IP Library › Granted Patent US 12,280,061
Granted Patent B2
US 12,280,061 · App. 17/262,902 · Granted Apr 22, 2025

Optimised dosage of diaminophenothiazines in populations

Inventors: Claude Michel Wischik (Aberdeen, GB); Björn Olaf Schelter (Aberdeen, GB); Helen Christine Shiells (Aberdeen, GB)
Assignee: WisTa Laboratories Ltd.
A61K31/5415A23L33/105A23L33/15A23L33/175A23L33/29A23L33/30A61K9/0053A61K9/20A61K9/48A61K31/13A61P25/28
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Quick Facts
Patent No.
US 12,280,061
App. No.
17/262,902
Granted
Apr 22, 2025
Kind
B2
Abstract

The invention provides novel dosing regimens for Leuco-Methylthioninium (LMT) compounds which maximise the proportion of subjects in which the MT concentration will exceed concentrations in which therapeutic efficacy in relation to treatment of neurodegenerative disorders such as Alzheimer's disease and rontotemporal dementias can be achieved, while maintaining a desirable clinical profile. Also provided are LMT-containing dosage units and other compositions.

Claims (30)

1. A method of therapeutic treatment of a neurodegenerative disorder of protein aggregation in a human subject,

which method comprises orally administering to said subject a methylthioninium (MT)-containing compound,

wherein said administration provides a total daily dose of between 20.5 and 60 mg of MT to the subject per day, optionally split into 2 or more doses,

wherein the MT-containing compound is LMTM:

and

wherein said neurodegenerative disorder is Alzheimer's disease.

2. The method as claimed in claim 1 wherein the total daily dose is between 20.5 and 40 mg.

3. The method as claimed in claim 2 wherein the total daily dose is 21 to 40 mg.

4. The method as claimed in claim 3 wherein the total daily dose is 21 to 32 mg.

5. The method as claimed in claim 4 wherein the total daily dose is 24 to 32 mg.

6. The method as claimed in claim 2 wherein the total daily dose is about 30 mg.

7. The method as claimed in claim 1 wherein the total daily dose of the MT-containing compound is administered as a split dose twice a day or three times a day.

8. The method as claimed in claim 1 wherein the subject has not historically received treatment with an acetylcholinesterase inhibitor or an N-methyl-D-aspartate receptor antagonist.

9. The method as claimed in claim 8 , wherein the acetylcholinesterase inhibitor is selected from donepezil; rivastigmine; and galantamine.

10. The method as claimed in claim 8 , wherein the N-methyl-D-aspartate receptor antagonist is memantine.

11. The method as claimed in claim 1 wherein the therapeutic treatment is combined with an acetylcholinesterase inhibitor or an N-methyl-D-aspartate receptor antagonist.

12. The method as claimed in claim 1 wherein the treatment is a combination treatment of a first agent which is the MT-containing compound at the specified dosage in combination with a second agent which is an inhibitor of the processing of amyloid precursor protein to beta-amyloid.

13. The method as claimed in claim 1 wherein the treatment is part of a treatment regimen which comprises:

(i) orally administering to said subject the MT-containing compound for a first period of time, wherein said administration provides a total daily dose of between 1 and 10 mg of MT to the subject per day;

(ii) orally administering to said subject the MT-containing compound for a further period of time, wherein said administration provides a total daily dose of between 20.5 and 60 mg of MT to the subject per day.

14. The method as claimed in claim 13 wherein the administration of step (i) provides a total daily dose of 8 mg of MT to the subject per day.

15. The method as claimed in claim 1 wherein the treatment is part of a treatment regimen which comprises:

(i) orally administering to said subject the MT-containing compound for a first period of time, wherein said administration provides a total daily dose of between 1 and 10 mg of MT to the subject per day;

(ii) orally administering to said subject the MT-containing compound for a further period of time, wherein said administration provides a total daily dose of between 20.5 and 40 mg of MT to the subject per day;

(iii) combining the treatment in (ii) with administration of an acetylcholinesterase inhibitor or an N-methyl-D-aspartate receptor for a further period of time.

16. The method as claimed in claim 15 wherein the administration of step (i) provides a total daily dose of 8 mg of MT to the subject per day.

17. The method as claimed in claim 1 wherein the MT-containing compound is administered once per day.

18. The method as claimed in claim 1 wherein the subject has historically received treatment with an acetylcholinesterase inhibitor or an N-methyl-D-aspartate receptor antagonist, but ceased that treatment at least 1, 2, 3, 4, 5, 6, 7, or 8 weeks prior to treatment with the MT-containing compound.

19. The method as claimed in claim 1 wherein the subject is selected as one who is receiving treatment with an acetylcholinesterase inhibitor or an N-methyl-D-aspartate receptor, wherein said treatment with the acetylcholinesterase inhibitor and/or N-methyl-D-aspartate receptor antagonist is discontinued prior to treatment with the MT-containing compound.

20. The method as claimed in claim 1 wherein administration provides a total daily dose of between 20.5 and 60 mg of MT to the subject per day, split into 2 or more doses.

Assignments (2)
CORRECTIVE ASSIGNMENT TO CORRECT THE THE ASSIGNEE'S NAME PREVIOUSLY RECORDED AT REEL: 059803 FRAME: 0848. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded May 13, 2022
From: WISCHIK, CLAUDE MICHEL; SCHELTER, BJORN OLAF; SHIELLS, HELEN CHRISTINE; THE UNIVERSITY COURT OF THE UNIVERSITY OF ABERDEEN; TAURX THERAPEUTICS LTD.
To: WISTA LABORATORIES LTD.
Reel/Frame 060063/0039 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 26, 2022
From: WISCHIK, CLAUDE MICHEL; SCHELTER, BJORN OLAF; SHIELLS, HELEN CHRISTINE; THE UNIVERSITY COURT OF THE UNIVERSITY OF ABERDEEN; TAURX THERAPEUTICS LTD.
To: LTD., WISTA L
Reel/Frame 059803/0848 →
Priority Claims (2)
GB 1812193 · Jul 26, 2018 · national
GB 1909458 · Jul 1, 2019 · national
Continuity (1)
Related Publication 20210236509A1 · Aug 5, 2021
References Cited (97)
US 9283230B2 · Clunas · 2016 [cited by examiner]
US 10842796B2 · Wischik et al. · 2020 [cited by applicant]
US 11065256B2 · Wischik · 2021 [cited by examiner]
US 11759469B2 · Wischik et al. · 2023 [cited by applicant]
US 20130184268A1 · Pahnke · 2013 [cited by applicant]
US 20190192530A1 · Wischik et al. · 2019 [cited by applicant]
US 20200016165A1 · Wischik et al. · 2020 [cited by applicant]
US 20220008431A1 · Wischik et al. · 2022 [cited by applicant]
US 20230031369A1 · Riedel et al. · 2023 [cited by applicant]
US 20230115931A1 · Schelter et al. · 2023 [cited by applicant]
US 20230165877A1 · Wischik et al. · 2023 [cited by applicant]
US 20230346794A1 · Wischik et al. · 2023 [cited by applicant]
WO WO9630766A1 · 1996 [cited by applicant]
WO WO02055720A2 · 2002 [cited by applicant]
WO WO2003101458A1 · 2003 [cited by applicant]
WO WO2006032879A2 · 2006 [cited by applicant]
WO WO2007110627A2 · 2007 [cited by applicant]
WO WO2007110629A1 · 2007 [cited by applicant]
WO WO2007110630A1 · 2007 [cited by applicant]
WO WO2008155533A2 · 2008 [cited by applicant]
WO WO2009044127A1 · 2009 [cited by applicant]
WO WO2009060191A2 · 2009 [cited by applicant]
WO WO2010104394A1 · 2010 [cited by examiner]
WO WO2011036561A2 · 2011 [cited by applicant]
WO WO2012107706A1 · 2012 [cited by applicant]
WO WO2018019823A1 · 2018 [cited by applicant]
WO WO2018041739A1 · 2018 [cited by applicant]
WO WO2020020751A1 · 2020 [cited by applicant]
International Search Report and Written Opinion for Application No. PCT/EP2017/068749, mailed May 10, 2017. [cited by applicant]
International Preliminary Report on Patentability for Application No. PCT/EP2017/068749, mailed Feb. 7, 2019. [cited by applicant]
International Search Report and Written Opinion for Application No. PCT/EP2017/071437, mailed Nov. 24, 2017. [cited by applicant]
International Preliminary Report on Patentability for Application No. PCT/EP2017/071437, mailed Mar. 14, 2019. [cited by applicant]
International Search Report and Written Opinion for Application No. PCT/EP2020/068422, mailed Sep. 28, 2020. [cited by applicant]
International Preliminary Report on Patentability for Application No. PCT/EP2020/068422, mailed Jan. 13, 2022. [cited by applicant]
Al-Hilaly et al., Cysteine-Independent Inhibition of Alzheimer's Disease-like Paired Helical Filament Assembly by Leuco-Methylthioninium (LMT). J Mol Biol. Oct. 19, 2018;430(21):4119-4131. doi: 10.1016/j.jmb.2018.08.010… [cited by applicant]
Atamna et al., Mitochondrial pharmacology: electron transport chain bypass as strategies to treat mitochondrial dysfunction. Biofactors. Mar.-Apr. 2012;38(2):158-66. doi: 10.1002/biof.197. Epub Mar. 15, 2012. [cited by applicant]
Baddeley et al., Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer's disease. J Pharmacol Exp Ther. Jan. 2015;352(1):110-8. doi: 10.1124/jpet.114.… [cited by applicant]
Congdon et al., Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol. Jul. 2018;14(7):399-415. doi: 10.1038/s41582-018-0013-z. [cited by applicant]
Douaud et al., Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A. Jun. 4, 2013;110(23):9523-8. doi: 10.1073/pnas.1301816110. Epub May 20, 2013. [cited by applicant]
Feldman et al., A phase 3 trial of the tau and TDP-43 aggregation inhibitor, leuco-methylthioninium-bis (hydromethanesulfonate) (LMTM), for behavioural variant frontotemporal dementia (bvFTD). J Neurochemistry. Jul. 18,… [cited by applicant]
Harrington et al., Cellular models of aggregation-dependent template-directed proteolysis to characterize tau aggregation inhibitors for treatment of Alzheimer's disease. J Biol Chem. Apr. 24, 2015;290(17):10862-75. doi… [cited by applicant]
Jaber et al., Addressing Alzheimer's Disease (AD) Neuropathology Using Anti-microRNA (AM) Strategies. Mol Neurobiol. Dec. 2019;56(12):8101-8108. doi: 10.1007/s12035-019-1632-0. Epub Jun. 10, 2019. [cited by applicant]
Kazim et al., Neural Regeneration as a Disease-Modifying Therapeutic Strategy for Alzheimer's Disease. Chapter 2 in: Neuroprotection in Alzheimer's Disease. 2017; 3-29. https://doi.org/10.1016/B978-0-12-803690-7.00002-8. [cited by applicant]
Mcgleenon et al., Acetylcholinesterase inhibitors in Alzheimer's disease. Br J Clin Pharmacol. 1999;48(4):471-480. doi:10.1046/j.1365-2125.1999.00026.x. [cited by applicant]
Mecocci et al., Nutraceuticals in cognitive impairment and Alzheimer's disease. Front Pharmacol. Jun. 23, 2014;5:147. doi: 10.3389/fphar.2014.00147. eCollection 2014. [cited by applicant]
Melis et al., Different pathways of molecular pathophysiology underlie cognitive and motor tauopathy phenotypes in transgenic models for Alzheimer's disease and frontotemporal lobar degeneration. Cell Mol Life Sci. Jun.… [cited by applicant]
Melis et al., Effects of oxidized and reduced forms of methylthioninium in two transgenic mouse tauopathy models. Behav Pharmacol. Jun. 2015;26(4):353-68. doi: 10.1097/FBP.0000000000000133. [cited by applicant]
Oz et al., Methylene blue and Alzheimer's disease. Biochem Pharmacol. Oct. 15, 2009;78(8):927-32. doi: 10.1016/j.bcp.2009.04.034. Epub May 9, 2009. [cited by applicant]
Panza et al., A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat Rev Neurol. Feb. 2019;15(2):73-88. doi: 10.1038/s41582-018-0116-6. [cited by applicant]
Pappas, Statistical Analysis Plan—Randomized Double-Blind, Placebo-Controlled, Parallel-Griup, 18-Month Safety and Efficacy Study of Leuco-methylthioninium bis(hydromethanesulfonate) in Subjects with Mild Alzheimer's Di… [cited by applicant]
Pappas, Statistical Analysis Plan (Addendum)- Randomized Double-Blind, Placebo-Controlled, Parallel-Griup, 18-Month Safety and Efficacy Study of Leuco-methylthioninium bis(hydromethanesulfonate) in Subjects with Mild Al… [cited by applicant]
Schirmer et al., “Lest we forget you—methylene blue . . . ”. Neurobiol Aging. Dec. 2011;32(12):2325.e7-16. doi: 10.1016/j.neurobiolaging.2010.12.012. Epub Feb. 12, 2011. [cited by applicant]
Smith, B vitamins can slow the disease process in early Alzheimer's disease. University of Oxford Impact case study (REF3b). Research Excellence Framework. 2014. 4 pages. [cited by applicant]
Stack et al., Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity. Hum Mol Genet. Jul. 15, 2014;23(14):3716-32. doi: 10.1093/hmg/ddu080. Epub Feb. 20, 2014. [cited by applicant]
Tsai et al., Therapy and clinical trials in frontotemporal dementia: past, present, and future. J Neurochem. Aug. 2016;138 Suppl 1:211-21. doi:10.1111/jnc.13640. Epub Jun. 15, 2016. [cited by applicant]
Tsai et al., Treatment of frontotemporal dementia. Curr Treat Options Neurol. Nov. 2014;16(11):319. doi: 10.1007/s11940-014-0319-0. [cited by applicant]
Ustyugo et al., New Therapeutic Property of Dimebon as a Neuroprotective Agent. Curr Med Chem. 2018;25(39):5315-5326. doi: 10.2174/0929867323666160804122746. [cited by applicant]
Wilkinson, Alzheimer's drug ‘halts’ decline. BBC News Jul. 29, 2008. Accessed at http://news.bbc.co.uk/go/pr/fr/-/2/hi/health/7525115.stm on Sep. 21, 2017. [cited by applicant]
Wischik et al., Modeling prion-like processing of tau protein in Alzheimer's disease for pharmaceutical development. J Alzheimers Dis. 2018;62(3):1287-1303. doi: 10.3233/JAD-170727. [cited by applicant]
Wischik et al., Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A. Jul. 1988;85(13):4884-8. doi: 10.1073/pnas.85.13.4884. [cited by applicant]
Yamashita et al., Methylene blue and dimebon inhibit aggregation of TDP-43 in cellular models. FEBS Lett. Jul. 21, 2009;583(14):2419-24. doi:10.1016/j.febslet.2009.06.042. Epub Jun. 26, 2009. [cited by applicant]
Zhao et al., Methylene blue exerts a neuroprotective effect against traumatic brain injury by promoting autophagy and inhibiting microglial activation. Mol Med Rep. Jan. 2016;13(1):13-20. doi: 10.3892/mmr.2015.4551. Epu… [cited by applicant]
International Search Report and Written Opinion for Application No. PCT/EP2019/069428, mailed Nov. 7, 2019. [cited by applicant]
International Preliminary Report on Patentability for Application No. PCT/EP2019/069428, mailed Feb. 4, 2021. [cited by applicant]
Alda et al., Methylene blue treatment for residual symptoms of bipolar disorder: randomised crossover study. Br J Psychiatry. Jan. 2017;210(1):54-60. doi: 10.1192/bjp.bp.115.173930. Epub Jun. 9, 2016. [cited by applicant]
Auchter et al., Methylene Blue Preserves Cytochrome Oxidase Activity Prevents and Memory Impairment in Rats With Chronic Cerebral Hypoperfusion. Cell Neurosci. May 20, 2020;14:130. doi: 10.3389/fncel.2020.00130. eCollec… [cited by applicant]
Bruchey et al., Behavioral, Physiological and Biochemical Hormetic Responses to the Autoxidizable Dye Methylene Blue. Am J Pharmacol Toxicol. Jan. 1, 2008;3(1):72-79. doi: 10.3844/ajptsp.2008.72.79. [cited by applicant]
Gauthier et al., Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet. Dec. 10, 2016… [cited by applicant]
Gonzalez-Lima et al., Protection against neurodegeneration with low-dose methylene blue and near-infrared light. Front Cell Neurosci. May 12, 2015;9:179. doi: 10.3389/fncel.2015.00179. eCollection 2015. [cited by applicant]
Naylor et al., A Two-Year Double-Blind Crossover Trial of the Prophylactic Effect of Methylene Blue in Manic-Depressive Psychosis. Biol Psychiatry. Aug. 1986;21(10):915-20. doi: 10.1016/0006-3223(86)90265-9. [cited by applicant]
Naylor et al., A Controlled Trial of Methylene Blue in Severe Depressive Illness. Biol Psychiatry. May 1987;22(5):657-9. doi: 10.1016/0006-3223(87)90194-6. [cited by applicant]
Panza et al., Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer's Disease. Biomed Res Int. 2016;2016:3245935. doi: 10.1155/2016/3245935. Epub Jun. 26, 2016. [cited by applicant]
Rodriguez et al., Multimodal Randomized Functional MR Imaging of the Effects of Methylene Blue in the Human Brain. Radiology. Nov. 2016;281(2):516-526. doi: 10.1148/radiol.2016152893. Epub Jun. 28, 2016. [cited by applicant]
Schelter et al., Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimer's Disease. J Alzheimers Dis. 2019;72(3):931-946. doi: 10.3233/JAD-190772. [cited by applicant]
Schelter et al., Meta-analysis of two tau aggregation inhibitor Phase 3 trials in mild Alzheimer's disease with low dose hydromethylthionine. JPAD. 2018; 5(1):S66. [cited by applicant]
Shiells et al., Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia. J Alzheimers Dis. 2020;75(2):… [cited by applicant]
Telch et al., Effects of post-session administration of methylene blue on fear extinction and contextual memory in adults with claustrophobia. Am J Psychiatry. Oct. 2014;171(10):1091-8. doi: 10.1176/appi.ajp.2014.131014… [cited by applicant]
Wilcock et al., Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer's Disease: Cohort Analysis as Modified Primary Outcome in a Phase III Clinical … [cited by applicant]
Kertesz, Behavioral and Psychological Symptoms and Frontotemporal Dementia (Pick's Disease). International Psychogeriatrics. 2000; 12(1): 183-187. [cited by applicant]
Albert et al., The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging—Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's dise… [cited by applicant]
Benedetti et al., Increasing uncertainty in CNS clinical trials: the role of placebo, nocebo, and Hawthorne effects. Lancet Neurol. Jun. 2016;15(7):736-747. doi: 10.1016/S1474-4422(16)00066-1. Epub Apr. 19, 2016. [cited by applicant]
Boxer et al., The advantages of frontotemporal degeneration drug development (part 2 of frontotemporal degeneration: the next therapeutic frontier). Alzheimers Dement. Mar. 2013;9(2):189-98. doi: 10.1016/j.jalz.2012.03.… [cited by applicant]
Cummings et al., The “rights” of precision drug development for Alzheimer's disease. Alzheimers Res Ther. Aug. 31, 2019;11(1):76. doi: 10.1186/s13195-019-0529-5. [cited by applicant]
Desmarais et al., Therapeutic trial design for frontotemporal dementia and related disorders. J Neurol Neurosurg Psychiatry. Apr. 2019;90(4):412-423. doi: 10.1136/jnnp-2018-318603. Epub Oct. 25, 2018. [cited by applicant]
Franzen et al., Diversity in Alzheimer's disease drug trials: The importance of eligibility criteria. Alzheimers Dement. Apr. 2022;18(4):810-823. doi: 10.1002/alz.12433. Epub Sep. 30, 2021. [cited by applicant]
Irwin, Tauopathies as clinicopathological entities. Parkinsonism Relat Disord. Jan. 2016;22 Suppl 1(01):S29-33. doi: 10.1016/j.parkreldis.2015.09.020. Epub Sep. 8, 2015. [cited by applicant]
Jutten et al., The Cognitive-Functional Composite is sensitive to clinical progression in early dementia: Longitudinal findings from the Catch-Cog study cohort. Alzheimers Dement (N Y). Apr. 17, 2020;6(1):e12020. doi: 1… [cited by applicant]
Jutten et al., Why a clinical trial is as good as its outcome measure: A framework for the selection and use of cognitive outcome measures for clinical trials of Alzheimer's disease. Alzheimers Dement. Feb. 2023;19(2):7… [cited by applicant]
Kim et al., Data-driven prognostic features of cognitive trajectories in patients with amnestic mild cognitive impairments. Alzheimers Res Ther. Jan. 22, 2019;11(1):10. doi: 10.1186/s13195-018-0462-z. [cited by applicant]
No Author Listed, TauRx Pharmaceuticals Press Release. Sep. 4, 2016. 3 pages. [cited by applicant]
Panza et al., Development of disease-modifying drugs for frontotemporal dementia spectrum disorders. Nat Rev Neurol. Apr. 2020;16(4):213-228. doi: 10.1038/s41582-020-0330-x. Epub Mar. 23, 2020. [cited by applicant]
Schneider et al., Current Alzheimer's disease clinical trials: Methods and placebo outcomes. Alzheimers Dement. Sep. 2009;5(5):388-97. doi: 10.1016/j.jalz.2009.07.038. [cited by applicant]
Snyder et al., Assessing cognition and function in Alzheimer's disease clinical trials: Do we have the right tools? Alzheimers Dement. Nov. 2014;10(6):853-60. doi: 10.1016/j.jalz.2014.07.158. Epub Nov. 15, 2014. [cited by applicant]
Sperling et al., Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging—Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. A… [cited by applicant]
Tariot et al., The Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease Trial: A study of crenezumab versus placebo in preclinical PSEN1 E280A mutation carriers to evaluate efficacy and safety in the… [cited by applicant]
Vos et al., Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage. Brain. May 2015;138(Pt 5):1327-38. doi: 10.1093/brain/awv029. Epub Feb. 17, 2015. [cited by applicant]
Weintraub et al., Measuring cognition and function in the preclinical stage of Alzheimer's disease. Alzheimers Dement (N Y). Feb. 13, 2018:4:64-75. doi: 10.1016/j.trci.2018.01.003. eCollection 2018. [cited by applicant]