TECHNICAL FIELD

[0001] Disclosed are therapeutic methods for reducing the rate of loss of functionality in patients suffering from amyotrophic lateral sclerosis (ALS) during the accelerated stage of this disease. The methods comprise treating such patients with a deuterated arachidonic acid or a prodrug thereof.

BACKGROUND

[0002] ALS is a debilitating and fatal neurodegenerative disease in humans that, despite the best efforts of researchers, remains incurable. As such, the attending clinician attempts to slow the progression of the disease and maintain the quality of life for the patient for as long as possible.

[0003] ALS typically occurs later in life and is a neurological disease with its corresponding pathological hallmarks including progressive muscle weakness, muscle atrophy, and spasticity all of which reflect the degeneration and death of upper or lower motor neurons. When diagnosed early, most patients exhibit an initial slower rate of disease progression where the extent of loss of muscular functionality is limited as compared to the accelerated loss of muscular functionality that occurs later. During this incipient phase of ALS, the patient retains significant levels of functionality even in the absence of therapy. [0004] The incipient phase of ALS precedes an accelerated phase where the loss of muscular functionality proceeds rapidly and then terminates in death typically within 3 to 4 years from diagnosis with some patients succumbing even earlier. While the underlying cause of death is ALS, patients often succumb to pneumonia that is induced by aspiration of food into the lungs resulting from the inability to swallow properly.

[0005] The underlying hallmarks of the disease involve lipid peroxidation (LPO) of polyunsaturated fatty acids (PUFAs) in the motor neurons. Central to this oxidative pathway is the presence of labile bis-allylic hydrogen atoms found in arachidonic acid, the dominant PUFA found in neurons. The structure of arachidonic acid including identification of the bis- allylic sites is as follows:

[0006] In the cellular membranes of neurons, arachidonic acids (ARAs) are stacked together. Oxidative processes involving reactive oxygen species (ROS) act as an initiator for autoxidation of arachidonic acid by extraction of a bis-allylic hydrogen and formation of an oxidative reactive species. Initial oxidation at a first bis-allylic site then leads to serial oxidation of further arachidonic acid groups in the membrane of the neuron. The oxidative process starts with hydrogen extraction at a bis-allylic site on the first arachidonic acid and proceeds serially to the next arachidonic acid and then the next arachidonic acid and so on. At some point, the oxidative process damages or destroys the viability of the neuron leading to the furtherance of the disease condition that is responsible for generation of the excessive amounts of ROS.

[0007] Heretofore, the art has disclosed that the loss of muscular functionality in ALS can be attenuated by deuteration at one or more of the bis-allylic sites of arachidonic acid found in the at-risk neurons. The stability of the deuterium-carbon bond against such oxidative processes is significantly stronger (more stable) than that of the hydrogen-carbon bond. This means that the generation of an oxidative species at the bis-allylic sites is so reduced by the carbon-deuterium bonds that the lipid peroxidative pathway is inhibited by these bonds. In turn, inhibition of this pathway leads to enhanced survival of the neurons and, as such, attenuates the progression of the disease.

[0008] While such treatment inhibits the rate of loss of functionality, there has been no disclosure of separating ALS patients into an incipient stage or an accelerated stage of the disease and using different treatment protocols for each stage. By classifying that subset of patients in the accelerated stage of the disease, these patients can be treated more aggressively by the attending clinician so as to retain as much muscular functionality for as long as possible. SUMMARY

[0009] Disclosed are methods to treat patients in the accelerated stage of ALS to mitigate the loss of muscular functionality. If otherwise untreated, the accelerated stage of ALS results in rapid increases in the loss of functionality and eventually results in the death of the patient. The methods are designated herein as “therapeutic” in nature as they are administered to patients during the accelerated stage of ALS where the disease and the corresponding loss of muscular functionality is otherwise substantial in the absence of therapy.

[0010] Accordingly, in one embodiment, there is provided a method to treat patients suffering from ALS wherein said patients are in the accelerated stage of ALS characterized by substantial loss of muscular functionality, said method comprises: a) ascertaining the current level of muscular functionality in each patient suffering from ALS prior to initiation of therapy using the ALSFRS-R (the ALS functional rating scale revised) scoring criteria; b) identifying those patients that score less than 38 points out of a total of 48 possible points; c) classifying those patients as being in the accelerated stage of ALS; and d) initiating or changing the patient's treatment by periodically administering to said patients in said accelerated phase of the disease with an accelerated dosing regimen of a deuterated arachidonic acid or a prodrug thereof thereby reducing the rate of loss of muscular functionality in said patients as compared to patients not so treated.

[0011] In another embodiment, a method is provided to treat a patient characterized as having an accelerated stage of amyotrophic lateral sclerosis (ALS), said method comprises: a) initiating or changing a patient's treatment by periodically administering to said patient characterized as being in an accelerated stage of ALS an accelerated dosing regimen of a deuterated arachidonic acid or a prodrug thereof thereby reducing the rate of loss of muscular functionality in said patient as compared to patients not so treated, wherein the patient characterized as having an accelerated stage of ALS is identified by

(i) ascertaining the current level of muscular functionality in the patient suffering from ALS before initiating the accelerated dosing regimen using the ALS Functional Rating Score Revised (ALSFRS-R) scoring criteria; (ii) identifying the patient having an ALSFRS-R score of fewer than 38 points out of a total of 48 possible points, wherein said patient having the ALSFRS-R score less than 38 is classified as being in the accelerated stage of ALS; and (iii) classifying those patients as being in the accelerated stage of ALS.

[0012] In one embodiment, said deuterated arachidonic acid or a prodrug thereof is 11,1 l-D2-linoleic acid or an ester thereof. In vivo, the ester is hydrolyzed to provide for 11,1 l-D2-linoleic acid. A portion of this acid is then enzymatically converted in vivo to 13,13-D2-arachidonic acid. This deuterated arachidonic acid is then transported into the cerebral spinal fluid where it is then taken up by the motor neurons.

[0013] In one embodiment, the prodrug is 11,1 l-D2-linoleic acid ethyl ester. This drug is administered daily to the patient at a dose of about 7.0 to about 12.0 grams/day. [0014] In one embodiment, the patient is evaluated for uptake of 13,13-D2- arachidonic acid. Such is accomplished by assessing the concentration of 13,13-D2- arachidonic acid in red blood cells as described in International Patent Application Serial No. PCT/US2022/015368 which is incorporated herein by reference in its entirety.

[0015] A steady state concentration of at least about 10%, or, preferably, at least about 15%, or, more preferably, at least about 20% of 13,13-D2-arachidonic acid is found in the red blood cells when a daily dosage of from about 8.5 to 12 grams of 11,1 l-D2-linoleic acid ethyl ester is administered to the patient for about 4 to about 10 weeks. This steady-state concentration is based on the total amount of arachidonic acid present therein including deuterated arachidonic acid. As to esters of 11,1 l-D2-linoleic acid, that portion of its weight attributable to the ester is discounted from the total weight as the ester is rapidly removed in vivo. In addition, there is a minor amount of impurities in the product that must be discounted from the amount of drug delivered. As such, when the ethyl ester of 11,11-D2- linoleic acid is employed, the net dosing of the 11,1 l-D2-linoleic acid delivered to the patient is calculated absent the ester moiety and accounting for impurities. For 9 grams of 11,1 l-D-2 linoleic acid ethyl ester, the net weight of active 11,1 l-D2-linoleic acid is calculated as being about 8.64 grams per day. If other esters are employed, the corresponding weight contribution of the ester is readily calculated and accounted for.

[0016] In one embodiment, the attending clinician continues the initial dosing of the drug until a target concentration of about 20% or more of 13,13-D2-arachidonic acid in the patient's red blood cells is achieved. In one embodiment, after reaching the target concentration of 13,13-D2-arachidonic acid in red blood cells, the attending clinician can maintain this initial dose for an extended period thereafter to ensure that high levels of 13,13- D2-arachidonic acid are maintained. In another embodiment, the attending clinician can reduce the amount of 11,1 l-D2-linoleic acid ester administered per day to maintain the steady-state concentration. For example, the amount of 13,13-D2-arachidonic acid or a prodrug thereof can be reduced by about 30 to about 80% from the initial or accelerated dosing. In either case, periodic analyses of the patient's red blood cells are conducted to determine that the concentration of 13,13-D2-arachidonic acid is maintained at the desired level. Such periodic analyses include once a month, once every other month, or once every 3 months. In all cases, unless specified otherwise, the percent of 13,13-D2-arachidonic acid recited herein is based on the total amount of arachidonic acid in the red blood cells including deuterated arachidonic acids.

[0017] In one embodiment, said deuterated arachidonic acid or a prodrug thereof is 7,7,10,10,13,13-D6-arachidonic acid or an ester thereof. In vivo, the ester is hydrolyzed to provide for 7,7,10,10,13,13-D6-arachidonic acid. A portion of this acid is then transported into the cerebral spinal fluid where it is then taken up by neurons including the at-risk neurons. As before, periodic testing of the concentration of 7,7,10,10,13,13-D6-arachidonic acid is conducted.

[0018] In one embodiment, the prodrug is 7,7,10,10,13,13-D6-arachidonic acid ethyl ester. In one embodiment, this drug is administered daily at a dose of about 0.1 to about 2 grams per day discounting for the removal of the ester and any impurities contained therein. In another embodiment, this drug is administered daily to the patient at a dose of about 0.25 to about 2 grams/day.

[0019] In one embodiment, the patient is evaluated for uptake of 7,7,10,10,13,13-D6- arachidonic acid. As above, this is accomplished by assessing the concentration of 7,7,10,10,13,13-D6-arachidonic acid in red blood cells.

[0020] In any of the embodiments contemplated, the amount of the deuterated arachidonic acid or prodrug thereof is administered to the subject three times a day, i.e. t.i.d. [0021] Another aspect disclosed is a pharmaceutical composition for the treatment of a patient characterized as having an accelerated stage of amyotrophic lateral sclerosis (ALS) as explained herein, wherein the pharmaceutical composition comprises a deuterated arachidonic acid or a prodrug thereof, wherein the patient characterized as having an accelerated stage of ALS is identified by: (i) ascertaining the current level of muscular functionality in the patient suffering from ALS before initiating the accelerated dosing regimen using the ALS Functional Rating Score Revised (ALSFRS-R) scoring criteria;

(ii) identifying the patient having an ALSFRS-R score of fewer than 38 points out of a total of 48 possible points, wherein said patient having the ALSFRS-R score less than 38 is classified as being in the accelerated stage of ALS; and

(iii) classifying those patients as being in the accelerated stage of ALS.

[0022] A further aspect is a use of a deuterated arachidonic acid or a prodrug thereof in the manufacture of a medicament for the treatment of ALS in a patient characterized as having an accelerated stage of amyotrophic lateral sclerosis (ALS), wherein the patient characterized as having an accelerated stage of ALS is identified by:

(i) ascertaining the current level of muscular functionality in the patient suffering from ALS before initiating the accelerated dosing regimen using the ALS Functional Rating Score Revised (ALSFRS-R) scoring criteria;

(ii) identifying the patient having an ALSFRS-R score of fewer than 38 points out of a total of 48 possible points, wherein said patient having the ALSFRS-R score less than 38 is classified as being in the accelerated stage of ALS; and

(iii) classifying those patients as being in the accelerated stage of ALS.

[0023] Another embodiment contemplates a composition comprising a deuterated arachidonic acid or a prodrug thereof is administered preferably three times a day to a patient characterized as having an accelerated stage of amyotrophic lateral sclerosis (ALS), wherein the patient characterized as having an accelerated stage of ALS is identified by:

(i) ascertaining the current level of muscular functionality in the patient suffering from ALS before initiating the accelerated dosing regimen using the ALS Functional Rating Score Revised (ALSFRS-R) scoring criteria;

(ii) identifying the patient having an ALSFRS-R score of fewer than 38 points out of a total of 48 possible points, wherein said patient having the ALSFRS-R score less than 38 is classified as being in the accelerated stage of ALS; and

(iii) classifying those patients as being in the accelerated stage of ALS.

[0024] It is contemplated that a steady state concentration of about 6% to about 20% and preferably at least about 10%, or at least about 15%, or at least about 20%, of 7,7,10,10,13,13-D6-arachidonic acid is found in the red blood cells after about 4 to 10 weeks from the start of therapy when a dosage of about 1 gram per day is administered to the patient. This concentration is based on the total amount of arachidonic acid present in the red blood cells including deuterated arachidonic acid.

BRIEF DESCRIPTIONS OF THE DRAWINGS

[0025] FIG. 1 illustrates the change in ALSFRS-R scores in patients in the incipient stage of ALS and treated with either 11,1 l-D2-linoleic acid ethyl ester or placebo over the first 24 weeks of a clinical study.

[0026] FIG. 2-A illustrates the change in ALSFRS-R scores in untreated patients in the accelerated stage of ALS after the first 24 weeks of a clinical study. FIG. 2-B compares the change in ALSFRS-R scores in patients in the accelerated stage of ALS treated as per this disclosure with those patients treated with a placebo.

DETAILED DESCRIPTION

[0027] Disclosed are methods for reducing the rate of loss of functionality occurring in patients during the accelerated stage of amyotrophic lateral sclerosis (ALS).

[0028] The following terms are defined below. Terms that are not defined are given their definition in context or are given their medically acceptable definition.

[0029] The terminology used herein is to describe particular embodiments only and is not intended to be limited to the methods or compositions described herein. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context indicates otherwise.

[0030] As used herein, the term “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0031] As used herein, the term “about” when used before a numerical designation, e.g., temperature, time, amount, concentration, and such other, including a range, indicates approximations that may vary by ( + ) or ( - ) 15,% 10%, 5%, 1%, or any subrange or sub value therebetween. Preferably, the term “about” when referencing an amount or other feature including a dose amount, means that that amount may vary by +/- 10%.

[0032] As used herein, the term “comprising” or “comprises” is intended to mean that the compositions and methods include the recited elements, but not excluding others.

[0033] As used herein, the term “consisting essentially of’ when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed methods, uses, and compositions. [0034] As used herein, the term “consisting of’ shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of the methods, compositions, and uses thereof.

[0035] As used herein, the term “linoleic acid” refers to the compound and a pharmaceutically acceptable salt thereof having the formula provided below and having the natural abundance of deuterium (i.e., about 0.0156% naturally occurring deuterium) at each hydrogen atom:

[0036] Esters of linoleic acid are formed by replacing the -OH group with -OR. Such esters are as defined herein below.

[0037] As used herein and unless the context dictates otherwise, the term “deuterated linoleic acid or an ester thereof’ refers to 11,1 l-D2-linoleic acid or a Ci-Ce alkyl ester, a glycerol ester (including monoglycerides, diglycerides, and triglycerides), sucrose esters, phosphate esters (e.g., phospholipids), and the like. The particular ester group employed is not critical provided that the ester group is pharmaceutically acceptable (non-toxic and biocompatible).

[0038] As used herein and unless the context dictates otherwise, the term “deuterated D2-arachidonic acid or an ester thereof’ refers to 13,13-D2-arachidonic acid or a Ci-Ce alkyl ester, a glycerol ester (including monoglycerides, diglycerides, and triglycerides), sucrose esters, phosphate esters (e.g., phospholipids), and the like. The particular ester group employed is not critical provided that the ester group is pharmaceutically acceptable (nontoxic and biocompatible).

[0039] As used herein, the term "7,7,10,10,13,13-D6-arachidonic acid" includes both 7,7,10,10,13,13-D6-arachidonic acid as well as compositions of 7,7,10,10,13,13-06- arachidonic acid that comprise, on average, at least about 80% of the hydrogen atoms at each of the bis-allylic sites having been replaced by deuterium atoms and, on average, no more than about 35% of the hydrogen atoms at the mono-allylic sites having been replaced by deuterium atoms. For example, in the case of 80% deuteration of the 3 bis-allylic sites in arachidonic acid and 35% deuteration of the mono-allylic sites, the total amount of deuteration is (6 x 0.8) + (4 x 0.35) = 6.2 exclusive of the nominal amount of naturally occurring deuterium in each of the remaining methylene and methyl groups within arachidonic acid. Methods for preparing such compositions of deuterated arachidonic acid are found in US Patent No. 10,730,821 which is incorporated herein by reference in its entirety.

[0040] As used herein, the term "7,7,10,10,13,13-D6-arachidonic acid ester" refers to 7,7,10,10,13,13-D6-arachidonic acid which has been esterified with a Ci-Ce alkyl ester, a glycerol ester (including monoglycerides, diglycerides, and triglycerides), sucrose esters, phosphate esters (e.g., phospholipids), and the like. The particular ester group employed is not critical provided that the ester group is pharmaceutically acceptable (non-toxic and biocompatible).

[0041] As used herein, the term “phospholipid” refers to all phospholipids that are components of the cell membrane. Included within this term are phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and sphingomyelin. In the motor neurons, the cell membrane is enriched in phospholipids comprising arachidonic acid.

[0042] As used herein, the term “pathology of a disease” refers to the cause, development, structural/functional changes, and natural history associated with that disease. The term “natural history” means the progression of the disease in the absence of treatment per the methods described herein.

[0043] In ALS, the rate of disease progression is measured by the Revised ALS Functional Rating Scale (ALS-FRS-R and may be referred to herein as “the Rating Scale”) which is found at mdcalc.com/revised-amyotrophic-lateral-sclerosis-functional- rating-scale- alsfrs-r which is incorporated herein by reference in its entirety.

[0044] This ALS-FRS-R Rating Scale evaluated 12 different components on a 0 (worse) to 4 (best) scale where the components are speech, salivation, swallowing, handwriting, walking, food handling, dressing and hygiene, turning in bed, walking, climbing stairs, dyspnea, orthopnea, and respiratory insufficiency. As used herein, patients diagnosed with ALS are first evaluated to determine their natural history which measures the extent of loss of muscular functionality due to the disease prior to initiation of therapy. [0045] As used herein, the term “incipient stage of ALS” refers to patients whose disease progression has evidenced only modest loss of muscular functionality. For the methods of treatment described herein, such a patient in the incipient stage of ALS is identified as having a natural history score of 39 or above.

[0046] As shown in Figure 1, patients in the incipient stage of ALS do not evidence a significant change in their ALSFRS-R scores 6 months (24 weeks) into a clinical trial regardless of whether the patients are being treated with 11,1 l-D2-linoleic acid ethyl ester or with placebo. Indeed, the average score for treated and untreated patients after 24 weeks is substantially identical. The data evidence that those patients in the incipient stage of ALS have yet to experience a significant loss of functionality as is found in the accelerated stage of the disease.

[0047] As used herein, the term “accelerated stage of ALS” refers to patients whose disease progression has evidenced a substantial rate of loss of muscular functionality. As used herein, a patient in the accelerated stage of ALS is identified as having a natural history score of 37 or less. As shown in Figure 2, patients in the accelerated stage of ALS and treated with a placebo demonstrated a significant rate of loss of functionality during the first 24 weeks of the clinical trial.

[0048] Given the above, the benefit of therapy as per the methods described herein is analyzed in patients designated to be in the accelerated stage of the disease. In particular, the therapy described herein is analyzed as being therapeutic. That is to say that the benefit exhibited by the therapy is measured 24 weeks after the start of therapy by comparing the net loss of functionality from the start of therapy to 24 weeks thereafter for patients on therapy (first cohort) and those on placebo (second cohort). The therapeutic benefit provided is ascertained by a benefit that is perceived if the delta for the first cohort is at least about 2 points higher on average than the placebo cohort. Preferably, the delta is at least about 3 points or at least about 4 points or more.

[0049] In one embodiment, the ALSFRS-R scores for each patient in both cohorts are conducted monthly, bimonthly, quarterly, or semi-annually.

[0050] As used herein, the term “patient” refers to a human patient or a cohort of human patients suffering from ALS.

[0051] Because ALS patients in the accelerated stage of the disease show substantial changes in their functionality during the first 6 months in the absence of the therapy described herein, the attending clinician can optionally maintain an accelerated dose of either 13,13-D2-linoleic acid including a prodrug thereof, or an accelerated dose of D6-arachidonic acid including a prodrug thereof for the duration of the therapy or until a target concentration of the deuterated arachidonic acid is achieved in red blood cells. Such an "accelerated dose" includes from about 7.00 grams to about 12.00 grams of l l,l l-D2-linoleic acid ethyl ester and preferably about 8.64 grams per day (or any 0.01 value within that range); or from about 0.50 grams to about 2.00 grams per day (or any 0.01 value within that range) of

7.7.10.10.13.13-D6-arachidonic acid.

[0052] As used herein, the term "target concentration" refers to the concentration of the deuterated arachidonic acid in red blood cells that enables the attending clinician to correlate that concentration to a therapeutic concentration in the at-risk neurons. For 13,13- D2-archidonic acid, a preferred target concentration is at least 10%, or at least 15%, or at least 20% based on the total weight of arachidonic acid in the red blood cells including deuterated arachidonic acid. For 7,7,10,10,13,13-D6-arachidonic acid, a preferred target concentration is at least 7%, or at least 10%, or at least 15%, or at least 20% based on the total weight of arachidonic acid in red blood cells including the deuterated arachidonic acid. [0053] In one embodiment, the clinician adjusts the dosing of l l,l l-D2-linoleic acid ethyl ester once the target concentration of 13,13-D2-arachidonic acid is achieved. In one embodiment, the clinician can reduce the dose to that less than the accelerated dose including for example, to about 30% to about 80% of the accelerated dose per day. In one embodiment, the clinician can adjust the dosing of 7,7,10,10,13,13-D6-arachidonic acid ethyl ester once the target concentration of 7,7,10,10,13,13-D6-arachidonic acid is achieved. In one embodiment, the clinician can reduce the dose to that less than the accelerated dose including, for example, 0.50 to 1.50 grams per day (or any 0.01 value within that range).

[0054] As used herein, the term “periodic dosing” refers to a dosing schedule that substantially comports to the dosing described herein. Stated differently, periodic dosing includes a patient who is compliant at least 75 percent of the time over a 30-day period and preferably at least 80% compliant. In embodiments, the dosing schedule contains a designed pause in dosing. For example, a dosing schedule that provides dosing 6 days a week is one form of periodic dosing. Another example is allowing the patient to pause administration for about 3 or 7 or more days, e.g., due to personal reasons, provided that the patient is otherwise at least 75 percent compliant.

[0055] As used herein, the term "prodrug of 13,13-D2-arachidonic acid includes both

13.13-D2-arachidonic acid esters or 11,1 l-D2-linoleic acid or an ester thereof. In vivo, the ester moiety rapidly de-esterifies and converts to l l,l l-D2-linoleic acid or 13,13-D2- arachidonic acid. In turn, a portion of 11,1 l-D2-linoleic acid absorbed is enzymatically converted to 13,13-D2-arachidonic acid.

[0056] As used herein, the term "prodrug of 7,7,10,10,13,13-D6-arachidonic acid includes 7,7,10,10,13,13-D6-arachidonic acid esters. In vivo, the ester moiety rapidly de- esterifies and converts 7,7,10,10,13,13-D6-arachidonic acid.

[0057] As used herein, the term “cohort” refers to a group of at least 5 patients whose results are to be averaged.

[0058] As used herein, the term “pharmaceutically acceptable salts” of compounds disclosed herein are within the scope of the methods described herein and include acid or base addition salts that retain the desired pharmacological activity and is not biologically undesirable (e.g., the salt is not unduly toxic, allergenic, or irritating, and is bioavailable). When the compound has a basic group, such as, for example, an amino group, pharmaceutically acceptable salts can be formed with inorganic acids (such as 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, naphthalene sulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid). When the compound has an acidic group, for example, a carboxylic acid group, it can form salts with metals, such as alkali and earth alkali metals (e.g., Na ⁺ , Li ⁺ , K ⁺ , Ca ²⁺ , Mg ²⁺ , and 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 isolation and purification of the compounds or by separately reacting the purified compound in its free base or free acid form with a suitable acid or base, respectively, and isolating the salt.

[0059] The phrase “excessive amounts of PUFAs,” “excessive PUFA intake,” and the like refer to the intake of total PUFAs (e.g., the total amount of PUFAs consumed by a subject per day) that result in reduced conversion of 11,1 l-D2-linoleic acid to 13,13-D2- arachidonic acid compared to a diet lower in total PUFA intake. In embodiments, the patient is on a diet that restricts the intake of linoleic acid, arachidonic acid, and/or other PUFA compounds. The amount of PUFAs that can be consumed by a patient is variable, depending on numerous factors such as the patient’s health, weight, age, other medications being taken, liver function, metabolism, and the like. [0060] In general, a patient on a 2,000 calorie per day diet consumes up to about 22 grams of polyunsaturated fatty acids (news.christianacare.org/2013/04/nutrition-numbers- revealed-fat-intake/), of which about 14 grams are linoleic acid when averaged for men and women (Jay Whelan, “Linoleic Acid,” Adv. Az/ tri. 4(3): 311-12, 2023). In addition, only about 10% of the average amount of linoleic acid consumed is hepatically converted to arachidonic acid. So, on average, about 1.4 grams of arachidonic acid is generated per day per subject. When a patient consumes excessive amounts of PUFAs, including linoleic acid, that excess dilutes the effective concentration of 11,1 l-D2-linoleic acid. In turn, this impacts the amount of 13,13-D2-arachidonic acid that is hepatically generated when all other factors remain constant.

[0061] When the amount of total PUFAs consumed is such that the amount of 13,13- D2-arachidonic acid hepatically generated is less than about 70% per day of that generated when the average amount of PUFAs is consumed, then that patient is considered to have excessive linoleic acid consumption.

Pathology

[0062] The discovery of several aldehydes that easily reacted with sulfhydryl groups, resulting in the inhibition of vital metabolic processes, led to the association of polyunsaturated fatty acid peroxidation as a component of the pathology of diseases such as ALS (Schauenstein, E.; Esterbauer, H., “Formation and properties of reactive aldehydes,” Ciba Found. Symp. (67): 225-244; 1978). Whether as a primary cause of the disease or a secondary consequence, such lipid peroxidation is attributed to oxidative stress, which leads to neuronal death and is implicated in the progression of ALS.

[0063] The oxidative stress responsible for peroxidation is due to an imbalance between routine production and detoxification of reactive oxygen species (“ROS”) that lead to an oxidative attack on the lipid membrane of cells. The membrane of motor neurons is highly enriched in arachidonic acid. Separating each of these 4 sites are 3 bis-allylic methylene groups and flanking both ends of these 4 sites are mono-allylic methylene groups. The bis-allylic groups are particularly susceptible to oxidative damage due to ROS, and to enzymes such as cyclooxygenases, cytochromes, and lipoxygenases, as compared to allylic methylene and methylene groups.

[0064] Moreover, once a bis-allylic methylene group in one arachidonic acid is oxidized by a ROS, a cascade of further oxidation of other arachidonic acid groups in the lipid membrane occurs. This is because a single ROS generates oxidation of a first arachidonic acid component through a free radical mechanism which, in turn, can oxidize a neighboring arachidonic acid through the same free radical mechanism which yet again can oxidize another neighboring arachidonic acid in a process referred to as lipid chain autooxidation. The resulting damage from the auto-oxidation includes a significant number of oxidized arachidonic acid components in the cell membrane.

[0065] Oxidized arachidonic acids negatively affect the fluidity and permeability of cell membranes in motor neurons. In addition, they can lead to the oxidation of membrane proteins as well as being converted into a large number of highly reactive carbonyl compounds. The latter include reactive species such as acrolein, malonic dialdehyde, glyoxal, methylglyoxal, etc. (Negre-Salvayre A, et al. Brit. J. Pharmacol. 153: 6-20, 2008). But the most prominent products of arachidonic acid oxidation are alpha, beta-unsaturated aldehydes such as 4-hydroxynon-2-enal (4-HNE; formed from n-6 PUFAs like LA or AA), and corresponding ketoaldehydes (Esterfbauer H, et al., Free Rad. Biol. Med. 11:81-128 (1991). As noted above, these reactive carbonyls cross-link (bio)molecules through Michael addition or Schiff base formation pathways leading which continues the underlying pathology of the disease.

Disease Progression

[0066] When a patient is first diagnosed with ALS, the clinician evaluates that patient's rate of disease progression by assessing the patient's loss of functionality in the absence of therapy as described herein. That rate of disease progression can be also referred to as the “natural history” of the disease and is typically measured by standardized tests that measure the extent of a patient's functionality over a set time period. For example, in the case of ALS, there is a standard test referred to as ALSFRS-R which determines the rate of loss of muscle functionality at a given point in time. Serial testing done over time provides a measure of disease progression and the patient's rate of loss of functionality.

[0067] The ALSFRS-R test has 12 components each of which is measured on a 0 (worst) to 4 (best) scale. In general, patients first diagnosed with ALS can be considered in the incipient stage of the disease if their score is 39 and above whereas patients scoring 37 or less are considered to be in the accelerated stage of the disease.

[0068] It is understood that patients in the incipient stage will eventually transition into the accelerated stage where there is a rapid loss of functionality. In addition, some patients newly diagnosed with ALS may already be considered in the accelerated stage of the disease, especially for those who were misdiagnosed initially. [0069] Heretofore, the treatment of ALS employed deuterated l l,l l-D2-linoleic acid or an ester thereof, including those in a lipid bilayer form, to stabilize polyunsaturated fatty acids against ROS. Examples of such treatments are found in: WO 2011/053870, WO 2012/148946, and WO 2020/102596, each of which is incorporated herein by reference in its entirety. Needless to say, the art did not appreciate or suggest that patients with ALS should be classified as being in the incipient or accelerated stage of ALS and that the corresponding therapy should be predicated on such a classification.

[0070] As to 11,1 l-D2-linoleic acid or an ester thereof, this compound acts as a prodrug for 13,13-D2-arachidonic acid - the therapeutic entity. Each of the above International Applications discloses the in vivo conversion of a portion of l l,l l-D2-linoleic acid to 13,13-D2-arachidonic acid which is then incorporated into the at-risk neurons to stabilize these neurons from oxidative damage. The in vivo accumulation of 13,13-D2- arachidonic acid occurs over months until a therapeutic concentration is achieved. Once a therapeutic concentration of 13,13-D2-arachidonic acids is achieved, continued administration of 11,1 l-D2-linoleic acid or ester thereof is necessary to maintain such a therapeutic concentration.

[0071] Still further, the dosing regimen employed must address the patient's need to promptly establish a therapeutic concentration in vivo which is necessary to avoid further loss of functionality such as when a therapeutic concentration of 13,13-D2-arachidonic acid is delayed. Accordingly, a dosing regimen suitable for the accelerated stage of ALS is employed (the “accelerated dosing regimen”) and is addressed below.

[0072] When deuterated arachidonic acid or ester thereof administered to the patient is 7,7,10,10,13,13-D6-arachidonic acid or an ester thereof, the accelerated dosing regimen employed takes into account that this drug or prodrug (in the case of the ester) does not need to be converted in vivo.

Compound Preparation

[0073] 11,1 l-D2-linoleic acid is known in the art and is commercially available. In addition, l l,l l-D2-linoleic acid and esters thereof are described, for example, in US Patent No. 10,052,299 which is incorporated herein by reference in its entirety. 7,7, 10, 10,13, 13-D6- arachidonic acid is described in US Patent No. 10,730,821 which is incorporated herein by reference in its entirety. Likewise, compositions of 7,7,10,10,13,13-D6-arachidonic acid that comprise, on average, about 80% of the hydrogen atoms at each of the bis-allylic sites having been replaced by deuterium atoms and, on average, no more than about 35% of the hydrogen atoms at the mono-allylic sites having been replaced by deuterium atoms are also disclosed in US Patent No. 10,730,821.

Methodology - ll,ll-D2-Linoleic Acid or Ester Thereof

[0074] In one embodiment, the methods described herein utilize in vivo conversion of linoleic acid to arachidonic acid by administering 11,1 l-D2-linoleic acid or an ester thereof to a patient to biosynthesize a therapeutic concentration of 13,13-D2-arachidonic acid for use in the methods described herein.

[0075] In one embodiment, an accelerated dosing regimen of l l,l l-D2-linoleic acid or ester thereof is administered to the patient in sufficient amounts to generate a target concentration in red blood cells of 13,13-D2-arachidonic acid of at least about 10%, or a least about 15% or at least about 20% based on the total amount of arachidonic acid, including deuterated arachidonic acid, found therein. In one embodiment, the accelerated dosing regimen is set to obtain a target concentration within about 8 weeks from the onset of therapy or earlier (e.g., 6 weeks or 4 weeks). As noted above, the earlier a patient reaches a therapeutic concentration in the red blood cells and hence the neurons, the more muscle functionality can be preserved in the patient. When the target concentration is achieved in red blood cells such as 20%, the attending clinician can associate that concentration with a therapeutic concentration in the neurons.

[0076] In one embodiment, the accelerated dosing regimen employs an ester of 11,11- D2-linoleic acid such as linoleic acid ethyl ester. Generally, the accelerated dosing regimen employs from about 7.00 to 12.00 grams of this ester per day and preferably about 9 grams per day. It is understood that when 9 grams of the prodrug are employed, the portion attributable to the ethyl ester needs to be accounted for in the dose administered as that ester is rapidly removed in vivo. In addition, a small amount of impurity is found in the composition which also needs to be accounted for. As such, 9 grams of the composition of the prodrug has been found to provide for about 8.64 grams of 11,1 l-D2-linoleic acid. The deuterated linoleic acid ester composition is preferably administered in three partial doses of 3 grams per day generally with breakfast, lunch, and dinner. Periodically, the clinician can ascertain the extent of conversion of this ester into 13,13-D2-arachidonic acid by testing red blood cells as described in International Patent Application No. PCT/US2022/15368 which is incorporated herein by reference in its entirety.

[0077] At the discretion of the attending clinician, once a steady state concentration of 13,13-D2-arachidonic acid in red blood cells is achieved (based on the total amount of arachidonic acid in said cell including deuterated arachidonic acid), a lower dose of 11,11- D2-linoleic acid ethyl ester can be administered such as at least about 30 to 80% of the accelerated dosing regimen. This includes about 5 grams or about 6 grams or about 7 grams per day provided that the concentration of 13,13-D2-arachidonic acid in red blood cells remains above the target concentration set by the clinician (e.g., about 20%). In such a case, the attending clinician should perform periodic blood tests to assess the concentration of 13,13-D2-arachidonic acid in red blood cells.

[0078] In one embodiment, the attending clinician may elect not to reduce the dosing of 11,1 l-D2-linoleic acid ethyl ester to ensure that the patient maintains more than a therapeutic concentration during the entirety of the therapy. Such is possible because the deuterated polyunsaturated fatty acids described herein are exceptionally well tolerated by the patients and have a broad therapeutic window. Nevertheless, periodic blood tests as described above should be conducted to ensure patient compliance, the amount of polyunsaturated fat consumed, etc.

[0079] When 11,1 l-D2-linoleic acid or an ester thereof is administered, a portion of this prodrug is enzymatically converted into the active 13,13-D2-arachidonic acid. However, this conversion is typically rate limited thereby limiting the amount of arachidonic acid that the body can enzymatically generate in a given day. As such, only a fraction of the linoleic acid consumed is converted to arachidonic acid with the majority of the linoleic acid including deuterated linoleic acid remaining unchanged. One factor affecting the amount of 13,13-D2-arachidonic acid that can be generated in vivo is the amount of fat consumed by the patient and especially the amount of linoleic acid consumed. Simply mass balance dictates that the more linoleic acid included in the patient’s diet coupled with a set amount of 11,11- D2-linoleic acid or ester thereof correlates to a reduction in the amount of 13,13-D2- arachidonic acid so generated. Accordingly, patients that evidence reduced rates of conversion can be placed on a diet restricted in the amount of linoleic acid consumed.

Methodology - 7,7,10,10,13,13-D6 Arachidonic Acid or Ester Thereof

[0080] Unlike linoleic acid, arachidonic acid or an ester thereof does not entail any in vivo conversion other than hydrolysis of the ester to the corresponding acid. As such, arachidonic acid is immediately available to the body for systemic uptake. As noted previously, only about 10% of linoleic acid is enzymatically converted to arachidonic acid. Since arachidonic acid does not require a similar conversion, the dose of 7,7,10,10,13,13-D6- arachidonic acid needs to be only one-tenth that of 11,1 l-D2-linoleic acid or about 864 milligrams per day. In addition, and as shown in the Examples, 7,7, 10, 10,13, 13-D6- arachidonic acid is a little more than twice as active in an inflammation model as is 13,13- D2-arachidonic acid. Using this activity differential, then it is possible that about 430 mg of 7,7,10,10,13,13-D6-arachidonic acid would be the equivalent of 8.64 grams of 11,11-D2- linoleic acid. Recognizing that the incipient dosing amount for 11,1 l-D2-linoleic acid can vary from as little as 5 grams per day to as much as 10 grams per day, the corresponding variance for 7,7,10,10,13,13-D6-arachidonic acid can be as low as about 200 mg per day to about 2 gm per day and preferably 0.5 to 2 grams per day.

EXAMPLES

[0081] The methods described herein are further understood by reference to the following examples, which are intended to be purely exemplary of the materials and methods disclosed herein. The methods and compositions used are not limited in scope by the exemplified embodiments, which are intended as illustrations of single aspects of the methods and compositions only. Any methods that are functionally equivalent to the described methods and compositions for use are also contemplated. Various modifications of the methods and compositions used in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications fall within the scope of the appended claims. In these examples, the following terms are used herein and have the following meanings. If not defined, the abbreviation has its conventional medical meaning.

Example 1 - Minimal Rate of Loss of Functionality for Patients in the Incipient Stage of ALS

[0082] In this example, 41 patients diagnosed with ALS were tested to ascertain their natural history. Of these 41 patients, 23 scored above 38 points in the ALSFRS-R scoring test and were assigned as having incipient ALS. Subsequently, these 23 patients were separated into a first cohort of 13 patients each treated with about 8.64 grams of 11,11-D2- linoleic acid (administered as about 9 grams of the corresponding ethyl ester) and 10 patients treated with placebo. Each cohort received three 1-gram pills t.i.d. (ter in die or three times a day) at breakfast, lunch, and dinner for a total of 9 pills.

[0083] Blood draws were taken periodically to assess the concentration of 13,13-D2- arachidonic acid in red blood cells. By week 8, the patients treated with 11,1 l-D2-linoleic acid ethyl ester evidenced a steady state concentration of 13,13-D2-arachidonic acid ranging from 8-15% based on the total amount of arachidonic acid including deuterated arachidonic acid.

[0084] After 24 weeks, each patient in each cohort was retested using the ALSFRS-R scoring test. The scores were then averaged for each cohort and the results are found in Figure 1. These results evidence that the treated and the untreated cohort experienced a minimal loss of functionality with almost identical scores at 24 weeks. Taken together, this suggests that patients in the incipient stage of ALS are agnostic to treatment because their loss of muscular functionality has not reached the accelerated stage of this disease.

Example 2 - Rate of Loss durins the Accelerated Stage of ALS

[0085] In this example, the same 41 patients diagnosed with ALS used in Comparative Example 1 were used. However, in this example, 12 patients were assigned as being in the accelerated stage of the disease as each had an ALSFRS-R score of less than 37. Subsequently, these 12 patients were separated into a first cohort of 7 patients each treated with 8.64 grams of l l,l l-D2-linoleic acid (administered as 9 grams of the corresponding ethyl ester) and 5 patients treated with placebo. Each cohort received three 1-gram pills t.i.d. at breakfast, lunch, and dinner for a total of 9 pills with the caveat that the placebo cohort's pills contained only a pharmaceutical excipient. Figure 2- A illustrates the rate of loss of functionality for the patients in the accelerated stage ALS cohort over the 24-week period. As can be seen, the loss of functionality was statistically significant.

Example 3 - Comparison of the Rate of Loss between treated and untreated Patients during the Accelerated Stage of ALS

[0086] Further to Example 2 above, blood draws were taken periodically to assess the concentration of 13,13-D2-arachidonic acid in red blood cells in the treated patients as well as the untreated patients. As to the latter group, their results evidenced no 13,13-D2- arachidonic acid. By week 8, the patients treated with 11,1 l-D2-linoleic acid ethyl ester evidenced a steady state concentration of 13,13-D2-arachidonic acid ranging from 5-17% based on the total amount of arachidonic acid including deuterated arachidonic acid.

[0087] After 24 weeks, each patient in each cohort was retested using the ALSFRS-R scoring test. The scores were then averaged for each cohort and the results are found in Figure 2-B. These results evidence that the untreated cohort experienced a substantial loss of functionality while the treated cohort exhibited substantially less loss of muscular functionality. Taken together, this suggests that the untreated patients in the accelerated stage of ALS rapidly experience loss of muscular functionality characteristic of this stage of the disease whereas the treated patients retained more functionality.

Example 4 - Control of LPS-Induced Inflammation

[0088] The purpose of this example is to evaluate the relative activity of 13,13-D2- arachidonic acid against 7,7,10,10,13,13-D6-arachidonic acid at least in one in vivo model. In this case, an LPS model was used where LPS administration is known to promote inflammation through various mechanisms including secretion of pro-inflammatory cytokines, eicosanoids and induction of ROS. This example employed LPS to ascertain the extent of inflammation arising from ROS induced oxidation of H-AA (/'.<?., arachidonic acid having the natural abundance of deuterium) versus D2-AA and D6-AA in the lungs of mice. D2-AA is 13,13,D2-arachadonic acid and D6-AA is 7,7,10,10,13,13-D6-arachidonic acid. Specifically, four groups of mice were used. The first group was control mice treated with H- LA (linoleic acid having the natural abundance of deuterium). The second group of mice received a 6- week course of 11,1 l-D2-linoleic acid ethyl ester. It is understood that in vivo conversion of a portion of both H-LA and D-LA (11,1 l,D2-linoleic acid) occurs to provide for AA and D2-AA respectively. The third group of mice received a 6-week course of H- AA. The fourth group of mice received a 6-week course of D6-AA. The animals are administered an ethyl ester which converts to the acid form in their stomach.

[0089] All groups then received a single intranasal administration of LPS to induce acute lung inflammation. The degree of the inflammatory response was based on the interalveolar septa distance where the larger the distance of the septa, the greater the degree of inflammation. The animals were sacrificed and the interalveolar septa distance was measured. Table 1 provides an average degree of spatial distance for the interalveolar septa for the results of all groups.

Table 1

[0090] The above results evidence about a 25% reduction in the spatial distance for the interalveolar septa for the mice treated with D-LA relative to those treated with H-LA. However, the mice treated D-AA had almost a 60% reduction in the same spatial distance evidencing the benefits of D-AA in treating inflammation.

EMBODIMENTS [0091] The following embodiments represent some of the aspects proposed by the methods and composition described above.

[0092] [1.] A method to treat patients suffering from ALS wherein said patients are in the accelerated stage of ALS characterized by substantial loss of muscular functionality, said method comprises: a) ascertaining the current level of muscular functionality in each patient suffering from ALS prior to initiation of therapy using the ALSFRS-R scoring criteria; b) identifying those patients that score less than 38 points out of a total of 48 possible points; c) classifying those patients as being in the accelerated stage of ALS; and d) initiating or changing the patient's treatment by periodically administering to said patients in said accelerated phase of the disease with an accelerated dosing regimen of a deuterated arachidonic acid or a prodrug thereof thereby reducing the rate of loss of muscular functionality in said patients as compared to patients not so treated.

[0093] [2.] The method of Embodiment [1], wherein said deuterated arachidonic acid or a prodrug thereof is 11,1 l-D2-linoleic acid or an ester thereof.

[0094] [3.] The method of Embodiment [2], wherein said 11,1 l-D2-linoleic acid or an ester thereof is an ester.

[0095] [4.] The method of Embodiment [3], wherein said l l,l l-D2-linoleic acid ester is an ethyl ester.

[0096] [5.] The method of Embodiment [4], wherein said 11,1 l-D2-linoleic acid ethyl ester is administered periodically to the patient at a dose of about 7 to about 12 grams/day.

[0097] [6.] The method of Embodiment [5], wherein the extent that 13,13-D2- arachidonic acid enzymatically generated in vivo from said l l,l l-D2-linoleic acid ethyl ester is assessed in each patient by measuring the concentration of 13,13-D2-arachidonic acid in red blood cells.

[0098] [7.] The method of Embodiment [1], wherein said deuterated arachidonic acid or a prodrug thereof is 7,7,10,10,13,13-D6-arachidonic acid or an ester thereof.

[0099] [8.] The method of Embodiment [7], wherein said 7,7, 10, 10,13, 13-D6- arachidonic acid or an ester thereof is an ester. [0100] [9.] The method of Embodiment [8]8, wherein said 7,7, 10, 10,13, 13-D6- arachidonic acid ester is an ethyl ester.

[0101] [10.] The method of Embodiment [9]9, wherein said 7,7, 10, 10,13, 13-D6- arachidonic acid ethyl ester is administered periodically to the patient at a dose of about 5 to about 10 grams/day.

[0102] [11.] The method of Embodiment [10], wherein the extent that

7,7,10,10,13,13-D6-arachidonic acid absorbed in vivo is assessed in each patient by measuring the concentration of 7,7,10,10,13,13-D6-arachidonic acid in red blood cells.

[0103] [12.] A method to treat a patient characterized as having an accelerated stage of amyotrophic lateral sclerosis (ALS), said method comprises: a) initiating or changing a patient's treatment by periodically administering to said patient characterized as being in an accelerated stage of ALS an accelerated dosing regimen of a deuterated arachidonic acid or a prodrug thereof thereby reducing the rate of loss of muscular functionality in said patient as compared to patients not so treated, wherein the patient characterized as having an accelerated stage of ALS is identified by

(i) ascertaining the current level of muscular functionality in the patient suffering from ALS before initiating the accelerated dosing regimen using the ALS Functional Rating Score Revised (ALSFRS-R) scoring criteria;

(ii) identifying the patient having an ALSFRS-R score of fewer than 38 points out of a total of 48 possible points, wherein said patient having the ALSFRS-R score less than 38 is classified as being in the accelerated stage of ALS; and

(iii) classifying those patients as being in the accelerated stage of ALS.

[0104] [13.] The method of Embodiment [12], wherein said deuterated arachidonic acid or a prodrug thereof is 11,1 l-D2-linoleic acid or an ester thereof.

[0105] [14.] The method of Embodiment [13], wherein said l l,l l-D2-linoleic acid or an ester thereof is an ester.

[0106] [15.] The method of Embodiment [14], wherein said l l,l l-D2-linoleic acid ester is an ethyl ester.

[0107] [16.] The method of Embodiment [15], wherein said l l,l l-D2-linoleic acid ethyl ester is administered periodically to the patient at a dose of about 7 to about 12 grams/day. [0108] [17.] The method of any of Embodiments [12] to [15], wherein the deuterated arachidonic acid or the prodrug thereof is administered three times a day to said patient.

[0109] [18.] The method of Embodiment [16], wherein a 13,13-D2-arachidonic acid enzymatically generated in vivo concentration in said patient from said l l,l l-D2-linoleic acid ethyl ester is assessed in said patient by measuring the concentration of 13,13-D2-arachidonic acid in red blood cells of said patient.

[0110] [19.] The method of Embodiment [12], wherein said deuterated arachidonic acid or a prodrug thereof is 7,7,10,10,13,13-D6-arachidonic acid or an ester thereof.

[0111] [20.] The method of Embodiment [19], wherein said 7,7, 10, 10,13, 13-D6- arachidonic acid or an ester thereof is an ester.

[0112] [21.] The method of Embodiment [20], wherein said 7,7, 10, 10,13, 13-D6- arachidonic acid ester is an ethyl ester.

[0113] [22.] The method of Embodiment [21], wherein said 7,7, 10, 10,13, 13-D6- arachidonic acid ethyl ester is administered periodically to the patient at a dose of about 5 to about 10 grams/day.

[0114] [23.] The method of Embodiment [22], wherein the extent that

7,7,10,10,13,13-D6-arachidonic acid absorbed in vivo is assessed in each patient by measuring the concentration of 7,7,10,10,13,13-D6-arachidonic acid in red blood cells.

[0115] [24.] The method of any of Embodiments [8] to [23], wherein the deuterated arachidonic acid or the prodrug thereof is administered three times a day to said patient.

[0116] [25.] A pharmaceutical composition for the treatment of a patient characterized as having an accelerated stage of amyotrophic lateral sclerosis (ALS) comprising a deuterated arachidonic acid or a prodrug thereof, wherein the patient characterized as having an accelerated stage of ALS is identified by:

(i) ascertaining the current level of muscular functionality in the patient suffering from ALS before initiating the accelerated dosing regimen using the ALS Functional Rating Score Revised (ALSFRS-R) scoring criteria;

(ii) identifying the patient having an ALSFRS-R score of fewer than 38 points out of a total of 48 possible points, wherein said patient having the ALSFRS-R score less than 38 is classified as being in the accelerated stage of ALS; and (iii) classifying those patients as being in the accelerated stage of ALS.

[0117] [26.] A use of a deuterated arachidonic acid or a prodrug thereof in the manufacture of a medicament for the treatment of ALS in a patient characterized as having an accelerated stage of amyotrophic lateral sclerosis (ALS), wherein the patient characterized as having an accelerated stage of ALS is identified by:

(i) ascertaining the current level of muscular functionality in the patient suffering from ALS before initiating the accelerated dosing regimen using the ALS Functional Rating Score Revised (ALSFRS-R) scoring criteria;

(ii) identifying the patient having an ALSFRS-R score of fewer than 38 points out of a total of 48 possible points, wherein said patient having the ALSFRS-R score less than 38 is classified as being in the accelerated stage of ALS; and

(iii) classifying those patients as being in the accelerated stage of ALS.

[0118] [27.] A composition comprising a deuterated arachidonic acid or a prodrug thereof for use in the treatment of ALS in a patient characterized as having an accelerated stage of amyotrophic lateral sclerosis (ALS), wherein the patient characterized as having an accelerated stage of ALS is identified by:

(i) ascertaining the current level of muscular functionality in the patient suffering from ALS before initiating the accelerated dosing regimen using the ALS Functional Rating Score Revised (ALSFRS-R) scoring criteria;

(ii) identifying the patient having an ALSFRS-R score of fewer than 38 points out of a total of 48 possible points, wherein said patient having the ALSFRS-R score less than 38 is classified as being in the accelerated stage of ALS; and

(iii) classifying those patients as being in the accelerated stage of ALS.