WO2023158641A1 - Polythérapie synergique pour traiter des sla - Google Patents
Polythérapie synergique pour traiter des sla Download PDFInfo
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- WO2023158641A1 WO2023158641A1 PCT/US2023/013051 US2023013051W WO2023158641A1 WO 2023158641 A1 WO2023158641 A1 WO 2023158641A1 US 2023013051 W US2023013051 W US 2023013051W WO 2023158641 A1 WO2023158641 A1 WO 2023158641A1
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- WIPO (PCT)
- Prior art keywords
- arachidonic acid
- ester
- prodrug
- deuterated
- dose
- Prior art date
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Classifications
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- 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
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- 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
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- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
Definitions
- ALS amyotrophic lateral sclerosis
- the methods use a synergistic combination of 3 -methyl- l-phenyl-2- pyrazoline-5-one (commercially available under the name "edaravone” from Millipore Sigma, St. Louis, Missouri, USA and sold for the treatment of ALS) and a prodrug of deuterated arachidonic acid.
- edaravone 3 -methyl- l-phenyl-2- pyrazoline-5-one
- prodrug of deuterated arachidonic acid When used in combination, edaravone and the prodrug have been shown to significantly reduce the rate of disease progression.
- ALS is a debilitating and fatal neurodegenerative disease in humans which despite the best efforts of researchers remain 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 is a fatal, late-onset, progressive 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.
- LPO lipid peroxidation
- PUFAs polyunsaturated fatty acids
- ROS reactive oxygen species
- edaravone an antioxidant and free radical scavenger
- the progression of ALS can be attenuated by deuteration at one or more of the bis-allylic sites of arachidonic acid in neurons.
- the stability of the deuterium-carbon bond against such oxidative processes is significantly stronger (more stable) than that of the hydrogen-carbon bond including deuterated arachidonic acid comprising two deuteriums substituted at the 13-position (each hydrogen replaced with a deuterium).
- This means that the generation of oxidative species at the bis-allylic sites is reduced by the carbon-deuterium bonds, inhibiting lipid peroxidation.
- inhibition of this pathway leads to enhanced survival of the neurons and, as such, attenuates the progression of the disease.
- a synergistic combination of edaravone and a deuterated arachidonic acid or a prodrug thereof When so used, patients treated with such a combination exhibit substantial reductions in the rate of loss of functionality that exceeds that of either drug alone. Indeed, patients treated with both drugs evidenced minimal loss of functionality over the duration of treatment.
- a method for reducing the rate of disease progression in ALS in a patient comprises administering to the patient an effective amount of edaravone or a pharmaceutically acceptable salt thereof in combination with an effective amount of a deuterated arachidonic acid or a prodrug thereof.
- this combination reduces the rate of loss of functionality by more than the additive amount achieved by either drug alone.
- a method for reducing the rate of loss of functionality in an ALS patient being treated with an effective amount of a deuterated arachidonic acid or a prodrug thereof comprises further administering to said patient an effective amount of edaravone or a pharmaceutically acceptable salt thereof.
- this combination reduces the rate of loss of functionality by more than the additive amount achieved by either drug alone.
- a method for reducing the rate of loss of functionality in an ALS patient being treated with an effective amount of edaravone or a pharmaceutically acceptable salt thereof comprises further administering to said patient an effective amount of a deuterated arachidonic acid or a prodrug thereof.
- this combination reduces the rate of loss of functionality by more than the additive amount achieved by either drug alone.
- edaravone or a pharmaceutically acceptable salt thereof is administered in accordance with the product insert for Radicava® (edaravone) which insert is incorporated herein by reference in its entirety.
- the deuterated arachidonic acid or a prodrug thereof is administered using a dosing regimen that includes a loading dose and a maintenance dose as described herein.
- the prodrug of a deuterated arachidonic acid is 11,11-D2- linoleic acid or an ester thereof. In vivo, a portion of this prodrug is converted to the corresponding 13,13-D2-arachidonic acid which is the active agent in the motor neurons. Generally, it takes several weeks / months to achieve a therapeutic concentration of 13,13- D2-arachidonic acid in the motor neurons by use of this prodrug. However, the use of the loading dose followed by the maintenance dose allows for more uptake of 13,13-D2- arachidonic acid (D2-AA) in the motor neurons thereby reducing the time from start of therapy to sustained protection against LPO.
- D2-AA 13,13-D2- arachidonic acid
- the prodrug of the deuterated arachidonic acid is an ester of 7,7,10,10,13,13-D6-arachidonic acid which, in vivo, is converted to 7,7, 10, 10,13, 13-D6- arachidonic acid (D6-AA).
- D6-AA 7,7, 10, 10,13, 13-D6- arachidonic acid
- the prodrug when the prodrug is 11,1 l-D2-linoleic acid ethyl ester, it is administered daily at a dose of between about 5.5 and about 12 grams per day or between about 7 and about 12 grams per day, e.g. about 9 grams/day (e.g., 8.64 grams/day) during the loading phase and then at a dose of between 3 and 8 grams per day, e.g. about 5 grams/day (e.g., 4.80 grams/day) or about 6 grams/day (5.76 gram/day) during the maintenance phase provided that the maintenance dose is less than the loading dose.
- a dose of between about 5.5 and about 12 grams per day or between about 7 and about 12 grams per day e.g. about 9 grams/day (e.g., 8.64 grams/day) during the loading phase and then at a dose of between 3 and 8 grams per day, e.g. about 5 grams/day (e.g., 4.80 grams/day) or about 6 grams/day (5.76 gram
- edaravone is provided as a formulation sold under the name Radicava (R) by Mitsubishi Tanabe, Osaka, Japan.
- edaravone is provided in an orally deliverable form in a water composition as per US Patent No. 10,987,341 which is incorporated herein by reference in its entirety.
- edaravone is combined with a deuterated arachidonic acid ethyl ester prodrug.
- 11,1 l-D2-linoleic acid ethyl ester is an oil at room temperature
- edaravone is preferably added to the oil.
- the recommended dose for edaravone is 60 mg per administration and, accordingly, in one embodiment, this dose is combined with capsules of 11,1 l-D2-linoleic acid ethyl ester taken daily by the patient.
- edaravone is added to the oil phase of D2-LA ethyl ester.
- edaravone can be added to three pills comprising D2-LA ethyl ester and appropriately marked so that these pills are taken together.
- the capsules containing edaravone can be colored differently from those that do not.
- the 60 mg of edaravone can be divided equally in all 9 pills (i.e., about 6.6 mg per pill). In either case, the two drugs can be mixed together to form a combination that is suitable for oral delivery.
- the prodrug of a deuterated arachidonic acid is 7,7,10,10,13,13- D6-arachidonic acid ethyl ester. Because this compound does not require in vivo conversion as does D2-LA and because only about 10% of D2-LA is converted to D2-AA, the amount of D6-AA ethyl ester required for therapy is about 10% of D2-LA. Still further and as shown in the Examples, D6-AA is shown to be about twice as active than D2-AA albeit in an inflammation model. However, such is considered a good yardstick for the improved activity herein. Accordingly, the amount of D6-AA required for treatment is about 0.05 to about 2 gram per day.
- either 1, 2, or 3 capsules can be used to administer D6-AA.
- this dose of D6-AA can be administered in one setting with the 60 mg dose of edaravone being included in either 1,2, or 3 of the D6-AA capsules or equally divided in all capsules when such is used.
- composition comprising edaravone and a deuterated arachidonic acid or a prodrug thereof.
- This composition is designed for oral administration, intravenous administration, or administration by infusion.
- said deuterated arachidonic acid prodrug is 11,1 l-D2-linoleic acid or an ester thereof.
- said deuterated arachidonic acid prodrug is a 7,7,10,10,13,13- D6-arachidonic ester.
- said ester is an ethyl ester.
- the present disclosure provides a kit of parts comprising at least one daily dose of 2,4-dihydro-3H-pyrazol-3-one or a pharmaceutically acceptable salt thereof and at least one daily dose of a deuterated arachidonic acid or a prodrug thereof.
- said 7,7,10,10,13,13-D6-arachidonic acid or ester thereof is administered daily at a dose of about 0.05 to about 5 grams/day during the loading phase and then at a dose this is from about 30% to about 70% of the loading dose during the maintenance phase.
- said 7,7,10,10,13,13-D6-arachidonic acid or ester thereof is administered daily at a dose of about 0.5 to about 5 grams/day during the loading phase.
- said 2,4-dihydro-3H-pyrazol-3-one or a pharmaceutically acceptable salt thereof is administered as an infusion, an injectable composition, or an oral composition.
- said 2,4-dihydro-3H-pyrazol-3-one or a pharmaceutically acceptable salt thereof is administered as an injectable composition or an oral composition.
- said 2,4-dihydro-3H-pyrazol-3-one or a pharmaceutically acceptable salt thereof is administered as an oral composition in combination with deuterated arachidonic acid or a prodrug thereof.
- the methods described herein further comprises restricting the patient’s consumption of excessive dietary polyunsaturated fatty acids during administration of said deuterated arachidonic acid or a prodrug thereof.
- FIG. 1 provides a correlation between the natural course of ALS with the corresponding loss of functionality versus the loss of functionality for patients on edaravone after 6 months of treatment.
- ALS amyotrophic lateral sclerosis
- the methods use a synergistic combination of 2,4-dihydro-3H-pyrazol-3- one (commercially available under the trademark Radicava® and sold for the treatment of ALS) and a prodrug of the deuterated arachidonic acid.
- the term “about” when used before a numerical designation, e.g., temperature, time, amount, concentration, and such other, including a range, indicates approximations which may vary by ( + ) or ( - ) 15,% 10%, 5%, 1%, or any subrange or subvalue there between.
- 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 invention.
- edaravone refers to 3-methyl-l-phenyl-2-pyrazoline-5- one or a salt thereof which can be represented by the formula:
- deuterated arachidonic acid refers to arachidonic acid comprising replacement of at least both hydrogen atoms at the 13 -position with two deuterium atoms as well as pharmaceutically acceptable salts thereof.
- deuterated arachidonic acids include but are not limited to 13,13-D2- arachidonic acid, 10, 10-13,13 -D4-arachidonic acid, and 7,7,10,10,13,13-D6-arachidonic acid and salts thereof.
- such compounds can further comprise modest deuteration at the mono-allylic sites (i.edeem the 4-position and the 16-position) arising from catalytic synthesis of this deuterated compound as described in US Patent No. 10,730,821 which is incorporated herein by reference in its entirety.
- about 40 percent or less of theaggregate of hydrogen atoms at these mono-allylic positions are replaced by deuterium with a higher deuterium load typically found at the 16-position than at the 4- position.
- a prodrug as used relative to deuterated arachidonic acid (“drug”) refers to compounds which, in vivo, provide for this drug.
- the prodrug is an ester of a deuterated arachidonic acid.
- deuterated arachidonic acids include 13,13-D2-arachidonic acid, 10,10-13,13-04- arachidonic acid, and 7,7,10,10,13,13-D6-arachidonic acid.
- the prodrug can comprise 11,1 l-D2-linoleic acid or an ester thereof.
- the ester group is removed to provide for 11,1 l-D2-linoleic acid and a portion of that compound is enzymatically converted to 13,13-D2-arachidonic acid. The nonconverted portion of that compound is absorbed into the body and subsequently is used as a source of energy.
- the prodrug can comprise 8,8,11,1 l-D4-linoleic acid or an ester thereof.
- the ester group is removed to provide for 8,8,11,1 l-D4-linoleic acid and a portion of that compound is enzymatically converted to 10,10,13,13-D4-arachidonic acid.
- the non-converted portion of that compound is absorbed into the body and subsequently is used as a source of energy.
- 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 or arachidonic acid are formed by replacing the -OH group with an -OR group using methods well known in the art. 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)
- deuterated arachidonic acid ester refers to such deuterated arachidonic acids having 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 any and 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.
- the term “reduced rate of disease progression” means that the rate of disease progression is attenuated after initiation of treatment as compared to the patient’s natural history.
- the rate of reduction in disease progression using the methods described herein results in a percentage reduction of at least 35% lower or at least 50% lower at a time point, e.g., 3 months to 24 months, e.g., 6 months or 1 year, after initiation of therapy when compared to the natural history of the patient.
- ALSFRS-R Revised ALS Functional Rating Scale
- This 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.
- the reduction in the rate of disease progression is confirmed by a reduction in the downward slope in the ALSFRS-R (flattening the curve) of a patient’s relative functionality during therapy as compared to the downward slope found in the patient’s natural history.
- the differential between the downward slope measured prior to treatment and the slope measured after at least 90 days from initiation of treatment has a flattening level of at least about 30%. So, a change of 7.5 degrees (e.g., a downward slope of 25 degrees during the natural history that is reduced to a downward slope of 17.5 degrees provides for a 40% decrease in the slope).
- the reduction in downward slope evidence that the patient has a reduced rate of disease progression due to the therapy.
- the term “patient” refers to a human patient or a cohort of human patients suffering from a neurodegenerative disease treatable by administration of a deuterated arachidonic acid or a prodrug thereof.
- loading or primer amount refers to an amount of a deuterated linoleic acid or an ester thereof that is sufficient to provide for a reduced rate of disease progression within at least about 45 days after initiation of administration and preferably within about 30 days.
- 11,1 l-D2-linoleic acid or an ester thereof have been found to be well tolerated by patients with a wide therapeutic window.
- a loading dose When a loading dose is employed, it provides for more rapid onset to a steady state concentration of 13,13-D2- arachidonic acid of at least about 12% in red blood cells based on the total amount of arachidonic acid in said cells including the deuterated arachidonic acid, preferably, at least about 15%, and, more preferably, at least about 20%.
- Other deuterated arachidonic acid prodrugs are also well tolerated in vivo.
- the term “maintenance dose” refers to a dose of 11,1 l-D2-linoleic acid that is less than the primer dose and is sufficient to maintain a therapeutic concentration of 13,13-D2-arachidonic acid in the cell membrane of red blood cells and, hence, in the cell membrane of motor neurons, so as to retain a stable rate of disease progression.
- 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 from about 3 or 7 or more days, e.g., due to personal reasons, provided that the patient is otherwise at least 75 percent compliant.
- the term “cohort” refers to a group of at least 2 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 which retain the desired pharmacological activity and is not biologically undesirable (e.g., the salt is not unduly toxic, allergenic, or irritating, and is bioavailable).
- pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., alginate, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalene sulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid).
- inorganic acids such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid
- organic acids e.g., alginate, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, ox
- the compound When the compound has an acidic group, such as for example, a carboxylic acid group, it can form salts with metals, such as alkali and earth alkali metals (e.g., Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+ ), ammonia or organic amines (e.g., dicyclohexylamine, trimethylamine, trimethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e.g., arginine, lysine, and ornithine).
- metals such as alkali and earth alkali metals (e.g., Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+ ), ammonia or organic amines (e.g., dicyclohexylamine, trimethylamine, trimethylamine, pyridine, picoline, ethanolamine, diethanol
- excessive amounts of PUFAs refer to intake of total PUFAs (e.g., total amount of PUFAs consumed 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 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 (www.ncbi.nlm. nih.gov/pmc/articles/PMC3650500/).
- 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.
- the oxidative stress responsible for such peroxidation is due to an imbalance between routine production and detoxification of reactive oxygen species (“ROS”) that leads to an oxidative attack on the lipid membrane of cells.
- ROS reactive oxygen species
- the lipid membrane as well as the endoplasmic reticulum and mitochondria of motor neurons are highly enriched in arachidonic acid (a 20-carbon chain polyunsaturated fatty acid (“PUFA”) having 4 sites of cisunsaturation). Separating each of these 4 sites are 3 bis-allylic methylene groups. These 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.
- PUFA 20-carbon chain polyunsaturated fatty acid
- Oxidized arachidonic acids negatively affect the fluidity and permeability of cell membranes in motor neurons. In addition, they can lead to 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. 2008; 153:6-20).
- ALSFRS-R a standard test referred to as ALSFRS-R which determines the loss of physical functionality over time and this is used to measure disease progression.
- This test has 12 components each of which are measured on a 0 (worse) to 4 (best) scale. The ability of a drug to attenuate the rate of disease progression evidences its efficacy. Even a modest reduction in the rate of functionality loss is considered significant.
- Each of these documents discloses the in vivo conversion of a portion of 11,11-D2- linoleic acid to 13,13-D2-arachidonic acid which is then incorporated into the motor 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.
- the dosing regimen employed must address the patient's need for rapid onset of therapy especially given that loss of functionality is typically very quick and quite often well before the end stage of the disease which typically ranges from about 2 to 5 years after diagnosis.
- any therapy for treating such neurodegenerative diseases must provide meaningful therapy within a month or less after the start of therapy thereby retaining as much of the patient's functionality as possible and furthermore providing for substantial reductions in the rate of disease progression.
- 11,11 -D2-linoleic acid is known in the art and is commercially available.
- 11,1 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.
- Deuterated arachidonic acid esters are also known in the art as provided in US Patent Nos. 10,577,304 and 10,730,821 each of which is incorporated herein by reference in its entirety.
- a patient afflicted with ALS is treated with 11,1 l-D2-linoleic acid or an ester thereof which is a prodrug for 13,13-D2-arachidonic acid.
- the 11,1 l-D2-linoleic acid undergoes in vivo conversion to 13,13-D2- arachidonic acid.
- 11, 1 l-D2-linoleic acid or ester thereof is administered to the patient in sufficient amounts to generate a synergistic concentration in vivo when used in combination with edaravone.
- a synergistic concentration is at least 3% percent 13,13-D2-arachidonic acid in red blood cells or plasma based on the total concentration of arachidonic acid including any deuterated arachidonic acid.
- sufficient 11, 1 l-D2-linoleic acid or ester thereof is administered to the patient to achieve a steady state concentration of 13,13-D2-arachidonic acid in red blood cells or plasma of at least about 12%, preferably, at least about 15% and, more preferably, at least about 20% based on the total amount of arachidonic acid, including deuterated arachidonic acid, found therein.
- deuterated LA or ester thereof is administered to the patient in sufficient amounts to generate a concentration of deuterated AA in red blood cells of at least about 3%, preferably at least 6%, more preferably at least 10%, and most preferably at least 15%, based on the total amount of arachidonic acid, including deuterated arachidonic acid, found therein.
- concentrations the attending clinician can correlate that found concentration to a therapeutic concentration of deuterated AA in the neurons.
- the percentage of deuterated AA compared to total amount of arachidonic acid in red blood cells, including deuterated AA may be between about 0.5% and about 60%.
- the percentage of deuterated AA compared to total arachidonic acid in red blood cells may be between about 5% and about 50%, between about 10% and about 40%, between about 15% and about 30%, and between about 15% and about 25%.
- the dose of deuterated LA is modified (e.g. increased) if the percentage of deuterated AA compared to total amount of arachidonic acid in red blood cells, including deuterated AA, is less than a target amount, e.g., less than about 3%, less than about 6%, less than about 10%, less than about 15%, less than about 20%, less than about 30%, less than about 40%, less than about 50%, or less than about 60%.
- such administration comprises the use of a dosing regimen that includes two dosing components.
- the first dosing component comprises a primer dose of 11, 1 l-D2-linoleic acid or an ester thereof.
- the second dosing component comprises a maintenance dose of 11,1 l-D2-linoleic acid or an ester thereof, wherein the amount of 11,11- D2-linoleic acid or an ester thereof in said second dosing component is less than that in the first dosing component.
- the amount of 11,1 l-D2-linoleic acid or an ester thereof employed is designed to provide rapid onset of therapy. Such therapy is measured by a reduction in the disease progression of neurodegenerative diseases as described below.
- the primer dose takes into account the various complicating factors, such as the amount of PUFAs consumed by the patient in a given day, the in vivo rate of conversion of 11,1 l-D2-linoleic acid to 13,13-D2-arachidonic acid, as well as the general turnover rate of lipids (half-life) in the patient's neurons.
- the lipid components of neurons are not static but, rather, are exchanged over time and have a finite half-life in the body. In general, only a fraction of the lipid components in cells are replaced each day. In the case of neurons, these cells are rich in arachidonic acid. The turnover of arachidonic acid in these membranes occurs from a stable pool of lipids comprising arachidonic acid in the spinal fluid. In turn, this stable pool is replaced and replenished over time by arachidonic acid included in the newly consumed lipids by the patient as part of the patient’s diet as well as by biosynthesis of arachidonic acid from linoleic acid by the liver. In embodiments, the maintenance dose of the 11,11-D2- linoleic acid is titrated such that the amount converted to 13,13-D2-arachidonic acid is set to at least match the rate of secretion from the body.
- the rate of arachidonic acid synthesized in vivo is typically rate limited to the extent that there is a maximum amount of arachidonic acid that the liver can generate in a given day. In turn, only a fraction of the linoleic acid consumed is converted to arachidonic acid with a majority of the linoleic acid remaining unchanged. This limited rate of synthesis of arachidonic acid from linoleic acid results in a delay in such synthesis after administration of the deuterated linoleic acid as the amount of 13,13-D2-arachidonic acid concentration in red blood cells continues to increase after converting from the primer dose to the maintenance dose of the dosing regimen.
- the choice of a dosing of 11,1 l-D2-linoleic acid or an ester thereof as described herein addresses each of the above components and sets a dosing level that allows for the accumulation of a sufficient amount of 11,1 l-D2-linoleic acid in the body and, hence, the generation of therapeutic levels of 13,13-D2-arachidonic acid in the red blood cells.
- the data in the Examples establish that there is a meaningful reduction in the rate of disease progression.
- the loading dose of the dosing regimen described herein includes sufficient amounts of 11, 1 l-D2-linoleic acid or an ester thereof that are absorbed into the patient so as to maximize the in vivo conversion of 11,1 l-D2-linoleic acid 13,13-D2- arachidonic acid.
- the resulting 13,13-D2-arachidonic acid accumulates in the body until it reaches a therapeutic concentration in the patient.
- 13,13-D2-arachidonic acid is systemically absorbed into the cells of the body including neurons, wherein the rate at which such absorption occurs is based on the exchange rate or turnover rate of lipids in the cell membrane of these motor neurons.
- the loading dose comprises about 7 to about 12 grams of 11,11- D2-linoleic acid or ester thereof per day and preferably about 8.64 grams per day of 11,11- D2-linoleic acid ethyl ester (administered 3 capsules, 3 times a day) and a maintenance dose that is less than that of the loading dose - for example, about 5.84 grams of 11,1 l-D2-linoleic acid (administered 3 capsules, 2 times a day or 2 capsules 3 times a day).
- daily or periodic dosing of 11,1 l-D2-linoleic acid or ester thereof in the primer dose ranges from about 5.5 to about 12 grams per day and includes about 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5 g, about 8 g, about 8.5 g, about 8.64 g, about 9 g, about 9.5 g, about 10 g, about 10.5 g, about 11 g, about 11.5 g, and about 12 g.
- daily or periodic dosing of 11,1 l-D2-linoleic acid or ester thereof in the primer dose ranges from about 5.5 to about 12 grams per day and includes about 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5 g, about 8 g, about 8.5 g, about 8.64 g, about 9 g, about 9.5 g, about 10 g, about 10.5 g, about 11 g, about 11.5 g, and about 12 g.
- a synergistic result using edaravone and 11,1 l-D2-linoleic acid or ester thereof can be achieved by using as little as about 1.5 grams to about 12 grams of 11,1 l-D2-linoleic acid or ester thereof.
- the goal of achieving a rapid onset to therapy is best achieved by using the loading dose and maintenance dose as described above.
- the primer or loading dose is continued for at least about 24 days or at least about 45 days, e.g., to rapidly achieve a therapeutic concentration of 11,11-D2- linoleic acid in vivo, thereby reducing the rate of disease progression.
- the maintenance dose is periodically administered.
- no more than about 70% of the primer dose of 11,1 l-D2-linoleic acid or an ester thereof per day is administered. Due to its safety profile, the primer or loading dose of D2-LA can be used throughout therapy at the option of the attending clinician.
- a deuterated arachidonic acid or ester thereof that is administered to the patient includes 7,7,10,10,13,13-D6-arachidonic acid or an ester thereof ("D6-AA”) as that term is defined herein. Because the three bis-allylic carbon atoms on these compounds have substantially all of the hydrogens replaced with deuterium, these compounds will provide superior reduction in the reducing or eliminating lipid autooxidation. As such, these compounds will provide a meaningful reduction in the rate of progression of ALS.
- the D-6 arachidonic acids or esters thereof are delivered in a tiered manner comprising a first and second dosing component.
- the first dosing component, the primer dose follows the protocol set forth above with the exception that the primer uses between about 0.05 to about 5 grams or about 0.5 and about 5 grams of D6-AA or an ester thereof daily or periodically.
- the maintenance dose that is employed is less than the loading dose and is generally between about 30% and about 70% of the loading dose.
- the primer or loading dose is continued for at least about 24 days or at least about 45 days, e.g., to rapidly achieve a therapeutic concentration of 7,7,10,10,13,13-D6-arachidonic acid in vivo, thereby reducing the rate of disease progression.
- the maintenance dose is periodically administered.
- no more than about 70% of the primer dose of 7,7,10,10,13,13-D6-arachidonic acid or an ester thereof per day is administered. Due to its safety profile, the primer or loading dose of D6-AA can be used throughout therapy at the option of the attending clinician.
- D6-AA or ester thereof is administered to the patient in sufficient amounts to generate a concentration of D6-AA in red blood cells or plasma of at least about 3%, preferably at least 6%, more preferably at least 10%, and most preferably at least 15%, based on the total amount of arachidonic acid, including deuterated arachidonic acid, found therein.
- the attending clinician can correlate that found concentration to a therapeutic concentration of D6-AA in the neurons.
- the percentage of D6-AA compared to total amount of arachidonic acid in red blood cells or plasma, including deuterated AA may be between about 0.5% and about 60%.
- the percentage of D6-AA compared to total arachidonic acid in red blood cells or plasma may be between about 5% and about 50%, between about 10% and about 40%, between about 15% and about 30%, and between about 15% and about 25%.
- the dose of D6-AA is modified (e.g. increased) if the percentage of D6-AA compared to total amount of arachidonic acid in red blood cells, including deuterated AA, is less than a target amount, e.g., less than about 3%, less than about 6%, less than about 10%, less than about 15%, less than about 20%, less than about 30%, less than about 40%, less than about 50%, or less than about 60%.
- such administration comprises the use of a dosing regimen that includes two dosing components.
- the first dosing component comprises a primer dose of D6- AA or an ester thereof.
- the second dosing component comprises a maintenance dose of D6- AA or an ester thereof, wherein the amount of D6-AA or an ester thereof in said second dosing component is less than that in the first dosing component.
- the amount of D6-AA or an ester thereof employed is designed to provide rapid onset of therapy. Such therapy is measured by a reduction in the disease progression of neurodegenerative diseases as described below.
- the primer dose takes into account the various complicating factors, such as the amount of PUFAs consumed by the patient in a given day, as well as the general turnover rate of lipids (half-life) in the patient’s neurons.
- the lipid components of neurons are not static but, rather, are exchanged over time and have a finite half-life in the body. In general, only a fraction of the lipids components in the lipids are replaced each day. In the case of neurons, these cells are rich in arachidonic acid. The turnover of arachidonic acid in these membranes occurs from a stable pool of lipids comprising arachidonic acid in the spinal fluid. In turn, this stable pool is replaced and replenished over time by arachidonic acid included in the newly consumed lipids by the patient as part of the patient’s diet as well as by biosynthesis of arachidonic acid from linoleic acid by the liver. In embodiments, the maintenance dose of the D6-AA or ester thereof is titrated such that the amount of D6-AA ester administered matches the rate of secretion of D6-AA from the body.
- the methods described herein are also based, in part, on the discovery that when the lipid membrane of neurons is stabilized against LPO, there is a substantial reduction in the progression of the neurodegenerative disease. This is believed to be due to the replacement of hydrogen atoms with deuterium atoms in arachidonic acid, rendering the deuterated arachidonic acid significantly more stable to ROS than arachidonic acid with only hydrogen atoms. As above, this stability manifests itself in reducing the cascade of lipid auto-oxidation and, hence, limiting the rate of disease progression.
- the methods described herein address this challenge by employing a dosing regimen which delivers D6-AA in amounts sufficient to provide for a therapeutic concentration of deuterated arachidonic acid in the neurons.
- the deuterated arachidonic acid reduces the degree of LPO which, in turn, effectively limits progression of ALS provided it is administered in appropriate amounts.
- a patient afflicted with ALS is treated with a D6-AA ester which is a prodrug of D6-AA.
- D6-AA including a pharmaceutically acceptable salt thereof, can be administered directly to the patient as the active drug thereof.
- the D6-AA ester is converted to D6-AA. In either case, this D6-arachidonic acid is readily absorbed by the body.
- Edaravone is commercially available from Millipore Sigma, Inc. and the methods for administering this drug are found on the product insert which is incorporated herein by reference.
- edaravone is administered as an infusion such as described in product insert for Radicava®, available from Mitsubishi Tanabe, Osaka, Japan.
- edaravone is administered intravenously in the manner described at https://medlineplus.gov/druginfo/meds/a617027.html which is incorporated herein by reference in its entirety.
- an oral dose of edaravone can be administered as described in US Patent No. 10,987,341 which is incorporated herein by reference in its entirety.
- edaravone can be formulated into a lipid based nanosystem as described by Parikh, et al., Drug Del., 24(l):962-978 (2017).
- the methods of this invention employ a synergistic combination of edaravone with a deuterated arachidonic acid or ester thereof or a prodrug thereof to significantly reduce the rate of decline in a patient suffering from ALS as compared to the use of each drug alone.
- Edaravone may be administered concurrently with the deuterated arachidonic acid or prodrug or ester thereof, prior to deuterated arachidonic acid or prodrug or ester thereof, or after deuterated arachidonic acid or prodrug or ester thereof.
- the deuterated arachidonic acid or prodrug or ester thereof may be administered in the same formulation as edaravone, or the drugs may be administered in different formulations.
- deuterated arachidonic acid or prodrug or ester thereof may be administered periodically, e.g. daily, every other day, etc.
- the current recommended dosage of edaravone is 60 mg administered as an intravenous infusion (30 mg/100 mL) over 60 minutes.
- Edaravone may also be administered orally, for example between 50 mg/day and 150 mg/day, e.g. 60 mg/day or 105 mg/day.
- edaravone is administered in an initial treatment cycle of daily dosing for 14 days followed by a 14-day drug-free period.
- edaravone is administered in subsequent treatment cycles: daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods.
- a method for reducing the rate of loss of functionality in a patient afflicted with ALS and undergoing treatment with edaravone which method comprises further treating said patient with an effective amount of a deuterated arachidonic acid or a prodrug thereof. When so administered, this combination reduces the rate of loss of functionality by more than the additive amount achieved by either drug alone.
- the form of administration of edaravone is not critical and any form that provides the desired therapy can be used. Such includes infusion administration, intravenous administration, oral delivery, transdermal delivery, intrapulmonary delivery, and the like.
- the deuterated arachidonic acid or ester thereof or a prodrug thereof having deuteration at the 13 -position is administered as a D2-LA or an ester thereof.
- a portion of D2-LA is bioconverted to D2-AA thereby providing the active deuterated D2-AA to the patient.
- D2-LA ethyl ester is administered in a tiered dosing schedule comprising a loading dose followed by a maintenance dose.
- the loading dose comprises from about 7 to about 12 grams per day of D2-LA which is orally delivered.
- the maintenance dose is less than the loading dose and is also orally delivered.
- the maintenance dose is no more than about 65% of the loading dose and preferably from about 30% to about 65% of the loading dose.
- the loading dose is continued for a period of time sufficient to achieve a steady state concentration of D2-AA in vivo which is typically at least about 30 day, or 45 days, or about 60 days from the start of therapy based on the attending clinician’s evaluation.
- the amount of D2-LA or an ester thereof that is administered to the patient can be reduced to reflect the synergy achieved with the combination described herein.
- dosing at levels of about 3 grams per day or 5 grams per day nevertheless evidence synergy when combined with edaravone.
- D6-AA such can be administered an ester prodrug or as D6-arachidonic acid or a pharmaceutically acceptable salt thereof.
- the drug is administered orally as described above. Again, periodic blood tests can be done to assess proper absorption of the drug. As above, a tiered dosing regimen is preferred. However, while not preferred, dosing at consistent amounts of the drug or prodrug can be used such as 0.6 grams per day.
- a method for reducing the rate of loss of functionality in a patient afflicted with ALS and undergoing treatment with an effective amount of a deuterated arachidonic acid or a prodrug thereof wherein said method comprises administering to said patient an effective amount of edaravone.
- this combination reduces the rate of loss of functionality by more than the additive amount achieved by either drug alone.
- the methods for administration described above can be used.
- the edaravone and the deuterated arachidonic acid or a prodrug thereof can be combined into a formulation for administration to the patient for uptake of the drugs systemically.
- D2-LA ethyl ester and D6-AA ethyl ester are both oils which can be used as a carrier for edaravone.
- edaravone can be added to either of such oils and then the combination can be encapsulated into capsules or administered as an oil.
- the combination can further comprise a sweetener, a stabilizer, a colorant, and the like.
- edaravone (as a free base) is added to D2-LA or D2-AA in an effective amount.
- the combination is agitated as necessary to provide for a homogenous oil solution. If necessary, especially for D2-AA, a small amount of a co-solvent such as AA can be intermixed to ensure homogenous solution.
- compositions suitable for administration to a patient which composition comprises D2-LA ester or D6-AA ester wherein the composition further comprises an effective amount of edaravone.
- a composition obviates the need to provide two separate drugs administered sequentially.
- ALSFRS-R ALS Functional Rating Scale-revised
- the rate of functional decline is predicated on measuring an individual’s, or a cohort’s progression for the natural history of disease prior to treatment.
- the individual or cohort average for the functional decline is determined at a period of time such as at 3, 6 or 12 months after initiation of therapy.
- the rate of decline based on the natural history of the cohort is set as the denominator.
- the numerator is set as the delta between the rate of the natural history of disease progression and the rate of functional decline after a set period of treatment per this invention.
- the resulting fraction is the multiplied by 100 to give a percent change. The following exemplifies this analysis.
- Cohort A has an average natural history rate of decline in functionality of 28 annualized for a one (1) year period. Six (6) months after initiation of treatment per this invention, Cohort A an annualized average rate of decline in functionality has dropped to 14. This provides a delta of 14 degrees. So, using 14 as the numerator and 28 as the denominator and then multiplying result by 100, one obtains a reduction in the annualized rate of decline of 50 percent.
- the methods of this invention provide for an average percent change in reduction in functionality for a cohort of at least 30% and, more preferably, at least about 35%, or at least about 40%, or at least about 45%, or at least about 50%, or at least about 55%, or at least about 60%.
- the change in reduction of functionality is measured over a time period, for example, 3 months to 24 months, e.gNeill at 3 months, at 6 months, or annually.
- the rate of decline can be measured over any time period intermediate between 3 months and 1 year.
- kits of parts For example, edaravone either as an injectable or as an infusion is designed to be administered one a day for 10 days followed by 18 days without administration.
- the kit of parts comprises a first set of edaravone capsules and a second set of capsules for the deuterated arachidonic acid or a prodrug thereof.
- the second set will contain a plurality of capsules for administration each day.
- the kit of parts can contain a first row containing 60 mg dose of edaravone in one capsule or two capsules containing 30 mg each.
- a second row could contain 9 capsules of D2-LA ester each containing 1/9 the daily dose.
- These capsules could be split into 3 groups of three capsules where each group is separated from the next group so as to define three separate dosing’s - morning, noon and evening.
- the edaravone capsule is colored to differentiate from the D2-LA ester capsules. For example, the edaravone capsule can be colored red and the D2-LA ester capsules colored green.
- the kit of parts may contain only a single day of dosing or multiple days of dosing per container or multiple days of dosing per container. Each of these containers could be labeled to indicate that the dosing contained therein is to be taken prior to any dosing of the D2-LA ester alone ("First Contained s)").
- the maximum number of doses for the combination in a single container is no more than 10 days for any given 28-day dosing period. This will prevent continued dosing of edaravone past the 10-day dosing period. It is understood that when the maintenance dose of D2-LA ester is used, the number of capsules required for administration could be reduced or not. In the case where the number of capsules is not reduced, then either the capsule size can be reduced, or a pharmaceutically acceptable excipient can be added to the capsules.
- the kit of parts could contain a further container or additional containers ("Second Container(s)") each of which contains a single day dosing amount of the D2-LA ester or multiple days of dosing.
- the Second Container(s) would include the remaining doses for the rest of the 28-day dosing period.
- the Second Containers are labeled to indicate that these containers are not to be used until after the doses in the First Container(s) have been taken.
- the dosing of D2-LA ester in the Second Container can be arranged as in the First Container and colored the same.
- the amount of drug required for therapy is contemplated to be less than that of D2-LA ester as described above. Accordingly, in this embodiment, the kit of parts will be substantially similarly to that described above but for the fact that there will be fewer capsules for the D6-AA ester than for the D2-LA ester.
- capsules could contain a combination of edaravone either mixed or solubilized into the deuterated arachidonic acid or a prodrug thereof.
- the kit of parts would comprise a container a first set of capsules wherein the daily dose of edaravone is included in the capsules containing D2-LA ester ("First Set of Capsules").
- this First Set of Capsules would have the dosing of edaravone in a single capsule or partitioned into the number of capsules required for D2-LA ester.
- the dose of D2-LA requires 9 separate capsules, then the entire dose of edaravone could be partitioned into 1 capsule, 3 capsules, 6 capsules, or 9 capsules. Any subset of capsules containing edaravone would need to be appropriately colored to distinguish from those capsules that do not. As above, the maximum number of doses in such a container would be ten in order to meet the dosing requirements now in place for edaravone.
- the First Set of Capsules for each day during the 10-day period could be provided in a single daily container, a multiple day container (e.g., 5 days) or a single container for all 10 days. It is understood that when the maintenance dose of D2-LA ester is employed, the number of capsules
- the kit of parts could contain a further container or additional containers for the capsules to be used from day 11 to day 28 of the treatment plan ("Second Set of Capsules").
- the daily dose of the Second Set of Capsules could be included in a single day container or a multiple day container.
- the container(s) for the Second Set of Capsules is labeled to indicate that this container or containers is/are not to be used until after doses provided by the First Set of Capsules have been taken.
- the dosing of D2-LA ester in these containers can be arranged in the same format as described above (3 x 3). As above, when the maintenance dose is to be used, the number of capsules can be reduced or retained the same using less active per capsule.
- the amount of drug required for therapy is contemplated to be less than that of D2-LA ester as described above. Accordingly, in this embodiment, the kit of parts will be substantially similarly to that described above but for the fact that there will be fewer capsules for the D6-AA ester than for the D2-LA ester.
- the kit of parts can contain both a single day dose of the D2-LA ester or the D6-AA ester as described above as well as a syringe containing the injectable edaravone composition or multiple daily doses.
- the kit of parts can contain a primary container or containers that hold multiple syringes up to a maximum of 10 and a corresponding number of daily doses of the D2-LA ester or the D6-AA ester.
- the primary container or containers limit the number of syringes to 10 and the capsules containing either ester can be arranged as previously described.
- a secondary container or containers can contain the remaining 18 days of capsules containing either ester to ensure a full 28-day pharmaceutical dosing regimen.
- the specifics for containers in each kit of parts embodiments can be varied provided that there is provided a specific dose of edaravone sufficient to meet the stated dosing regimen of 60 mg per day for 10 days and either a loading dose or a maintenance dose of the D2-LA ester or the D6-AA ester for all 28 days of the dosing regimen. It is contemplated that sufficient containers can be provided such that multiple 28 days of the dosing regimen can be shipped to a hospital, pharmacy, the attending clinician, the patient's care giver or the patient.
- the container used is not critical and can include blister packs for capsules, closed boxes comprising paper, plastic, or metal, one or more bottles, and the like.
- the container should be appropriately labeled and/or contain such a label to ensure that the care giver or patient is instructed to the proper administration of both drugs.
- This example reports the results of an expanded access program treating 17 patients with ALS with D2-LA. Of these 7 patients, 3 patients were also treated both before and during therapy with D2-LA with edaravone and 4 patients were treated only with D2-LA during the treatment protocol. While the current dosing regimen employs a loading dose of about 8.64 grams/day of D2-LA for about 1 month followed by a maintenance dose of about 4.80 grams/day or about 5.76 gram/day of D2-LA during the maintenance phase, the patients in this study were all treated with a daily dose of 2.88 gram/day LA for two weeks followed by a dose of 5.76 grams/day of D2-LA for the remainder of the study.
- ALSFRS-R scores between just before start of therapy were then compared between the two groups based on the scores adjusted to 6 months of therapy.
- Table 1 below provides the average results in the ALSFRS-R scores after 6 months of treatment for patients treated with D2-AA alone (12 patients) as well as for patient treated with D2-AA plus Radicava® (5 patients).
- FIG. 1 provides data from the manufacturer of edaravone (Mitsubishi Tanabe). That data states that over a 6-month period, edaravone provides a 2.49 score benefit over control.
- the minimum synergistic results would be those that assume that pre-treatment did not reach 6 months before the start of D2-LA administration.
- a portion of the benefit of edaravone treatment would need to be accounted for in the reported numbers for the natural history.
- This example assesses the relative reduction in LPO in an inflammation model to provide for an assessment of the relative activity of D2-AA (obtained by bioconversion of D2-LA) as compared to D6-AA.
- 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 versus D2-AA (achieved by administration of D2-LA) versus D6-AA in the lungs of mice.
- four groups of mice were used. The first group was control mice treated with H-LA control mice. The second group of mice received a 6-week course of D2-LA.
- D6-AA provides at least 2x the benefit than that of D2- AA in this inflammation model.
- Such data is used as a basis to estimate the protection against LPO accorded by D6-AA as compared to D2-AA.
- the amount of D6-AA required to achieve a similar result to D2-LA can be projected to be one-tenth of 8.64 grams/day (due to obviating the need for bioconversion) x 0.5 (accounting for about twice the activity of D6-AA versus D2-AA) or 0.43 grams per day.
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Abstract
Des méthodes d'inhibition de la progression de la sclérose latérale amyotrophique (SLA) chez l'homme sont divulguées. Les méthodes utilisent une combinaison synergique de 2,4-dihydro-3 H-pyrazol-3-one et d'acide arachidonique deutéré ou d'un promédicament de celui-ci, tel que l'acide 11,11-D2-linoléique ou un ester de celui-ci.
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US202263310541P | 2022-02-15 | 2022-02-15 | |
US202263310544P | 2022-02-15 | 2022-02-15 | |
US63/310,541 | 2022-02-15 | ||
US63/310,544 | 2022-02-15 | ||
US202263313190P | 2022-02-23 | 2022-02-23 | |
US63/313,190 | 2022-02-23 | ||
US17/684,279 | 2022-03-01 | ||
US17/684,279 US20220249442A1 (en) | 2021-02-05 | 2022-03-01 | Synergistic combination therapy for treating als |
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20180318261A1 (en) * | 2015-06-10 | 2018-11-08 | Jiangsu Simcere Pharmaceutical Co., Ltd | Use of composition for preparing a medicament for treatment of amyotrophic lateral sclerosis |
US20190282529A1 (en) * | 2016-11-17 | 2019-09-19 | Retrotope, Inc. | Isotopically modified components and therapeutic uses thereof |
US20210069144A1 (en) * | 2018-04-04 | 2021-03-11 | Retrotope, Inc. | Isotopically modified composition and therapeutic uses thereof |
US20210186990A1 (en) * | 2019-12-16 | 2021-06-24 | Amylyx Pharmaceuticals, Inc. | Methods and compositions for treating various disorders |
US20220009950A1 (en) * | 2018-11-15 | 2022-01-13 | Retrotope, Inc. | Deuterated compounds, compositions, and methods of use |
WO2022170134A2 (fr) * | 2021-02-05 | 2022-08-11 | Retrotope, Inc. | Protocoles de dosage pour l'administration d'acide arachidonique deutéré ou d'un promédicament de celui-ci |
WO2023023397A1 (fr) * | 2021-08-20 | 2023-02-23 | Retrotope, Inc | Méthodes d'inhibition de la progression de maladies neurodégénératives |
-
2023
- 2023-02-14 WO PCT/US2023/013051 patent/WO2023158641A1/fr unknown
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20180318261A1 (en) * | 2015-06-10 | 2018-11-08 | Jiangsu Simcere Pharmaceutical Co., Ltd | Use of composition for preparing a medicament for treatment of amyotrophic lateral sclerosis |
US20190282529A1 (en) * | 2016-11-17 | 2019-09-19 | Retrotope, Inc. | Isotopically modified components and therapeutic uses thereof |
US20210069144A1 (en) * | 2018-04-04 | 2021-03-11 | Retrotope, Inc. | Isotopically modified composition and therapeutic uses thereof |
US20220009950A1 (en) * | 2018-11-15 | 2022-01-13 | Retrotope, Inc. | Deuterated compounds, compositions, and methods of use |
US20210186990A1 (en) * | 2019-12-16 | 2021-06-24 | Amylyx Pharmaceuticals, Inc. | Methods and compositions for treating various disorders |
WO2022170134A2 (fr) * | 2021-02-05 | 2022-08-11 | Retrotope, Inc. | Protocoles de dosage pour l'administration d'acide arachidonique deutéré ou d'un promédicament de celui-ci |
WO2023023397A1 (fr) * | 2021-08-20 | 2023-02-23 | Retrotope, Inc | Méthodes d'inhibition de la progression de maladies neurodégénératives |
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