile neuroaxonal disease (INAD), Parkinson's disease, or progressive supranuclear palsy (PSP).

8. 5. The method of claim 4, wherein the oxidative retinal disease is wet and dry age-related macular degeneration (including associated geographic atrophy), retinal degeneration, cataract, retinitis pigmentosa, diabetic retinopathy, glaucoma, or Stargardt's disease.

9. A pharmaceutical composition comprising about 100 mg to about 1250 mg of D-DHA, optionally in the presence of a pharmaceutically acceptable carrier, in one or more pharmaceutically acceptable units for daily administration.

10. 10. The pharmaceutical composition of claim 9, wherein the composition comprises about 200 to about 1,000 mg of D-DHA in one or more pharmaceutically acceptable units for daily administration.

11. 10. The pharmaceutical composition of claim 9, wherein the composition comprises at least about 250 mg of D-DHA in one or more pharmaceutically acceptable units for daily administration.

12. 10. The pharmaceutical composition of claim 9, wherein the composition comprises at least about 500 mg of D-DHA in one or more pharmaceutically acceptable units for daily administration.

13. 10. The pharmaceutical composition of claim 9, wherein the composition comprises at least about 1,000 mg of D-DHA in one or more pharmaceutically acceptable units for daily administration.

14. The pharmaceutical composition according to any one of claims 9 to 13, which provides at least 4 days / month of explainable non-compliance days.

15. 15. The pharmaceutical composition of claim 14, which provides at least 7 days / month of accountable non-compliance days.

16. 1. A method for reducing the rate of disease progression of an oxidative retinal disease or a neurodegenerative disease in a patient, the method comprising periodically administering to said patient a composition comprising deuterated docosahexaenoic acid of formula (I) or an ester thereof: 【Chemical 1】 wherein R is hydrogen, C １ -C １０ alkyl or a pharmaceutically acceptable salt thereof; each X is independently hydrogen or deuterium, and the sum of the amounts of deuterium defined by both X groups is such that, on average, the total amount of deuteration on carbon atoms is less than about 5%; Each X １ are independently hydrogen or deuterium, and both X １ The total amount of deuterium, defined by １ an amount such that less than about 25% of the groups are deuterium, the remainder being hydrogen; Each Y is independently hydrogen or deuterium, and a particular value of each Y is, on average: a) about 87 to about 92 percent of the Y groups on each carbon atom are deuterium; b) greater than about 5 percent to about 12 percent of the Y groups on each carbon atom are substituted with a single hydrogen and a single deuterium; and c) less than about 2 percent of the Y groups have each carbon atom replaced with two hydrogen atoms; provided that the sum of all Y groups is chosen to be equal to 10].

17. A composition comprising a sample of plasma or red blood cells from a patient being treated with D-DHA, said sample containing a mixture of D-DHA and DHA, wherein the absolute amount of each component in said sample can be assessed.

18. 18. The composition of claim 17, wherein the sample was obtained at a time when the concentration of D-DHA had reached a steady state in the patient.

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