WO2022266455A1 - Therapeutically effective oral administration of a 2 arylbenzimidazole - Google Patents

Therapeutically effective oral administration of a 2 arylbenzimidazole Download PDF

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Publication number
WO2022266455A1
WO2022266455A1 PCT/US2022/034012 US2022034012W WO2022266455A1 WO 2022266455 A1 WO2022266455 A1 WO 2022266455A1 US 2022034012 W US2022034012 W US 2022034012W WO 2022266455 A1 WO2022266455 A1 WO 2022266455A1
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Prior art keywords
tqs
salt
dose
plasma
administered
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English (en)
French (fr)
Inventor
Jonas O'gara HANNESTAD
Steven August SMITH
Sanjay Kumar Kakkar
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Tranquis Therapeutics Inc
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Tranquis Therapeutics Inc
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Priority to EP22825909.9A priority Critical patent/EP4355326A4/en
Priority to US18/571,177 priority patent/US20240307356A1/en
Priority to CN202280053507.6A priority patent/CN117794531A/zh
Priority to JP2023578189A priority patent/JP2024522820A/ja
Publication of WO2022266455A1 publication Critical patent/WO2022266455A1/en
Anticipated expiration legal-status Critical
Priority to US19/019,406 priority patent/US20250281462A1/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the 2-arylbenzimidazole compound TQS-168 2-(4-tert-butylphenyl)-1H- benzimidazole — previously known as ZLN-005, is an activator of Ppargc1 ⁇ (PGC-1 ⁇ ) gene expression.
  • PPC-1 ⁇ Ppargc1 ⁇
  • TQS-168 When administered orally at 25- 50 mg/kg to mice, TQS-168 has been shown to suppress myeloid-mediated inflammation and reduce disease severity in murine models of neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS). See US Pat. No.10,272,070.
  • TQS-168 When administered orally to mice at 25 mg/kg, TQS-168 has also been shown to suppress metabolic dysfunction in microglia in older mice, inhibit inflammatory cytokine production in microglia in older mice, suppress systemic inflammation in older mice, and alleviate behavioral dysfunction in older mice. See US Pat. No.10,653,669. TQS-168 and structurally related 2-arylbenzimidazoles have also been shown to be effective in treating systemic immune activation. See WO 2021/262617. [0003] TQS-168 is highly insoluble. In the animal model experiments reported in US Pat. No.10,272,070 and 10,653,669, TQS-168 was prepared as an oral suspension and administered to experimental animals by oral gavage.
  • Plasma and brain concentrations of the compound after administration were not reported, providing no pharmacokinetic (PK) information.
  • PK pharmacokinetic
  • TQS-168 induces PGC-1 ⁇ protein expression in vitro in a murine myeloid cell line, BV2, at concentrations ranging from 0.7 ⁇ M (175.21 ng/mL) to 20 ⁇ M (5006 ng/mL), and that TQS-168 suppresses LPS-induced secretion of pro- inflammatory cytokines from BV2 cells and human primary myeloid cells in vitro at concentrations ranging from 0.3 ⁇ M (75.09 ng/mL) to 20 ⁇ M (5006 ng/mL).
  • TQS-168 plasma free-drug and brain concentrations of TQS-168 in the range of 0.3 – 20 ⁇ M (75.09-5006 ng/mL) should suppress myeloid-mediated neuroinflammation.
  • TQS-168 When administered orally at 25-50 mg/kg, TQS-168 was previously shown to suppress myeloid-mediated inflammation and reduce disease severity in murine models of neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • mean plasma C max of TQS-168 was 93.4 ng/ml, or 0.37 ⁇ M, and mean brain C max was higher, at 542.0 ng/ml, or 2.16 ⁇ M.
  • concentrations are within the range of concentrations shown to induce PGC-1 ⁇ protein expression and to reduce LPS- mediated inflammatory cytokine release in vitro.
  • concentrations of TQS-168 in the range of 0.3 ⁇ M – 20 ⁇ M should suppress myeloid- mediated neuroinflammation.
  • the evidence of accumulation in brain suggests that plasma concentrations of TQS-168 lower than 0.37 ⁇ M may also be effective in treating neuroinflammation.
  • methods for reducing neuroinflammation and/or treating a neurodegenerative disease in a subject.
  • the method comprises: orally administering to a subject with neuroinflammation and/or a neurogenerative disease at least one dose of a pharmaceutical composition comprising the compound of formula (I) (TQS-168), or a pharmaceutically acceptable salt thereof, in amount that provides, after administration, a mean peak concentration (C max ) of TQS-168 in plasma of at least 750 ng/mL.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean plasma Cmax of TQS-168 of at least 1000 ng/mL, at least 1250 ng/mL, at least 1500 ng/mL, or at least 1750 ng/mL.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, an AUC0-t of at least 3000 ng•hr/ml, at least 4000 ng•hr/ml, at least 5000 ng•hr/ml, at least 5500 ng•hr/ml, at least 6000 ng*hr/ml, or at least 7,000 ng*hr/ml.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, an AUC0-t of about 6000 ng•hr/ml.
  • the time to plasma Cmax (Tmax) of TQS-168 is no more than 2 hours, no more than 90 minutes, or no more than 75 minutes.
  • the TQS-168 plasma Tmax is about 60 minutes.
  • methods are provided for reducing neuroinflammation and/or treating a neurodegenerative disease in a human subject.
  • the method comprises: orally administering to a subject with neuroinflammation and/or a neurogenerative disease a pharmaceutical composition comprising the compound of formula (I) f ormula (I) (TQS-168), or a pharmaceutically acceptable salt thereof, in amount that provides following administration, a mean peak plasma concentration (C max ) of the compound of Formula (II) (TQS-621) of at least 1000 ng/mL.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a plasma C max of TQS-621 of 200-2750 ng/mL, 300-2200 ng/mL, or 400-1800 ng/mL.
  • methods for reducing neuroinflammation and/or treating a neurodegenerative disease in a subject.
  • the method comprises: orally administering to a subject with neuroinflammation and/or a neurogenerative disease a pharmaceutical composition comprising the compound of formula (I) f ormula (I) (TQS-168), or a pharmaceutically acceptable salt thereof, in amount that provides following administration, (a) a mean peak concentration (C max ) of TQS-168 in plasma of at least 750 ng/mL, with (b) a mean time to C max (T max ) of TQS-168 in plasma of no more than 75 minutes; and (c) a mean peak concentration (C max ) of the compound of Formula (II) (TQS-621) in plasma of at least 1000 ng/mL, with (d) a mean time to C max (T max ) of TQS-621 in plasma of no more than 4 hours.
  • a pharmaceutical composition comprising the compound of formula (I) f ormula (I) (
  • TQS-168, or salt thereof is administered in a daily oral dose of 200-800 mg, 300-700 mg, 400-600 mg, or 400-500 mg. In particular embodiments, TQS-168, or salt thereof, is administered in a daily oral dose of 400 mg or 450 mg.
  • TQS-168 or salt thereof is administered in a liquid suspension. In certain embodiments, TQS-168 or salt thereof is administered in a liquid solution.
  • TQS-168 or salt thereof is administered in a solid dosage form. In particular solid form embodiments, TQS-168 or salt thereof is crystalline.
  • embodiments, TQS-168 or salt thereof is amorphous, and in specific amorphous embodiments, is a spray-dried dispersion or hot melt extrusion.
  • the solid dosage form is a sachet, a capsule, or a tablet.
  • the subject has a neurodegenerative disease selected from a motor neuron disease, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, vascular dementia, frontotemporal degeneration (frontotemporal dementia), dementia with Lewy bodies, Parkinson’s disease, Huntington’s disease, demyelinating disease, and multiple sclerosis (MS).
  • the subject has a motor neuron disease.
  • the subject has ALS. In particular embodiments, the subject has Alzheimer’s disease.
  • the subject is at least 40 years old and does not have a prior- diagnosed neurodegenerative disease. In particular embodiments, the subject is at least 60 years old or at least 65 years old. 3. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS [0022]
  • FIG.2 is a Western blot showing the dose response of the increase in PGC-1 ⁇ protein expression in BV2 cells contacted with TQS-168 in vitro.
  • FIG.3 is a bar graph quantifying protein expression levels measured from scans of the Western Blot shown in FIG.2.
  • PD indicates PD169316, a p38 MAPK inhibitor.
  • Rosi refers to rosiglitazone (AVANDIA), a PPAR ⁇ agonist.
  • FIGs.4a-4f show the in vitro secretion of cytokines by BV2 cells after LPS activation in the presence of two positive controls, a negative control, and TQS-168 at 4 different concentrations.
  • FIGs.5a-5b show inhibition of TNF ⁇ production by LPS-stimulated BV2 myeloid cells in vitro by 5 ⁇ M (FIG.5a) and 20 ⁇ M (FIG.5b) TQS-168 treatments, respectively.
  • FIGs.6a-6d show the dose response of TQS-168-mediated inhibition of pro- inflammatory cytokine TNF ⁇ release from LPS-stimulated microglia BV2 cells at 24 hours, using an ELISA.
  • FIG.6a and FIG.6c show the absolute (FIG.6a) and relative (FIG.6c) inhibition of TNF ⁇ secretion by BV2 cells stimulated with 0.3 ng/mL of LPS.
  • FIG.6b and FIG.6d show the absolute (FIG.6b) and relative (FIG.6d) inhibition of TNF ⁇ secretion by BV2 cells stimulated with 1 ng/mL of LPS.
  • FIG.7 shows inhibition of LPS-induced TNF ⁇ secretion in human PBMC cells treated in vitro with TQS-168 at various concentrations.
  • FIGs.8a-8c show the average plasma (FIG.8a), liver (FIG.8b), and brain (FIG.8c) concentrations of TQS-168 at various time points following a single oral dose of 25 mg/kg TQS-168 in mice.
  • FIGs.9a-9c show the plasma concentrations of TQS-168 at various time points following a single oral dose of 50 mg/kg in wild type mice.
  • FIG.10 shows the plasma concentration of TQS-168 at various time points following a single intravenous (IV) dose of 0.5 mg/kg in three individual mice.
  • FIG.11 shows the mean plasma concentration of TQS-168 at various time points following a single intravenous (IV) dose of 0.5 mg/kg in three mice.
  • FIG.12a shows the plasma concentrations of TQS-168 at various time points following a single oral dose of 50, 150, or 500 mg/kg in rats.
  • FIG.12b shows the mean brain concentration of TQS-168 at various time points after a single oral dose of 500 mg/kg in rats.
  • FIG.13 shows dose-dependent C max (ng/mL) values of TQS-168 after oral dosing of 50 mg/kg, 150 mg/kg, and 500 mg/kg in rats.
  • FIG.14 shows the dose-dependent AUC (ng*min/mL) of TQS-168 after oral dosing of 50 mg/kg, 150 mg/kg, and 500 mg/kg in rats.
  • FIG.15 shows the plasma concentrations of TQS-168 at various times points following a single intravenous (IV) dose of 0.5 mg/kg in three rats.
  • FIG.16 shows the average plasma concentrations of TQS-168 at various times points following single intravenous (IV) dose of 0.5 mg/kg in rats.
  • FIG.17 shows the plasma concentrations of TQS-168 at various times points following single intravenous (IV) dose of 0.5 mg/kg in three dogs.
  • FIG.18 shows the average plasma concentrations of TQS-168 at various times points following single intravenous (IV) dose of 0.5 mg/kg in dogs.
  • FIG.19A shows average plasma concentrations of TQS-168 after an oral dose of TQS-168 of 45 mg/kg in mice.
  • FIG.19B shows average brain concentrations of TQS-168 after an oral dose of TQS-168 of 45 mg/kg in mice.
  • FIG.20 illustrates the phase 1 metabolites from liver metabolism of TQS-168 following oral administration.
  • FIG.21A shows absolute inhibition of LPS-stimulated IL-6 secretion by TQS-168 metabolite TQS-621 from previously frozen PBMCs obtained from a first healthy human volunteer donor.
  • FIG.21B shows the relative inhibition of IL-6 inhibition expressed as percentage activity.
  • FIG.22A shows absolute inhibition of LPS-stimulated IL-6 secretion by TQS-168 metabolite TQS-621from previously frozen PBMCs obtained from a second healthy human donor.
  • FIG.22B shows the relative inhibition of IL-6 inhibition expressed as percentage activity.
  • FIG.23A shows absolute inhibition of LPS-stimulated TNF ⁇ secretion by TQS-168 and metabolite TQS-621 from previously frozen PBMCs of the first donor.
  • FIG.23B shows the relative inhibition of IL-6 inhibition expressed as percentage activity.
  • FIG.24A shows the absolute inhibition of LPS-stimulated TNF ⁇ secretion by TQS-168 and metabolite TQS-621from previously frozen PBMCs obtained from the second donor.
  • FIG.24B shows relative inhibition of TNF ⁇ inhibition expressed as percentage activity.
  • FIGS.25A-25C plot plasma concentration of TQS-168 over time after a single oral dose of TQS-168 in mice administered 50 mg/mL TQS-168 in different formulations.
  • FIGS.26A-26C plot plasma concentration of TQS-621 over time after a single oral dose in mice administered 50 mg/mL TQS-168 in different amounts.
  • FIGS.27A-B plot plasma concentration of TQS-168 over time after a single oral dose of 60 mg, 180 mg or 540 mg TQS-168 methylcellulose powder suspension formulation in humans.
  • FIG 27A is a linear plot.
  • FIG.27B is a logarithmic plot.
  • FIGS.28A-B plot plasma concentration of metabolite TQS-621 over time after a single oral dose of 60 mg, 180 mg or 540 mg TQS-168 methylcellulose powder suspension formulation in humans.
  • FIG 28A is a linear plot.
  • FIG.28B is a logarithmic plot.
  • FIGS.29A-B plot plasma concentration of TQS-168 and metabolite TQS-621 over time after a single oral dose of 60 mg TQS-168 methylcellulose powder suspension oral formulation in humans.
  • FIG 29A is a linear plot.
  • FIG.29B is a logarithmic plot.
  • FIGS.30A-B plot plasma concentration of TQS-168 and metabolite TQS-621 over time after a single oral dose of 180 mg TQS-168 methylcellulose powder suspension oral formulation in humans.
  • FIG 30A is a linear plot.
  • FIG.30B is a logarithmic plot.
  • FIGS.31A-B plot plasma concentration of TQS-168 and metabolite TQS-621 over time after a single oral dose of 540 mg TQS-168 methylcellulose powder suspension oral formulation in humans.
  • FIG 31A is a linear plot.
  • FIG.31B is a logarithmic plot.
  • FIGS.32A-B plot plasma concentration of TQS-168 over time after a single dose of 60 mg, 180 mg, or 540 mg TQS-168 methylcellulose (MC) powder for oral suspension in the fasted state, 90 mg spray dried dispersion (SDD) powder for oral suspension in the fed state, 180 mg SDD powder for oral suspension in the fasted state, or 180 mg of hot melt extrusion (HME) powder in the fasted state.
  • FIG 32A is a linear plot.
  • FIG.32B is a logarithmic plot.
  • FIGS.33A-B plot plasma concentration of metabolite TQS-621 over time after a single dose of 60 mg, 180 mg, or 540 mg TQS-168 methylcellulose (MC) powder for oral suspension in the fasted state, 90 mg spray dried dispersion (SDD) powder for oral suspension in the fed state, 180 mg SDD powder for oral suspension in the fasted state, or 180 mg of hot melt extrusion (HME) powder in the fasted state.
  • FIG 33A is a linear plot.
  • FIG.33B is a logarithmic plot.
  • FIGS.34A-B plot plasma concentration of TQS-168 and metabolite TQS-621 over time after a single dose of 90 mg TQS-168 spray dried dispersion (SDD) powder suspension (oral formulation) in fed state humans.
  • FIG 34A is a linear plot.
  • FIG.34B is a logarithmic plot.
  • FIGS.35A-B plot plasma concentration of TQS-168 over time after a single dose of 90 mg spray dried dispersion (SDD) powder suspension (oral formulation) in fed and fasted state humans.
  • FIG 35A is a linear plot.
  • FIG.35B is a logarithmic plot.
  • FIGS.36A-B plot plasma concentration of metabolite TQS-621 over time after a single dose of 90 mg spray dried dispersion (SDD) powder suspension (oral formulation) in fed and fasted state humans.
  • FIG 35A is a linear plot.
  • FIG.35B is a logarithmic plot.
  • FIGS.37A-B plot plasma concentration of TQS-168 and metabolite TQS-621 over time after a single oral dose of 90 mg TQS-168 spray dried dispersion (SDD) powder suspension (oral formulation) in fasted state humans.
  • FIG 37A is a linear plot.
  • FIG.37B is a logarithmic plot.
  • FIGS.38A-B plot plasma concentration of TQS-168 over time after a single dose of 90 mg, 180 mg or 270 mg TQS-168 spray dried dispersion (SDD) powder suspension (oral formulation) in fasted state humans.
  • FIG 38A is a linear plot.
  • FIG.38B is a logarithmic plot.
  • FIGS.39A-B plot plasma concentration of metabolite TQS-621 over time after a single dose of 90 mg, 180 mg or 270 mg TQS-168 spray dried dispersion (SDD) powder suspension (oral formulation) in fasted state humans.
  • FIG 39A illustrates a linear plot.
  • FIG. 39B illustrates a logarithmic plot.
  • FIGS.40A-B plot plasma concentration of TQS-168 over time after a single dose of 90 mg or 120 mg spray dried dispersion (SDD) powder suspension (oral formulation) in fed and fasted state humans respectively (Day 1).
  • FIG 40A is a linear plot.
  • FIG.40B is a logarithmic plot.
  • FIGS.41A-B plot plasma concentration of TQS-168 over time after seven consecutive days of single daily dose 90 mg or 120 mg spray dried dispersion (SDD) powder suspension (oral formulation) in fed and fasted state humans respectively.
  • FIG 41A is a linear plot.
  • FIG.41B is a logarithmic plot.
  • FIGS.42A-B plot plasma concentration of metabolite TQS-621 over time after a single dose of 90 mg or 120 mg TQS-168 spray dried dispersion (SDD) powder suspension (oral formulation) in fed and fasted state humans respectively.
  • FIG 42A is a linear plot.
  • FIG. 42B is a logarithmic plot.
  • FIGS.43A-B plot plasma concentration of metabolite TQS-621 over time after seven consecutive days of single dose 90 mg or 120 mg TQS-621 spray dried dispersion powder suspension (oral formulation) in fed and fasted state humans, respectively.
  • FIG 43A is a linear plot.
  • FIG.43B is a logarithmic plot.
  • FIGS.44A-B plot plasma concentration of TQS-168 over time after a single dose of TQS-168 methylcellulose (MC) powder suspension formulation, spray dried dispersion (SDD) powder suspension formulation, or hot melt extrusion (HME) powder suspension formulation in varying doses in humans.
  • FIG.44A is a linear plot.
  • FIG.44B is a logarithmic plot.
  • FIGS.45A-B plot plasma concentration of TQS-621 over time after a single dose of TQS-168 methylcellulose (MC) powder suspension formulation, spray dried dispersion (SDD) powder suspension formulation, or hot melt extrusion (HME) powder suspension formulation in varying doses.
  • FIG 45A is a linear plot.
  • FIG.45B is a logarithmic plot.
  • FIGS.46A-B plot plasma concentration of TQS-168 and metabolite TQS-621 over time after a single dose of 180 mg TQS-168 spray dried dispersion (SDD) powder suspension (oral formulation) in fasted state humans.
  • FIG 46A is a linear plot.
  • FIG.46B is a logarithmic plot.
  • FIGS.47A-B plot plasma concentration of TQS-168 and metabolite TQS-621 over time after a single dose of 180 mg TQS-168 hot melt extrusion (HME) powder suspension (oral formulation) in fasted state humans.
  • FIG 34A is a linear plot.
  • FIG.34B is a logarithmic plot.
  • FIGS.48A-B plot plasma concentration of TQS-621 over time after a single dose of TQS-168 methylcellulose (MC) powder suspension formulation, spray dried dispersion (SDD) powder suspension formulation, or hot melt extrusion (HME) powder suspension formulation in varying doses in fasted state humans.
  • FIG 48A is a linear plot.
  • FIG.48B is a logarithmic plot.
  • FIGS.49A-B plot plasma concentration of TQS-168 over time following consecutive single daily doses 120 mg spray dried dispersion (SDD) powder suspension (oral formulation) in fasted state humans.
  • FIG 49A is a linear plot.
  • FIG.49B is a logarithmic plot.
  • FIGS.50A-B plot plasma concentration of metabolite TQS-621 over time following consecutive single daily dose of TQS-168120 mg spray dried dispersion (SDD) powder suspension (oral formulation) in fasted state humans.
  • FIG 50A is a linear plot.
  • FIG.50B is a logarithmic plot.
  • FIGS.51A-B plot plasma concentration of TQS-168 over time after a single dose of 90 mg, 120 mg or 300 mg spray dried dispersion (SDD) powder suspension (oral formulation) in fed/fasted state humans (Day 1).
  • FIG 51A is a linear plot.
  • FIG.51B is a logarithmic plot.
  • FIGS.52A-B plot plasma concentration of TQS-168 over time after seven consecutive days of single daily dose 90 mg, 120 mg, or 300 mg spray dried dispersion (SDD) powder suspension (oral formulation) in fed/fasted state humans respectively.
  • FIG 52A is a linear plot.
  • FIG.52B is a logarithmic plot.
  • FIGS.53A-B plot plasma concentration of metabolite TQS-621 over time after a single dose of 90 mg, 120 mg or 300 mg spray dried dispersion (SDD) powder suspension (oral formulation) in fed/fasted state humans (Day 1).
  • FIG 53A is a linear plot.
  • FIG.53B is a logarithmic plot.
  • FIGS.54A-B plot plasma concentration of metabolite TQS-621 over time after seven consecutive days of single dose TQS-16890 mg, 120 mg or 300 mg spray dried dispersion (SDD) powder suspension (oral formulation) in fed/fasted state humans (Day 1).
  • FIG 54A is a linear plot.
  • FIG.54B is a logarithmic plot.
  • FIGS.55A-B plot plasma concentration of TQS-168 over time after a single dose of TQS-168 methylcellulose (MC) powder suspension formulation, spray dried dispersion (SDD) powder suspension formulation, or hot melt extrusion (HME) powder suspension formulation in varying doses.
  • FIG 55A is a linear plot.
  • FIG.55B is a logarithmic plot.
  • “Patient” refers to a human subject, including a healthy human donor.
  • the terms “treating,” “treatment,” and grammatical variations thereof are used in the broadest sense understood in the clinical arts. Accordingly, the terms do not require cure or complete remission of disease, and encompass obtaining any clinically desired pharmacologic and/or physiologic effect. Unless otherwise specified, “treating” and “treatment” do not encompass prophylaxis.
  • the phrase “therapeutically effective amount” refers to the amount of a compound that, when administered to a mammal or other subject for treating a disease, condition, or disorder, is sufficient to effect treatment of the disease, condition, or disorder.
  • the “therapeutically effective amount” may vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated.
  • pharmaceutically acceptable salt refers to a salt that is acceptable for administration to a subject.
  • Examples of pharmaceutically acceptable salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,
  • compositions and methods that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis
  • Compounds included in the present compositions and methods that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • Compounds included in the present compositions and methods that include a basic or acidic moiety can also form pharmaceutically acceptable salts with various amino acids.
  • the compounds of the disclosure can contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.
  • Ranges throughout this disclosure, various aspects of the invention are presented in a range format. Ranges include the recited endpoints. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6, should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc. as well as individual number within that range, for example, 1, 2, 3, 4, 5, 5.3, and 6.
  • the articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
  • an element means one element or more than one element.
  • the term “about” is understood as within range of normal tolerance in the art, for example within 2 standard deviations of the mean, and is meant to encompass variations of ⁇ 20% or ⁇ 10%, more preferably ⁇ 5%, even more preferably ⁇ 1%, and still more preferably ⁇ 0.1% from the stated value.
  • pharmaceutically acceptable excipient “pharmaceutically acceptable diluent,” “pharmaceutically acceptable carrier,” and “pharmaceutically acceptable adjuvant” are used interchangeably and refer to an excipient, diluent, carrier, or adjuvant that is useful in preparing a pharmaceutical composition that are generally safe, non-toxic and neither biologically nor otherwise undesirable, and include an excipient, diluent, carrier, and adjuvant that are acceptable for veterinary use as well as human pharmaceutical use.
  • pharmaceutically acceptable excipient includes both one and more than one such excipient, diluent, carrier, and/or adjuvant.
  • sustained release refers to prolonged or extended release of the therapeutic agent or API of the pharmaceutical formulation. These terms may further refer to composition which provides prolonged or extended duration of action, such as pharmacokinetics (PK) parameters of a pharmaceutical composition comprising a therapeutically effective amount of the active pharmaceutical ingredient as described herein.
  • PK pharmacokinetics
  • reference to or depiction of a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium.
  • Racemic mixtures of R-enantiomer and S-enantiomer, and enantio-enriched stereomeric mixtures comprising of R- and S-enantiomers, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology.
  • the compounds described herein may exist as solvates, especially hydrates, and unless otherwise specified, all such solvates and hydrates are intended. Hydrates may form during manufacture of the compounds or compositions comprising the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds.
  • TQS-168 induces PGC-1 ⁇ gene and protein expression in vitro in a murine myeloid cell line, BV2, at concentrations ranging from 0.7 ⁇ M to 20 ⁇ M, and that TQS-168 suppresses LPS-induced secretion of pro-inflammatory cytokines from BV2 cells and from human primary myeloid cells in vitro at concentrations ranging from 0.3 ⁇ M to 20 ⁇ M.
  • TQS-168 induces PGC-1 ⁇ gene and protein expression in vitro in a murine myeloid cell line, BV2, at concentrations ranging from 0.7 ⁇ M to 20 ⁇ M, and that TQS-168 suppresses LPS-induced secretion of pro-inflammatory cytokines from BV2 cells and from human primary myeloid cells in vitro at concentrations ranging from 0.3 ⁇ M to 20 ⁇ M.
  • These in vitro experiments predict that plasma and brain concentrations of TQS- 168 in the range of 0.3 – 20 ⁇ M should suppress myeloid
  • TQS-168 When administered orally at 25-50 mg/kg, TQS-168 was previously shown to suppress myeloid-mediated inflammation and reduce disease severity in murine models of neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • TQS-168 potently inhibits LPS-induced IL-6 and TNF ⁇ secretion from primary human PBMCs.
  • TQS-168 potently inhibits LPS-induced IL-6 and TNF ⁇ secretion from primary human PBMCs.
  • the method comprises orally administering to a subject with neuroinflammation and/or a neurogenerative disease a pharmaceutical composition comprising the compound of formula (I) (TQS-168) (MW 250.3), or a pharmaceutically acceptable salt thereof, in amount that provides, following administration, (a) a mean peak blood or plasma TQS-168 concentration (C max ) of at least 50 nM (12.515 ng/mL). In certain embodiments, the amount provides (a) a mean peak blood or plasma TQS-168 concentration (C max ) of at least 50 nM (12.515 ng/mL) with (b) a mean time to C max (T max ) of TQS-168 in blood or plasma of no more than 360 minutes.
  • a pharmaceutical composition comprising the compound of formula (I) (TQS-168) (MW 250.3), or a pharmaceutically acceptable salt thereof, in amount that provides, following administration, (a) a mean peak blood or plasma TQS-168 concentration (C max ) of at least 50 nM (1
  • C max and T max are measured in plasma.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean blood or plasma C max of TQS-168 of at least 100 nM (25.03 ng/mL), 150 nM (37.545 ng/mL), 200 nM (50.06 ng/mL), 250 nM (62.575 ng/mL), 300 nM (75.09 ng/mL), 350 nM (87.605 ng/mL), 400 nM (100.12 ng/mL), 450 nM (112.635 ng/mL), 500 nM (125.15 ng/mL), 550 nM (137.665 ng/mL), 600 nM (150.18 ng/mL), 650 nM (162.695 ng/mL), 700 nM (175.21 ng/mL), 750 nM (187.725 ng
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean blood or plasma Cmax of TQS-168 of at least 3.5 ⁇ M (876.05 ng/mL), 4 ⁇ M (1001.2 ng/mL), 4.5 ⁇ M (1126.35 ng/mL), 5 ⁇ M (1151.5 ng/mL), 5.5 ⁇ M (1376.65 ng/mL), 6 ⁇ M (1501.8 ng/mL), 6.5 ⁇ M (1626.95 ng/mL), 7 ⁇ M (1752.1 ng/mL), 7.5 ⁇ M (18778.25 ng/mL), or 8 ⁇ M (2002.4 ng/mL).
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean blood or plasma Cmax of TQS-168 of at least 4 ⁇ M (1001.2 ng/mL), 4.5 ⁇ M (1126.35 ng/mL), 5 ⁇ M (1151.5 ng/mL), or 5.5 ⁇ M (1376.65 ng/mL).
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean blood or plasma Cmax of TQS-168 between 2 ⁇ M (500.6 ng/mL) and 8 ⁇ M (2002.4 ng/mL), 2.5 ⁇ M (625.75 ng/mL) and 7.5 ⁇ M (1877.25 ng/mL), 3 ⁇ M (750.9 ng/mL) and 7 ⁇ M (1752.1 ng/mL), 3.5 ⁇ M (876.05 ng/mL), 6.5 ⁇ M (1626.95 ng/mL), or 4 ⁇ M (1001.2 ng/mL) to 6 ⁇ M (1501.8 ng/mL).
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean blood or plasma Cmax of TQS-168 between 4 ⁇ M (1001.2 ng/mL) and 5 ⁇ M (1151.5 ng/mL).
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean blood or plasma Cmax of TQS-168 of about 4.5 ⁇ M (1126.35 ng/mL).
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean blood or plasma Cmax of TQS-168 of at least 700 ng/mL 750 ng/mL 800 ng/mL 850 ng/mL 900 ng/mL 950 ng/mL 1000 ng/mL 1500 ng/mL or 2000 ng/mL.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean blood or plasma Cmax of TQS- 168 of at least 900 ng/mL, 950 ng/mL, 1000 ng/mL, 1500 ng/mL or 2000 ng/mL.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean blood or plasma Cmax of TQS-168 of at least 1000 ng/mL, 1100 ng/mL, 1200 ng/mL, 1300 ng/mL, 1400 ng/mL, 1500 ng/mL, 1600 ng/mL, 1700 ng/mL, 1800 ng/mL, 1900 ng/mL, or 2000 ng/mL.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean blood or plasma Cmax of TQS-168 between 900 ng/mL and 1300 ng/mL or 1000 ng/mL and 1200 ng/mL. [00113] In some embodiments, TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean blood or plasma Cmax of TQS-168 of about 1100 ng/mL.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean brain C max of TQS-168 of at least 50 nM, 100 nM, 150 nM, 200 nM, 250 nM, 300 nM, 350 nM, 400 nM, 450 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, 950 nM, 1 ⁇ M, 2 ⁇ M, 2.5 ⁇ M , 3 ⁇ M, 3.5 ⁇ M, 4 ⁇ M, 4.5 ⁇ M, 5 ⁇ M, 5.5 ⁇ M, 6 ⁇ M, 6.5 ⁇ M, 7 ⁇ M, 7.5 ⁇ M, 8 ⁇ M, 8.5 ⁇ M, 9 ⁇ M, 9.5 ⁇ M, 10 ⁇ M, 10.5 ⁇ M, 11 ⁇ M, 1
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a brain-to-plasma ratio of TQS-168 of 0.5-10.
  • TQS-168 is administered in an amount that provides, following administration, a brain-to-plasma ratio of TQS-168 of 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, or 5.
  • TQS-168 is administered in an amount that provides, following administration, a brain-to-plasma ratio of TQS-168 of at least 1.0, at least 1.5, at least 2.0, at least 2.5, at least 3.0, at least 3.5, at least 4.0, at least 4.5 or at least 5.0.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, an AUC0-t of TQS-168, measured in plasma, of at least 2000 ng•hr/ml, 2500 ng•hr/ml, 3000 ng•hr/ml, 3500 ng•hr/ml, 4000 ng•hr/ml, 4500 ng•hr/ml, 5000 ng•hr/ml, 5500 ng•hr/ml, 6000 ng•hr/ml, 6500 ng•hr/ml, 7000 ng•hr/ml, 7500 ng•hr/ml, 8000 ng•hr/ml, 8500 ng•hr/ml, or 9000 ng•hr/ml.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, an AUC0-t of TQS-168 in plasma of at least 4000 ng•hr/ml, 4500 ng•hr/ml, 5000 ng•hr/ml, 5500 ng•hr/ml, 6000 ng•hr/ml, 6500 ng•hr/ml, or 7000 ng•hr/ml. [00117] In certain embodiments, TQS-168 or salt thereof is administered in an amount that provides, following administration, an AUC0-t of TQS-168 in plasma of between 4000 ng•hr/ml and 8000 ng•hr/ml.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, an AUC0-t of TQS-168 in plasma of between 5000 ng•hr/ml and 7000 ng•hr/ml. In specific embodiments, TQS-168 or salt thereof is administered in an amount that provides, following administration, an AUC0-t of TQS-168 in plasma of about 6000 ng•hr/ml. [00118] In some embodiments, TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean T max of TQS-168 in blood or plasma of no more than 360 minutes.
  • TQS-168 or salt thereof is administered in a formulation that provides a mean T max in blood or plasma of no more than 360 minutes, 350 minutes, 340 minutes, 330 minutes, 320 minutes, 310 minutes, 300 minutes, 290 minutes, 280 minutes, 270 minutes, 260 minutes, 250 minutes, 225 minutes, 200 minutes, or 180 minutes.
  • TQS-168 or salt thereof is administered in a formulation that provides a mean T max in blood or plasma of no more than 90 minutes, 60 minutes, or 45 minutes.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean T max of TQS-168 in blood or plasma of no more than 120 minutes, 90 minutes or 60 minutes.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean T max of about 60 minutes.
  • methods are provided for treating neuroinflammation and/or treating a neurodegenerative disease in a subject.
  • the method comprises orally administering to a subject with neuroinflammation and/or a neurogenerative disease a pharmaceutical composition comprising TQS-168, or a pharmaceutically acceptable salt thereof, in amount that provides following administration, (a) a mean peak plasma concentration (C max ) of the compound of Formula (II) (TQS-621) (MW 266.3), of at least 50 nM, with (b) a mean time to C max (T max ) of TQS-621 in plasma of no more than 360 minutes.
  • C max mean peak plasma concentration
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean blood or plasma C max of TQS-621 of at least 100 nM, 150 nM, 200 nM, 250 nM, 300 nM, 350 nM, 400 nM, 450 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, 950 nM, 1 ⁇ M, 2 ⁇ M, 2.5 ⁇ M , 3 ⁇ M, 3.5 ⁇ M, 4 ⁇ M, 4.5 ⁇ M, 5 ⁇ M, 5.5 ⁇ M, 6 ⁇ M, 6.5 ⁇ M, 7 ⁇ M, 7.5 ⁇ M, 8 ⁇ M, 8.5 ⁇ M, 9 ⁇ M, 9.5 ⁇ M, 10 ⁇ M, 10.5 ⁇ M, 11 ⁇ M, 11.5 ⁇
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean blood or plasma C max of TQS-621 of at least 75 ng/mL, 100 ng/mL, 125 ng/mL, 150 ng/mL, 175 ng/mL, 200 ng/mL, 225 ng/mL, 250 ng/mL, 250 ng/mL, 300 ng/mL, 350 ng/mL, 400 ng/mL, 450 ng/mL, 500 ng/mL, 550 ng/mL, or 600 ng/mL.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean blood or plasma C max of TQS-621 of 100-700 ng/mL, 200-600 ng/mL, or 300-500 ng/mL.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean brain C max of TQS-621 of at least 50 nM, 100 nM, 150 nM 200 nM 250 nM 300 nM 350 nM 400 nM 450 nM 500 nM 550 nM 600 nM 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, 950 nM, 1 ⁇ M, 2 ⁇ M, 2.5 ⁇ M , 3 ⁇ M, 3.5 ⁇ M, 4 ⁇ M, 4.5 ⁇ M, 5 ⁇ M, 5.5 ⁇ M, 6 ⁇ M, 6.5 ⁇ M, 7 ⁇ M, 7.5 ⁇ M, 8 ⁇ M, 8.5 ⁇ M, 9 ⁇ M, 9.5 ⁇ M, 10 ⁇ M, 10.5 ⁇ M, 11 ⁇ M, 11.5 ⁇ M,, 12 ⁇ M
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a brain-to-plasma ratio of TQS-621 of 0.5-10.
  • TQS-168 is administered in an amount that provides, following administration, a brain-to-plasma ratio of TQS-168 of 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, or 5.
  • TQS-168 is administered in an amount that provides, following administration, a brain-to-plasma ratio of TQS-168 of at least 1.0, at least 1.5, at least 2.0, at least 2.5, at least 3.0, at least 3.5, at least 4.0, at least 4.5 or at least 5.0.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean T max of TQS-621 in blood or plasma of no more than 360 minutes.
  • TQS-168 or salt thereof is administered in a formulation that provides a mean T max in blood or plasma of no more than 360 minutes, 350 minutes, 340 minutes, 330 minutes, 320 minutes, 310 minutes, 300 minutes, 290 minutes, 280 minutes, 270 minutes, 260 minutes, 250 minutes, 225 minutes, 200 minutes, or 180 minutes. In certain embodiments, TQS-168 or salt thereof is administered in a formulation that provides a mean T max in blood or plasma of no more than 90 minutes, 60 minutes, or 45 minutes. [00127] In another aspect, methods of treating neuroinflammation and/or a neurodegenerative disease in a subject are provided.
  • the methods comprise orally administering to a subject with neuroinflammation and/or a neurogenerative disease a pharmaceutical composition comprising TQS-168 or pharmaceutically acceptable salt thereof in an amount that provides, following administration, (a) a mean peak concentration (C max ) of TQS-168 in plasma of at least 50 nM, with (b) a mean time to C max (T max ) of TQS-168 in plasma of no more than 360 minutes; and (c) a mean peak concentration (C max ) of (TQS-621) in plasma of at least 50 nM, with (d) a mean time to C max (T max ) of TQS-621 in plasma of no more than 360 minutes.
  • a mean peak concentration (C max ) of TQS-168 in plasma of at least 50 nM with
  • a mean time to C max (T max ) of TQS-621 in plasma of no more than 360 minutes.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean blood or plasma C max of TQS-168 of at least 100 nM, 150 nM, 200 nM, 250 nM, 300 nM, 350 nM, 400 nM, 450 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, 950 nM, 1 ⁇ M, 2 ⁇ M, 2.5 ⁇ M , 3 ⁇ M, 3.5 ⁇ M, 4 ⁇ M, 4.5 ⁇ M, 5 ⁇ M, 5.5 ⁇ M, 6 ⁇ M, 6.5 ⁇ M, 7 ⁇ M, 7.5 ⁇ M, 8 ⁇ M, 8.5 ⁇ M, 9 ⁇ M, 9.5 ⁇ M, 10 ⁇ M, 10.5 ⁇ M, 11 ⁇ M, 11.5 ⁇
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean brain C max of TQS-168 of at least 50 nM, 100 nM, 150 nM, 200 nM, 250 nM, 300 nM, 350 nM, 400 nM, 450 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, 950 nM, 1 ⁇ M, 2 ⁇ M, 2.5 ⁇ M , 3 ⁇ M, 3.5 ⁇ M, 4 ⁇ M, 4.5 ⁇ M, 5 ⁇ M, 5.5 ⁇ M, 6 ⁇ M, 6.5 ⁇ M, 7 ⁇ M, 7.5 ⁇ M, 8 ⁇ M, 8.5 ⁇ M, 9 ⁇ M, 9.5 ⁇ M, 10 ⁇ M, 10.5 ⁇ M, 11 ⁇ M, 1
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a brain-to-plasma ratio of TQS-168 of 0.5-10.
  • TQS-168 is administered in an amount that provides, following administration, a brain-to-plasma ratio of TQS-168 of 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, or 5.
  • TQS-168 is administered in an amount that provides, following administration, a brain-to-plasma ratio of TQS-168 of at least 1.0, at least 1.5, at least 2.0, at least 2.5, at least 3.0, at least 3.5, at least 4.0, at least 4.5 or at least 5.0.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean blood or plasma C max of TQS-621 of at least 100 nM, 150 nM, 200 nM, 250 nM, 300 nM, 350 nM, 400 nM, 450 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, 950 nM, 1 ⁇ M, 2 ⁇ M, 2.5 ⁇ M , 3 ⁇ M, 3.5 ⁇ M, 4 ⁇ M, 4.5 ⁇ M, 5 ⁇ M, 5.5 ⁇ M, 6 ⁇ M, 6.5 ⁇ M, 7 ⁇ M, 7.5 ⁇ M, 8 ⁇ M, 8.5 ⁇ M, 9 ⁇ M, 9.5 ⁇ M, 10 ⁇ M, 10.5 ⁇ M, 11 ⁇ M, 11.5 ⁇
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a mean brain C max of TQS-621 of at least 50 nM, 100 nM, 150 nM, 200 nM, 250 nM, 300 nM, 350 nM, 400 nM, 450 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, 950 nM, 1 ⁇ M, 2 ⁇ M, 2.5 ⁇ M , 3 ⁇ M, 3.5 ⁇ M, 4 ⁇ M, 4.5 ⁇ M, 5 ⁇ M, 5.5 ⁇ M, 6 ⁇ M, 6.5 ⁇ M, 7 ⁇ M, 7.5 ⁇ M, 8 ⁇ M, 8.5 ⁇ M, 9 ⁇ M, 9.5 ⁇ M, 10 ⁇ M, 10.5 ⁇ M, 11 ⁇ M, 1
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, a brain-to-plasma ratio of TQS-621 of 0.5-10.
  • TQS-168 is administered in an amount that provides, following administration, a brain-to-plasma ratio of TQS-168 of 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, or 5.
  • TQS-168 is administered in an amount that provides, following administration, a brain-to-plasma ratio of TQS-168 of at least 1.0, at least 1.5, at least 2.0, at least 2.5, at least 3.0, at least 3.5, at least 4.0, at least 4.5 or at least 5.0.
  • Inhibition of inflammation in the periphery can provide benefit in treating neuroinflammation.
  • fingolimod now approved for treating relapsing-remitting multiple sclerosis (MS), acts to reduce MS pathology by reducing lymphocyte egress from lymph nodes.
  • TQS-168 is administered in an amount that provides optimal concentrations of TQS-168 and metabolite TQS-621 in both peripheral and central compartments
  • TQS-168 is administered in an amount that provides optimal concentration ratios of one or more of: TQS-168 plasma:TQS-168 brain TQS-621 plasma:TQS-621 brain TQS-168 plasma:TQS-621 plasma TQS-168 brain:TQS-621 brain.
  • the daily oral dose of TQS-168 is at least 0.5 mg/kg. In various embodiments, the oral dose of TQS-168 is at least 1 mg/kg.
  • the dose is at least 2 mg/kg, at least 3 mg/kg, at least 4 mg/kg, at least 5 mg/kg, at least 6 mg/kg, at least 7 mg/kg, at least 8 mg/kg, at least 9 mg/kg, or at least 10 mg/kg.
  • the daily oral dose of TQS-168 is at least 10 mg/kg.
  • the dose is at least 15 mg/kg, at least 20 mg/kg, at least 25 mg/kg, 30 mg/kg, at least 35 mg/kg, at least 40 mg/kg, at least 45 mg/kg, at least 50 mg/kg, at least 55 mg/kg, at least 60 mg/kg, at least 65 mg/kg, at least 70 mg/kg, at least 75 mg/kg, at least 80 mg/kg, at least 85 mg/kg, at least 90 mg/kg, at least 95 mg/kg, at least 100 mg/kg, at least 150 mg/kg, at least 175 mg/kg, or at least 200 mg/kg.
  • the dose is 250 mg/kg, 300 mg/kg, 350 mg/kg, 400 mg/kg, 450 mg/kg, 500 mg/kg, 600 mg/kg, 650 mg/kg, 700 mg/kg, 750 mg/kg, 800 mg/kg, 850 mg/kg, 900 mg/kg, 950 mg/kg, or 1000 mg/kg.
  • the oral dose is 0.5 mg/kg to 100 mg/kg per day.
  • the oral dose is 2 mg/kg to 100 mg/kg per day.
  • the oral dose is 25 mg/kg to 1000 mg/kg per day. [00137]
  • the oral daily dose of TQS-168 is 25 mg/kg.
  • the dose is at least 25 mg/kg. In certain embodiments, the dose is at least 50 mg/kg, at least 100 mg/kg, at least 150 mg/kg, at least 175 mg/kg, or at least 200 mg/kg. In certain embodiments, the dose is 250 mg/kg, 500 mg/kg, 750 mg/kg, or 1000 mg/kg. In certain embodiments, the oral dose is 25 mg/kg to 1,000 mg/kg per day. [00138] In various embodiments, the daily oral dose is 10-5000 mg.
  • the dose is 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg. .
  • the dose is 1500 mg, 2000 mg, 2500 mg, 3000 mg, 3500 mg, 4000 mg, 4500 mg, or 5000 mg. [00139]
  • the daily dose is 25-2000 mg.
  • the dose is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1000 mg.
  • the daily oral dose is 200-800 mg.
  • the daily oral dose is 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, or 500 mg.
  • the dose is 400 mg or 450 mg.
  • the daily oral dose is 400 mg or 450 mg in a spray dried dispersion formulation. 4.3.3.
  • Oral dosage form [00141]
  • TQS-168 or salt thereof is administered in a suspension.
  • TQS-168 or salt thereof is administered in a solution.
  • TQS-168 or salt thereof is administered in a solid dosage form.
  • the solid dosage form is a capsule. In particular embodiments, the solid dosage form is a tablet. In specific embodiments, TQS-168 is in a crystalline or amorphous form. In particular embodiments, TQS-168 is in amorphous form. 4.3.4. Patients [00142] In various embodiments, the subject has neuroinflammation. In certain embodiments, the subject does not have a diagnosed neurodegenerative disease. In particular embodiments, the subject does not have a diagnosed neurodegenerative disease and is at least 40, 45, 50, 55, 60, 65, 70, or 75 years old. In particular embodiments, the subject does not have a diagnosed neurodegenerative disease but has one or more signs or symptoms of cognitive impairment. In specific embodiments, the subject has mild cognitive impairment (MCI).
  • MCI mild cognitive impairment
  • the subject has a neurodegenerative disease.
  • the neurodegenerative disease is selected from a motor neuron disease, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, vascular dementia, frontotemporal degeneration (frontotemporal dementia), dementia with Lewy bodies, Parkinson’s disease, Huntington’s disease, demyelinating disease, and multiple sclerosis (MS).
  • ALS amyotrophic lateral sclerosis
  • vascular dementia frontotemporal degeneration
  • frontotemporal dementia frontotemporal dementia
  • MS demyelinating disease
  • MS multiple sclerosis
  • the subject has a motor neuron disease.
  • the subject has ALS.
  • the subject has Alzheimer’s disease.
  • the subject has vascular dementia.
  • the subject has frontotemporal dementia (FTD).
  • the subject has dementia with Lewy bodies (Lewy body disease).
  • the subject has Parkinson’s disease.
  • the subject has Huntington’s disease.
  • the subject has demyelinating disease.
  • the subject has MS. 4.3.5. Further embodiments [00145] Further embodiments are provided in the following numbered clauses. 1.
  • a method of treating neuroinflammation and/or a neurodegenerative disease in a subject comprising: orally administering to a subject with neuroinflammation and/or a neurogenerative disease a pharmaceutical composition comprising the compound of formula (I) (TQS-168) or a pharmaceutically acceptable salt thereof, in amount that provides after administration, (a) a mean peak concentration (C max ) of TQS-168 in plasma of at least 50 nM, with (b) a mean time to Cmax (T max ) of TQS-168 in plasma of no more than 360 minutes.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, (a) a mean plasma TQS-168 C max of at least 100 nM, 250 nM, or 500 nM. 3.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, (a) a mean plasma TQS-168 C max of at least 750 nM. 4.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, (a) a mean plasma TQS-168 C max of at least 1 ⁇ M. 5.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, (a) a mean plasma TQS-168 C max of at least 5 ⁇ M. 6.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, (a) a mean plasma TQS-168 C max of at least 7.5 ⁇ M. 7.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, (a) a mean plasma TQS-168 C max of at least 10 ⁇ M. 8.
  • TQS-168 or salt thereof is administered in a formulation that provides (b) a mean plasma TQS-168 T max of no more than 275 minutes.
  • TQS-168 or salt thereof is administered in a formulation that provides (b) a mean plasma TQS-168 T max of no more than 250 minutes.
  • TQS-168 or salt thereof is administered in a formulation that provides (b) a mean plasma TQS-168 T max of no more than 225 minutes.
  • TQS-168 or salt thereof is administered in a formulation that provides (b) a mean plasma TQS-168 T max of no more than 180 minutes, 90 minutes, 60 minutes or 45 minutes.
  • a method of treating neuroinflammation and/or a neurodegenerative disease in a subject comprising: orally administering to a subject with neuroinflammation and/or a neurogenerative disease a pharmaceutical composition comprising the compound of formula (I) f ormula (I) (TQS-168), or a pharmaceutically acceptable salt thereof, in amount that provides following administration, (a) a mean peak plasma concentration (C max ) of the compound of Formula (II) (TQS-621) of at least 50 nM, with (b) a mean time to C max (T max ) of TQS-621 in plasma of no more than 360 minutes.
  • C max mean peak plasma concentration
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, (a) a mean plasma TQS-621 C max of at least 100 nM, 250 nM, or 500 nM. 14. The method of clause 13, wherein TQS-168 or salt thereof is administered in an amount that provides, following administration, (a) a mean plasma TQS-621 C max of at least 750 nM. 15. The method of clause 14, wherein TQS-168 or salt thereof is administered in an amount that provides, following administration, (a) a mean plasma TQS-621 C max of at least 1 ⁇ M 16.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, (a) a mean plasma TQS-621 C max of at least 5 ⁇ M. 17.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, (a) a mean plasma TQS-621 C max of at least 7.5 ⁇ M. 18.
  • TQS-168 or salt thereof is administered in an amount that provides, following administration, (a) a mean plasma TQS-621 C max of at least 10 ⁇ M. 19.
  • TQS-168 or salt thereof is administered in a formulation that provides (b) a mean plasma TQS-621 T max of no more than 275 minutes.
  • TQS-168 or salt thereof is administered in a formulation that provides (b) a mean plasma T max of TQS-168 of no more than 250 minutes.
  • TQS-168 or salt thereof is administered in a formulation that provides (b) a mean plasma T max of TQS-168 of no more than 180 minutes, 90 minutes, 60 minutes or 45 minutes.
  • a method of treating neuroinflammation and/or a neurodegenerative disease in a subject comprising: orally administering to a subject with neuroinflammation and/or a neurogenerative disease a pharmaceutical composition comprising the compound of formula (I) f ormula (I) (TQS-168), or a pharmaceutically acceptable salt thereof, in amount that provides following administration, (a) a mean peak concentration (C max ) of TQS-168 in plasma of at least 50 nM, with (b) a mean time to C max (T max ) of TQS-168 in plasma of no more than 360 minutes; and (c) a mean peak concentration (C max ) of the compound of Formula (II) (TQS-621) in plasma of at least 50 nM, with (d) a mean
  • TQS-168 is in amorphous form.
  • ALS amyotrophic lateral sclerosis
  • Alzheimer’s disease vascular dementia
  • frontotemporal degeneration frontotemporal dementia
  • dementia with Lewy bodies Parkinson’s disease
  • Parkinson’s disease Huntington’s disease
  • demyelinating disease demyelinating disease
  • MS multiple sclerosis
  • the method of clause 43, wherein the dose of TQS-168 is at least 4 mg/kg. 45. The method of clause 44, wherein the dose of TQS-168 is at least 8 mg/kg. 46. The method of clause 45, wherein the dose of TQS-168 is at least 12 mg/kg. 47. The method of clause 46, wherein the dose of TQS-168 is at least 14 mg/kg. 48. The method of clause 47, wherein the dose of TQS-168 is at least 16 mg/kg. 49. The method of clause 48, wherein the dose is 2 mg/kg. 50. The method of clause 49, wherein the dose is 4 mg/kg. 51. The method of clause 50, wherein the dose is 8 mg/kg. [00146] 5.
  • Example 1 – TQS-168 induces PGC-1 ⁇ protein expression in a murine myeloid cell line in vitro at 20 ⁇ M
  • Frozen BV2 murine microglia cells were thawed and propagated in complete media (RPMI, 10% heat-inactivated FBS, 1% L-glutamine, 1% Pen-Strep) until the growth rate reached log phase.
  • RPMI RPMI, 10% heat-inactivated FBS, 1% L-glutamine, 1% Pen-Strep
  • DMSO (1:1000 final dilution) or TQS-168 in DMSO (1:1000 final dilution) at 20 ⁇ M was added to cell cultures. After 24 hours stimulation, supernatant was discarded and cell lysis buffer (Cell Signal) was added to adherent cells to extract protein.
  • Cell Signal cell lysis buffer
  • TQS-168 induces PGC-1 ⁇ protein expression in murine BV2 microglia cells at 20 ⁇ M in vitro. 5.2.
  • Example 2 – TQS-168 induces PGC-1 ⁇ protein expression in a murine myeloid cell line in vitro at concentrations of 0.7 to 20 ⁇ M
  • DMSO (1:1000 final dilution) or TQS-168 in DMSO (1:1000 final dilution) at 20 ⁇ M, 6.8 ⁇ M, 2.2 ⁇ M, and 0.7 ⁇ M were added to BV2 cell cultures. After 24 hours’ stimulation, supernatant was discarded and cell lysis buffer (Cell Signal) was added to adherent cells to extract protein.
  • FIG.3 is a bar graph quantifying protein expression levels measured from scans of the Western Blot shown in FIG.2.
  • PD refers to PD169316, a p38 MAPK inhibitor.
  • FIGS.2 and 3 demonstrate that TQS-168 induces PGC-1 ⁇ protein expression in murine BV2 cells in vitro at concentrations ranging from 0.7 ⁇ M to 20 ⁇ M. 5.3.
  • Example 3 – TQS-168 inhibits inflammatory cytokine secretion from LPS-stimulated BV2 cells in vitro at concentrations ranging from 1 ⁇ M to 20 ⁇ M (CBA assay)
  • LPS Lipopolysaccharide
  • LPS was used to induce cytokine secretion from BV-2 cells.
  • TQS-168 was prepared in DMSO.
  • CBA Multiplexed cytometric bead array
  • BV2 cells treated with 100 ng/ml LPS displayed strong release of TNF ⁇ and IL-6 pro-inflammatory cytokines, while secretion of INF- ⁇ , IL-10, IL-12 and MCP-1 were not significantly induced.
  • TQS-168 was able to reduce the LPS-induced secretion of TNF ⁇ and IL-6 from BV2 cells at concentrations ranging from 1 ⁇ M – 20 ⁇ M. Reductions of both TNF ⁇ (FIG.4a) and IL-6 (FIG.4b) by TQS-168 were concentration- dependent. 5.4.
  • Example 4 – TQS-168 inhibits LPS-induced TNF ⁇ secretion from BV2 myeloid cells in vitro at 5 ⁇ M and 20 ⁇ M (CBA assay)
  • CBA assay CBA assay
  • DMSO (1:1000 final dilution) or TQS-168 in DMSO (1:1000 final dilution) at either 5 ⁇ M or 20 ⁇ M were added to cell cultures. After 24 hours stimulation, supernatant was collected for cytokine analysis with CBA assays (BD Biosciences) per manufacturer’s protocols. TNF ⁇ express was normalized to DMSO treated condition. [00166] ANOVA was used for statistical analysis with significant threshold at p-value ⁇ 0.05. Conclusion [00167] As shown in FIGs.5a and 5b, TQS-168 at 5 ⁇ M and 20 ⁇ M, respectively, can suppress TNF ⁇ production by LPS-stimulated BV-2 myeloid cells, as compared to control. 5.5.
  • TQS-168 inhibits TNF ⁇ release by BV2 cells stimulated with LPS in vitro at concentrations of 0.3 ⁇ M to 10 ⁇ M (ELISA) TNF ⁇ ELISA Procedure
  • 100 ⁇ L of supernatant was removed from Cell Plate and transferred to a Dilution Plate, which was then centrifuged at 216xg for 10 minutes to remove particulates. The dilution plate was either assayed immediately or aliquots were taken and stored at ⁇ -20 °C; repeated freeze-thaw cycles were avoided.
  • a standard curve was prepared by first pipetting 900 ul of Calibrator Diluent RD5K into the 700 pg/mL tube, followed by 200 ⁇ l of the appropriate calibrator diluent in the remaining tubes. The stock solution was used to produce a dilution. The resulting tubes were then thoroughly mixed. The Mouse TNF ⁇ Standard (700 pg/mL) served as the high standard, and the Calibrator Diluent RD5T served as the zero standard at 0 pg /ml. [00170] Assay Diluent RD1-63 (50 uL) was then added to the center of each well and mixed before and during its use.
  • a concentration range of 0.1 ng/mL to 1,000 ng/mL was tested.
  • 0.3 ng/ml LPS produced enough TNF ⁇ release (8-10 fold above background) from these cells after 22 hours stimulation without saturating the linear range of the ELISA detection system. If higher LPS concentrations are used for stimulating BV-2 cells, a sample solution is advised to stay within the linear range of the detection system.
  • the current TNF ⁇ protocol uses 10,000 cells per well in 96 well plate. A cell count titration can optimize S/B ratio. Miniaturization from 96 well to 384 well is also feasible with this assay.
  • FIGs.6a-6d show the dose response of TQS-168-mediated decrease of pro- inflammatory cytokine TNF ⁇ release from microglia BV2 cells using ELISA at 24 hours.
  • FIG.6a and FIG.6c show the absolute (FIG.6a) and relative (FIG.6c) inhibition of TNF ⁇ secretion by BV2 cells stimulated with 0.3 ng/mL of LPS.
  • FIG.6b and FIG.6d show the absolute (FIG.6b) and relative (FIG.6d) inhibition of TNF ⁇ secretion by BV2 cells stimulated with 1 ng/mL of LPS.
  • TQS-168 suppressed TNF ⁇ production in a concentration-dependent manner, with up to about 25% suppression observed for cells administered with 10 ⁇ M of TQS-168.
  • administration of TQS-168 suppressed TNF ⁇ production in a concentration-dependent manner, with up to about 35% inhibition for cells administered with 10 ⁇ M of TQS-168.
  • TQS-168 inhibits LPS-induced TNF- ⁇ production by primary human myeloid cells Study Methodology
  • PBMC Peripheral blood mononuclear cells
  • Fresh blood samples were collected at Stanford Blood Center and processed for PBMC isolation with Ficoll gradient.
  • PBMC samples were stored in liquid nitrogen at -80 °C for subsequent analysis of TNF- ⁇ production.
  • frozen PBMC samples were thawed and rested at 37 °C before cells were stimulated with 100 ng/ml of LPS for 24 hours.
  • DMSO (1:1000 final dilution) or TQS-168 in DMSO (1:1000 final dilution) at various concentrations was added to cell cultures of LPS-stimulated PBMC to evaluate the effects of T-168 on TNF- ⁇ production by human primary myeloid cells.
  • CBA cytometric bead array
  • TNF- ⁇ was quantified by median fluorescent intensity reading (MFI). Samples were analyzed directly after staining with LSRII flow cytometer.
  • TQS-168 tissue concentrations after single oral dose in mice Study Methodology
  • a total of 3-4 male C57BL6/J mice were administered a single dose of TQS-168 by oral gavage at 25 mg/kg.
  • TQS-168 was prepared for oral gavage as a suspension with 0.5% methylcellulose in PBS.
  • Tissues were collected at various time points after dosing and processed for LC- MS analyses of TQS-168 concentrations.
  • the tissues analyzed include plasma, brain, and liver. Animals were perfused thoroughly with 20 mL ice cold PBS before brain and liver collection to remove contaminating blood. Data are shown in Table 1 (TQS-168 concentrations in ng/mL). Conclusion [00184] Average plasma C max was 93.4 ng/ml, or 0.37 ⁇ M. Average brain C max was 542.0 ng/ml, or 2.16 ⁇ M. Average concentration of TQS-168 (ng/ml) is graphed in FIG.8 for plasma (FIG.8a), liver homogenate (FIG. 8b), and brain homogenate (FIG.8c). [00185] In a second experiment, mice were administered 50 mg/kg TQS-168 by oral gavage.
  • TQS-168 was prepared at a concentration of 5.0 mg/mL in a suspension with 0.5% methylcellulose in PBS.
  • TQS-168 was prepared at a concentration of 5.0 mg/mL as a solution in 10% polyethylene glycol (PEG) 400
  • Plasma exposures for Group 1 mice are presented in Table 2 and for Group 2 mice in Table 3.
  • FIGs.9a-9c show the plasma concentration of TQS-168 over time in Group 1 mice and Group 2 mice.
  • C max in plasma was 2137 ng/mL, or 8.54 ⁇ M, with a time to C max (T max ) of 50 mins. 5.8.
  • T max time to C max
  • mice were administered a single oral dose of 45 mg/kg TQS-168.
  • TQS-168 was prepared at a concentration of 5.0 mg/mL as a solution in 10% polyethylene glycol (PEG) 400
  • PEG polyethylene glycol
  • FIG.21A shows absolute inhibition of LPS-stimulated IL-6 secretion by TQS-168 metabolite TQS-621 from PBMCs obtained from a first donor.
  • FIG.21B shows the relative inhibition of IL-6 inhibition expressed as percentage activity.
  • the structure of TQS-621 is shown below as Formula II: [00195]
  • FIG.22A shows absolute inhibition of LPS-stimulated IL-6 secretion by TQS-168 metabolite TQS-621 from PBMCs obtained from a second donor.
  • FIG.22B shows the relative inhibition of IL-6 inhibition expressed as percentage activity.
  • FIG.23A shows absolute inhibition of LPS-stimulated TNF ⁇ secretion by TQS-168 and metabolite TQS-621 from PBMCs of the first donor.
  • FIG.23B shows the relative inhibition of TNF ⁇ inhibition expressed as percentage activity.
  • FIG.24A shows the absolute inhibition of LPS-stimulated TNF ⁇ secretion by TQS-168 and metabolite TQS-621 from PBMCs obtained from the second donor.
  • FIG. 24B shows relative inhibition of TNF ⁇ inhibition expressed as percentage activity.
  • phase 1 metabolite TQS-621 is a potent inhibitor of LPS- stimulated IL-6 and TNF ⁇ secretion from human PBMCs, demonstrating that at least some of the therapeutic effect observed after oral administration of TQS-168 can likely be attributed to activity of active metabolite TQS-621. 5.10.
  • Example 10 Plasma concentrations of TQS-168 and active metabolite TQS-621 after a single oral dose of TQS-168 in mice
  • C57BL/6 male mice were administered a single dose of TQS-168 at 50 mg/kg using one of three formulations: Group 1 - 5.0 mg/ml suspension in 0.5% methylcellulose in PBS; Group 2 - 5.0 mg/ml solution in PEG400 (Fluka) 10%
  • TQS-168 and TQS-621 Plasma concentrations of TQS-168 and TQS-621 were measured over time.
  • Table 6 presents the TQS-168 plasma concentration data for Group 1 mice;
  • Table 7 presents the TQS-168 plasma concentration data for Group 2 mice;
  • Table 8 provides the TQS-168 plasma concentration data for Group 3 mice.
  • TQS-621 plasma C max of the Group 2 mice which received the solution formulation was 449 ng/mL, providing a C max ratio of metabolite TQS-621 to parent TQS-168 of 0.152, and an AUClast ratio of 0.136.
  • Results are plotted in FIGS.26A (Group 1), 26B (Group 2), and 26C (Group 3). 5.11.
  • TQS-168 was prepared as a 4.5 mg/ml solution in PEG40010%
  • FIG.12a concentration of TQS-168 (ng/ml) in plasma
  • Fig.12b brain homogenate
  • FIGs.12a and 12b show that TQS-168 was detected in both plasma and brain tissues of treated rats.
  • the maximum concentrations of TQS-168 (C max ) were detected at 240 minutes in both plasma and brain following oral administration of TQS-168.
  • C max and AUC0-t values from the plasma tissues were calculated using PKSolver (Compute Methods Programs Biomed.2010 Sep;99(3):306-14. doi: 10.1016/j.cmpb.2010.01.007. Epub 2010 Feb 21) with the underlying data plotted FIG.12a. The results are shown in FIGs. 13 (C max ) and 14 (AUC), respectively, and the values are summarized in Table 14.
  • TQS-168 was detected in both plasma and brain tissues with dose-dependent C max and AUC. 5.13.
  • TQS-168 plasma concentrations following single intravenous dose in mice Study Methodology Three male 7-9 week old male CD-1 mice from Lingchang were treated intravenously with 0.5 mg/kg of TQS-168. TQS-168 was prepared in solution of 31.6% DMAC + 36.8% Ethanol + 31.6% Propylene glycol. Blood was collected at 0.5, 3, 10, 30, 60, 120, 240, 480 and 720 minutes after a single dose of TQS-168 and then processed.
  • TQS-168 Plasma samples were collected via saphenous vein puncture into a K2EDTA tube, centrifuged at 4°C at 4600 rpm for 5 minutes and plasma collected and stored at less than -20°C prior to being analyzed by LC-MS for TQS- 168 concentrations. Data are presented as concentration and mean concentration of TQS-168 per volume of plasma (ng/mL), as shown in FIG.10 (individual mice) and FIG.11 (average), respectively. Conclusion [00211] Following intravenous dose of 0.5 mg/kg of TQS-168 in mice, TQS-168 was detected in the plasma. Terminal elimination half life was 0.14 hr (8.4 mins). 5.14.
  • a total of 3 male, 7-9 week old, Sprague Dawley rats from Vital River were administered a single intravenous dose of TQS-168 at 0.5mg/kg, in a volume of 0.5 mL/kg.
  • TQS-168 was prepared in solution of 31.6% DMAC + 36.8% ethanol + 31.6% propylene glycol.
  • Blood samples were collected at 0.5, 3, 10, 30, 60, 120, 240, 480 and 720 minutes after a single dose of TQS-168 and then processed.
  • TQS-168 Plasma samples were collected via saphenous vein puncture into a K2EDTA tube, centrifuged at 4°C at 4600 rpm for 5 minutes, and plasma collected and stored at less than -20°C prior to being analyzed by LC-MS for TQS-168 concentrations. Data are presented as concentrations of TQS-168 (ng/mL) in plasma and graphed in FIGs.15 (individual rats) and 16 (average). Conclusion [00214] Following administration of a single intravenous dose of 0.5 mg/kg in rats, TQS-168 was detected in plasma. Half-life was 0.162 hrs (9.72 mins) with a clearance rate (L/hr/kg) of 9.29. 5.15.
  • TQS-168 Example 15 – Detection of TQS-168 in plasma following single intravenous dose in dogs Study Methodology
  • Blood samples were collected at 0.5, 3, 10, 30, 60, 120, 240, 360, 480, 720 and 1440 minutes after a single dose of TQS-168 and then processed.
  • Example 16 – Part 1 SAD phase 1 trial - double-blind randomized study of subjects receiving single ascending doses of TQS-168 or placebo. 5.16.1.
  • Trial design A double-blind, randomized, placebo-controlled clinical study was conducted to characterize and compare the pharmacokinetic (PK) profile of TQS-168 and its metabolite TQS-621 following single ascending doses of TQS-168, presented in 3 different formulations, or placebo, in healthy subjects.
  • Subjects This randomized, double-blind, placebo-controlled phase 1 single ascending dose [SAD] trial was conducted in healthy male subjects aged 18 to 55 years with body mass index (BMI) 18.0 to 32.0 kg/m 2 as measured at screening. Subjects all weighed at least 55 kg at screening.
  • BMI body mass index
  • Trial Design The trial was performed in multiple cohorts with a minimum of 7 subjects in each. In Cohorts 1-3 of Part 1, subjects received a single oral dose of TQS-168 methyl cellulose (MC) suspension, or spray dried dispersion (SDD) suspension, or hot melt extrusion (HME) suspension or placebo in the fasted state.
  • MC methyl cellulose
  • SDD spray dried dispersion
  • HME hot melt extrusion
  • Subjects were allocated to study treatment in a ratio of 6 TQS-168 to 2 placebo per cohort.
  • Subjects in Cohort 1 were provided Regimen A, 60 mg TQS-168 MC.
  • Subjects in Cohort 2 were provided Regimen B, 180 mg TQS- 168.
  • Cohort 3 was divided into three separate Periods, the subjects of which were the recipient of a single regimen.
  • Subjects in Cohort 3 Period 1 were provided Regimen C, 540 mg TQS-168 MC suspension on day 1.
  • the same subjects in Cohort 3 Period 2 were provided Regimen D, 180 mg TQS-168 SDD suspension on day 1, and in Part 1 Cohort 3 Period 2 the same subjects were provided Regimen E, 180 mg TQS-168 HME suspension on day 3. See Table 15.
  • the randomization schedule was constructed such that one of the subjects dosed on the first day received the TQS-168 suspension and one received the placebo. Per protocol, all treatments were to be taken once daily following an overnight fast ( ⁇ 10 hours fasted) except in cohorts in which the effect of food was evaluated.
  • For Cohorts 3 Period 2 subjects were admitted in the morning on the day before dosing (Day -1) and remained onsite until their discharge, 48 hours post-dose (Day 5).
  • Timestamp 1.5 to 12 hour post-dose samples were taken within ⁇ 10 min of the nominal post-dose sampling time. Timestamp 16 to 48 hour post-dose samples will be taken within ⁇ 30 minutes of the nominal post-dose sampling time. Samples were collected into appropriate containers and were processed to isolate plasma. PK analysis were carried out on plasma samples using validated bioanalytical methods. [00226] Statistical Analyses: The sample sizes for the study were chosen based on practical considerations and experience from previous studies of a similar design. The numbers of subjects in each cohort (group) were considered to be adequate to assess the main objectives of each study. Pharmacokinetic parameters were determined by non-compartmental techniques using WinNonlin software version 8.0 or higher (Certara USA. Inc., USA).
  • TQS-168 methylcellulose (MC) powder suspension formulation A methylcellulose (MC) powder suspension formulation of 2-(4-tert-butylphenyl)-1H- benzimidazole (TQS-168; compound of formula I) was prepared by reconstitution as a suspension in a methylcellulose vehicle formulation of Table 17 (“the vehicle formulation”). [00227] The Vehicle formulation was prepared by heating the water (1986 g) to 80 °C (+5 °C) then adding the methylcellulose (10 g) and stirring for 30 minutes or more until the methyl cellulose was fully dispersed.
  • TQS-168 single ascending dose (SAD) PK profile Cohort 3 Period 1 received 540 mg TQS-168 (Regimen C) and provided the highest TQS-168 C max of 323 ng/mL (1.29 ⁇ M). Cohort 2 received 180 mg TQS-168 (Regimen B) and provided a TQS-168 C max of 53.1 ng/mL (0.21 ⁇ M). Cohort 1 received 60 mg TQS-168 (Regimen A) and provided a TQS-168 C max of 26.7 ng/mL (0.11 ⁇ M). Results are plotted in FIG.27.
  • Metabolite TQS-621 PK profile Cohort 3 Period 1 displayed higher metabolite TQS-621 C max (1110 ng/mL) (4.17 ⁇ M) than Cohort 2 (199 ng/mL) (0.75 ⁇ M) and Cohort 1 (65.3 ng/mL) (0.25 ⁇ M). Results are plotted in FIG. 28.
  • C max ,AUC (0-24) and AUC (0-inf) When observing the entire dose range from 60 mg – 540 mg, C max ,AUC (0-24) and AUC (0-inf) all increased supra-proportionally by 12.1-fold, 20.2-fold and 21.2-fold respectively. See FIGs 27, 29-31.
  • plasma C max , AUC (0-24) and AUC (0-inf) appeared to increase proportionally to dose following single doses from 60 to 180 mg TQS-168.
  • C max , AUC (0-24) and AUC (0-inf) increased supra-proportionally with a 5.6-, 8.9- and 9.4-fold increase, respectively for a 3-fold increase in dose.
  • TQS-168 Following a dose of 180 mg TQS-168, the maximum plasma concentrations of TQS- 168 occurred between 1 and 4 hours post-dose. A median T max of 1 hour post-dose was observed. Maximum plasma metabolite TQS-621concentrations occurred between 1-4 hours post dose, with a median T max of 1.5 hours post-dose. [00238] Following administration of 540 mg TQS-168, the maximum plasma concentration of TQS-168 occurred between 1 and 10 hours post-dose, with a median T max of 2.25 hours post- dose. Metabolite TQS-621 displayed maximum plasma concentrations between 2 and 12 hours post dose, with a median T max of 4 hours post-dose.
  • TQS-168 plasma concentrations of TQS-168 were quantifiable from 0.5 hours post- dose and remained quantifiable up to the final sample time point of 48 hours post-dose. Concentrations of TQS-621 were also quantifiable from 0.5 hours post-dose and remained quantifiable up to the final sampling time point of 48 hours post-dose. 5.16.4.
  • SDD Spray-dried dispersion
  • the reaction mixture was then removed from the homogenizer and amorphous silicon dioxide (Syloid® 244 FP) was slowly added with stirring, placed back under the homogenizer and stirred for an additional 15 minutes or more until the amorphous silicon dioxide was fully dispersed.
  • the resulting suspension is referred to herein as the “Feedstock Formulation.” 5.16.4.3 Manufacturing Procedure for Spray Dried Dispersion (SDD) Formulation of Compound of Formula I
  • the spray dryer unit (ProCepT 4M8 Spray Dryer) was set up with a compressed air supply. Once the outlet temperature stabilized, the feed pump was initiated and 2-propanol (blank solution) was sprayed through the nozzle as a fine spray into the collection chamber.
  • the spray dryer parameters were adjusted to achieve a feed rate within the range set out in Table 22 below.
  • the feedstock formulation was stirred under a homogenizer at a speed appropriate to maintain a homogenous dispersion without generating bubbles.
  • the feedstock formulation was then sprayed through the nozzle as a fine spray into the collection chamber of the spray dryer unit (ProCepT 4M8 Spray Dryer, using parameters as set up with the blank solution and outlined in Table 3) where the solvent was evaporated quickly to generate particles containing compound of formula I polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (Soluplus) and silicon dioxide (Syloid® 244 FP) (SDD formulation of compound 1).
  • the feedstock formulation was replaced with 2-propanol (blank solution) and sprayed through the nozzle of the spray dryer for 5 minutes or more to allow collection of any remaining “feedstock formulation” within the air stream.
  • TQS-168 single ascending dose (SAD) PK profile Cohort 3 Part 2 received Regimen D, 180 mg TQS-168 SDD powder for oral suspension in the fasted state and provided a TQS-168 Cmax of 218 ng/mL (0.87 ⁇ M).
  • Cohort 4 received Regimen F 90 mg TQS-168 SDD powder for oral suspension in the fed state and provided a TQS-168 Cmax of 47.1 ng/mL (0.19 ⁇ M).
  • Cohort 5 received Regimen G 90 mg TQS-168 SDD powder for oral suspension in the fasted state and provided a TQS-168 Cmax of 111 ng/mL (0.44 ⁇ M).
  • Metabolite TQS-621 PK profile Regimen D (180 mg TQS 168) provided higher metabolite TQS-621 Cmax (742 ng/mL, 2.79 ⁇ M) than Regimen H (621 ng/mL, 2.33 ⁇ M), Regimen G (214 ng/mL, 0.80 ⁇ M) and Regimen F (122 ng/mL, 0.46 ⁇ M). Results are plotted in FIG.45.
  • Metabolite TQS-621 displayed maximum plasma concentrations between 1.5 and 4 hours post dose, with a median T max of 2 hours post- dose. See FIGS 38-39.
  • the terminal half-life (T1 ⁇ 2) of TQS-168 following the 90 mg fed state, 90 mg fasted state, 180 mg fasted state and 270 mg fasted state TQS-168 SDD was dose-dependent at 3.52, 4.85, 5.64 and 10.4 hours, respectively.
  • the terminal half-life of TQS-168 metabolite TQS-621 at dose 90 mg fed state, 90 mg fasted state, 180 mg fasted state and 270 mg in the fasted state was 5.17, 4.79, 7.12 and 10.4 hours, respectively.
  • TQS-168 plasma concentrations of TQS-168 were quantifiable from 0.5 hours post-dose and remained quantifiable up to the final sample time point of 48 hours post-dose. Concentrations of TQS-621 were also quantifiable from 0.5 hours post-dose and remained quantifiable up to the final sampling time point of 48 hours post-dose. 5.16.6.
  • HME Hot-Melt Extrusion
  • HME 2-(4-tert-butylphenyl)-1H- benzimidazole
  • TQS-168 A hot-melt extrusion (HME) formulation of 2-(4-tert-butylphenyl)-1H-benzimidazole (compound of formula I; TQS-168) having the composition set out in Table 24 was prepared as set out below.
  • the compound of formula I blend was added to the feeder to fill approximately 3 ⁇ 4 of the feeder, and the extrudate was collected and discarded for approximately the first 5 minutes of the extrusion process.
  • the feeder was refilled to maintain approximately 50% volume in the feeder throughout the process, and extrusion was continued until all the compound of formula I blend was extruded and collected (“compound of formula I HME extrudate”).
  • HME Results [00261] Healthy male subjects were administered a single oral dose of TQS-168 HME powder oral suspension at 180 mg in the fasted state (Regimen E). Plasma concentrations of TQS-168 and metabolite TQS-621 were measured over time, and key pharmacokinetic parameters determined. [00262] Table 27 and Table 28 present the geometric mean of TQS-168 and metabolite TQS-621 key pharmacokinetic parameters in the subjects following oral administration of TQS-168 SDD formulation.
  • TQS-168 single ascending dose (SAD) PK profile Cohort 3 Period 2 received Regimen E, 180 mg TQS-168 HME powder in oral suspension in the fasted state. The single dose provided a TQS-168 Cmax of 123 ng/mL (0.49 ⁇ M) and an AUC0-24 of 358 hr*ng/mL. Data are plotted in FIGS.47A-B.
  • Metabolite TQS-621 PK profile Regimen E provided metabolite TQS-621 Cmax of 481 ng/mL (1.81 ⁇ M) and AUC 0-24 of 3090 hr*ng/mL. Illustrated in FIGS. 47A-B. 5.16.8.
  • TQS-168 MC powder for oral suspension displayed plasma concentrations of TQS-168 quantifiable from 0.5 hours post-dose that remained quantifiable up to between 10 and 48 hours post-dose. Concentrations of TQS-621 were also quantifiable from 0.5 hours post-dose and remained quantifiable up to between 24 and 48 hours post-dose. [00267] Maximum plasma TQS-168 concentrations occurred between 1 and 4 hours post dose, with a median Tmax of 1 hour post-dose. The resultant T1 ⁇ 2 was 7.36 hours.
  • Geometric mean (CV%) Cmax and AUC(0-inf) values were 53.1 ng/mL (55%) and 180 ng*h/mL (53.1%) respectively.
  • Maximum plasma TQS-621 concentrations occurred between 1 and 4 hours post dose, with a median Tmax of 1.5 hours post-dose.
  • the resultant geometric mean T1 ⁇ 2 was 9.10 hours.
  • Geometric Mean (CV%) Cmax and AUC(0-inf) values were 199 ng*hr/mL (33.5%) and 1350 ng*h/mL (45.1) respectively.
  • TQS-168 SDD powder for oral suspension Plasma concentrations of TQS-168 were quantifiable from 0.5 hours post-dose and remained quantifiable up to between 24 and 36 hours post-dose. Note, one subject displayed plasma concentrations of TQS-168 quantifiable at pre-dose as a result of some carry-over from the previous dosing regimen. Concentration of TQS-621 was quantifiable from pre-dose in all subjects as a result of some carry-over from the previous dosing regimen. It remained quantifiable up to the final sampling time point of 48 hours post-dose (Day 5). Note all quantifiable pre-dose concentrations were less than 5% of Cmax.
  • the geometric mean Cmax, AUC(0-last) and AUC(0-inf) of TQS-168 following administration of 180 mg HME (Regimen E) compared to its MC counterpart (Regimen B) resulted in a 2.32-, 2.14-, and 2.06-fold increase respectively.
  • the geometric mean Cmax, AUC(0-last) and AUC(0-inf) of TQS-621 following administration of 180 mg HME compared to its MC counterpart resulted in a 2.42-, 2.46-, and 2.44-fold increase respectively.
  • the SDD formulation showed significant improvement in exposure over the MC and the HME formulations of the same TQS-168 dosage, as well as in exposure of metabolite TQS-621. See FIG 48A-B.
  • Example 17 – Part 2 Multiple dose phase 1 trial – double-blind randomized study of subjects receiving multiple doses of TQS-168 or placebo 5.17.1.
  • Trial design [00277] Part 2 is a double-blind, randomized, placebo-controlled clinical study that was conducted to characterize and compare the pharmacokinetic (PK) profile of TQS-168 and its metabolite TQS-621 following multiple doses of a TQS-168 spray dried dispersion (SDD) powder for oral suspension formulation in healthy subjects. See Table 32 for description of dose regimens.
  • PK pharmacokinetic
  • SDD spray dried dispersion
  • This randomized, double-blind, placebo-controlled phase 1 multiple dose trial was conducted in healthy male subjects aged 18 to 55 years with body mass index (BMI) 18.0 to 32.0 kg/m 2 as measured at screening. Subjects all weighed at least 55 kg at screening. Key criteria for exclusion were subjects with evidence of current SARS-CoV-2 infection, clinical manifestation of significant cardiovascular, renal, hepatic, dermatological, chronic respiratory or gastrointestinal disease, or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 X the upper limit of normal (ULN). Subjects were recruited at a single site in the United Kingdom. Each patient provided written informed consent. [00279] The trial was performed in 3 cohorts.
  • Blood samples for pharmacokinetic assessments were collected from each subject prior from Day -1, ( ⁇ 1 hr) to each dose, and at intervals throughout the study until 48 hours post final dose as applicable.
  • Blood samples for plasma PK analysis were collected at regular time intervals. Venous blood samples were collected from the subjects by a trained member of the clinical team. Pre-dose samples were taken ⁇ 1 h before dosing. Timestamp 0 to 1 hour post-dose samples were taken within ⁇ 2 minutes of the nominal post- dose sampling time. Timestamp 1.5 to 12 hour post-dose samples were taken within ⁇ 10 min of the nominal post-dose sampling time. Timestamp 16 to 48 hour post-dose samples were taken within ⁇ 30 minutes of the nominal post-dose sampling time.
  • SDD Spray-dried dispersion
  • SDD Spray-dried dispersion
  • Table 21 A spray-dried dispersion (SDD) of 2-(4-tert-butylphenyl)-1H-benzimidazole (compound of formula I) having the composition set out in Table 20 was prepared by spray drying a feedstock formulation set out in Table 21.
  • the spray dryer parameters were adjusted to achieve a feed rate within the range set out in Table 22 below.
  • the feedstock formulation was stirred under a homogenizer at a speed appropriate to maintain a homogenous dispersion without generating bubbles.
  • the feedstock formulation was then sprayed through the nozzle as a fine spray into the collection chamber of the spray dryer unit (ProCepT 4M8 Spray Dryer, using parameters as set up with the blank solution and outlined in Table 3) where the solvent was evaporated quickly to generate particles containing compound of formula I polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (Soluplus) and silicon dioxide (Syloid® 244 FP) (SDD formulation of compound of formula I).
  • the feedstock formulation was replaced with 2-propanol (blank solution) and sprayed through the nozzle of the spray dryer for 5 minutes or more to allow collection of any remaining “feedstock formulation” within the air stream.
  • Regimen I Subjects received an oral dose of 120 mg TQS-168 spray dried dispersion (SDD) powder in oral suspension, or placebo, once a day for 7 consecutive days in the fasted state.
  • Regimen J Subjects received an oral dose of 90 mg TQS-168 spray dried dispersion (SDD) powder in oral suspension, or placebo, once a day for 7 consecutive days in the fed state. Subjects were provided a high fat breakfast on Day 1 and 7, and a standard breakfast on Days 2- 6.
  • Regimen K Subjects received an oral dose of 300 mg TQS-168 spray dried dispersion (SDD) powder in oral suspension, or placebo, once a day for 7 consecutive days in the fed state.
  • TQS-168 Regimen I PK profile Subjects in Cohort 1 received a single 120 mg TQS-168 SDD p.o. QD in the fasted state for seven consecutive days. [00292] On Day 1, following a single administration of Regimen I, plasma concentrations of TQS-168 were quantifiable from 0.5 hours post-dose for all subjects, and remained quantifiable up to between 16 and 24 hours post-dose.
  • TQS-168 Regimen J PK profile Subjects in Cohort 2 received a single 90 mg TQS-168 SDD p.o. QD in the fed state for seven consecutive days.
  • TQS-168 Spray Dried Dispersion (SDD) Powder for Oral Suspension plasma concentrations of TQS-168 were quantifiable from 0.5 hours post-dose for all subjects, and remained quantifiable up to between 16 and 24 hours post-dose. Concentrations of TQS-621 on Day 1 were also quantifiable from 0.5 h post-dose and remained quantifiable up to 24 hours post-dose in all subjects. [00300] Maximum plasma TQS-168 concentrations on Day 1 occurred between 1.5 and 4.0 hours post-dose, with a median Tmax of 3.0 hours post-dose.
  • Geometric mean (CV%) Cmax and AUC(0-tau) values were 47.4 ng/mL (27.4%) and 223 ng.h/mL (30.9%), respectively. Comparison with Regimen I illustrated in FIG 40A-B [00301] Maximum plasma TQS-621 concentrations on Day 1 occurred between 4.0 and 6.0 hours post-dose, with a median Tmax of 4.0 hours post-dose. Geometric mean (CV%) Cmax and AUC(0-tau) values were 189 ng/mL (40.1%) and 1400 ng*h/mL (42.6%), respectively.
  • TQS-168 Spray Dried Dispersion (SDD) Powder for Oral Suspension to healthy subjects in the fed state for 7 days, plasma concentrations of TQS-168 were quantifiable at pre-dose in all but three subjects who became quantifiable at 0.5 hours post-dose, and remained quantifiable up to between 16 and 36 hours post-dose. Concentrations of TQS-621 were quantifiable at the pre-dose time-point in all subjects, and remained quantifiable up to the final sampling time point of 48 hours post-dose.
  • Maximum plasma TQS-168 concentrations on Day 7 occurred between 1.0 and 4.0 hours post-dose, with a median Tmax of 3.0 hour post-dose.
  • TQS-168 Regimen K PK profile Subjects in Cohort 3 received a single 300 mg TQS- 168 SDD QD in the fed state for seven consecutive days. [00309] On Day 1, following a single administration of 300 mg TQS-168 Spray Dried Dispersion (SDD) Powder for Oral Suspension, plasma concentrations of TQS-168 were quantifiable from 0.5 hours post-dose for all subjects, and remained quantifiable up to the final sampling point of 24 h post dose in all subjects. [00310] Maximum plasma TQS-168 concentrations on Day 1 occurred between 1.5 and 4.0 hours post-dose with a median Tmax of 2.0 hours post-dose.
  • SDD Spray Dried Dispersion
  • Geometric mean (CV%) Cmax and AUC(0-tau) values were 229 ng/mL (38.3%) and 1210 ng*h/mL (55.1), respectively. See FIGS. 51A-B for illustrated comparison with Regimen I and J.
  • Maximum plasma TQS-621 concentrations on Day 1 occurred between 4.0 and 10.0 hours post-dose, with a median Tmax of 4.0 hours post-dose.
  • Geometric mean (CV%) Cmax and AUC(0- tau) values were 400 ng/mL (79.3%) and 2010 ng*h/mL (88.3%), respectively.
  • Geometric mean (CV%) accumulation ratios were 1.74 (54.6%) and 1.66 (29.5%), based on Cmax and AUC(0- tau), respectively. See FIGS. 52A-B for illustrated comparison with Regimen I and J. [00314] Maximum plasma TQS-621 concentrations on Day 7 occurred between 4.0 and 6.0 hours post-dose, with a median Tmax of 5.0 hours post-dose. Concentrations then declined yielding a mean elimination half-life of 7.29 hours.
  • a metabolite exposure of AUC(0-tau) 9730 hr*ng/mL was recorded for Day 1.
  • Part 2 of this trial provided healthy male subjects with consecutive seven QD doses of TQS-168 in the fed or fasted state at different dosages of TQS-168 SDD powder for oral suspension. The data reveals that increase in dosage corresponds to an increase in plasma concentration of TQS-168 and TQS-168 metabolite TQS-621. 6.

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* Cited by examiner, † Cited by third party
Title
See also references of EP4355326A4 *
ZHANG ET AL.: "Novel Small-Molecule PGC-1 alpha Transcriptional Regulator With Beneficial Effects on Diabetic db/db Mice", DIABETES, vol. 62, April 2013 (2013-04-01), pages 1297 - 1307, XP055391937, Retrieved from the Internet <URL:https://pubmed.ncbi.nlm.nih.gov/32343674> [retrieved on 20220811], DOI: 10.2337/db12-0703 *

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