[go: up one dir, main page]

WO2025160116A1 - Méthodes de traitement de la sclérose latérale amyotrophique par administration orale de fasudil - Google Patents

Méthodes de traitement de la sclérose latérale amyotrophique par administration orale de fasudil

Info

Publication number
WO2025160116A1
WO2025160116A1 PCT/US2025/012513 US2025012513W WO2025160116A1 WO 2025160116 A1 WO2025160116 A1 WO 2025160116A1 US 2025012513 W US2025012513 W US 2025012513W WO 2025160116 A1 WO2025160116 A1 WO 2025160116A1
Authority
WO
WIPO (PCT)
Prior art keywords
als
fasudil
patient
treatment
day
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/012513
Other languages
English (en)
Inventor
Thomas Macallister
Sven Jacobson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Woolsey Pharmaceuticals Inc
Original Assignee
Woolsey Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Woolsey Pharmaceuticals Inc filed Critical Woolsey Pharmaceuticals Inc
Publication of WO2025160116A1 publication Critical patent/WO2025160116A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep

Definitions

  • ALS Amyotrophic Lateral Sclerosis
  • Lou Gehrig Lou Gehrig
  • ALS is a fatal neurodegenerative disease that affects motor neurons, resulting in a progressive loss of control of voluntary movements. It is associated with degeneration of upper motor neurons and their corticospinal axonal tracts (lateral sclerosis) and associated with the loss of lower motor neurons and their axons, which leads to muscle wasting (amyotrophy) and paralysis of voluntary muscles (Mitsumoto et al., 1998).
  • Upper motor neurons originate in the motor region of the cerebral cortex or brain stem and move motor information underneath motor neurons that are directly responsible for stimulation of the target muscle. Their dysfunction causes stiffness due to continuous muscle contraction that interferes with walking, movement and speech.
  • Lower motor neurons connect the brainstem and spinal cord to muscle fibers. Their dysfunction causes muscle atrophy, spasms small, local, involuntary muscle contraction. Many individuals with ALS die from respiratory failure within 48 months from the onset of symptoms and most within 3 to 5 years from onset.
  • ALS is thought to be caused by a combination of genetic factors, environmental factors, and aging-related dysfunction, similar to other neurodegenerative conditions. Apart from genetic factors, age and male sex increase the risk for ALS.
  • environmental risk factors for ALS such as smoking, body mass index, physical exercise, occupational and environmental exposures to metals, pesticides, 0- methylamino-L-alanine, head injury, and viral infections.
  • the causal relationship of these factors with ALS remains to be established (Masrori 2020).
  • ALS is also associated with protein inclusions in motor neurons and the CNS.
  • TDP-43 abnormal accumulation TAR DNA-binding protein 43
  • TDP-43 is the primary misfolded, mis-localized, ubiquitinated protein composing the major form of neuropathological aggregates in motor neurons in ALS.
  • TDP-43 is a DNA/RNA binding protein that regulates RNA splicing and stability and microRNA. TDP-43 normally localizes to the nucleus where it functions in transcription, but misfolded TDP-43 aggregates in the cytosol, leading to a nuclear loss-of-function that might cause transcription deficits.
  • TDP-43 mutations along with mutations in a gene with similar function (FUS) are also associated with ALS.
  • Rho Kinase (ROCK) Inhibitors ALS There are a number of publications addressing the use of rho kinase inhibitors in various animal models of neurodegeneration, including ALS. (Tonges 2013). Most models are deficient in that they fail to reproduce the ALS (or other neurodegenerative disease) phenotype or are pertinent only to familial ALS which is only 5-10% of ALS patients. As one example, U.S. 9,980,972 describes using fasudil in the SOD1 G93 mouse model, which harbors a mutation in the superoxide dismutase (SOD) protein.
  • SOD superoxide dismutase
  • a specific problem with using fasudil in rodents is that the metabolism fasudil and its active metabolite hydroxyfasudil (M3) is not at all reflective of humans. While both compounds are similar in terms of the rho kinase inhibitory activity, they do not have the same profile with respect to inhibiting other kinases and cannot be expected to be equivalent in their distribution throughout the body. Illustrating this point is the fact that there is a pronounced gender effect following oral fasudil administration in drinking water. Female rats exhibit a much higher fasudil bioavailability compared to the active metabolite hydroxyfasudil (M3).
  • fasudil In female rats 61% of the circulating drug is fasudil, while in males, only 11% is fasudil, with the remainder being converted to M3. Male rats have nearly 7-fold more M3 than female rats, and more total combined M3 and fasudil than female rats. (Liu 2020). Moreover, the overall bioavailability' of fasudil plus M3 in female rats orally administered fasudil is about 25% of that of male rats.
  • Takata 2013 described experiments similar to Tonges 2013, but used male SOD mice, and observed that both the 30 mg/kg and 100 mg/kg doses of fasudil delayed symptom onset (motor performance, motor neuron loss) and prolonged survival time.
  • Gunther 2017 treated both male and female SOD mice with fasudil at 30 mg/kg and 100 mg/kg beginning at disease onset and observed that fasudil significantly improved motor behavior with both doses in male mince but not in female mice.
  • Fasudil was administered intravenously to three (3) human ALS patients on a compassionate use basis (Koch et al. 2020). One patient had familial ALS and the two other patients had probable ALS. Patients were dosed with 30 mg of intravenously administered fasudil twice daily over 20 consecutive working days (not weekends). There were no conclusive results beyond safety. Currently, there are clinical trials in progress in Germany, Switzerland and France for infusion of fasudil according to the same intravenous administration and dosing schedule. (Lingor et al., 2019). The trial is designed to treat three parallel groups: fasudil 15 mg twice daily, fasudil 30 mg twice daily, and matching placebo. No updates on this trial were available in September 2022 except for a publication detailing the unanticipated legal, administrative and financial complexities of a multi-national trial to which U.S. -based trials were proposed added but were not. (Lingor 2021).
  • HED Human equivalent dose
  • the disclosed embodiments relate to the treatment of an ALS patient using fasudil.
  • the ALS patient has sporadic ALS.
  • the patient has classic ALS. In a specific embodiment, the patient has only lower motor neuron involvement. [0017] In another specific embodiment, the patient has only upper motor neuron involvement.
  • the patient has ALS with frontotemporal dementia (ALS- FTD).
  • ALS- FTD frontotemporal dementia
  • the ALS or ALS-FTD patient treated has a total score of 120 or lower on the EC AS.
  • the ALS or ALS-FTD patient treated has a total score of 105 or lower on the EGAS.
  • the ALS or ALS-FTD patient treated has a score of 77 or less on the ALS-specific portion of the ECAS.
  • the ALS or ALS-FTD patient treated has a score of 24 or less on the non- ALS-specific portion of the ECAS.
  • the ALS or ALS-FTD patient treated has a score of 26 or less on the language portion of the ECAS.
  • the ALS or ALS-FTD patient treated has a score of 14 or less on the verbal fluency portion of the ECAS.
  • the ALS or ALS-FTD patient treated has a score of 13 or less on the memory portion of the ECAS.
  • the ALS or ALS-FTD patient treated has a score of 10 or less on the visuospatial portion of the ECAS
  • the familial ALS patient treated has a mutation in the superoxide dismutase 1 (SOD1) gene.
  • SOD1 superoxide dismutase 1
  • fasudil is administered orally.
  • the fasudil is fasudil hydrochloride hemihydrate.
  • fasudil is administered to the patient three times daily for a total of 300 mg/patient/per day.
  • the ALS patient treated is genetically male.
  • the ALS patient treated is genetically female.
  • treatment of an ALS patient results in a greater-than fifty- percent reduced rate of decline on the revised ALS Functional Rating Scale (ALSFRS-R) as measured over six to twelve months.
  • ALSFRS-R revised ALS Functional Rating Scale
  • treatment of a sporadic ALS patient results in a stabilization of the revised ALSFRS-R for at least 6 months.
  • treatment of an ALS patient results in a reduction in the rate of decline of at least one of the twelve domains of the ALSFRS.
  • the patient who is treated with fasudil is experiencing a rate of decline prior to treatment of less than 1 point per month using the ALSFRS scale.
  • the patient who is treated with fasudil is experiencing a rate of decline prior to treatment of between about 0.5 and 0.1 points per month using the ALSFRS scale.
  • the patient who is treated with fasudil is experiencing a rate of decline prior to treatment of between about 0.2 and 0.5 point per month using the ALSFRS scale.
  • treatment of an ALS patient results in reduced muscle wasting and reduced paralysis of voluntary muscles.
  • Still other embodiments contemplate the treatment of an ALS patient with reduced slow vital capacity (SVC) as predicted by the patient’s gender, age and the patient does not present with bulbar symptoms.
  • SVC slow vital capacity
  • Certain embodiments involve the treatment of an ALS patient with an ALSFRS score of ⁇ 36.
  • treatment of the ALS patient with fasudil begins at least 24-months from disease onset.
  • fasudil treatment can alleviate sleep disturbances in ALS patients.
  • sleep disturbances are evaluated using the International Classification of Sleep Disorders-3 (ECSD-3).
  • fasudil treatment can alleviate sleep disturbances in ALS patients without Lyme Disease.
  • fasudil treatment can mitigate or alleviate weight loss or the rate of weight loss in ALS patients.
  • Some embodiments involve treating an ALS patient with fasudil hydrochloride, wherein the patient is also treated with riluzole and/or edaravone.
  • an ALS patient is treated with fasudil hydrochloride, wherein the patient is also treated with taurursodiol and sodium phenylbut rate.
  • the disclosed embodiments are based on the surprising discovery 7 that patients with sporadic and familial amyotrophic lateral sclerosis can readily tolerate daily doses of oral fasudil hydrocholoride exceeding 240 mg per day. Such treatment previously was thought to result in unacceptable reductions in kidney function.
  • the disclosed methods may include the administration of a rho kinase (ROCK) inhibitor in the treatment of a disease or condition.
  • ROCK rho kinase
  • Two mammalian ROCK homologs are known, ROCK1 (aka R0K
  • ROCK1 and ROCK2 are located on chromosome 18.
  • the two ROCK isoforms share 64% identity in their primary amino acid sequence, whereas the homology in the kinase domain is even higher (92%) (Jacobs 2006; Yamaguchi 2006).
  • Both ROCK isoforms are serine/threonine kinases and have a similar structure.
  • Isoquinoline derivatives are a preferred class of ROCK inhibitors.
  • the isoquinoline derivative fasudil was the first small molecule ROCK inhibitor developed by Asahi Chemical Industry (Tokyo, Japan).
  • the characteristic chemical structure of fasudil consists of an isoquinoline ring, connected via a sulphonyl group to a homopiperazine ring. Fasudil is a potent inhibitor of both ROCK isoforms.
  • fasudil In vivo, fasudil is subjected to hepatic metabolism to form its active metabolite hydroxy fasudil (aka, M3).
  • M3 active metabolite hydroxy fasudil
  • isoquinoline derived ROCK inhibitors include dimethylfasudil and ripasudil.
  • ROCK inhibitors are based on 4-aminopyridine structures. These were first developed by Yoshitomi Pharmaceutical (Uehata et al., 1997) and are exemplified by Y-27632. Still other preferred ROCK inhibitors may include indazole, pyrimidine, pyrrolopyridine, pyrazole, benzimidazole, benzothiazole, benzathiophene, benzamide, aminofurazane, quinazoline, and boron derivatives (Feng et al., 2015). Some exemplary ROCK inhibitors are shown below:
  • ROCK inhibitors may have more selective activity for either ROCK1 or ROCK2 and usually have vary ing levels of activity 7 on PKA, PKG, PKC, and MLCK. Some ROCK inhibitors may be highly specific for ROCK1 or ROCK2 and have much lower activity against PKA, PKG, PKC, and MLCK.
  • a particularly preferred ROCK inhibitor is fasudil.
  • Fasudil may exist as a free base or salt and may be in the form of a hydrate, such as a hemihydrate.
  • Fasudil is a selective inhibitor of protein kinases, such as ROCK, PKC and MLCK; and treatment with fasudil results in a potent relaxation of vascular smooth muscle, resulting in enhanced blood flow (Shibuya 2001).
  • a particularly important mediator of vasospasm, ROCK induces vasoconstriction by phosphorylating the myosin-binding subunit of myosin light chain (MLC) phosphatase, thus decreasing MLC phosphatase activity 7 and enhancing vascular smooth muscle contraction.
  • MLC myosin light chain
  • fasudil increases endothelial nitric oxide synthase (eNOS) expression by stabilizing eNOS mRNA, which contributes to an increase in the level of the potent vasodilator nitric oxide (NO), thereby enhancing vasodilation (Chen 2013).
  • eNOS endothelial nitric oxide synthase
  • Fasudil has a short half-life of about 25 minutes, but it is substantially converted in vivo to its 1 -hydroxy (M3) metabolite. M3 has similar effects to its fasudil parent molecule, with slightly enhanced activity and a half-life of about 8 hours (Shibuya 2001). Thus, M3 is likely responsible for the bulk of the in vivo pharmacological activity of the molecule. M3 exists as two tautomers, depicted below:
  • the ROCK inhibitors used in the disclosed embodiments include pharmaceutically acceptable salts and hydrates. Salts that may be formed via reaction with inorganic and organic acid.
  • Those inorganic and organic acids may include: hydrochloric acid, hydrobromide acid, hydriodic acid, sulphuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, maleic acid, maleic acid, oxalic acid, oxalic acid, tartaric acid, malic acid, mandelic acid, trifluoroacetic acid, pantothenic acid, methane sulfonic acid, or para-toluenesulfonic acid.
  • TDP-43 is an essential DNA/RNA binding protein that is primarily located in the nucleus and is ubiquitously expressed. Deletion of the TARDBP (TDP-43 -encoding gene) is lethal at the embryonic stage in mice.
  • TDP-43 is a primary component of ubiquitinated and hyper-phosphorylated cytosolic aggregates observed from post-mortem tissue of patients with ALS.
  • Abnormal TDP-43 exists in about 97% of ALS patients, primarily in the motor neurons of the cerebral cortex but also in spinal cord. Over 50 mutations in the TARDBP are known.
  • pathological TDP-43 in ALS is in a truncated form of either 25 or 35 kD. There is frequent mis-localization of TDP-43 from the nucleus to the cytoplasm in ALS, which could block cellular trafficking in the motor neurons.
  • ALS is also associated with mutations in genes encoding proteins involved in protein degradation and membrane degradation pathways, suggesting that an impairment of protein clearance is pathologic in ALS (and FTD). These include mutations in p62, valosin- containing protein (VCP), ubiquitin 2, and optineurin, which are all effectors of the autophagy and/or ubiquitin-proteasome system (UPS) protein degradation pathways. This suggestion is bolstered by the observations with C9orf72 insufficiency.
  • VCP valosin- containing protein
  • UPS ubiquitin-proteasome system
  • HRE hexanucleotide repeat expansions
  • HRE in C9orf72 result in aborted RNA transcripts which then sequester RNA-binding proteins involved in transcription and splicing resulting in protein/RNA aggregates in the nuclei of the motor and frontal cortex neurons, hippocampus, cerebellum, and spinal cord.
  • Mutations in genes associated with familial ALS include single gene mutations in genes selected from C9orf72, SOD1 , TARDBP, FUS and TANK-binding kinase 1 (TBK1).
  • the disclosed embodiments may exclude familial (inherited) ALS due to those gene mutations.
  • compositions of ROCK inhibitors are generally oral and may be in the form of tablets or capsules and may be immediate-release formulations or may be controlled- or extended-release formulations, which may contain pharmaceutically acceptable excipients, such as com starch, mannitol, povidone, magnesium stearate, talc, cellulose, methylcellulose, carboxymethylcellulose and similar substances.
  • a pharmaceutical composition comprising a ROCK inhibitor and/or a salt thereof may comprise one or more pharmaceutically acceptable excipients, which are known in the art.
  • Formulations include oral films, orally disintegrating tablets, effervescent tablets and granules or beads that can be sprinkled on food or mixed with liquid as a slurry or poured directly into the mouth to be washed down.
  • compositions containing ROCK inhibitors, salts and hydrates thereof can be prepared by any method known in the art of pharmaceutics.
  • preparatory methods include the steps of bringing a ROCK inhibitor or a pharmaceutically acceptable salt thereof into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.
  • Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition in the disclosed embodiments may vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition used in accordance with the methods of the disclosed embodiments may comprise between 0.001% and 100% (w/w) active ingredient.
  • compositions may include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils.
  • Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • the pharmaceutical composition may comprise a diluent.
  • diluents may include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • the pharmaceutical composition may comprise a granulating and/or dispersing agent.
  • exemplary granulating and/or dispersing agents may include potato starch, com starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cationexchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked polyvinylpyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (VEEGUM), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
  • VEEGUM magnesium aluminum silicate
  • the pharmaceutical composition may comprise a binding agent.
  • binding agents may include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly Vinylpyrrolidone).
  • VEEGUM. RTM magnesium aluminum silicate
  • larch arabogalactan alginates
  • polyethylene oxide polyethylene glycol
  • inorganic calcium salts silicic acid
  • poly methacrylates waxes, water, alcohol, and/or mixtures thereof.
  • the pharmaceutical composition may comprise a preservative.
  • exemplary preservatives may include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • the preservative may be an antioxidant.
  • the preservative may be a chelating agent.
  • the pharmaceutical composition may comprise an antioxidant.
  • antioxidants may include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxy toluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • the pharmaceutical composition may comprise a chelating agent.
  • chelating agents may include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate. dipotassium edetate. and the like), citric acid and salts and hydrates thereof (e g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • citric acid and salts and hydrates thereof e.g., citric acid monohydrate
  • fumaric acid and salts and hydrates thereof e.g., malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof,
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide. cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • the pharmaceutical composition may comprise a buffering agent together with the ROCK inhibitor or the salt thereof.
  • buffering agents may include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide
  • the pharmaceutical composition may comprise a lubricating agent.
  • lubricating agents may include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
  • the pharmaceutical composition of containing a ROCK inhibitor or salt thereof may be administered as a liquid dosage form.
  • Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, com. germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • conjugates of the disclosed pharmaceutical compositions are mixed with solubilizing agents such as CremophorTM, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
  • the active ingredient may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, poly vinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and g
  • compositions of the disclosed embodiments relate to extended- or controlled-release formulations. These may be, for example, diffusion-controlled products, dissolution-controlled products, erosion products, osmotic pump systems or ionic resin systems. Diffusion-controlled products may comprise a water-insoluble polymer which controls the flow of water and the subsequent egress of dissolved drug from the dosage from. Dissolution-controlled products may control the rate of dissolution of the drug by using a polymer that slowly solubilizes or by microencapsulation of the drug - using varying thicknesses to control release. Erosion products may control release of drug by the erosion rate of a carrier matrix.
  • Osmotic pump systems may release a drug based on the constant inflow of water across a semi permeable membrane into a reservoir which contains an osmotic agent.
  • Ion exchange resins can be used to bind drugs such that, when ingested, the release of drug is determined by the ionic environment within the gastrointestinal tract.
  • the disclosed embodiments relate to treating ALS with ROCK inhibitors, specifically fasudil.
  • ALS diagnosis is made using El Escorial diagnostic criteria (Brooks 1994) successively updated in Airlie House and Awaji-shima criteria (de Carvalho 2008) (Brooks 2011).
  • the Awaji criteria proposed two changes to the revised El Escorial. The first change was to use both electromyography and clinical data simultaneously to determine the presence of lower motor neuron (LMN) dysfunction. The second proposed change was to consider fasciculation potentials as evidence of ongoing denervation, equivalent in importance to fibrillation potentials.
  • ALS diagnosis requires: (1) the presence of evidence of LMN degeneration by clinical, electrophysiological or neuropathological examination. (2) presence of upper motor neuron (UMN) degeneration by clinical examination, (3) presence of progressive spread of symptoms or signs within a region or other regions, as determined by history, clinical examination or electrophysiological tests, and (4) absence of electrophysiological or pathological evidence of other disease processes that might explain the observed clinical and electrophysiological signs.
  • UPN upper motor neuron
  • Diagnostic categories include: definite ALS (clinical or electrophysiological evidence by the presence of LMN as well as UMN signs in the bulbar region and at least two spinal regions or the presence of LMN and UMN signs in three spinal regions), probable ALS (clinical or electrophysiological evidence by LMN and UMN signs in at least two regions with some UMN signs necessarily rostral to the LMN signs, and possible ALS (clinical or electrophysiological signs of UMN or LMN dysfunction in only one region or UMN signs alone in two or more regions or LMN rostral to UMN signs).
  • the disclosed embodiments relate to treating definite, probable and possible ALS.
  • Classification according to ALS phenotype is mainly based on the relative UMN versus LMN involvement and the regional distribution of involvement.
  • Electro-physiological testing includes without limitation electromyography (EMG). Ultrasound of the muscles can detect fasciculations that can aid in the diagnosis of ALS. In some instances, a muscle biopsy, which involves taking a small sample of muscle under local anesthesia, is performed.
  • EMG electromyography
  • Imaging of the brain and spinal cord by techniques including MRI is often used to rule out other diseases, but use of imaging to confirm ALS is less established due to the heterogeneity of ALS.
  • Various imaging techniques are reviewed in Turner et al. 2012. The most sensitive and specific techniques to diagnose the disease are diffusion-tensor MRI, MR spectroscopy, PET, a combination of several neuroimaging methods, and neuroimaging with transcranial magnetic stimulation. Diffusion-tensor MRI and MR spectroscopy can be used to monitor and predict the disease course. (Bakulin 2019).
  • ALS-FTSD frontotemporal spectrum disorder
  • Other symptoms of the motor neuron degeneration may be socially disabling and/or affect the patient’s quality of life include sialorrhoea (drooling, excessive salivation, thickened saliva), pseudobulbar emotional lability (pathological weeping, laughing, or yawning), cramps (especially at night), spasticity, depression and anxiety, insomnia (caused by depression, cramps, pain, and respiratory distress), constipation, and fatigue (of central and/or peripheral origin).
  • sialorrhoea dirooling, excessive salivation, thickened saliva
  • pseudobulbar emotional lability pathological weeping, laughing, or yawning
  • cramps especially at night
  • spasticity depression and anxiety
  • insomnia caused by depression, cramps, pain, and respiratory distress
  • constipation and fatigue (of central and/or peripheral origin).
  • Many patients report difficulties in effectively clearing bronchial secretions including tenacious sputum, and mucus accumulation is a negative prognostic factor.
  • Cognitive and behavioral changes are an intrinsic component of some forms of ALS. As mentioned above, 5-15% of patients with ALS also have frontotemporal dementia (FTD), and up to 50% of patients with ALS have cognitive or behavioral changes within the spectrum of FTD. Disease presentations with cognitive or behavioral changes that do not fulfil formal diagnostic criteria can be grouped into 1 of 3 categories: ALS with behavioral impairment; ALS with executive dysfunction; and ALS non-executive dysfunction. Apathy and loss of sympathy are the most common behavioral symptoms, while fluency, language, social cognition, and executive function are the cognitive domains that are most often affected (van Es 2017).
  • FTD frontotemporal dementia
  • Cognitive impairment in ALS patients or ALS/FTD patients can be measured using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS).
  • ECAS Edinburgh Cognitive and Behavioral ALS Screen
  • This screen includes an ALS-specific score that evaluates executive functions and social cognition; fluency; and language; and it includes an ALS Non-specific score that measures memory and visuospatial functions. It also has a screen that evaluates five domains of FTD. There is a maximum score of 136 and the cutoff for cognitive impairment is 105. There are subscores cut-offs for ALS-specific (77), non-ALS-specific (24), language (26). verbal fluency (14), executive function (33), memory, and visuospatial impairment (13).
  • Sleep disturbances may also be a quality -of-life issue for ALS patients.
  • Degeneration of motor neurons causes muscle cramps and fasciculations, especially in the lower limbs.
  • Sleep disordered breathing such as sleep-related hypoventilation and sleep apnea are particularly increased in ALS patients, especially males. This causes sleep fragmentation, non-restorative sleep, and daytime fatigue.
  • Sleep disturbances in ALS or ALS-FTD patients, and improvements with fasudil can be evaluated using e.g., the International Classification of Sleep Disorders (ICSD-3). (Sateia 2014).
  • the patient to be treated w ith oral fasudil may have sporadic ALS.
  • the ALS patient may have TDP-43-associated ALS.
  • the patient may have classical ALS. In another specific embodiment, the patient may have bulbar-onset ALS. [0102] In another embodiment, the patient to be treated with oral fasudil has familial
  • the ALS patient may not have another proteinopathy- associated neurodegenerative disease.
  • the ALS patient treated with oral fasudil may not have frontotemporal dementia (FTD).
  • the ALS patient may have ALS-FTSD or ALS-FTD.
  • the ALS patient treated with oral fasudil may be genetically male.
  • the ALS patient treated with oral fasudil may be between the ages of 40-75.
  • the sporadic ALS patient treated with oral fasudil may be between the ages of 50-65.
  • the ALS patient treated with oral fasudil may be between the ages of 20-39.
  • the ALS patient may be treated with oral fasudil hydrochloride hemihydrate.
  • a therapeutically effective amount of a ROCK inhibitor or a pharmaceutically acceptable salt thereof may be administered to an ALS patient one or more times a day.
  • the lowest therapeutically effective amount of fasudil for example, may be 90 mg per day, generally administered in 2 to 3 equal portions to obtain the full daily dose.
  • the highest therapeutically effective dose may be determined empirically as the highest dose that remains effective in alleviating one or more ALS symptoms but does not induce an unacceptable level of adverse events.
  • One preferred dosing regimen involves the treatment with 60 mg of fasudil hydrochloride hemihydrate three times per day using an oral immediate-release formulation, for a total daily dose of 180 mg. Other daily doses may range from 90 mg to 320 mg per day b.i.d.
  • a further dosing regimen may involve the treatment with 100 mg of fasudil hydrochloride hemihydrate three times per day using an immediate-release formulation, for a total daily dose of 300 mg.
  • fasudil hydrochloride may be administered once a day using an immediate-release formulation at 180 mg or 240 mg.
  • dosing may be extended up to about 480 mg per day. but generally may be limited to about 320 mg per day. Above 480 mg per day, kidney effects of the drug may be generally unacceptable. Based on ROCK inhibitory activity, one skilled in the art can readily extrapolate the provided dosing ranges for fasudil to other ROCK inhibitors.
  • Another embodiment involves treatment with 90-300 mg of fasudil hydrochloride hemihydrate once per day in an extended-release dosage form.
  • Treatment with an extended-release total daily dose of 240-300 mg fasudil hydrochloride hemihydrate may be preferred.
  • an extended-release dosage form may contain between 180 and 320 mg of fasudil hydrochloride hemihydrate.
  • the ALS patient may be treated according to the following dosing regimen:
  • the patient may be treated for at least 5 days during the first and /or second treatment phases.
  • the first and second off- treatment periods may each be between one month and six months.
  • the duration of the first and second treatment phases may each be one month and the duration of the first and second off-treatment phases may each be one month.
  • This regimen can be repeated at least once, up to the duration of the patient’s life.
  • compositions according to the disclosed embodiments may generally be continued for at least one day. Some preferred methods maytreat for up to 30 days or up to 60 days or even up to 90 days or even more. Treatment for more than 60 days is preferred and treatment for at least 6 months is particularly preferred. The precise duration of treatment may depend on the patient's condition and response to treatment. Most preferred methods contemplate that treatment begins after the onset or appearance of symptoms.
  • dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • fasudil may be administered in combination with a second therapeutic agent that treats ALS or symptoms thereof.
  • the second therapeutic agent may be selected from riluzole, edaravone, tetrabenazine, masitinib, tofersen, ravuhzumab — wevz, mesenchymal stem cell (MSC)-neurotrophic factor (NTF) cells, AMX0035 (phenylbutyrate and taurursodiol), talampanel, tamoxifen, methylcobalamine, Aeol 10150.
  • the ALS patient may be administered fasudil in combination with riluzole or edavarone at about 50 to 100 mg a day.
  • riluzole may be administered 50 mg twice daily.
  • Other agents can be co-administered to treat symptoms of ALS or associated comorbidities, including respiratory disfunction, eating disorders, depression and anxiety, pain, dysarthria, dysphagia, sialorrhoea, insomnia, undesirable behavior or mood, and constipation.
  • such agents may include antidepressants, benzodiazepines, amiltriptyline, dextromethorphan hydrobromide/ quinidine sulfate, anti-inflammatories, muscle relaxants (e.g., baclofen, botulinum toxin), anticonvulsants (e.g., gabapentin, sodium valproate), anti-cholinergic drugs (e.g., glycopyrronium bromide), atorvastatin.
  • antidepressants e.g., benzodiazepines, amiltriptyline, dextromethorphan hydrobromide/ quinidine sulfate
  • anti-inflammatories e.g., muscle relaxants (e.g., baclofen, botulinum toxin), anticonvulsants (e.g., gabapentin, sodium valproate), anti-cholinergic drugs (e.g., glycopyrronium bromide), atorvastatin.
  • lithium carbonate lithium carbonate
  • avanier 07-ACR-123 Zenvia®
  • SB-509 thalidomide
  • arimoclomol olanzapine
  • memantine tamoxifen
  • pioglitazone creatine monohydrate
  • botulinum toxin type B botulinum toxin type B
  • dronabinol coenzyme Q10
  • escital opram Lindelapro®
  • sodium phenylbutyrate sodium phenylbutyrate
  • R(+) pramipexole dihydrochloride monohydrate sodium valproate
  • cyclosporin corticosteroids
  • modafinil modafinil
  • the second therapeutic agent may be to be administered sequentially or simultaneously.
  • the patient may be administered fasudil in combination with tetrabenzaine.
  • tetrabenzaine may be administered in a dose from 12.5 to 100 mg/patient/day.
  • the patient may be administered fasudil in combination with an agent that enhances proteasome activity.
  • agents may include proflavine pimozide, cyclosporin A, mifepristone, chlorpromazine, loperamide, dipyrimidole, methylbenzethonium, verapamil, ursolic acid, betulinic acid, rolipram, DPCPX, PD 169316, PAP1, PA26, PA28, TCH-165, MK-886, and AM-404.
  • the 12 domains of the ALSFRS assess speech, salivation, swallowing, cutting food, dressing and hygiene, turning in bed, walking, climbing stairs, dyspnea, orthopnea and respiratory- insufficiency.
  • Several subscores of the ALSFRS can be calculated and improvements in one or more of which may be considered meaningful.
  • Speech, salivation and swallowing scores (questions 1-3) are combined for a bulbar score (maximum score of 12).
  • Handwriting, cutting food, dressing and hygiene, turning in bed, yvalking and climbing stairs (questions 4-9) are combined for a motor score (maximum score of 24).
  • Progression of muscle weakness can also include strength testing (muscles), peripheral nerve and muscle imaging with ultrasound and MRI to measure muscle atrophy, respiratory function assessment (pulmonary testing), and bulbar dysfunction testing (swallowing, tongue, lip and cheek strength).
  • Handheld dynamometry (HHD, also called quantitative myometry) is a commonly used methodology for assessment of muscle strength in ALS clinical trials. Electrophysiological assessments of muscles can also be used to measure disease progression. These may include compound motor action potential (CMAP) and motor unit number estimates (MUNE, MUNIX) which are nerve conduction assessments used to quantify the numbers of motor units innervating an individual muscle. Isometric testing using e.g.. Tufts Quantitative Neuromuscular Exam (TQNE) or the accurate test of limb isometric strength (ATLIS) can be used to measure upper and lower extremity muscles. (Andres 2013). ATLIS measures isometric strength in 12 muscle groups in the arms and legs. Electrical impedance myography (EIM) may also be used to evaluate how electrical currents flow through muscle.
  • CMAP compound motor action potential
  • MUNE motor unit number estimates
  • Isometric testing using e.g.. Tufts Quantitative Neuromuscular Exam (TQNE) or the accurate test of limb isometric strength
  • FVC forced vital capacity
  • lung measurements that can be used include the maximum mid-flow expiratory flow rate and peak cough flow. The latter involves coughing once the lungs have been emptied. Respiratory pressure meters can also assess respiratory strength to determine the maximum inspiratory pressure (MEP).
  • MEP maximum inspiratory pressure
  • treatment of an ALS patient with fasudil may reduce or reverse the progression ALS.
  • this is measured using the ALSFRS-R and treatment with fasudil may slow the rate of decline in one or more of the twelve domains.
  • the average rate of decline may be one point per month, but it should be determined empirically over two to twelve months prior to fasudil treatment and then the effectiveness of fasudil treatment may be determined by assessing progression over the same duration following starting fasudil treatment. Slowing or stopping the decline based on the ALSFRS is considered a successful treatment, as is reversing the decline.
  • treatment of an ALS patient with fasudil may improve muscle deterioration (atrophy), reduce muscle paralysis or contraction, and reduce or prevent spreading of muscle fasciculations (twitches).
  • treatment of an ALS patient with fasudil may reduce extremity muscle deficits.
  • Muscle w eakness can be evaluated using any method, e g., strength testing, dynamometry (including hand-held), force transducers (strain gauges), electrophysiological assessments, isometric testing, and peripheral nerve and muscle imaging with ultrasound and MRI.
  • treatment of an ALS patient with fasudil may improve respiratory function.
  • fasudil treatment may improve FVC% and oxygen saturation.
  • treatment of an ALS patient may reduce fatigue, improve poor balance, reduce tripping, and improve grip.
  • the improvement may be measured by improvements in the 48-point ALSFRS-R rating scale score, or any sub-scale thereof such as the activities of daily living (ADL) sub-score, relative to the score before being treated with fasudil hydrochloride.
  • the scale may be the ALSAQ-40, which is a diseasespecific questionnaire that was created specifically to assess health-related quality of life in patients with ALS. (Jenkinson et al.. 1999).
  • improvement may occur with a higher score from baseline.
  • a consistent score over time without dropping may be evidence of delayed progression of ALS.
  • the improvement may be measured by delayed reductions in the ALSFRS-R rating scale score relative to patients with ALS not being treated with fasudil.
  • treatment of an ALS patient with fasudil may reduce motor neuroinflammation.
  • a method includes reducing, reversing, or preventing the accumulation of TDP-43 in an ALS patient, the method comprising administering to said subject an effective amount of fasudil or a pharmaceutically acceptable salt thereof.
  • TDP-43 cytoplasmic mis-localization may be reduced upon treatment of an ALS patient with fasudil.
  • the TDP-43 aggregation, phosphorylation and/or ubiquitination may be reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%. at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% upon treating an ALS patient with fasudil.
  • fasudil treatment may reduce or mitigate symptoms of ALS.
  • treatment of an ALS patient may improve survival (delaydeath).
  • survival may be extended beyond the typical 2 years.
  • survival may be extended beyond 2 years, beyond 3 years, beyond 4 years, or beyond 5 years.
  • survival may be extended by 3 months to a year.
  • the ALS patient may be treated with fasudil at least 24 months after a disease onset.
  • Certain patient sub-populations such as renally impaired patients and/or older patients (e.g., 65 or older) may need lower doses or extended-release formulations instead of immediate release formulations. Fasudil hydrochloride hemihydrate may have higher steadystate concentrations when given at usual doses to patients with renal disease and lower doses to lower the Cmax or delay the time to Cmax (increase the Tmax) may be required.
  • Renal dysfunction may occur with advanced age and as the result of numerous disorders, including liver cirrhosis, chronic kidney disease, acute kidney injury (for example, due to administering a contrast agent), diabetes (Type 1 or Type 2). autoimmune diseases (such as lupus and IgA nephropathy), genetic diseases (such as polycystic kidney disease), nephrotic syndrome, urinary tract problems (from conditions such as enlarged prostate, kidney stones and some cancers), heart attack, illegal drug use and drug abuse, ischemic kidney conditions, urinary tract problems, high blood pressure, glomerulonephritis, interstitial nephritis, vesicoureteral, pyelonephritis, sepsis. Kidney dysfunction may occur in other diseases and syndromes, including non-kidney-related diseases that may occur along with kidney dysfunction, for example pulmonary' artery' hypertension, heart failure, and cardiomyopathies, among others.
  • Kidney function is most often assessed using serum (and/or urine) creatinine. Creatinine is a breakdown product of creatine phosphate in muscle cells, and it is produced at a constant rate. It is excreted by the kidneys unchanged, principally through glomerular filtration. Accordingly, elevated serum creatinine is a marker for kidney dysfunction, and it is used to estimate glomerular filtration rate (GFR).
  • GFR glomerular filtration rate
  • Patient size is an important factor to consider when using creatinine-based estimates of renal function.
  • the units of drug clearance are volume/time (mL/min), whereas the units of estimated GFR for chronic renal disease are volume/time/standard size (mL/min/1.73m2).
  • doses may be adjusted down (e.g., 40-50 mg per day) for smaller patients and up for larger (e.g., 120 mg per day) for obese patients.
  • a smaller male may be about 160 pounds or less.
  • a smaller female patient may weigh about 130 pounds or less.
  • Patients having a Body Mass Index of 30 and higher may be considered obese.
  • older patients may need a lower dose at initiation, with a gradual increase to the recommended dose after days or weeks.
  • older patients may need lower doses, e.g., 90 mg/day, for the duration of treatment, with anticipated titration up to a dose greater than 240 mg/day dose.
  • dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • the aim of the study is to assess the preliminary safety, efficacy, and effect on biomarkers of oral Fasudil HC1 hemihydrate 180 mg per day (60 mg tid) and 240 mg/day (80 mg tid) (immediate release tablets) for 24 weeks, in patents with ALS.
  • Patients can maintain their current doses of riluzole or edaravone.
  • Use of more than one of the following drug classes will be disallowed: long-achng nitrates, beta-blockers, or calcium channel blockers. (Note: subjects may be on one of the drug classes.)
  • the study will evaluate the effects of Fasudil on changes in the slope of decline in the Revised ALS Functional Rating Scale (ALSFRS-R), slow vital capacity (SVC) and hand-held dynamometry (HHD). Specifically, the study objectives are:
  • CSF cerebrospinal fluid
  • Participants will have an in-person or telephone visit at Week 1 (V4) to assess for safety' and drug compliance. Additional follow-up visits will occur at Weeks 4 (V5), 8 (V6), 12 (V7), 18 (V8) and 24 (V9), during which ALS assessments of ALSFRS- R/SVC/HHD will be performed. A final visit (V10) will be conducted at Week 25 (or 7 ⁇ 2 days after early termination) for post-treatment follow-up evaluations.
  • Plasma biomarker collection will occur between enrollment and commencement of treatment, and at Week 12 (V7) and Week 24 (V9).
  • CSF biomarker collection will occur between enrollment and commencement of treatment, and at Week 24 (V9).
  • Safety will be assessed by examining the incidence of AEs and SAEs, clinically significant abnormal physical and neurological examination findings, changes in vital signs, 12-lead ECG, and hematology, blood chemistry, liver function, and urine tests. Efficacy. The following efficacy endpoints wall be evaluated;
  • ALSFRS-R The ALSFRS-R is a validated rating instrument for monitoring the progression of disability in patients with ALS and is utilized for monitoring functional change in ALS patients. The score assesses various 4 domains including: (i) bulbar function (speech, salivation, swallowing);
  • Each item within a domain is attributed a score of 0 (complete loss of function) to 4 (normal), yielding a maximum score of 48 when the function is preserved.
  • ALSFRS-R Evaluators performing ALSFRS-R must be certified by the Northeast Amyotrophic Lateral Sclerosis Consortium (NEALS). Use of alternative certifications must be approved in writing by the Sponsor. The ALSFRS-R should be performed by the same rater at each visit if feasible.
  • NEALS Northeast Amyotrophic Lateral Sclerosis Consortium
  • SVC amyotrophic lateral sclerosis
  • the vital capacity will be determined using the upright SVC method.
  • the SVC will be measured using the study-approved portable spirometer, and assessments will be performed using a face mask.
  • Three SVC trials are required for each testing session, however up to 5 trials may be performed if the variability between the highest and second highest SVC is 10% or greater for the first 3 trials. Only the 3 best trials are recorded on the electronic case report form (eCRF). The highest SVC recorded is utilized for eligibility’. At least 3 measurable SVC trials must be completed to score SVC for all visits after screening.
  • Predicted SVC values and percent-predicted SVC values will be calculated using the Quanjer Global Lung Initiative equations.
  • Evaluators performing the SVC must be certified by NEALS. Use of alternative certifications must be approved in writing by the Sponsor. The SVC should be performed by the same rater at each visit if feasible.
  • Muscle strength will be assessed by hand-held dynamometer (HHD). A spring-loaded device that '‘breaks” at pre-set forces will be used to assess readings obtained by HHD throughout the study. Grip strength dynamometry for both hands will be acquired, and the mean force in kilograms will be calculated. Measures will be obtained from each hand in triplicate.
  • HHD hand-held dynamometer
  • Changes in plasma biomarkers of neurodegeneration e.g., neurofilament light chain [NfL] and phosphorylated neurofilament heavy subunit [pNfH]
  • inflammatory markers e.g., IFN-y, VCAM-1, ICAM-1, IL-1, IL-6, IL-17a, TNF-a and Clq
  • markers of inflammation and neurodegeneration in neuronal and/or astrocytic exosomes e.g., IL-6, tau, protein kinase B [AKT] and phosphorylated-AKT [p- AKT]
  • CSF biomarkers of axonal degeneration and/or apoptosis e.g., tau and NfL
  • inflammation e.g., inflammation
  • markers of drug target engagement e.g., species of phosphory lated tau [p-tau], p-NfL PTEN and AKT/p-AKT
  • Changes in plasma biomarkers of muscle loss e.g., actin, myosin, myosin light chain, troponin, titin, myozenin, alpha-actinin, nebulin, cofilin 2, tropomyosin 2, creatine kinase, myoglobin, sarcospan, integrin alpha 7, agrin, laminin 211, collagen IV, collagen VI, and collagen fragments
  • actin e.g., actin, myosin, myosin light chain, troponin, titin, myozenin, alpha-actinin, nebulin, cofilin 2, tropomyosin 2, creatine kinase, myoglobin, sarcospan, integrin alpha 7, agrin, laminin 211, collagen IV, collagen VI, and collagen fragments
  • CSF will be analyzed for biomarkers of neurodegeneration, which may include but are not limited to:
  • phosphorylated tau species e.g., P-taul81, pS202, pS386, Thr245, Thr377, Ser409
  • markers of inflammation e.g.. IFN-y, VCAM-1, ICAM-l, IL-1, IL-6, 1L-I7a, TNF-a, dq
  • ALSFRS-R ALS Functional Rating Scale
  • SVC a reduction in the slope since the slope is correlated with disease progression. Looks like on the order of a 20-50% decline in the monthly rate. In another embodiment, the decline is less than the average 2.5-3.0% per month. In a specific embodiment, the rate of respiratory decline is slowed to an average of 1.5 percentage points per month.
  • HHD Hand-held dynamometry
  • Biomarkers.lt is anticipated that Fasudil treatment will reduce the presence of and/or levels of of biomarkers associated with neuronal and axonal degeneration and reduce the amount of biomarkers associated with muscle loss by 25-50%.
  • treatment with Fasudil is expected to reduce the presence of and/or levels of biomarkers associated with neuronal and axonal degeneration and reduce the presence of biomarkers associated with muscle loss as compared to that reported for patients not administered Fasudil.
  • Subjects had a diagnosis of probable laboratory-supported, probable, or definite ALS (as defined by El Escorial Revised ALS diagnostic criteria) with an average decrease in ALSFRS-R of 0.5 to 3 points per month and ALS symptom onset (weakness and/or dysarthria, and/or dysphagia) within 48 months.
  • Patients were required to have an estimated glomerular filtration rate (eGFR) at baseline of > 45 mL/min/1.73m 2 .
  • Patients were treated with oral fasudil hydrochloride at a total daily dose of 180 mg per day, administered as 60 mg three times per day for 6 months.
  • Kidney function was assessed at baseline (prior to drug treatment), one week (V2), one month (V3), months 2, 3, 4.5 and 6 (V4-V7, respectively).
  • eGFR was calculated using creatinine (Cockroft-Gault equation) and also using the cystatin-C method. As ALS involves muscle wasting, generating abnormally high levels of creatinine, cystatin-c should give a more accurate estimate of kidney function. Results are presented below.
  • EXAMPLE 3 TREATMENT OF ALS WITH FASUDIL- A Phase 2b Double-Blinded, Placebo-Controlled Study of Fasudil HC1 in Patients with ALS
  • the aim of the study is to assess the preliminary safety, efficacy, and effect on biomarkers of oral Fasudil HC1 hemihydrate 180 mg per day (60 mg tid) and 300 mg/day (100 mg tid) (immediate release tablets) for 24 weeks, in patients with ALS. At 24 weeks, all patients are treated with the 300 mg/day dose for an additional 24 weeks. Patients can maintain their current doses of riluzole, edaravone or tauroursodeoxy cholic acid (TUDCA). Use of more than one of the following drug classes will be disallowed: long-acting nitrates, beta-blockers, or calcium channel blockers. (Note: subjects may be on one of the drug classes.)
  • ALSFRS-R, SVC, HHD and NfL are performed at baseline and every three months, as are safety assessments. Participants have an in-person or telephone visit at Week 1 and Week 25 to assess for safely and drug compliance. A final visit is be conducted at Week 49 (or 7 ⁇ 2 days after early termination) for post-treatment follow-up evaluations.
  • visits/study procedures may be performed outside of the clinic (e.g., at home or other sample collection site), and interviews may be performed by telephone and/or telemedicine as appropriate.
  • Safety are assessed by examining the incidence of AEs and SAEs, clinically significant abnormal physical and neurological examination findings, changes in vital signs, 12-lead ECG, and hematology, blood chemistry, liver function, and urine tests. Efficacy. The following efficacy endpoints are evaluated;
  • NfL NfL. It is anticipated that fasudil will reduce NfL levels in a dose-dependent manner, with the 180 mg dose reducing levels from pre-treatment by about 15% (25% compared to placebo) and the 300 mg dose reducing levels by about 25% (35% compared to placebo) at 6 months
  • ALSFRS-R ALS Functional Rating Scale
  • SVC A dose-dependent reduction in the slope of decline on the order of a 20- 50% decline in the monthly rate. In another embodiment, the decline is less than the average 2.5-3.0% per month. In a specific embodiment, the rate of respiratory decline is slowed to an average of 1.5 percentage points per month.
  • HHD Hand-held dynamometry
  • the ALSFRS-R a revised ALS functional rating scale that incorporates assessments of respiratory function.
  • BDNF ALS Study Group Phase III. J Neurol Sci. 1999 Oct 31; 169(1- 2): 13-21.
  • Gurkar A.U. et al. Identification of ROCK1 kinase a critical regulator of Beclinl -mediated autophagy 7 during metabolic stress. Nat. Commun. 2013; 4:2189.
  • Gurney ME et al. Motor neuron degeneration in mice that express a humand Cu,Zn superoxide dismutase mutation. Science. 1994; 264(5166): 1722-25.
  • ALS-FTSD Amyotrophic lateral sclerosis - frontotemporal spectrum disorder
  • Fasudil a rho kinase inhibitor

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurosurgery (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Neurology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hospice & Palliative Care (AREA)
  • Epidemiology (AREA)
  • Psychiatry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Une méthode comprend le traitement d'un patient atteint de SLA sporadique avec du fasudil oral à une dose dépassant 240 mg/jour. Il en résulte une réduction anticipée de 25 à 50 % du déclin moyen sur au moins trois mois telle que mesurée à l'aide de l'échelle d'évaluation fonctionnelle SLA révisée.
PCT/US2025/012513 2024-01-23 2025-01-22 Méthodes de traitement de la sclérose latérale amyotrophique par administration orale de fasudil Pending WO2025160116A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202463623922P 2024-01-23 2024-01-23
US63/623,922 2024-01-23

Publications (1)

Publication Number Publication Date
WO2025160116A1 true WO2025160116A1 (fr) 2025-07-31

Family

ID=96545623

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2025/012513 Pending WO2025160116A1 (fr) 2024-01-23 2025-01-22 Méthodes de traitement de la sclérose latérale amyotrophique par administration orale de fasudil

Country Status (1)

Country Link
WO (1) WO2025160116A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150031683A1 (en) * 2012-03-12 2015-01-29 Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts, Universitätsmedizin Rho kinase inhibitors for use in treating amyotrophic lateral sclerosis
US20230120945A1 (en) * 2021-10-15 2023-04-20 Woolsey Pharmaceuticals, Inc. Method of treating amyotrophic lateral sclerosis

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150031683A1 (en) * 2012-03-12 2015-01-29 Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts, Universitätsmedizin Rho kinase inhibitors for use in treating amyotrophic lateral sclerosis
US20230120945A1 (en) * 2021-10-15 2023-04-20 Woolsey Pharmaceuticals, Inc. Method of treating amyotrophic lateral sclerosis

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE Woolsey Pharmaceuticals 8 April 2025 (2025-04-08), ANONYMOUS: "Rho Kinase Inhibitor in Amyotrophic Lateral Sclerosis (REAL) | ClinicalTrials.gov", XP093339120, Database accession no. NCT05218668 *

Similar Documents

Publication Publication Date Title
US20250228868A1 (en) Method of treating amyotrophic lateral sclerosis
US11771704B1 (en) Methods of using rho kinase inhibitors to treat alzheimer's disease
US20230285409A1 (en) Methods of using rho kinase inhibitors to treat vascular dementia
JP2022543242A (ja) ヒトアミノステロールｅｎｔ－０３化合物、それを含む関連組成物、およびそれを使用する方法
EP4125910B1 (fr) Inhibiteurs de la kinase associée à rho pour traiter la démence fronto-temporale
EP4429667A1 (fr) Méthode de traitement de la sclérose latérale amyotrophique et régime posologique associé
EP4103187B1 (fr) Fasudil pour traiter un affect pseudo-bulbaire
WO2025160116A1 (fr) Méthodes de traitement de la sclérose latérale amyotrophique par administration orale de fasudil
EP4601636A1 (fr) Méthode de traitement de la sclérose latérale amyotrophique par administration orale de fasudil
EP4551227A1 (fr) Traitement de la sclérose latérale amyotrophique apparue 24 mois avant le traitement
WO2023063959A1 (fr) Procédé de traitement de la sclérose latérale amyotrophique
EP4551228A1 (fr) Régime pour le traitement de la sclérose latérale amyotrophique apparue au moins 24 mois avant le traitement
US20250381197A1 (en) Regimen for Treating Amyotrophic Lateral Sclerosis Having Onset 24 Months Prior to Treatment
WO2025207476A1 (fr) Méthodes de traitement de la sla avec un inhibiteur de la rho kinase sur la base de l'utilisation d'un biomarqueur de chaîne légère de neurofilament
US12503485B2 (en) Human aminosterol ENT-03 compounds, related compositions comprising the same, and methods of using the same
WO2025240562A1 (fr) Procédé de traitement de la sclérose latérale amyotrophique avec de la trimétazidine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25745609

Country of ref document: EP

Kind code of ref document: A1