WO2023220058A1 - Méthodes thérapeutiques pour traiter la sla - Google Patents

Méthodes thérapeutiques pour traiter la sla Download PDF

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Publication number
WO2023220058A1
WO2023220058A1 PCT/US2023/021543 US2023021543W WO2023220058A1 WO 2023220058 A1 WO2023220058 A1 WO 2023220058A1 US 2023021543 W US2023021543 W US 2023021543W WO 2023220058 A1 WO2023220058 A1 WO 2023220058A1
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als
patient
arachidonic acid
accelerated
alsfrs
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PCT/US2023/021543
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English (en)
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Peter Milner
Nadia Litterman
Mark MIDEI
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Retrotope, Inc.
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Publication of WO2023220058A1 publication Critical patent/WO2023220058A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • ALS amyotrophic lateral sclerosis
  • the methods comprise treating such patients with a deuterated arachidonic acid or a prodrug thereof.
  • 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.
  • 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.
  • pathological hallmarks including progressive muscle weakness, muscle atrophy, and spasticity all of which reflect the degeneration and death of upper or lower motor neurons.
  • ALS 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.
  • 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.
  • LPO lipid peroxidation
  • PUFAs polyunsaturated fatty acids
  • ARAs arachidonic acids
  • ROS reactive oxygen species
  • 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.
  • inhibition of this pathway leads to enhanced survival of the neurons and, as such, attenuates the progression of the disease.
  • 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.
  • 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 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.
  • 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
  • said deuterated arachidonic acid or a prodrug thereof is 11,1 l-D2-linoleic acid or an ester thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the attending clinician can reduce the amount of 11,1 l-D2-linoleic acid ester administered per day to maintain the steady-state concentration.
  • 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.
  • Period 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.
  • said deuterated arachidonic acid or a prodrug thereof is 7,7,10,10,13,13-D6-arachidonic acid or an ester thereof.
  • 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.
  • periodic testing of the concentration of 7,7,10,10,13,13-D6-arachidonic acid is conducted.
  • the prodrug is 7,7,10,10,13,13-D6-arachidonic acid ethyl ester.
  • 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.
  • this drug is administered daily to the patient at a dose of about 0.25 to about 2 grams/day.
  • 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.
  • the amount of the deuterated arachidonic acid or prodrug thereof is administered to the subject three times a day, i.e. t.i.d.
  • ALSFRS-R ALS Functional Rating Score Revised
  • 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:
  • 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:
  • ALS amyotrophic lateral sclerosis
  • 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.
  • 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.
  • 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.
  • ALS amyotrophic lateral sclerosis
  • the term “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur and that the description includes instances where the event or circumstance occurs and instances where it does not.
  • the term “about” when used 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.
  • the term “about” when referencing an amount or other feature including a dose amount means that that amount may vary by +/- 10%.
  • compositions and methods are intended to mean that the compositions and methods include the recited elements, but not excluding others.
  • compositions and methods when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed methods, uses, and compositions.
  • 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.
  • leic 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:
  • Esters of linoleic acid are formed by replacing the -OH group with -OR. Such esters are as defined herein below.
  • 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).
  • 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).
  • 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.
  • 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).
  • 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.
  • pathology of a disease refers to the cause, development, structural/functional changes, and natural history associated with that disease.
  • natural history means the progression of the disease in the absence of treatment per the methods described herein.
  • ALS-FRS-R Revised ALS Functional Rating Scale
  • the Rating Scale Revised ALS Functional Rating Scale
  • 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.
  • 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.
  • 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.
  • accelerated stage of ALS refers to patients whose disease progression has evidenced a substantial rate of loss of muscular functionality.
  • a patient in the accelerated stage of ALS is identified as having a natural history score of 37 or less.
  • 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.
  • the benefit of therapy as per the methods described herein is analyzed in patients designated to be in the accelerated stage of the disease.
  • 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.
  • the delta is at least about 3 points or at least about 4 points or more.
  • the ALSFRS-R scores for each patient in both cohorts are conducted monthly, bimonthly, quarterly, or semi-annually.
  • the term “patient” refers to a human patient or a cohort of human patients suffering from ALS.
  • 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
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • prodrug of 13,13-D2-arachidonic acid includes both
  • the ester moiety rapidly de-esterifies and converts to l l,l l-D2-linoleic acid or 13,13-D2- arachidonic acid.
  • a portion of 11,1 l-D2-linoleic acid absorbed is enzymatically converted to 13,13-D2-arachidonic acid.
  • 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.
  • the term “cohort” refers to a group of at least 5 patients whose results are to be averaged.
  • 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).
  • 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).
  • 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, ox
  • the compound when it 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).
  • 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
  • excessive amounts of PUFAs 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.
  • 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.
  • 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).
  • 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.
  • ROS reactive oxygen species
  • 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.
  • 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).
  • ALSFRS-R 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.
  • the ALSFRS-R test has 12 components each of which is measured on a 0 (worst) to 4 (best) scale.
  • 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.
  • 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.
  • 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.
  • 11,1 l-D2-linoleic acid is known in the art and is commercially available.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the accelerated dosing regimen employs an ester of 11,11- D2-linoleic acid such as linoleic acid ethyl ester.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Example 1 Minimal Rate of Loss of Functionality for Patients in the Incipient Stage of ALS
  • Example 3 Comparison of the Rate of Loss between treated and untreated Patients during the Accelerated Stage of ALS
  • Example 2 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • a method to treat a patient characterized as having an accelerated stage of amyotrophic lateral sclerosis 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
  • Embodiment [15] 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.
  • 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.
  • 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:

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Abstract

L'invention concerne des méthodes thérapeutiques permettant de réduire le taux de perte de fonctionnalité chez des patients souffrant de sclérose latérale amyotrophique (SLA) pendant les stades accélérés de cette maladie.
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