OPTIMISED DOSAGE OF DIAMINOPHENOTHIAZINES IN POPULATIONS

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

1.-71. (canceled)

72. 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 an LMTX compound of the following formula: ##STR00020## wherein each of H.sub.nA and H.sub.nB (where present) are protic acids which may be the same or different, wherein p=1 or 2; q=0 or 1; n=1 or 2; (p+q)×n=2, wherein said neurodegenerative disorder is behavioral-variant frontotemporal dementia (bvFTD), and wherein the therapeutic treatment is not combined with an acetylcholinesterase inhibitor or an N-methyl-D-aspartate receptor antagonist.

73. A method as claimed in claim 72, wherein the total daily dose is between 20.5 and 40 mg.

74. A method as claimed in claim 73, wherein the total daily dosage is 21 to 40 mg; 21 to 32 mg; or 24 to 32 mg.

75. A method as claimed in claim 73, wherein the total daily dose is about 30 mg.

76. A method as claimed in claim 72, wherein the total daily dose of the MT-containing compound is administered as a split dose twice a day or three times a day.

77. A method as claimed in claim 72, wherein the subject: (a) has not historically received treatment with an acetylcholinesterase inhibitor or an N-methyl-D-aspartate receptor antagonist, or (b) 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, or (c) 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.

78. A method as claimed in claim 72, 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.

79. A method of prophylactic treatment of a neurodegenerative disorder of protein aggregation in a human subject, which method comprises orally administering to said patient an 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 an LMTX compound of the following formula: ##STR00021## wherein each of H.sub.nA and H.sub.nB (where present) are protic acids which may be the same or different, wherein p=1 or 2; q=0 or 1; n=1 or 2; (p+q)×n=2, wherein said neurodegenerative disorder is behavioral-variant frontotemporal dementia (bvFTD), and wherein the prophylactic treatment is not combined with an acetylcholinesterase inhibitor or an N-methyl-D-aspartate receptor antagonist.

80. A method as claimed in claim 79, wherein the subject has been assessed as being susceptible to, or at risk of, the disorder, optionally based on familial or genetic or other data.

81. A method as claimed in claim 72, wherein: (a) the compound has the following formula, where HA and HB are different mono-protic acids: ##STR00022## or (b) the compound has the following formula, wherein each of H.sub.nX is a protic acid: ##STR00023## or (c) the compound has the following formula and H.sub.2A is a di-protic acid: ##STR00024##

82. A method as claimed in claim 81, wherein the MT-containing compound has the following formula and is a bis-monoprotic acid salt: ##STR00025##

83. A method as claimed in claim 72, wherein the or each protic acid is an inorganic acid.

84. A method as claimed in claim 83, wherein each protic acid is a hydrohalide acid.

85. A method as claimed in claim 72, wherein the or each protic acid is an organic acid.

86. A method as claimed in claim 85, wherein the or each protic acid is selected from methanesulfonic acid, 1,2-ethanedisulfonic acid, ethansulfonic acid, naphthalenedisulfonic acid, p-toluenesulfonic acid.

87. A method as claimed in claim 72, wherein the MT-containing compound is LMTM: ##STR00026##

88. A method as claimed in claim 72, wherein the MT-containing compound is selected from the list consisting of: ##STR00027##

89. A method as claimed in claim 72, wherein the MT-containing compound is administered once per day.

Description

FIGURES

[0292] FIG. 1. Schematic of the simplified population PK model for MT.

[0293] FIGS. 2a and b. Histogram of Bayesian post-hoc estimates of steady-state parent MT Cmax in AD patients from Studies 005 and 015 who received LMTM 4 mg BID or c. 200 mg/day.

[0294] FIG. 3a and 3b. ADAS-cog change over 65 weeks for pooled 8 mg/day dose as mono- or add-on therapy in AD subjects from Studies 005 and 015 according to estimated steady-state Cmax. Note the lower p-value in ‘strata.Acmem’ is due to larger number of subjects receiving LMTM as add-on treatment.

[0295] FIG. 4. Analysis of AD subjects showing reduced brain atrophy and ventricular expansion in high Cmax group both as monotherapy and as add-on.

[0296] FIG. 5. Estimation of proportion of AD subjects in high Cmax group according to dose. The Y axis shows the % over the threshold. 4 mg BID is 50% reflecting the original median split of the high and low Cmax groups at this dosage.

[0297] FIG. 6. Distribution of estimated Cmax values for 8 and 200 mg/day in bvFTD trial subjects

[0298] FIG. 7. Difference in decline on ACE-R scale according to Cmax group in bvFTD patients receiving LMTM 8 mg/day as monotherapy for treatment of bvFTD

[0299] FIG. 8. Difference in decline on ACE-R scale according to Cmax group in bvFTD patients receiving LMTM 200 mg/day as monotherapy for treatment of bvFTD

[0300] FIG. 9. Difference in decline on FAQ scale according to Cmax group in bvFTD patients receiving LMTM 8 mg/day as monotherapy

[0301] FIG. 10. Difference in decline on FAQ scale according to Cmax group in bvFTD patients receiving LMTM 8 mg/day or 200 mg/day as monotherapy

[0302] FIGS. 11a, b and c. Difference in WBV, FTV and LVV according to Cmax group in bvFTD patients receiving LMTM 8 mg/day as monotherapy.

[0303] FIG. 12. Sigmoid E.sub.max analysis for ADAS-cog.sub.11 decline at week 65 with model covariates at population mean values and 90% bootstrap confidence intervals using C.sub.max,SS at day 1 for low dose AD patients from studies TRx-237-005 and TRx-237-015.

[0304] FIG. 13. Concentration-response relationships for clinical and MRI volumetric endpoints for C.sub.max,ss groupings of AD patients receiving LMTM at a dose of 8 mg/day

[0305] FIG. 14. Comparison of primary clinical and MRI volumetric endpoints for all AD patients: categorized by C.sub.max,ss above (“high exposure”) or below (“low exposure”) parent MT threshold of 0.373 ng/mL.

[0306] FIG. 15. Expected percentage of AD patients above the critical therapeutic threshold for C.sub.max,ss (0.393 ng/ml) and C.sub.ave,ss (0.223 ng/ml) according to once daily (qd) and twice daily (bid) dosing regimes.

[0307] FIG. 16. Comparison of primary clinical and MRI endpoint in AD patients receiving LMTM, 8 mg/day: categorised by C.sub.max,ss above (“high exposure”) or below (“low exposure”) parent MT threshold of 0.373 ng/ml and AChEl and/or memantine use status.

[0308] FIG. 17. Pharmacokinetic-pharmacodynamic response on the ADAS-cog scale over 65 weeks in AD patients taking LMTM at a dose of 8 mg/day and categorized by co-medication status with AD-labelled treatments.

[0309] FIG. 18. Concentration-response relationships for ACE-R, FAQ, FTV, LVV and WBV in bvFTD patients.

[0310] FIG. 19. Estimated change from baseline over time in clinical and MRI neuroimaging endpoints in bvFTD patients taking 8 mg/day categorized by plasma levels above or below the C.sub.max,ss threshold of 0.346 ng/ml.

[0311] FIG. 20. Fit of expanded Hill equation with change in whole brain volume over 52 weeks for bvFTD patients.

EXAMPLES

Example 1— Provision of MT-Containing Compounds

[0312] Methods for the chemical synthesis of the MT-containing compounds described herein are known in the art. For example:

[0313] Synthesis of compounds 1 to 7 can be performed according to the methods described in WO2012/107706, or methods analogous to those.

[0314] Synthesis of compound 8 can be performed according to the methods described in WO2007/110627, or a method analogous to those.

Example 2— Provision of AD Symptomatic Treatments

[0315] AD symptomatic treatments includes those which directly modify synaptic neurotransmission in the brain are commercially available as acetylcholinesterase inhibitors (AChEls) or NMDA receptor antagonists.

[0316] Examples of AChEls include tacrine (Cognex™, First Horizon), donepezil (Aricept™, Eisai/Pfizer), rivastigmine (Exelon™, Novartis), and galantamine (Razadyne™, formerly Reminyl™, Ortho-McNeil). Memantine is available as Ebixa™ or Namenda™ e.g. from Forest.

Example 3— a Novel Population PK Model for MT

[0317] In an initial model (not shown), the disposition of all MT moieties (parent MT, desmethyl MT, and LMT-conjugate) was simultaneously characterized by a multi-compartment model. The disposition of parent MT post PO administration was adequately described by a two-compartment model with binding occurring in the plasma and tissue compartments and a delayed absorption occurring through two transit compartments. This model has a fixed Vc.

[0318] There was a trend for absorption rate to be slower with increasing dose, which is incorporated into the model using a dose-dependent absorption rate constant (Ka). Apparent oral clearance (CL/F) of parent MT was related to renal function such that a small portion of the variability in parent CL is described by normalized creatinine clearance (CLCRN). A minor fraction of parent MT was metabolized into desmethyl MT, and the disposition of desmethyl MT was described by a two-compartment model with linear elimination. Parent MT was also converted into LMT-glucuronide, and its disposition was described by a one-compartment model with linear elimination. Of note, a fraction of LMT-conjugate underwent enterohepatic recycling (EHR), which was physiologically mimicked via a latent gallbladder compartment with a pulsatile pattern of bile secretion.

[0319] The above-described model was applied to the data from a single- and multiple-dose Phase 1 study in elderly subjects (Study 036) in order to assess the ability of the model to predict steady-state PK of parent MT. The model was successfully fit to data obtained from subjects who received either 4 mg BID or 10 mg QD of LMTM in Study 036.

[0320] This, the PK model was then further developed and simplified to a two compartment model fit to the parent MT concentrations only. A schematic of this simplified population PK model for MT is provided in FIG. 1. This model has a fixed Vc, but the dose-dependent Ka is removed.

[0321] This model was derived from Study 036 discussed above. The disposition of parent MT post PO administration of LMTM was adequately described by a two-compartment model with and a delayed absorption occurring through two transit compartments. Apparent oral clearance (CL/F) of parent MT was related to renal function such that a small portion of the variability in parent CL is described by normalized creatinine clearance (CLCRN).

[0322] The model was successfully fit to data obtained from subjects who received either 4 mg BID or 10 mg QD of LMTM in Study 036.

[0323] The simplified model provides similar fit to the previous more sophisticated model, but allows co-modelling of all of the data from Study 036.

[0324] Overall, excellent fits to the individual subject data were obtained suggesting that the model provided an adequate description of the PK of parent MT after administration of LMTM.

Example 4—Estimation of Cmax of Parent MT in the Patients Who Received 4 mg BID in the Phase 3 AD Studies (Studies “005” and “015”)

[0325] The trial design for the Phase 3 AD studies “005” and “015” are described in Examples 4 and 3 respectively of WO2018/019823, which Examples also discuss those results. The disclosure of those Examples is specifically incorporated herein by reference. Briefly, those Phase 3 trials compared high doses of LMTM (150-250 mg/day) with a low dose (8 mg/day) intended as a mask for potential urine discolouration (Gauthier 2016; Wilcock 2018). These showed the potential utility for LMTM, particularly as monotherapy, in delaying disease progression on clinical and brain imaging endpoints, and that the high doses conferred no greater potential benefit than the 8 mg/day dose.

[0326] The population PK model was then used to estimate Cmax of parent MT in the patients who received 4 mg or high dose (c. 200 mg/day) in these Phase 3 AD studies. This Bayesian process involved fixing the population mean and inter-individual variability parameters to the estimates from the fit of the population PK model to the steady-state data from Study 036 and allowing the program to select a set of parameters, given those Bayesian priors, which best predicts the parent MT concentrations from Day 1 in each individual.

[0327] The distribution of resultant Cmax estimates are provided in FIGS. 2a and 2b. The ˜200 mg/day group represents pooled high dose subjects from Study 015 (150 & 250 mg/day) and Study 005 (200 mg/day).

[0328] In these Figures the vertical black line indicates median for each distribution, which can be used to divide patients into low and high Cmax groups.

Example 5— Assessment of Different Effects of Pooled 8 mg/Day Dose as Mono- or Add-on Therapy from Studies 005 and 015 in High and Low Cmax Groups at Steady-State

[0329] Using an Mixed effect Model Repeat Measurement (MMRM) approach, ADAS-cog change over 65 weeks for pooled 8 mg/day dose as mono- or add-on therapy from Studies 005 and 015 was then calculated for the “High Cmax” and “Low Cmax” groups, in each case divided into those receiving LMTM as monotherapy, or in combination (“add-on”) with symptomatic treatments (AChEls and\or memantine). The results are shown in FIGS. 3a and 3b which show the same data. Patients using symptomatic treatments are labelled “Achmem”.

[0330] FIG. 3a emphasises the findings in WO2018/019823 that Symptomatic treatments interfere with LMTM treatment effect. The mean difference between monotherapy and add-on can be seen to be ˜4 ADAS-cog units.

[0331] As highlighted in FIG. 3b, unexpectedly, the analysis of this low (8 mg/day) dose also revealed a difference between Cmax high and low groups for monotherapy of ˜2.4 ADAS-cog units, and a difference between Cmax high and low groups for the add-on groups of ˜2.7 ADAS-cog units i.e. the same concentration-dependent difference seen for monotherapy and add-on treatment.

[0332] In further analyses, FIG. 4 shows that the high Cmax group has less whole brain and temporal lobe atrophy, and less expansion of ventricles both as monotherapy and add-on therapy. As expected there was less brain atrophy in monotherapy than in add-on groups. It should be noted that the differences achieve statistical significance only for the add-on group, which had substantially larger number of subjects.

[0333] Corresponding analysis of the pooled high dose group (average 200 mg/day) did not show a corresponding different treatment effect between Cmax high and low groups, whether as monotherapy or add-on (data not shown).

Example 6— Safety and Adverse Events: Benefits in Using Minimal Effective Dose of LMT Compounds

[0334] Three Phase 3, double-blind, controlled studies of LMTM have been completed (one each in subjects with mild and mild to moderate AD and one in subjects with bvFTD). Results of the AD studies have been published (Gauthier et al., 2016; Wilcock et al., 2018).

[0335] In these three studies, 1897 subjects received at least one dose of LMTM (Safety Population [Five additional subjects with AD, participating at one site in Study TRx-237-005, received a dose of study drug but were excluded from all analyses due to GCP violations], 1679 subjects with AD and 218 subjects with bvFTD). Of these, 860 subjects received the control (LMTM 8 mg/day, 750 with AD and 110 with bvFTD) and 1037 subjects received at least one dose of LMTM in the higher doses of 150 to 250 mg/day (929 with AD and 108 with bvFTD).

[0336] The mean ages of study participants were 71 years (ranging up to 89 years) for subjects with AD and 63 years (ranging up to 79 years) for subjects with bvFTD. Overall, there was a comparable representation by sex (55% female), with more AD subjects being female (58%) and more bvFTD subjects being male (63%). Most subjects were White (88% AD and 91% bvFTD). Approximately 17% of the AD subjects received LMTM as monotherapy (as recorded on the concomitant medication case report form rather than by stratification [overall, 87% of subjects were receiving AChEl and/or memantine based on the stratified randomisation]), with the remainder receiving concomitant AChEl and/or memantine. On the other hand, most subjects with bvFTD received LMTM as monotherapy (79%). Psychiatric disorders/symptoms were common, with depression reported for 23% of the subjects overall and anxiety for 12%. Concomitant use of antidepressants and antipsychotics was more common in subjects with bvFTD (50% and 22%, respectively) as compared with AD (36% and 10%, respectively).

[0337] The most common Treatment emergent adverse events (TEAEs) considered at least possibly associated with LMTM given in a dose of 8 mg/day are GI (mostly diarrhea and nausea), genitourinary (mostly pollakiuria and urinary incontinence), haematologic (anaemia, decreased folate, and folate deficiency), and nervous system related (mostly fatigue, dizziness, headache, agitation, and insomnia). Other common events are considered to represent events that are expected in these patient populations over a 12- to 18-month duration.

[0338] At the higher LMTM doses studied, 150 to 250 mg/day, there was a dose-related increase in the incidence of anaemia-related TEAEs (decreased haemoglobin in addition to anaemia, decreased folate, and folate deficiency), gastrointestinal events (including vomiting and the possibly associated observation of decreased weight in addition to diarrhoea and nausea), and genitourinary events (including dysuria, micturition urgency, and apparent urinary tract infections in addition to pollakiuria and urinary incontinence). The lack of a dose response in falls and nervous system/psychiatric events (other than agitation) suggests that these are associated with the subjects' underlying condition rather than treatment.

[0339] The incidence of the most common TEAEs are summarised by dose in the following Table EX1. This includes TEAEs that occurred at an incidence of ≥2.0% either in subjects randomised to LMTM 8 mg/day or higher doses (150 to 250 mg/day). The subset of TEAEs that were severe in intensity are also included. As can be seen, few events occurred in severe intensity, regardless of dose.

TABLE-US-00008 TABLE EX1 Incidence of Treatment-emergent Adverse Events in ≥2.0% of Subjects by Dose: LMTM 8 mg/day versus Higher Doses (Phase 3, Double-blind, LMTM Pooled Safety Population) LMTM 8 mg/day Higher Doses (150-250 mg/day) (N = 860) (N = 1037) Severe Severe MedDRA System Organ All Intensity All Intensity Class/Preferred Term n (%) n (%) n (%) n (%) No. (%) of Subjects 720 (83.7%) 86 (10.0%) 902 (87.0%) 126 (12.2%)  Reporting at Least One TEAE Blood and Lymphatic System Disorders Anaemia 19 (2.2%) 1 (0.1%) 59 (5.7%) 0 Cardiac Disorders Atrial fibrillation 17 (2.0%) 3 (0.3%) 10 (1.0%) 2 (0.2%) Gastrointestinal Disorders Abdominal pain 16 (1.9%) 1 (0.1%) 30 (2.9%) 1 (0.1%) Abdominal pain upper 10 (1.2%) 1 (0.1%) 21 (2.0%) 0 Constipation 23 (2.7%) 2 (0.2%) 24 (2.3%) 1 (0.1%) Diarrhoea 109 (12.7%) 5 (0.6%) 278 (26.8%) 14 (1.4%)  Nausea 39 (4.5%) 1 (0.1%) 86 (8.3%) 1 (0.1%) Vomiting 20 (2.3%) 0 80 (7.7%) 3 (0.3%) General Disorders and Administration Site Conditions Fatigue 26 (3.0%) 0 38 (3.7%) 1 (0.1%) Oedema peripheral 19 (2.2%) 0 20 (1.9%) 0 Infections and Infestations Bronchitis 27 (3.1%) 0 19 (1.8%) 0 Nasopharyngitis 40 (4.7%) 0 43 (4.1%) 0 Upper respiratory tract 35 (4.1%) 0 34 (3.3%) 0 infection Urinary tract infection 76 (8.8%) 1 (0.1%) 116 (11.2%) 3 (0.3%) Injury, Poisoning and Procedural Complications Contusion 24 (2.8%) 0 15 (1.4%) 0 Fall  90 (10.5%) 4 (0.5%) 78 (7.5%) 7 (0.7%) Laceration 17 (2.0%) 0 14 (1.4%) 1 (0.1%) Investigations Blood creatine 18 (2.1%) 0 31 (3.0%) 0 phosphokinase increased Blood folate decreased 45 (5.2%) 0 76 (7.3%) 0 Creatinine renal clearance 20 (2.3%) 0 26 (2.5%) 0 decreased Haemoglobin decreased  6 (0.7%) 0 34 (3.3%) 0 Vitamin B12 decreased 23 (2.7%) 0 21 (2.0%) 0 Weight decreased 18 (2.1%) 0 39 (3.8%) 0 Metabolism and Nutrition Disorders Decreased appetite 13 (1.5%) 0 39 (3.8%) 1 (0.1%) Dehydration 17 (2.0%) 4 (0.5%) 18 (1.7%) 2 (0.2%) Folate deficiency 17 (2.0%) 0 45 (4.3%) 0 Musculoskeletal and Connective Tissue Disorders Arthralgia 28 (3.3%) 0 31 (3.0%) 1 (0.1%) Back pain 31 (3.6%) 1 (0.1%) 44 (4.2%) 2 (0.2%) Pain in extremity 19 (2.2%) 1 (0.1%)  17(1.6%) 0 Nervous System Disorders Cerebral microhaemorrhage 24 (2.8%) 0 16 (1.5%) 0 Dizziness 49 (5.7%) 3 (0.3%) 64 (6.2%) 2 (0.2%) Headache 55 (6.4%) 1 (0.1%) 61 (5.9%) 3 (0.3%) Syncope 26 (3.0%) 1 (0.1%) 28 (2.7%) 5 (0.5%) Tremor 20 (2.3%) 0 13 (1.3%) 0 Psychiatric Disorders Agitation 46 (5.3%) 1 (0.1%) 61 (5.9%) 7 (0.7%) Anxiety 52 (6.0%) 0 39 (3.8%) 2 (0.2%) Confusional state 22 (2.6%) 2 (0.2%) 45 (4.3%) 2 (0.2%) Depression 41 (4.8%) 0 37 (3.6%) 2 (0.2%) Hallucination 13 (1.5%) 0 21 (2.0%) 4 (0.4%) Insomnia 29 (3.4%) 0 32 (3.1%) 0 Suicidal ideation 27 (3.1%) 2 (0.2%) 30 (2.9%) 0 Renal and Urinary Disorders Dysuria  6 (0.7%) 0 75 (7.2%) 1 (0.1%) Micturition urgency 11 (1.3%) 0 35 (3.4%) 0 Pollakiuria 19 (2.2%) 0 71 (6.8%) 2 (0.2%) Urinary incontinence 34 (4.0%) 0 63 (6.1%) 1 (0.1%) Respiratory, Thoracic and Mediastinal Disorders Cough 37 (4.3%) 0 42 (4.1%) 0 Skin and Subcutaneous Tissue Disorders Rash 21 (2.4%) 0 30 (2.9%) 0 Vascular Disorders Hypertension 20 (2.3%) 0 22 (2.1%) 1 (0.1%)

[0340] The TEAEs are further analysed by using groupings of related MedDRA (Medical Dictionary for Regulatory Activities) preferred terms to better estimate the incidence of potentially treatment related adverse events. The incidence of all groupings for subjects categorised by dose (8 mg/day versus higher doses of 150 to 250 mg/day) is shown in the following Table EX2:

TABLE-US-00009 TABLE EX2 Incidence of Treatment-emergent Adverse Events groupedLMTM 8 mg/day versus Higher Doses (Phase 3, Double-blind, LMTM Pooled Safety Population) LMTM 8 mg/day Higher Doses (150-250 mg/day) TauRx Grouping Term (N = 860) n (%) (N = 1037) n (%) Affective/Anxiety Symptoms 60 (7.0%) 55 (5.3%) Anaemia 111 (12.9%) 219 (21.1%) Behavioral Symptoms 114 (13.3%) 118 (11.4%) Falls and Related Terms 188 (21.9%) 202 (19.5%) Hepatic Function Impairment 13 (1.5%) 34 (3.3%) Hypersensitivity 42 (4.9%) 63 (6.1%) Ischaemic Events, Inclusive of 20 (2.3%) 35 (3.4%) Myocardial Infarction Psychotic Symptoms 28 (3.3%) 34 (3.3%) Renal Function Impairment 29 (3.4%) 42 (4.1%) Renal and Urinary Disorders 135 (15.7%) 326 (31.4%) (Including Infections) Sleep Disorders 41 (4.8%) 48 (4.6%) Targeted Gastrointestinal Events 183 (21.3%) 401 (38.7%)

[0341] The groupings occurring in ≥10.0% of subjects treated with LMTM 8 mg/day include falls and related terms (22%), GI events (21%), renal and urinary disorders including infections (16%), behavioural symptoms and terms indicative of anaemia (each grouping in 13%).

[0342] There is a dose-related trend for increased incidence for all of these (other than falls and behavioural symptoms). For the less common groupings, there is also evidence of a dose-related trend for hepatic function impairment.

[0343] The fact that several TEAEs appear to be dose related clearly indicates the desirability of utilising a minimal effective dose of MT.

Example 7— Effect of Cmax on Treatment Effects Using Other Scales

[0344] From the data available, the Cmax effect was not seen when assessing Temporal lobe FDG-PET decline. For this measure it appeared that high dose LMTM (pooled 200 mg/day) actually attenuated benefit otherwise seen for LMTM monotherapy, although some monotherapy benefit remained (results not shown).

[0345] From the data available, the Cmax effect was not seen when assessing outcome measures: Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) decline.

Example 8— Providing an Optimised Dosage Regimen in AD Subject Populations

[0346] In summary a PK model has been developed on the basis of data from closely-sampled Phase 1 studies. From this per-subject steady state Cmax was estimated and used to split patients taking 8 mg/day dose into high (above median) and low (below median) Cmax groups. Unexpectedly, High and low Cmax groups differed in cognitive decline (as assessed using ADAS-cog) by ˜2.5 units, with the effect being was observed in both monotherapy and add-on treatment groups. Interestingly there was evidence of an inverse dose-response relationship for FDG-PET at high doses.

[0347] Thus treatment response is determined by two factors: [0348] 1 Monotherapy vs add-on treatment status [0349] 2 Plasma concentration, which will vary in subject populations even for a given dose.

[0350] For both groups (mono-therapy and add-on) there is therefore benefit in dosing at sufficient level to maximise the proportion of subjects in the high Cmax group (while also avoiding high dosages which have a less desirable clinical profile). FIG. 5 estimates the proportion of subjects expected to be in the high Cmax group according to dose.

[0351] By Way of Illustration:

[0352] At 4 mg bid, 50% of subjects above Cmax threshold, with a predicted treatment effect relative to placebo ˜5 ADAS-cog units over 65 weeks

[0353] By utilising at least 16 mg bid, or more preferably ˜20 mg/day (10 mg bid), for which the estimated proportion is ˜100%, even higher ADAS-cog treatment effects may be seen.

[0354] Thus, based on FIG. 5, a dosage regimen of higher than 4 mg bid is desirable. However there is likely to be little benefit in exceeding around 20 mg bid (40 mg total), since at that level it is estimated that the vast majority of the treated subjects will be in the high Cmax group irrespective of whether the dose is split.

[0355] There are at least two distinct reasons for wanting to use the minimal concentration which maximises the cognitive benefit treatment effect. Firstly TEAEs, most notably GI events, renal and urinary disorders including infections, and haemolytic anaemia, occurred in a dose-related fashion. Hence avoiding higher dosages than are necessary is clearly desirable in order to maintain an optimal clinical profile. Secondly, there is evidence of an inverse dose-response relationship for FDG-PET at high doses i.e. that benefit may actually be attenuated at high doses.

[0356] Overall these novel findings indicate that there is benefit in using slightly higher “low dose” LMT treatments than had previously been assumed, and further indicate that LMT treatments can be used as add-on to symptomatic treatments (albeit with less effect than for monotherapy).

Example 9—Providing an Optimised Dosage Regimen in bvFTD Subject Populations

[0357] The trial design for the Phase 3 trial of LMTM in behavioural variant frontotemporal dementia (bvFTD) is described in Examples 3 to 10 of WO2018/041739, which Examples also discuss those results. The disclosure of those Examples is specifically incorporated herein by reference.

[0358] It was concluded in WO2018/041739 that there was less cognitive decline (as assessed using ACE-R) seen at 4 mg b.i.d. and 100 mg b.i.d. than would have been predicted from historical studies. This could be explained if both the 4 mg b.i.d. (the “control” arm) and 100 mg b.i.d. (the “active” arm) demonstrated efficacy.

[0359] Furthermore AD-comedication status and severity were found to be significant covariates. Taking account of these covariates showed significant benefits on ACE-R in patients taking LMTM in combination with off-label AD treatments (acetylcholinesterase inhibitors and/or memantine) versus LMTM alone. There also appeared to be directionally supportive benefits on FAQ, MMSE and temporal volume.

[0360] The population PK model described above was used to estimate Cmax of parent MT in the patients in the bvFTD study. As with the AD trials described above, the median value at each dose was taken as a threshold for dividing patients into “High Cmax” and “Low Cmax” groups.

[0361] FIG. 6 shows the distribution of Cmax values in bvFTD. Vertical black line indicates median dividing low from high Cmax groups.

[0362] FIG. 7 shows the difference in decline on Addenbrooke's Cognitive Examination—revised (ACE-R) scale according to Cmax group in bvFTD patients receiving LMTM 8 mg/day as monotherapy. The decline in Cmax low group was found to be −13.3±1.8 (which is comparable to Kipps et al., (2008)=−15.3±1.4). However the decline in the Cmax high group was much reduced (−6.1±1.8). All efficacy analyses are based on an MMRM approach

[0363] The difference between the low and high Cmax groups at 32 weeks was 4.2±2.0 (p=0.0389) and at 52 weeks 7.3±2.6 (p=0.0059).

[0364] As illustrated in FIG. 8, highly significant difference between Cmax high/low groups for 8 mg/day. For 200 mg/day there appeared actually to be an inverse dose-response.

[0365] FIG. 9 shows the difference in decline on the Functional Activities Questionnaire (FAQ) scale according to Cmax group in bvFTD patients receiving LMTM 8 mg/day as monotherapy. Again decline was lower in the high C max group on this scale (decline in Cmax low group at 52 wk: 8.3±0.9; decline in Cmax high group at 52 wk: 2.9±0.9; difference at 32 weeks: −3.6±1.2 (p=0.0022); difference at 52 weeks:−5.4±1.3 (p<0.0001).

[0366] FIG. 10 illustrates that the FAQ benefit seen for high Cmax at 8 mg/day is greatly reduced at 200 mg/day. Furthermore there is an inverse dose-response so that the overall benefit is reduced for 200 mg/day.

[0367] FIGS. 11a, 11b and 11c shows the corresponding changes in whole brain volume (WBV), temporal atrophy and lateral ventricular volume (LVV) in bvFTD patients.

[0368] For WBV in FIG. 11a the decline in Cmax low group at 52 wk was −24.5±2.6 (cm.sup.3). The decline in the Cmax high group at 52 wk was −15.3±2.5. The difference at 52 weeks was 9.2±3.5 (p=0.0089).

[0369] FIG. 11b shows the difference in progression fronto-temporal atrophy according to Cmax group in bvFTD patients receiving LMTM 8 mg/day as mono (decline in Cmax low group at 52 wk: −2.3±0.2 (cm.sup.3); decline in Cmax high group at 52 wk: −1.7±0.2; difference at 52 weeks: 0.6±0.3 (p=0.0247)).

[0370] FIG. 11c difference in ventricular expansion according to Cmax group in patients receiving LMTM 8 mg/day as mono (increase in Cmax low group at 52 wk: 8.3±0.8 (cm.sup.3); increase in Cmax high group at 52 wk: 5.0±0.8; difference at 52 weeks: −3.3±1.1 (p=0.0027)).

[0371] Interestingly, in ACE-R, there was again an inverse dose-response for high dose, 200 mg/day.

[0372] As was concluded in WO2018/041739, this further analysis confirmed additional benefit from combination with symptomatic treatments, with triple therapy (MT, acetylcholinesterase inhibitors and memantine) potentially offering benefits. For the combined therapy the benefit of exceeding Cmax (in relation to ACE-R and FAQ) could not be confirmed, having regard to the smaller groups and hence larger error bars in the estimates (data not shown). Furthermore the same data indicated that the addition of symptomatic treatments overcomes high dose impairment (inverse dose response), at least in relation to these scales (data not shown). Significant MRI volumetric benefits for Cmax were best seen as add-on therapy (data not shown).

[0373] These results confirmed the concentration-response relationship for 8 mg/day monotherapy for cognitive function in bvFTD similar to that seen in AD. There was also a concentration-response relationship for 8 mg/day monotherapy on functional FAQ scale in bvFTD and an inverse dose-response for high dose monotherapy (i.e. 200 mg/day was worse than 8 mg/day).

[0374] Overall, a low dose administered in a regimen ensuring high Cmax (e.g. ˜20 mg/day (10 mg bid)) appears to be an optimal monotherapy treatment for bvFTD.

[0375] However, as previously seen, and in contrast to AD, there is an additional benefit from combination with symptomatic treatments, which can particularly be seen in the low Cmax group.

[0376] In light of these factors one regimen may be starting with LMTX monotherapy at 8 mg/day and then increasing dose to ˜20 mg/day, with the possibility of adding AD symptomatic treatments in bvFTD as the disease progresses.

Example 10— Further Analyses in Relation to Optimised Dosage Regimen in AD Subject Populations

[0377] A more informative approach which permits statistical analyses to be conducted is to categories patients receiving LMTM at a dose of 8 mg/day on the basis of C.sub.max,ss using a threshold that defines the upper limit of the lowest 35% of patients, corresponding to the 35% of patients with plasma levels below the validated limit of quantitation (0.2-10 ng/ml; N=208) following the first dose on day 1. That threshold was <0.373 ng/mL.

[0378] The remaining 65% were categorized into three C.sub.max,ss groups of comparable size (N˜128 per group) to permit better visualisation of the concentration-response relationship. Higher doses were grouped according to dose (N=187-329 per group). The model-based estimates of plasma exposure in these groups, as well as the higher doses, are shown in the Table EX3 below:

TABLE-US-00010 TABLE EX3 Plasma-modelled parent MT C.sub.max, ss for all patients with available plasma data in studies TRx-237-015 and TRx-237-005 according to either plasma C.sub.max, ss subgroups (LMTM, 8 mg/day) or dose (LMTM, 150-250 mg/day): C.sub.max, ss (ng/mL) Dose groups n (%) Mean (SD) Range 8 mg/day - Group 1 208 (35%) 0.334 (0.0251) 0.257-0.373 8 mg/day - Group 2 127 (21%) 0.393 (0.0125) 0.373-0.414 8 mg/day - Group 3 129 (22%) 0.449 (0.0189) 0.415-0.478 8 mg/day - Group 4 128 (22%) 0.565 (0.0810) 0.479-0.812 150 mg/day  188 (100%) 7.820 (1.787)   5.099-18.611 200 mg/day  329 (100%) 10.126 (2.374)   6.557-21.291 250 mg/day  187 (100%) 12.573 (2.460)   8.833-21.188

[0379] Least squares mean and standard error estimates for change in ADAS-cog.sub.11, ADCS-ADL.sub.23, LVV, and WBV show clear concentration-responses as a function of C.sub.max,ss grouping in patients receiving LMTM at a dose of 8 mg/day (FIG. 13). There is a general tendency for outcomes to be worse at the high exposure levels associated with doses in the range 150-250 mg/day, implying the existence of a biphasic dose-response.

Example 11— Analyses Based on Critical Therapeutic C.SUB.max,ss .Threshold of 0.393 ng/ml in Relation to Optimised Dosage Regimen in AD Subject Populations

[0380] Based on splitting of patients according to the threshold of 0.373 ng/ml, the treatment difference in patients receiving the 8 mg/day dose is −3.4 ADAS-cog units (see Table EX4 below; cf. Example 8 concerning median split showing about ˜2 to 3 ADAS-cog units):

TABLE-US-00011 TABLE EX4 B. Patients receiving LMTM, 8 mg/day, split A. All patients split by C.sub.max,ss 0.373 ng/mL by C.sub.max,ss 0.373 ng/mL Difference ± Difference ± SEM CI p-value N.sub.low N.sub.high SEM CI p-value N.sub.low N.sub.high ADAS-cog −2.99 ± 0.67 −4.32 − −1.67 <0.0001 193 969 −3.41 ± 0.76 −4.89 − −1.92 <0.0001 193 373 ADCS-ADL  0.54 ± 0.94 −1.30 − 2.38   0.5634 192 967  1.22 ± 1.01 −0.77 − 3.21   0.2283 192 373 LVV (cm.sup.3) −1.52 ± 0.34 −2.18 − −0.83 <0.0001 184 863 −1.78 ± 0.38 −2.53 − −1.03 <0.0001 184 335 WBV (cm.sup.3)  3.55 ± 1.06 1.48 − 5.62  0.0008 180 859  4.39 ± 1.18 2.07 − 6.71  0.0002 180 332

[0381] The corresponding longitudinal trajectories over 65 weeks according to C.sub.max,ss above or below the threshold value of 0.373 ng/mL are shown in FIG. 14.

[0382] Since only 65% of patients receiving the 8 mg/day have plasma concentrations above the threshold required for significant treatment benefit, it is desirable to determine the minimum dose at which 100% patients would be expected to have plasma levels within the therapeutic range. Given the population variability observed in the large available data set, it was possible to estimate the expected percentage of patients above the critical therapeutic threshold for C.sub.max,ss (0.393 ng/ml) and C.sub.ave,ss (0.223 ng/ml) according to once daily (QD) and twice daily (BID) dosing regimes. As can be seen in FIG. 15, using either criterion and dosing regime, LMTM needs to be given at a dose of at least 16 mg/day for 100% of patients to have plasma levels in the therapeutic range.

Example 12— Incorporation of Discriminator Between Monotherapy and Add-on Therapy

[0383] A further consideration is whether patients are dosed with LMTM alone or in combination with approved treatments for AD (AChEls and/or memantine). Patients receiving the 8 mg/day dose were examined further according co-medication status with these drugs. As can be seen in the Table EX5 below, the differences between patients having steady-state plasma levels below or above a threshold of 0.373 ng/ml reach statistical significance whether LMTM is taken as monotherapy or as add-on therapy on cognitive (ADAS-cog) and brain atrophy (LVV and WBV) endpoints.

TABLE-US-00012 TABLE EX5 Comparison of AD patients receiving LMTM, 8 mg/day, with C.sub.max,ss above or below parent MT threshold of 0.373 ng/mL: categorized according to AChEI and/or memantine use status at baseline. LMTM, 8 mg/day, as monotherapy LMTM, 8 mg/day, as add-on therapy Difference ± Difference ± SEM CI p-value N.sub.low N.sub.high SEM CI p-value N.sub.low N.sub.high ADAS-cog.sub.11 −2.60 ± 1.16 −4.88 − −0.33 0.0251 33 67 −3.52 ± 0.78 −5.05 − −2.00 <0.0001 160 306 ADCS-ADL.sub.23  0.46 ± 1.47 −2.43 − 3.34  0.7552 32 67  1.32 ± 1.04 −0.71 − 3.36   0.2016 160 306 LVV (cm.sup.3) −1.46 ± 0.45 −2.33 − −0.58 0.0011 33 61 −1.35 ± 0.37 −2.08 − −0.62  0.0003 151 274 WBV (cm.sup.3)  2.76 ± 1.66 −0.49 − 6.01  0.0966 32 61  4.69 ± 1.21 2.32 − 7.06  0.0001 148 271

[0384] The corresponding longitudinal trajectories over 65 weeks are illustrated below for ADAS-cog.sub.11, ADCS-ADL.sub.23, LVV and WBV in FIG. 16.

Example 13— Analysis of ADAS-Cog.SUB.11 .Decline Vs. Plasma Concentration

[0385] A further analysis of ADAS-cog decline over 65 weeks was undertaken using a modified form of the Hill equation (Wagner, 1968) in order to estimate the minimum and maximum plasma concentrations for expected treatment response over 65 weeks. The Hill equation was applied under the assumption of non-cooperativity and used an imposed overall zero where there was no-effect level was taken as 11 units at a C.sub.max,ss concentration of 0.29 ng/ml based on visual inspection of the data. Use of different limiting values did not meaningfully change the results. In addition, a linear term was added to permit trends occurring at high concentrations to be included in the model using data for doses in the range 150-250 mg/day. The expanded Hill equation was applied to the data in the form:

change in parameter=E.sub.min−(E.sub.max*([C]−−0.29))/(EC.sub.50+([C]−0.29))+(A*([C]−0.29))

where E.sub.min is the imposed zero value, E.sub.max is the maximum treatment effect assumed in the standard Hill equation, EC.sub.50 is the C.sub.max,ss at which the treatment effect is 50% of the maximum assumed in the standard Hill equation and A is a further linear term estimated by the model to take account of a potential biphasic response. C.sub.max,ss was also expressed as the estimated equivalent mean dose using a relationship obtained by fitting a linear model to the mean plasma concentrations at the 8, 150, 200 and 250 mg/day doses:

estimated dose(mg/day)=0.045*C.sub.max,ss+0.016

[0386] As can be seen from FIG. 17, there is an overall biphasic concentration-response for LMTM taken alone or in combination with symptomatic treatments. The dose range in which the treatment response is estimated to be maximal is 20-60 mg/day.

[0387] Compared with monotherapy, the estimated maximum treatment is reduced by about 4 ADAS-cog units when LMTM is combined with symptomatic treatments. A further effect is to shift the C.sub.max,ss concentration required for half-maximal treatment response to the right from 0.32±0.01 ng/ml to 0.40±0.05 ng/ml.

[0388] It will be apparent that the effects of plasma concentration and co-medication status are additive. This permits an overall estimate of treatment benefit comparing patients receiving the 8 mg/day dose as monotherapy and having plasma levels above the threshold of 0.373 ng/ml with patients receiving the same dose in combination with symptomatic treatments and having plasma levels below this threshold. As can be seen from FIG. 17, the latter group comes nearest to approximating the minimum measurable treatment response. This analysis shows that treatment effect for the 8 mg/day dose as monotherapy in patients with therapeutic plasma levels of the drug is −7.53 (CI−9.93−5.13, p<0.0001) ADAS-cog.sub.11 units, with corresponding treatment effects for ADCS-ADL.sub.23, LVV and WBV (Table EX6 below):

TABLE-US-00013 TABLE EX6 Comparison of LMTM as add-on versus monotherapy and between low C.sub.max add-on and high C.sub.max monotherapy. Comparison of LMTM, 8 mg/day, low C.sub.max add-on vs high C.sub.max monotherapy Difference ± SEM CI p-value N.sub.low, add-on N.sub.high, mono ADAS-cog11 −7.53 ± 1.22 −9.93-−5.13 <0.0001 160 67 ADCS-ADL23  6.14 ± 1.64 2.93-9.34 0.0002 160 67 LVV (cm.sup.3) −3.15 ± 0.62 −4.37-−1.93 <0.0001 151 61 WBV (cm.sup.3) 11.54 ± 1.87  7.88-15.21 <0.0001 148 61

Example 14— Implications of Findings Relating to Monotherapy Vs. Add-on Therapy in Relation to Dosing Regimens

[0389] As is evident from the foregoing, there is a reduction in the maximum effect of LMTM when it is combined with symptomatic treatments. It should be noted however, that this relates to a context in which patients have received LMTM against a background of chronic pre-treatment with symptomatic drugs. The mechanism of this has been elucidated in a series of experiments in a well characterised tau transgenic mouse model. If these animals are pretreated chronically with a cholinesterase inhibitor (rivastigmine), almost all of the neurobiological effects seen when LMTM is administered alone are reduced or eliminated entirely, leading to elimination of the beneficial effect of LMTM on spatial learning memory. Pre-treatment with memantine likewise eliminated the effect on spatial learning memory (results not shown).

[0390] The mechanism appears to be a generalised homeostatic downregulation affecting many synaptic and neurotransmitter systems in the brain that counteracts the activating effects of the symptomatic drugs. Thus, LMTM-induced effects are subject to dynamic downregulation if the brain is already subject to prior chronic stimulation by symptomatic treatments.

Example 15— Further Analysis in Relation to Providing an Optimised Dosage Regimen in FTD Subject Populations

[0391] The cut-off that defined the upper limit of the lowest 35% group (corresponding to the percentage of patients with plasma levels below the validated limit of quantitation in Day 1) was 0.346 ng/ml for the bvFTD population.

[0392] As for AD (see Example 10) the remainder with Day 1 plasma levels within the validated range of quantitation at the 8 mg/day dose were distributed in 3 groups having approximately equal numbers (22% each; see Table EX7 below).

TABLE-US-00014 TABLE EX7 Plasma-modelled parent MT C.sub.max, ss for LMTM groups C.sub.max, ss (ng/mL) Dose groups n (%) Mean (SD) Range 8 mg/day 8 mg/day - Group 1 32 (35%) 0.321 (0.0198) 0.281-0.346 8 mg/day - Group 2 20 (22%) 0.355 (0.0082) 0.346-0.372 8 mg/day - Group 3 19 (21%) 0.387 (0.0121) 0.373-0.409 8 mg/day - Group 4 20 (22%) 0.470 (0.0537) 0.413-0.583 200 mg/day 81 9.040 (1.6259) 6.800-14.235

[0393] There is a similar concentration-response relationship for measures of progression of brain atrophy by MRI (frontotemporal volume, lateral ventricular volume, whole brain volume). This is shown in FIG. 18.

[0394] Alternative efficacy analyses were performed in which the group of patients with minimal systemic exposure to the drug was used as a proxy for placebo. These are shown in the Table EX8 below and illustrated in FIG. 19.

Example 16— Analysis of Chance in Outcomes Vs. Plasma Concentration

[0395] As can be seen from FIG. 18 above, treatment effects were worse at the high dose of 200 mg/day on all outcomes, implying a biphasic concentration-response relationship in bvFTD.

[0396] As for AD, an expanded Hill equation was applied under the assumption of non-cooperativity and used imposed overall zero values where the no-effect level was taken as −12 ACE-R units, 8 FAQ units or −30 cm.sup.3 for whole brain volume at a C.sub.max,ss concentration of 0.29 ng/ml based on visual inspection of the data. Use of different limiting values did not meaningfully change the results. In addition, a linear term was added to permit trends occurring at high concentrations to be included in the model using mean decline occurring at the 200 mg/day dose.

[0397] The expanded Hill equation provided a robust fit to the mean concentration-response for change in ACE-R, FAQ and whole brain volume over 52 weeks. The model fit for all outcomes is consistent with the assumption that the lower limiting plasma concentration required for treatment response is 0.29 ng/ml in patients receiving the 8 mg/day dose. Subgrouping the whole brain volume data in patients receiving the 200 mg/day dose into terciles (FIG. 20) made it possible to estimate the maximum limiting concentration at which the treatment effect was lost, namely 13.57 ng/ml (corresponding to a predicted dose of 301 mg/day).

TABLE-US-00015 TABLE EX8 Comparison of patients categorized by above (“high”) or below (“low”) parent MT threshold of 0.346 ng/mL All patients Patients receiving LMTM 8 mg/day Difference ± Difference ± Decline ± SEM for SEM for SEM for C.sub.max,ss > C.sub.max,ss > C.sub.max,ss ≤ 0.346 ng/ml CI p-value N.sub.low N.sub.high 0.346 ng/ml CI p-value N.sub.low N.sub.high 0.346 ng/ml ACE-R 1.37 ± 2.60 −3.73 − 6.47  0.5973 31 125 5.06 ± 2.62 −0.08 − 10.21  0.0536 31 57 −11.33 ± 2.09   FAQ −2.98 ± 1.10  −5.15 − −0.82 0.0069 31 114 −3.27 ± 1.32  −5.85 − −0.69  0.0131 31 57 7.13 ± 1.06 WBV 9.05 ± 3.06  3.06 − 15.04 0.0031 28 112 11.67 ± 3.41   5.00 − 18.36  0.0006 28 51 −27.72 ± 2.73   (cm.sup.3) LVV −3.41 ± −0.95 −5.27 − −1.55 0.0003 28 104 −4.12 ± 1.06  −6.19 − −2.05 <0.0001 28 45 9.13 ± 0.82 (cm.sup.3) FTV 0.73 ± 0.24 0.26 − 1.19 0.0023 28 112 0.72 ± 0.27 0.19 − 1.26  0.0076 28 51 −2.47 ± 0.22  (cm.sup.3)

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